Welcome To The Biotivia Blog

Free Radical Theory Of Aging: Is Your Body Under Attack?

Friday, September 23rd, 2011

Free radicals may be the culprit to common aging signs: wrinkles, loose skin, hair loss and other dangerous diseases.

Everywhere you look you see something about free radicals. Depending on what you’ve read, seen, or heard about them, it would seem they are dangerous entities that form out of nowhere and steal your life force. This is not a science fiction plot and free radicals may be responsible for cell damage that is occurring in your body right now. Free Radical Theory on Aging (FRTA) is based on cell damage created by free radicals which may cause oxidative damage leading to signs of aging.

Free Radical Theory on Aging (FRTA) was first brought to scientific attention by Denham Harman in the 1950s. At that time, it was widely believed that free radicals were too volatile to exist in biological systems. However, Harman argued that oxygen free radicals could cause cumulative damage (aging) which would eventually lead to loss of function, certain diseases and finally, death.

For any atom or molecule to be stable, it’s outer electron layer must have paired electron sets. Should either atom or molecule have a single unpaired electron in the outer electron layer, this is considered a free radical.

For example, if an outer layer of an atom requires 8 electrons to be stable and there are only 7 or 1 electron in that outer layer, it is seeking another electron or looking to lose 1 to become stable. Either way, by changing the shape of the atom, the essential function of that atom changes as well.

The danger of a free radical lies within it’s capability to cause oxidative damage. Whenever this give and take process occurs within the cells in the body, it may cause oxidative stress, which has been linked to several diseases such as heart failure, Alzheimer’s disease, and Parkinson’s disease.

FRTA supports when cells undergo damage from free radicals, it causes the external effects of aging: wrinkles, loose skin, weight gain, hair loss, all the signs of aging may stem from cell aging. However, studies have shown that the body creates natural antioxidants to limit the oxidative damage by causing free radicals to undergo passivation.

Many general life processes release free radicals and not all of them are bad. According to Consumerhealth.org, our bodies release free radicals to fight bacteria, fungus, and infection. Some other causes of free radical excess are cholesterol, fat, smoking, alcohol, food preservatives and pesticides, environmental pollution, sunlight, chemotherapy and radiation, metabolism, and intense activity.

It is inconclusive whether or not the addition of antioxidants to a diet may help with the damage that free radicals may cause. Many people will add fruits such as pomegranates, raspberries, red grapes, blueberries, blackberries, lychee, and dark cherries to their diets for their natural antioxidant values. Antioxidants are also available now in extract form at many supplement retailers. Examples of these additional antioxidants are resveratrol, green tea, grape seed extract, CoQ10, astaxanthin, and lycopene.

Antioxidants may be helpful in the battle against free radicals but be sure to do your research before spending too much money on supplements. Examine your diet and lifestyle first – making healthy decisions now should be your first line of defense against aging.

The Biology of Aging: Implications for Diseases of Aging and Healthcare in the 21st Century

Friday, September 23rd, 2011

Douglas F. Watt, Ph.D.

Neuropsychology Department,

Cambridge City Hospital

Harvard Medical School

Alzheimer’s Center/

Clinic for Cognitive Disorders

Quincy Medical Center

DrDougWatt@Gmail.com

Do not go gentle into that good night,
Old age should burn and rave at close of day;
Rage, rage against the dying of the light.

Dylan Thomas

Aging is arguably the most familiar

yet least-well understood aspect of human biology.

Murgatroyd, Wu, Bockmühl, and Spengler (2009)

“Old age is no place for sissies”

Bette Davis

Abstract

 

Aging, now the focus of a rapidly expanding if still immature biological science, remains one of the most fundamental and yet mysterious aspects of biology.  The science of aging has explored the cellular and molecular basis of aging largely in three target organisms with fully sequenced genomes and short lifespans (yeast, roundworms, and fruit flies) as well as an increasing number of in vivo studies in mammalian animal models.  Evidence argues that multiple pathways modulating aging in these three target organisms are well conserved in mammals, primates and humans, although perhaps with additional modifications.  The science of aging has made progress in describing and analyzing several critical phenotypes or components of aging, including sarcopenia, glycation, inflammation and oxidative stress, apoptosis, telomere loss and cellular senescence, genomic damage and instability, mitochondrial dysfunction and decline, and increasing junk protein and declining autophagy (removal of damaged or ‘junk’ proteins).  Although the relationships between these various aspects of aging remain incompletely mapped, evidence is increasing that they are indeed deeply interactive, perhaps reflecting the many linked ‘faces’ or facets of aging.  Increasing evidence links most if not all of these processes to the major diseases of aging and most neurodegenerative disorders.

 

Evolutionary perspectives argue that aging must be a process against which natural selection operates minimally, in a post-reproductive animal.  In other words, basic selection processes assure that enough members of the species (absent predation or other accidental death) survive to a period of maximum reproductive competence (or else a species wouldn’t exist), but selection does not assure longevity much past a peak reproductive period.  Aging is the result of this relative absence of selection for an extended post-reproductive adaptation.  In this sense, evolution ‘does not care too much about aging’, although there may be some partial exceptions to this principle in humans, due to the likely contribution of tribal elders to an extended ‘group fitness’, which may help explain why humans are longer lived than almost all other mammals, currently poorly understood.  Such evolutionary perspectives also suggest that aging (and its deceleration) are likely to be highly polygenetic, and not easily radically modified, arguing strongly against any wild optimism about improvements to maximum human lifespan beyond its documented maxima (~120 years) being easily achievable.

 

Aging research has however extensively probed highly conserved protective effects associated with dietary or calorie restriction, the gold standard in terms of a basic environmental manipulation that slows aging in virtually every species in which it has been closely studied, from yeast to mammals.  Calorie restriction (CR) functions as a global metabolic ‘reprogramming’ for most organisms, reflecting a shift of biological priorities from growth and reproduction towards stasis and conservation.  CR physiology was presumably selected by allowing organisms to survive times of nutrient shortage and then resume the critical business of growth and procreation, once back into environments more supportive of fecundity.  CR extends lifespan and reduces penetration of the diseases of aging significantly if not dramatically in almost every species in which it has been studied, but does not appear to be a viable healthcare strategy for the vast majority of individuals (due to the intrinsic stresses of chronic hunger).  CR mimetics (substances offering at least some of the physiology of CR without the stress of chronic hunger) may offer some or many of the benefits of CR, protective effects of enormous relevance to Western societies as they undergo progressive demographic shifts in the direction of a larger percentage of elderly citizens than at any point in prior human history, with an impending tsunami of diseases of aging.  However, clinical and long term data on CR mimetics is badly lacking outside of animal models, where they show impressive protective effects.  CR mimetics are currently being studied in multiple diseases of aging, including cancer, heart disease, Alzheimer’s disease, diabetes, and several others.

 

Last, but not least, there is also accumulating evidence that Western lifestyles, and an associated pandemic of obesity, reflecting a radical departure from our evolutionary environment, will expose us to increased penetration by the diseases of aging, despite (or perhaps because of) increasing life expectancy.  These multifactorial lifestyle changes (poorer sleep, little exercise, complex dietary shifts, increased social isolation) may increase many of the phenotypes or components of aging, including oxidative stress, inflammation, glycation, insulin resistance, telomere loss, increased junk proteins, and DNA damage.  Fundamental shifts in healthcare strategy and priorities will be needed in coming decades, away from high-technology interventions aimed at an advanced disease of aging (often one at which little real prevention was ever aimed), towards a re-prioritizing of meaningful prevention, via substantive lifestyle modifications.  Such a shift in healthcare priorities is likely to be politically contentious, but the current (and unsustainable) escalation of healthcare spending will eventually force basic changes in both healthcare policy and clinical practice.  The science of aging may eventually heuristically integrate much of our currently fragmented approach to the diseases of aging, and merits not only much more attention and review in medical school curriculums but also in basic biomedical research initiatives.

The Biology of Aging: Implications For Diseases of Aging

and Health Care in the 21^st Century

 

Aging and Mortality

All complex organisms age and eventually die[1], with highly variable limits to their typical life spans, a variability still poorly understood.  The outer biological limit to the human lifespan is generally thought to be approximately 120 years or so, as the oldest carefully verified human known was Jeanne Calment of France (1875–1997), who died at age 122 years, 164 days (Robine and Allard, 1995).  As far as we know, we are the only species with a vivid awareness of, and preoccupation with, our own mortality (and perhaps at other times, a equally great denial).  Cultures from the earliest recorded history have been preoccupied with themes of dying versus immortality, and whether it would be possible to escape death or find a true “fountain of youth.”  Wishes for and even expectations of immortality are a powerful driver in many organized religions and spiritual traditions.  Yet despite such perennial and fundamental human wishes, no way of truly preventing aging or achieving any version of biological immortality has ever been achieved in human history.  Aging, and our eventual demise from it, both seem as unavoidable as the next sunrise.  Benjamin Franklin is credited with the famous quote “the only thing certain in life are death and taxes”.  More humorous perspectives on these existential challenges include George Bernard Shaw’s lament that youth was a wonderful thing, and a shame that it had to be wasted on the young.  When I was too young to fully appreciate the humor, my own father, who passed away during the writing of this chapter at the age of 93, offered that “aging is vastly overrated, but most of the time, it beats the alternative.”  But ultimately, aging is no joking matter, exposing humans to slow and inevitable degradation of virtually every organ system, progressive disability, and eventual outright physiologic failure of one sort or another, with inevitably fatal consequences.  And yet, if we didn’t age and die, humans and their progeny would quickly overrun the planet, and totally exhaust its ecology and resources, causing not only mass extinctions for many other species, but potentially our own as well.  Thus, any true ‘fountain of youth’ for humans might prove to be a seductive but ultimately deadly Faustian bargain.  And yet, who does not want more life, particularly if in decent health and with preserved functional capacities?  Such primordial motivation and longing was surely captured in Dylan’s Thomas’ haunting poem ‘Do not go gentle into that good night’, tapping universal sentiments in the face of aging and mortality.

 

In this context, one might ask why a chapter on the biology of aging appears in a Textbook of Geriatric Neurology.  Trivially, the obvious answer is that aging has everything to do with all things geriatric.  However, less trivially and less obviously, one might argue that an understanding of the basic biology of aging could function as a ‘touchstone’ or integrative ‘hub’ around which much of the science of geriatric neurology might eventually be organized.  Central questions here could include: what is aging, what drives the progressive deterioration of the human organism over time, and why does it lead to what have been called the ‘diseases of aging’?  These diseases would include not just classic neurodegenerative disorders (most paradigmatically, Alzheimer’s disease, but also Parkinson’s disease, frontotemporal dementias, and motor neuron diseases  – all core clinical concerns for geriatric neurologists, neuropsychologists and psychiatrists), but also coronary artery and cerebrovascular disease, other forms of age-related vascular disease, diabetes, cancers, macular degeneration and glaucoma, arthritis, failing immunocompetence, and perhaps many if not most forms of end-stage organ disease.

 

Additional central questions potentially addressed by a science of aging include: what can we do about slowing aging and extending the lifespan, or, for that matter, protecting ourselves from the diseases of aging?  Exactly how does aging lead into the various diseases of aging, and what determines which disease of aging an individual gets?  Does someone truly die just from ‘old age’, or do they die of a disease of aging?  What are the core biological processes responsible for aging?  Is this a few biological processes, or many dozens?  What are the potential relationships (interactions) between various core processes implicated in aging?  What is the relationship between aging in the brain and aging of the body in general?  Can the brain be differentially protected from aging and age-related disease?  Would a slowing of aging itself potentially delimit the penetration by the diseases of aging in some or even all individuals?  How radically?  Is it possible to substantially slow aging, or perhaps even to arrest it?  Even more radically, could aging ever be substantially reversed?  Many of these questions do not have well-validated scientific answers, as of yet.  Most of these questions could be considered central biological questions for all the healthcare disciplines, and also questions around which there is now a rich and emerging, if still fundamentally young and incomplete, science of aging.

 

Implications of an Aging Demographic in Western Societies

for Priorities in Healthcare: Prevention vs High Technology Medicine

 

Unfortunately, very little of an emerging science of aging has trickled down into the healthcare system and into the awareness of most healthcare professionals, where a largely fragmented approach to the diseases of aging predominates theory, clinical research and treatment.  In addition, almost none of it seems to inform the way our healthcare system currently works, where substantive prevention in relationship to diseases of aging (let alone any concerted focus on potentially slowing aging) garners little substantive attention or meaningful share of fiscal resources, while high technology intervention, often around an advanced disease of aging (at which little if any prevention was typically ever aimed), consumes an enormous fraction of medical resources and costs (Conrad, 2009).  Recent estimates are that no more than 5% of the healthcare is spent on prevention broadly defined, whereas 75 to 85% is spent on an established illness, typically a disease of aging (CDC, 2010).  In 2010, at least $55 billion was spent on the last two months of life, and an enormous fraction of total medical costs are spent on end-of-life care (SSAB, 2009), oftentimes with little evidence that this considerable expenditure improves quality of life at all (and may even deteriorate it in some instances).  If one were to extrapolate our current (average) end-of-life care costs to the baby boomers (a roughly 60,000,000 person demographic), this could potentially yield a total price tag of roughly $6 trillion for end-of-life care for the baby boomer generation (see graphic below from Lynn & Adamson, 2003).  Obviously these trends are unsustainable, but there is little evidence of progress towards addressing let alone reversing them.

 

 

 

 

 

 

 

The emerging and expanding science of the biology of aging, as a vigorous area of scientific inquiry, takes place at a time when the demographics of Western societies are tilting towards an increasingly high percentage of elderly citizens.  At the beginning of the 20^th century, when life expectancy was ~ 47 years in the United States, until today, there has been a roughly 30-year increase in life expectation at birth (Minino et al., 2002).  Roughly 25 years of this 30 year gain in life span can be attributed to one primary factor, namely the lessening the impact from early mortality due to infectious diseases in children and young adults, in the context of better hygiene and the creation of effective antibiotics and vaccines (CDC, 1999).  This has yielded a situation in which many Western societies are now for the first time in human history facing the prospect of having more people over the age of 60 than under the age of 15.  Although currently roughly 13% of the United States is over age 65, within the next 20 years, this percentage is expected to increase by more than half again, to roughly 20%.  By the end of the century, fully one third of the world’s population will be over 60 (Lutz et al, 2008).  These demographic shifts will centrally include a huge increase in the very old in the coming four decades.  In 2010, more than an estimated 5.5 million Americans were 85 years or older; by the year 2050, that number is expected to almost quadruple to 19 million.  Currently, number of centenarians in this country (Americans 100 years and older) is estimated at roughly 80,000, but by 2050 there will be more than 500,000 Americans age 100 years or older.  This is unprecedented in human history.  These significant increases in lifespan however have not been accompanied by concomitant increases in ‘healthspan’ or in our ability to substantially prevent (or successfully treat and delimit) the disabling illnesses of later life, the major diseases of aging (cardiovascular disease, stroke, Alzheimer’s disease and cancer), which remain largely refractory to amelioration.  Some evidence (summarized later in this chapter) argues that these diseases may be in large part diseases of Western civilization (primarily due to modern lifestyles) and relatively rare in elders from hunter-gatherer societies compared to Western societies, even when the younger mortality of hunter-gatherers is taken into account (Eaton et al., 1988).

 

The impact of these large demographic shifts and the associated increased penetration of diseases of aging on healthcare economics, combined with the increasing costs of technologically-driven healthcare interventions, is quietly anticipated to be fiscally catastrophic, involving or a steady annual escalation of healthcare costs to unsustainable levels (GAO, 2007; Conrad, 2009).  The impact on healthcare economics of an aging demographic, combined with an increasing emphasis on high technology, is increasingly penetrant and, frankly, worrisome, particularly in terms of its impact on healthcare economics in this country.  In 2010, health care expenditures in the United States are expected to be approximately 18% of GDP, almost twice as much, in terms of percentage of GDP, as any other Western society.  Even just within the only next several years, at a current rate of increase of roughly 6-8% a year, by 2018/2019, roughly 20% of the US GDP (one dollar in every five) could be spent on healthcare expenses, an unprecedented fraction of our national wealth and resources.  The health care expense as a proportion of GDP is projected (without substantive changes in practice trends or chronic illnesses) to rise to 28 percent in 2030 (more than one dollar in every four) and to 34 percent by 2040 (more than one dollar in every three) (CEA, 2009).  These are frightening statistics, suggesting that the current rate of escalation in health care expenditures is unsustainable.  However, the demographic shifts towards an aging population are only one contributing factor in these accelerating expenditures, and are paired with escalating cost of first-line drugs, high-technology interventions and the high overhead associated with the burgeoning healthcare and health insurance bureaucracy itself (CEA, 2009).  Evidence suggests that as much as three quarters of the increasing costs are due to factors other than an aging demographic (CEA, 2009).  Despite these enormous and escalating financial outlays in healthcare, overall health may be actually declining in the United States, as measured by several indices (currently the United States ranks around 50^th in life expectancy, while other indices, such as infant mortality are also worrisome and rank 46^th, behind all of Western Europe and Canada) (CIA Factbook).

 

Reflecting the major disease of aging with special relevance for this textbook, costs for Alzheimer’s disease in 2010 were roughly $170 billion in the United States alone (not counting an additional roughly $140 billion in unpaid caretaker costs – suggesting a real cost of over $300 billion in 2010 alone) (Alzheimer’s Association, 2010).  These total costs of Alzheimer’s disease (assuming current costs continue and no cure or highly effective treatment is found) are expected to potentially reach $2 trillion per year in the United States alone by 2050, with 65 million expected to suffer from the disease in 20 years worldwide, at a cost of many trillions of dollars (Olshansky et al., 2006).  As the baby boomers enter the decades of greatest risk for cancers, heart disease, stroke, arthritis, Alzheimer’s disease, macular degeneration, and other diseases of aging, the evidence is that the healthcare system (as it is currently structured) will eventually undergo a slowly progressive but fundamental collapse, in the context of these unsustainable cost escalations.  Meaningful strategic options to prevent this fiscal implosion have not yet been developed.

 

In addition to its financial impact on healthcare economics, aging in the Western societies is also anticipated to have a more generalized and severely deleterious impact on Western economies, as an increasing percentage of retired elderly severely strain basic social safety net and entitlement programs such as Medicare and Social Security, deteriorate tax and revenue margins, and stretch virtually every societal resource (refs).  In this context, scientific work on the biology of aging, particularly if it might reduce or substantially delay penetration by the diseases of aging into an aging population, and extend ‘healthspan’ (as distinct from lifespan), appears vitally relevant, if not badly needed.  Despite these considerations, the funding of research into all aspects of aging and age-related disease garners only 11% of the $31 billion NIH budget (Freudenheim, 2010), and research into calorie restriction, the primary and well replicated lifestyle intervention to slow aging and reduce diseases of aging, garners less than 100^th of 1% of all biomedical research monies (Guarente, 2003).

 

 

Historical and Basic Evolutionary Perspectives on Aging

 

Aging appears somehow woven into the very fabric of life itself; a still controversial question is whether this is ‘accidental’ (evolution in a sense ‘didn’t worry much about aging’, as post-reproductive deterioration in a complex biological system is inevitable) or whether aging is selected (as nearly immortal organisms would destroy their environment and thus render themselves extinct).  These may not be mutually exclusive perspectives.  Aging is difficult to define, and has no single pathognomonic biomarker, but to paraphrase a famous quote about obscenity, “you’ll know it when you see it.”  Aging can be defined operationally as a progressive and time-dependent ‘loss of fitness’ that begins to manifest itself after the organism attains its maximum reproductive competence (Vijg, 2009).  Aging consists of a composite of characteristic and often readily recognizable phenotypic changes, and can be defined statistically as a point at which normal or expectable development shows an increasing probability of death from all-cause mortality (excepting traumatic injury, starvation or poisoning or other accidental death) with increasing chronological age of the organism.  Intrinsic to aging is that its characteristic phenotypic changes are progressive, and affect virtually every aspect of physiology and every organ of the body, from the skin, to cardiac and muscle tissue, to the brain.  Ontologically, aging may reflect ‘entropy’s revenge’, as fundamental aspects of life organization become increasingly disorganized, presumably due to a complex composite of processes (Hayflick, 2007).  Modern biological thought holds it axiomatic that purposeful genetic programs drive all biological processes occurring from the beginning of life to reproductive maturity.  However, once reproductive competence is attained, current thinking is still divided on the question of whether aging is a continuation of some collection of genetic programs or whether it is the result of the accumulation of random, irreparable losses in cellular organization.  These are again not mutually exclusive.

 

There are references to aging in the earliest human cultures, writings and records, suggesting human have been keenly aware of aging for millennia.  The Bible referred to aging and death as “the wages of sin,” at best a colorful metaphor and of course totally scientifically inadequate.  However, a modern biology of aging suggests that the metaphor of aging as a ‘wage’ is both appropriate and insightful: aging may readily reflect the ‘wages’ of growth, metabolism and reproduction (excess junk proteins, oxidative stress, glycation of proteins, and damage to both mitochondrial and nuclear DNA) and also to the ‘wages’ of organism defense and repair (AKA inflammation).

 

Additionally, one must accept evolutionary principles as fundamental here and grounding any discussion of any biological phenomenon, suggesting that aging must in a direct sense reflect an relative absence of selection against aging itself (see below).  However, what this might mean is not clear.  Initial evolutionary theories of aging hypothesized that aging was ‘programmed’ in order to limit population size (immortal organisms would destroy their environment and render themselves quickly extinct) and/or to accelerate an adaptive turnover of generations, thereby possibly enhancing adaptation to shifting environments.  However, this argument has at best modest evidence for it, as senescence typically contributes minimally to mortality in the wild (Kirkwood and Austad, 2000).  Instead, mortality in wild populations (as opposed to that seen in protected populations) is mostly due to ‘extrinsic’ factors such as infection, predation, starvation, etc., and occurs mainly in younger animals (refs).  As a general rule, many if not most wild animals simply do not live long enough to grow old, again due to these ‘extrinsic’ factors and not to aging.  In this sense, natural selection has a limited opportunity to exert any direct influence over the processes of aging.  Even in species where aging and senescence does make some contribution to mortality in the wild (for example in larger mammals and some birds) any hypothetical ‘aging genes’ would be clearly deleterious and thus it is highly unlikely that it would be selected.

 

Indeed, the relative rarity of aged animals in the wild is an important clue about how fundamental evolutionary processes relate to aging.  Due to extrinsic factors being primary causes of mortality, there is invariably a progressive weakening in the force of selection with increasing age (Kirkwood and Austad, 2000).  By the time an animal in the wild reaches an age when the percentage of a given population surviving has declined to very low levels, the force of selection is likely far too weakened (if not almost nonexistent, given the low probability of reproductive success in an aged animal) to effectively weed out the accumulation of genes with ‘late-acting’ deleterious (in other words, pro-aging) effects.  This constitutes a ‘selection gap’ that allows any alleles with late deleterious (pro-aging) effects to accumulate over many generations, with little or no intrinsic ‘counter mechanism’ (referred to as the ‘mutation accumulation’ theory of aging).  A prediction emerging from this theory is that since the negative alleles are basically unselected mutations, there might be considerable heterogeneity in their distribution within a population of individuals.  There is some evidence both for and against this (Kirkwood and Austad, 2000).

 

A substantial modification of this basic idea is found in the notion of aging as ‘antagonistic pleiotropy’ (Williams, 1957): that evolution would favor genes that have good effects early in development (for example, genes promoting growth and fecundity) even if these genes had clearly bad effects at later stages of life.  In this sense, a small but reproductively significant benefit early in life derived from a particular gene or allele would easily outweigh (in terms of selection effect) later deleterious effects, even if those later effects guaranteed eventual senescence and death.  This of course suggests that aging may express some kind of intrinsic trade-off, a theme also echoed in the widely quoted ‘disposable soma’ theory of aging (refs) which suggests a balance of allocation of metabolic resources between somatic maintenance and reproduction.  Effective maintenance of the organism is required only for as long as it might survive in the wild.  For example, because roughly 90% of wild mice die in their first year of life, biologic programming for metabolically expensive body maintenance programs beyond this age at most benefits only 10% of the total population (Phelan & Austad, 1989).  Given that a primary cause for early mortality in wild mice is excessive cold (refs), the disposable soma theory suggests that mice would not benefit from body maintenance and repair programs that would slow aging nearly as much as investing metabolic resources into thermogenesis and thermoregulatory mechanisms.

 

Thus, longevity may be determined in large part by the level of ‘extrinsic’ mortality in the natural environmental niche (Kirkwood and Austad, 2000).  If this level is high (life expectancy thus is quite short) there is little chance that the force of selection would create a high level of protracted and successful somatic maintenance – the more critical issue is making sure that organisms would either reproduce quickly before extrinsic mortality takes its toll, or to have high fecundity and reproduction rates to ensure that early mortality for many members of a species does not eliminate reproduction for all members of a species (rendering them extinct).  On the other hand, if ‘extrinsic’ mortality is relatively low over long periods of time, selection effects might well direct greater resources towards building and maintaining a more durable organism, by modulating genes that might otherwise contribute to rapid aging.  If this set of assumptions is correct, one would predict that in organisms in relatively safe environments (those with low extrinsic mortality), aging will evolve to be more retarded, while it would be predicted to be more rapid in hazardous environments (slowed aging in these environments would make little difference to procreative success and species survival) – and these predictions are generally well supported (Kirkwood and Austad, 2000).  Additionally, evolutionary developments that reduce extrinsic mortality (for example, wings or other adaptations to reduce vulnerability to predation, highly protective armor (such as shells), or large brains enabling transition from prey species to top predator status) appear linked to increased longevity (birds, turtles, and humans).

 

However, disposable soma theory has been criticized (Blagosklonny, 2010) as failing to account for many aspects of aging, most particularly the greater longevity of women, and the role of specific genetic pathways (such as mTOR – mammalian target of rapamycin – see later sections) that may heavily modulate aging.  Aging is increasingly thought to be not ‘pre-programmed’, but more likely the result of a relative absence of selection for ‘perfect’ maintenance of the organism, past the period of reproductive competence.  Another way of putting this is that aging is simply the “fading out of adaptation”, with the achievement of the age of reproductive success and onset of increasing post-reproductive age (Rose, 2009).  In other words, there is no basis for evolution to have selected against aging and for much better body maintenance, as these issues would escape selection unless there was a specific selection pressure towards this.  An example of a basic selection pressure that could reduce aging significantly might be progressively delayed reproduction (procreating at slightly later and later ages), which has been shown in animal models to result in significant enhancement of longevity, in complete concert with basic evolutionary principles (Teotónio et al, 2009).  In animal models of aging, this is referred to as ‘experimental evolution.’ (Bennett, 2003).  Intriguingly, experimental work with delayed reproduction has successfully developed longer lived species (for example, longer lived Drosophila – fruit flies) but with the cost of depression of early life fecundity, suggesting again intrinsic trade-offs between slowing of aging versus growth and reproduction (Sgro and Partridge, 1999).

 

However, there is expert opinion (Johnson, Sinclair, and Guarente, 1999) that there could well be selection to slow the pace of aging, as such organisms could potentially have a more protracted period of reproductive fitness, conferring an adaptive advantage.  Additionally, in hominid lines, evolutionary perspectives suggest that the existence of tribal elders, with greater accumulated wisdom and experience, would have improved evolutionary fitness for their tribal groups, despite being largely past a reproductive age, suggesting another potential selection mechanism driving ‘anti-aging’ (‘group fitness’ or ‘inclusive fitness’ in highly social species such as hominids) (Carey, 2003).

 

Basic cellular and molecular theories of aging probably come in two fundamental forms: 1) aging as a genetically modulated process (under the control of discrete genes and molecular pathways – but not ‘pre-programmed’); 2) aging as an ‘error’ or stochastic or ‘wear and tear’ process (the best-known of these being the oxidative damage/stress theory).  Neither ‘pure’ type of theory is able to explain all aspects of aging, suggesting that aging is ‘quasi-programmed’ (Blagosklonny, 2009), and perhaps related to both growth programs (which are continued past the period of peak reproductive competence, as an example of ‘antagonistic pleiotropy’) and to stochastic cellular damage/’wear and tear’ aspects.  Calorie restriction, as the only conserved ‘anti-aging’ physiology yet discovered (see later discussion of CR and CR mimetics) may impact both of these (reducing growth programs and also attenuating factors such as oxidative stress and inflammation that drive stochastic damage).  Again, one has to assume that these issues do not contradict or replace a basic evolutionary perspective (in which aging reflects a relative absence of selection against wear and tear, stochastic damage, or failure of inhibition of many genes/pathways that might accelerate or drive age-related decline).  Ultimately, these ‘wear and tear’ (‘stochastic damage’) versus genetic/molecular pathway perspectives on aging may be complementary instead of truly competing perspectives, as cellular defense, maintenance and repair (under the control of specific genes and molecular pathways) must counter or oppose stochastic damage.  Additionally, age-related cellular and organ damage may not be truly ‘stochastic’ (random) and may have critical loci (Hayflick, 2007).  Kirkwood and Austad (2000) summarize these considerations for an evolutionary genetics of aging as three basic predictions (p. 236):

 

1)      Specific genes selected to promote ageing are unlikely to exist.

2)      Aging is not programmed but results largely from accumulation of somatic damage, owing to limited investments in maintenance and repair. Longevity is thus regulated by genes controlling levels of activities such as DNA repair and antioxidant defense.

3)      In addition, there may be adverse gene actions at older ages arising either from purely deleterious genes that escape the force of natural selection or from pleiotropic genes that trade benefit at an early age against harm at older ages.

 

Thus, aging could reflect the species-variable interactions and intrinsic ‘tug-of-war’ between deleterious and degrading changes (and the declining influence of selection/adaptation in a post-reproductive animal), with many of these intrinsic to growth, metabolism, inflammation and other aspects of physiology (‘antagonistic pleiotropy’), versus various (and selected) counterbalanced repair, protection and maintenance programs.  Of course, if aging itself potentially deteriorates those counterbalanced cellular repair and maintenance programs, this suggests that aging in a sense is a losing ‘tug-of-war’ between forces of cellular protection versus forces of cellular degradation, and that perhaps as the tug-of-war metaphor suggests, as one side loses, it may lose at accelerating rate.  There is indeed some evidence, although it is hardly conclusive, that aging may actually accelerate (refs).  Few elderly would find this surprising.

 

Cellular and molecular aspects of aging that might map onto these various considerations about the evolutionary basis for aging suggest a dizzying composite of phenotypic changes, including changes in mitochondrial, nuclear, and ribosomal DNA, subsequent genomic and chromatin changes and instability, increasing levels of oxidative stress (including pleiotropic and differential expression of oxidative stress on membranes and lipids, proteins, and nucleic acids, particularly mitochondrial), increasing systemic inflammation (‘inflammaging’), paradoxically concomitant with declining immunocompetence, increasing glycation of proteins (and increasing amounts of AGE – advanced glycation end products which potentiate inflammation), increasing cellular senescence and loss of telomeres, dysregulation of apoptosis (programmed cell death is over- or under- recruited), and increasing junk proteins, combined with impaired protein turnover and declining removal of damaged (and glycated) proteins (declining ‘autophagy’).  Last but certainly not least, even our stem cells age, and reach senescence.  A clear sense of what are ‘leading’ versus ‘trailing’ edges in this process (in other words, clearly distinguished ‘causes’ versus ‘effects’) is unclear.  However, there is evidence for each of these various aspects of cellular change as direct contributors to the phenotypes of aging, including evidence linking virtually all of these processes directly to all the diseases of aging.  Like many aspects of biological regulation, and indeed life itself, recursive interactions between these various processes may be essential; in other words, the many mechanisms of aging be highly interactive, suggesting that there cannot be a ‘single pathway’ into aging (see discussion of the network of molecular pathways in calorie restriction effects), and that instead that aging probably reflects a complex and recursive network of (still incompletely understood) changes.  This is consistent with limitations of all ‘linear causality’ models in biological systems, where causality is intrinsically more recursive, circular, and multifactorial (Freeman, 2000.)  As critical examples of this principle of reciprocal interaction, inflammation and oxidative stress are increasingly linked and seen as mutually reinforcing (Jesmin et al. 2010), oxidative stress is thought to drive DNA damage (both mitochondrial and nuclear), glycation promotes inflammation, and declining removal of junk (including glycated) proteins may be related to increased oxidative stress (Kurz, Terman, and Brunk, 2007) and mitochondrial decline.  All of these may be interlinked aspects of declining biological organization and increasing entropy, as basic phenotypes of aging.  At the same time, several molecular pathways (such as mammalian target of rapamycin – mTOR and many molecular and cell signaling pathways with which mTOR interacts) may be particularly critical to aging and the modulation of age-related change.  At the end of this chapter, we will also summarize evidence that lifestyle factors modulate risk for diseases of aging (and perhaps aging itself), accelerating or retarding it at least to some degree.  We will also examine the difference between the current Western technological environment versus our original evolutionary environment, in terms of the impact that multiple lifestyle variables may have on the cellular mechanisms and physiology of aging and the diseases of aging.

 

 

Basic Molecular and Cellular Perspectives on Aging:

Phenotypes of Aging

 

Oxidative Stress and Associated Mitochondrial Perspectives

 

A basic assumption about aging is that it must have a fundamental cellular basis, and cellular and molecular perspectives on aging have dominated the scientific landscape of aging research and theory.  Perhaps the oldest and most widely quoted molecular theory about aging is derived from Harman (1956), who postulated that oxidizing ‘free radicals’ damaged and degraded cells over time, causing aging.  Harman’s early work on radiation with experimental animals demonstrated that aging had important similarities to the after-effects of massive exposure to radiation, particularly cancer, inflammation, apoptosis, and other tissue changes not dissimilar to classic phenotypes of aging in older animals and humans.  Harman’s hypothesis emerged from his familiarity with work on radiation exposure, and early findings that large doses of ionizing radiation generated enormous quantities of free radicals.  Harman subsequently published what may be the first dietary antioxidant study (1957), studying effects of dietary 2-mercaptoetylamine, the most potent radioprotective compound known at the time, and demonstrating a modest 20% increase in average lifespan, although the mechanism of action of this compound is still debated.  In 1972, Harmon published an important extension to the free radical theory, suggesting that the mitochondria were the primary source for oxidative stress, as well as the primary site for oxidative damage, and that the mitochondria therefore represented a kind of ‘biological clock’ which he argued determined maximum lifespan, concluding that his inability to extend maximum lifespan with dietary supplements must derive from the fact that most exogenous antioxidants do not get into the mitochondria.  He hypothesized that oxidative stress in the mitochondria (versus its endogenous antioxidant defenses) set an outer limit on a given species longevity.  Some work have suggested that OS is mostly generated by mitochondrial complex 1 (refs).

 

This led to a second ‘vicious circle hypothesis’ about oxidative stress in relationship to the mitochondria: that oxidative stress caused deterioration in mitochondrial antioxidant defense systems and mitochondrial function in general, leading to more oxidative stress, in turn driving more damage and increasing age-related deterioration.  Although this is clearly the most widely quoted and accepted molecular theory of aging, and all-too-frequently quoted, particularly in the popular media and product advertising, as established biological fact, the most comprehensive and wide-ranging review of this theory to date (Lustgarten, Mueller, and Van Remmen, 2011) concludes that hard support for the theory is actually surprisingly mixed.  Therefore the authors conclude that this theory remains unproven (but also not falsified), at least in the original ‘hard’ form of the hypothesis (that oxidative stress in the mitochondria was the driver of aging, as opposed to simply a softer form of the hypothesis that oxidative stress in the mitochondria may significantly contribute to aging).  It has also been known for some time that oxidative stress markers increase with aging, although debate still rages about how much this is cause or effect of aging (Sohal and Weindruch, 1996).  There are many data points both for and against the oxidative-stress-in-the-mitochondria theory of aging, which might readily lead even the advanced student of aging to a sense of confusion and frustration.

 

Much experimental work to test the basic hypothesis has focused on genetic manipulations of antioxidant enzyme systems in short-lived species.  Support for the hypothesis could be drawn from the results of knockouts of superoxide dismutase 2 (Perez et al., 2009) and glutathione perioxidase 4 (Ran et al., 2007), both of which show lethal effects.  Other primary data points in favor of the hypothesis emerges from work correlating species longevity with lowered mtDNA mutation (Sanz et al, 2006).  Additionally, longer lived rodents (white-footed mouse Peromyscus leucopus) exhibit lower levels of reactive oxygen species (superoxide and hydrogen peroxide) compared to the shorter-lived house mouse (Mus musculus) and show higher cellular concentrations of some antioxidant enzymes (catalase and glutathione peroxidase), and lowered markers for protein oxidative damage (Sohal, Ku, & Agarwal, 1993).  Schriner et al. (2005) generated transgenic mice that overexpressed human catalase localized to peroxisome, nucleus, or mitochondria (MCAT). Median and maximum life spans were maximally increased (averages of 5 months and 5.5 months, respectively) in MCAT group.  Cardiac pathology and cataract development were both delayed, markers for oxidative damage were reduced, peroxide production attenuated, and mitochondrial DNA deletions (perhaps the most serious form of MITO damage) were also reduced.  These results were seen as strong support for the free radical theory of aging, that the mitochondria are the primary source of these free radicals.  In general, there is also broad, although occasionally inconsistent correlation, between oxidative stress in the mitochondria, rates of mitochondrial DNA damage, and longevity (Sanz, Pamplona and Barja G, 2006; Barja and Herrero, 2000).

 

There is however some equally compelling data against this classic hypothesis.  The naked mole rat (NMR) demonstrates an unusual phenotype of significantly delayed aging and the longest lifespan of any rodent (~30 years), five times the expected lifespan based on body size, and exceptional cancer resistance, despite elevated markers for oxidative stress, and short telomeres (Buffenstein et al., 2009).  Additionally, the lack of a significant lifespan decrease or accelerated aging phenotypes in superoxide dismutase (SOD) 2^-/+ mice (missing one copy of the gene), despite evidence for increased oxidative stress (Mansouri et al., 2006), and increased mitochondrial DNA damage (Osterod et al., 2001) are data points against this classic theory.  Further complicating the picture however is evidence that while oxidation of mitochondrial DNA is elevated in SOD 2^-/+ mice, mitochondrial DNA deletions (thought to reflect the most serious form of mitochondrial DNA damage) are not increased (Lin et al. 2001).  This suggests that this particular partial knockout model may not adequately probe the question of the relationship between mitochondrial oxidative stress and longevity.

 

Other animal models demonstrate that increased expression of the major antioxidant enzymes involved in protection from mitochondrial oxidative stress, including upregulation of the two isoforms of superoxide dismutase (Mn superoxide dismutase, Cu/Zn superoxide dismutase) and catalase, individually or in various combinations, does not extend maximum life span in mouse models (see (Lustgarten, Mueller, and Van Remmen, 2011 for detailed review).  Mice with genetically reduced individual components of the antioxidant defense system have also been extensively studied, including knockouts of two isoforms of SOD (MnSOD and Cu/ZnSOD), glutathione peroxidases (Gpx-1, Gpx-2, and Gpx-4), catalase, thioredoxin and peroxiredoxin.  Complete ablation of individual components of antioxidant defense can often be embryonically lethal (specifically, homozygous knockout of thioredoxin 2, glutathione perioxidase 4, or MnSOD), but simply a loss of one allele (generating ~50% loss in activity) in heterozygous knockout mouse models ( SOD1^+/−, SOD2^+/−, and Gpx4^+/−) does not result in reduced life span (Lustgarten, Mueller, and Van Remmen, 2011).  Lastly, recent work shows that combining a heterozygous knockout of MnSOD and homozygous glutathione perioxidase 1 knockout clearly results in increased oxidative stress, indexed through several classic markers (both protein carbonyls and oxidized nucleic acids), but no decrease in lifespan (Zhang et al., 2009).

 

Such negative results, on face value, might suggest that the ‘hard’ form of the mitochondrial oxidative stress hypothesis (OS is the primary driver of aging and mortality) is not well supported.  However, some very recent work argues that antioxidant defense in the mitochondria involves factors beyond these classic antioxidant enzyme systems, and requires activation of one of the seven sirtuins, (SIRT 3), which promotes acetylation of antioxidant enzymes, significantly enhancing their effectiveness (refs).  Although initial work on OS and CR emphasized the role of SIRT1 (Sinclair), recent work has demonstrated that SIRT3 appears essential for CR-mediated reduction in oxidative stress (Qiu et al. (2010), as homonymous knockout of SIRT3 prevents the expected reduction of oxidative stress during CR. SIRT3 reduces oxidative stress by increasing activity of SOD2 through deacetylation (Tao et al., 2010; Qiu et al 2010). In addition to regulating SOD2, SIRT3 also reduces oxidative stress by modulating the activity of isocitrate dehydrogenase 2 (IDH2), a mitochondrial enzyme generating NADPH (part of antioxidant defense in the MITO) (Someya et al, 2010).  Thus, there may be many players in the defense against OS in the MITO, arguing that a true test of the oxidative stress hypothesis of aging may be challenging to design, and that single or even combined manipulations of anti-oxidant enzyme systems may be insufficient.

 

A major practical challenge to both test the basic hypotheses of oxidative stress perspectives on aging and also explore therapeutic implications of this idea has been the question of how to deliver antioxidants into the mitochondria (as the primary cellular nexus for oxidative stress versus antioxidant protection).  Most organic compounds conventionally regarded as antioxidants (particularly the so-called ‘antioxidant’ vitamins A, E and C) do not get into the mitochondria in meaningful quantities, nor do others common in the diet, such as many polyphenols.  Work by Skulachev et al. (2009) however suggests that one can design molecules which do materially affect oxidative stress, (‘SkQs’ in this case comprising plastoquinone (an antioxidant moiety), a penetrating cation, and a decane/pentane link).  In vitro work indeed confirms that SkQ1 accumulates almost exclusively in mitochondria.  In several species of varying phylogenetic complexity (the fungus Podospora anserina, the crustacean Ceriodaphnia affinis, Drosophila, and mice), SkQ1 prolonged lifespan, especially at the early and middle stages of aging.  In mammals, SkQs inhibited development of age-related diseases and involutional markers (cataract, retinopathy, glaucoma, balding, canities, osteoporosis, involution of the thymus, hypothermia, torpor, peroxidation of lipids and proteins).  SkQ1 manifested “a strong therapeutic action on some already pronounced retinopathies, in particular, congenital retinal dysplasia”.  With eye drops containing 250 nM SkQ1, vision was restored to 67 of 89 animals (dogs, cats, and horses) that became blind because of a retinopathy.  Moreover, SkQ1 pretreatment of rats significantly decreased hydrogen peroxide or ischemia-induced arrhythmia of the heart, reducing the damaged area in myocardial infarction or stroke and preventing the death of animals from kidney ischemia.  In p53 (-/-) knockout mice, 5 nmol/kg/day SkQ1 decreased ROS levels in spleen and inhibited lymphomas.  Thus, such ‘designer antioxidants’ show promise in slowing aging, and in both preventing and potentially treating diseases of aging.

 

Intriguingly, and underlining the intrinsic connections between the many biological phenotypes of aging, in recent years, the oxidative stress theory of aging has had increasing connections to inflammation and inflammatory signaling, with many positive feedback loops between the two processes, such that neatly separating these two processes is difficult (see section on inflammation).  Recent work on gene interactions (Jesmin et al. 2010) suggests that oxidative stress is the common denominator underpinning the intimate associations between obesity, type II diabetes and hypertension, and that obesity itself may increase oxidative stress (Fernández-Sánchez et al. 2011).  There is also much evidence that cancers and Alzheimer’s disease are also hinged to oxidative stress, suggesting that its long-term reduction in aging may have significant health benefits and offer protection against many diseases of aging.

 

 

Calorie Restriction: Evolutionary and Animal Models

 

Although the effects of calorie restriction on longevity were described more than one hundred and fifteen years ago (Jones, 1894), and its protection against the diseases of aging have been appreciated for almost a century (Rous, 1914), only more recently have we begin to unravel the molecular mechanisms by which calorie restriction extends life span and protects the organism from age-related change.  Calorie restriction (CR) functions as a kind of global metabolic reprogramming for virtually all organisms, extends lifespan and reduces penetration of the diseases of aging significantly if not dramatically in every species in which it has been studied.  Although the precise molecular pathways and cellular effects of calorie restriction are still being studied and debated, in general it is viewed as a selected and phylogenetically conserved trade-off between reproductive fecundity and physiological conservation/preservation.  A basic speculation has been (refs) that some version of a basic CR mechanism arose relatively early in evolution, during commonplace periods of nutrient shortfalls, in order to allow organisms to trade off reproduction for conservation (when major energy shortages would have made reproductive efforts too metabolically costly), allowing an adaptive shift back to growth and reproduction at a time when nutritional supplies were more abundant.  Recent work has confirmed that calorie restriction effects are conserved virtually throughout the entire animal kingdom, starting with organisms as primitive as yeast, and extending into insects and other invertebrates, lower vertebrates such as fish, mammals (Fernandes et al., 1976), primates (Lane et al., 2001; Roth et al, 2001), and even humans (Rochon et al., 2011), although longer term studies on calorie restriction affects in humans are still lacking (shorter term studies clearly demonstrate that the basic physiology of CR in well conserved in humans, but life extension (confirming that aging is indeed slowed) has not yet been empirically confirmed, although most researchers anticipate that this will be eventually demonstrated.

 

Calorie restriction (CR) or dietary restriction (DR) lacks a precise quantitative definition, but might be considered to reflect a roughly 30% reduction in calories from eating freely until satiation (Richardson, 1985).  CR effects might begin at around a ~ 25%-30% reduction and extend to a 50-65% reduction, at which point CR transitions into starvation, a process which does not demonstrate any of the protective effects of CR and is destructive of health.  CR also requires that basic macro- and micro-nutrients be obtained (vitamins, minerals, fatty acids, and at least some protein).  Calorie or dietary restriction is probably not a simple ‘homogeneous’ issue, and can include differential restriction of proteins, carbohydrates, and fats, with these different forms of dietary restriction probably activating different cellular pathways involved in nutrient sensing and therefore having somewhat different physiologic effects.  However, protein and amino acid restriction clearly appears to be the most central component, as protein restriction without calorie restriction elicits a significantly more robust profile of CR effects (Simpson 2010) than the reverse (calorie restriction but without protein restriction) (Kim et al. 2010).  Reasons for this may hinge on the importance of protein restriction for down regulation of mTOR which is required for maximal CR benefits (see section on mammalian target of rapamycin).

 

Protein restriction may cause down-regulation of growth factors and growth hormones (particularly GH but also IGF), as well as provide downstream inhibition of TOR pathways (see below), improving autophagy and decreasing protein synthesis, among other effects, and be particularly protective in relationship to carcinogenesis (Anisimov et al. 2010), while calorie restriction without protein restriction may not be nearly as protective in relationship to cancers (Baur et al. 2006).  Carbohydrate and glucose restriction on the other hand may more directly modulate insulin pathways and their several downstream targets.  Intriguingly, there is evidence that single amino acid restriction (specifically limiting dietary methionine or tryptophan) can yield calorie restriction effects (Caro et al., 2009), with subsequent reduced reactive oxygen species in the mitochondria, lowered insulin and blood sugar levels, improved insulin sensitivity, etc (in other words, a calorie restriction physiology).  This suggests an intriguing and perhaps less burdensome option to classic calorie restriction approaches, one without at least some of the aversive effects of classic calorie restriction diets (foods high in methionine include eggs, fish, soy and many seeds, esp. sesame).  Calorie restriction without protein restriction on the other hand may not produce lifespan extension, probably because of a blunting of the CR protective effects against carcinogenesis, and more limited down regulation of IGF (and perhaps other growth factors as well) and lessened overall inhibition of TOR (Anisimov et al. 2010) (see next sections).

 

 

Calorie Restriction: Genes & Pathways

 

Many genes and molecular pathways are implicated in calorie restriction effects, consistent with the above discussion.  Indeed, many researchers and theorists at this point believe that calorie restriction involves a whole family or network of interacting molecular pathways, (including insulin signaling 1/2, IGF and other growth factors, PI3 kinase, AKT (protein kinase B), forkhead transcription factors, PGC1-ά, AMP kinase, and mTOR (see graphic on following page), instead of any version of a single primary pathway being responsible for CR effects (refs), suggesting a pleiotropic phenotype, and that CR operates through a network of linked molecular pathways.  Although a class of transcription factors called surtuins, particularly SIRT1, were initially conceptualized as critical regulators of CR effects (Sinclair , recent work suggests that they may operate on some but not all of the CR network.  However, research suggests that CR centrally upregulates AMPK (Baur, 2006) while down regulating mTOR, upregulates several surtuins (Sinclair, ), promotes mitochondrial biogenesis, reduces inflammation (refs) (see graphic below).  Effects form inhibition of TOR are increasingly thought critical, to mediating lifespan extension and the slowing of the aging process from dietary restriction, such that this pathway has supplanted the surtuins as the most studied and intriguing pathway in aging (and anti-aging) science.  As such, it merits a detailed overview.

 

 

mTOR (Mammalian Target of Rapamycin)

 

Target of rapamycin (TOR) belongs to a conserved group of kinases from the PIKK (phosphatidylinositol) family.  Rapamycin, an immunosuppressive macrolide, was first discovered as the product of a soil bacteria from Easter Island, which directly and potently inhibits the activity of TOR (at least TORC1 (TOR complex 1) but not TORC2).  TOR was first identified in yeast, but then subsequently has been found to exist in all eukaryotic organisms.  TOR complex 1 (rapamycin sensitive) is thought to be the central element of the TOR signaling network, monitoring and integrating a large set of intra-and extra cellular processes, and controlling growth, proliferation, and lifespan by a host of complex downstream effects (refs).  TOR complex 2 (TORC2) is rapamycin-insensitive on the other hand, but contributes to the full activation of AKT, an upstream and critical signaler of TOR complex 1, and mediates spatial control of cell growth by regulating the actin cytoskeleton (Hall, 2008).  TOR plays a highly conserved and central role in coupling nutrient sensing to growth signals integrating signals from wnt (important to stem cell differentiation), glucose and lipid availability (signaled by AMP kinase), protein and amino acids deficiency/availability (growth resources), signals from multiple other growth factors and hormones, and even oxygen availability/hypoxia signals to dynamically determine the envelope of growth versus conservation signaling in the cell.  TORC1 is thus thought to act as a growth ‘checkpoint’ and signal integrator, determining whether the extra- and intra- cellular milieu is favorable to growth or not, and if not, producing effects consistent with a calorie restriction (CR) phenotype.  TOR complex 1 has many output targets, altered in either CR or in CR mimetic effects from rapamycin, including messenger RNA translation (inhibited in CR), autophagy (increased in CR), transcription and ribosome biogenesis (inhibited in CR), metabolism, proliferation and growth (inhibited in CR), and several other key cellular processes including stress resistance (increased by CR) (for a fine technical review of TOR research see Kapahi et al, 2010).  Inhibition of mTOR by rapamycin has been shown experimentally to increase lifespan, even when given to mice in middle age (Harrison et al, 2009), a finding suggesting that rapamycin is a more powerful CR mimetic than resveratrol which has failed to extended lifespan outside of obese animals (Baur et al., 2006; Miller et al 2011).  On the basis of age at 90% mortality, rapamycin led to an increase of 14% for females and 9% for males, and intriguingly, patterns of mortality and disease in rapamycin-treated mice did not differ from those of control mice, suggesting that treatment with rapamycin globally delays aging and age-related disease in a non-specific and fairly ‘even’ fashion (Harrison et al, 2009). Inhibition of TOR’s major downstream targets, such as S6K, a kinase involved in ribosome biogenesis, appear to be important to the protective (antiaging) effects of TOR inhibition, and a knockout of this gene also increases lifespan in mice and intriguingly generates activation of AMP kinase, suggesting dynamic relationships between mTOR and AMP kinase (Selman et al. 2009).

 

 

 

 

 

 

 

 

 

 

 

 

 

FIGURE 1

 

 

 

 

 

 

 

 

 

 

FIGURE 2

 

Figure 1 presents a simple schematic for the molecular pathway of mTOR as ‘antagonistic pleiotropy’ – that aging in some sense is simply the flip side of a protracted growth process that is not turned down or turned off after a peak reproductive period (from Blagosklonny, 2009).  The second graphic (Figure 2) provides a simple schematic of some of the cellular pathways implicated in calorie restriction, aging, and the slowing of aging.  Nutrients, GF (growth factors) and insulin activate the TOR pathway, which is involved in aging and age-related diseases. Other genetic factors and environmental factors (e.g., smoking, sedentary lifestyles, obesity etc) contribute to age-related diseases. Several potential anti-aging modalities (metformin, calorie restriction and rapamycin and several polyphenols) all directly or indirectly (via impact on AMP kinase) inhibit the TOR pathway. Both graphics from Blagosklonny, 2009

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

FIGURE 3

 

 

 

 

Figure 3 (from Simpson, 2010 with permission) schematically summarizes relationships between AMP kinase and (mammalian) target of rapamycin (mTOR).  These two kinases are increasingly viewed as possibly integrating much of calorie restriction physiology, with an up-regulation of AMP kinase and a down regulation of mTOR (target of rapamycin) potentially orchestrating through their conjoint activity, the entire range of CR effects.  These two kinases are differentially involved in nutrient sensing, with target of rapamycin activated by high amino acid/glucose ratios (in other words plenty of amino acids and proteins to build new tissue, thus releasing a go signal to anabolic processes and growth), and AMP kinase activated by low amino acid/glucose ratios.  Thus protein/carbohydrate dietary ratio may influence differential activation/inhibition of TOR and of AMP kinase (and these two integrators of CR physiology are interactive, with AMP kinase inhibiting mTOR).

 

These differential nutrient sensing systems may help explain why calorie restriction without at least some protein restriction may not be as effective as a general anti-aging strategy (Blagosklonny, 2010), particularly in relationship to prevention of cancers, because such a diet does not maximally downregulate mTOR.  Additionally, this graphic may explain why resveratrol by itself (a primary activator of AMP kinase but not a primary or direct inhibitor of mTOR)[2] does not produce lifespan extension in animal models (outside of obesity) because it does not inhibit mTOR sufficiently.  Indeed in the powerful 2006 study on resveratrol and obesity, resveratrol did not produce lifespan extension and did not protect against a common lymphoma as a cause of mortality in mice that were not obese.  This suggests that a complete or ideal CR mimetic might activate both AMP kinase and directly inhibit mTOR (not indirectly through AMPK activity) and do so without toxicities or major side effects, a design target that no single known compound at this time successfully reaches (see discussion in next sections).  Inhibition of mTOR (through use of rapamycin as a CR mimetic) has shown promising protection against diseases of aging in mammalian animal models (Stanfel et al, 2009).

 

 

Calorie Restriction Mimetics

 

Given the intrinsically stressful and unpleasant nature of basic calorie restriction approaches (e.g., calorie restricted animals typically cannot be housed together because they are too irritable and will fight), many believe that calorie restriction is simply not a viable health maintenance strategy for most people.  If anything, the recent pandemic of obesity has underlined that most individuals, when given ready access to tasty and addicting high calorie density foods, are simply not going to restrict their calorie intake voluntarily, irrespective of the well known and widely appreciated negative consequences.  This has led to increasing interest ‘calorie restriction mimetics’, defined as any substance which potentially mimics the molecular effects and physiology of calorie restriction (without the stress of being hungry much of the time).  There are probably many substances that cause mild nausea, visceral upset or other G.I. distress, and which subsequently inhibit food intake, and while these can show CR effects in sustained administration in animal models, these cannot be considered CR mimetics.  Additionally, drugs that may directly modulate appetite (such as Rimonabant, an endocannabinoid-1 receptor blocker) can also show calorie restriction effects in sustained administration by modulating consumption and hunger drive at central levels, but also cannot be considered true calorie restriction mimetics.  One prediction emerging might be that calorie restriction mimetics will occupy an increasingly central role in primary prevention in relationship to the diseases of aging in the coming decades, but an enormous amount of basic research remains to be done before widespread implementation of calorie restriction mimetics would be advisable or feasible, and long term data in both preclinical and clinical populations is lacking (although data collection and trials of CR mimetics are underway in relationship to many disease of aging).

 

There are actually a number of calorie restriction mimetics with accumulating research supporting CR effects, but the most famous of these is clearly resveratrol, a molecule which has received enormous research attention in the last 15 years.  In addition, metformin (a drug commonly used to treat type II diabetes and rarely categorized in conventional medical literature as a CR mimetic), along with 2-deoxyglucose are also calorie restriction mimetics (2-deoxyglucose was actually the first described calorie restriction mimetic and interferes with glycolysis, preventing glucose utilization by cells even when abundant glucose is available but his cardio-toxic in chronic administration).  Fisetin, derived from Fustet shrubs, is a flavonoid polyphenol that has also demonstrated CR mimetic effects.  Rapamycin (as a primary inhibitor of TOR – target of rapamycin) is also a potent CR mimetic, and to date only rapamycin has demonstrated lifespan extension in mammals, (most CR mimetics have demonstrated lifespan extension in other target species such as yeast, fruit flies, fish and worms).  Other polyphenols (a very large group of compounds found in fruits and vegetables totaling perhaps as many as 6000 substances) besides resveratrol may have mild calorie restriction effects, particularly quercetin (Belinha et al., 2007).  Single polyphenol regimens particularly resveratrol have not shown lifespan extension (Pearson et al. 2008), except in obese animals (protecting mice from premature mortality and the undesirable physiology of obesity – (Baur et al., 200)), or, when resveratrol was combined with every other day dieting (EOD) -  a mild calorie restriction alternative (also demonstrated in a mouse model in Pearson et al., 2008).  Although resveratrol was initially assumed to have its protective effects through SIRT 1 activation, recent work has clarified that AMP kinase is the necessary and sufficient target for the protective effects of resveratrol (.  Recent work has suggested that pterostilbene may be even an more effective CR mimetic, with better bioavailability than resveratrol, and also a better activator of PPAR-α (refs), with more beneficial effects on lipid profiles.

 

These lines of evidence suggest that resveratrol (along with metformin, and quercetin) are only partial CR mimetics, and specifically, that even moderately high dose resveratrol (20 to 30 mg per kilogram) does not appear to protect mice against late-life cancers (particularly a form of virally induced lymphoma, a very common cause of death in aged laboratory mice) (Pearson et al. 2008).  Intriguingly, a nutraceutical combination of resveratrol and quercetin appeared to provide better ‘mimicking’ of calorie restriction physiology than resveratrol alone (Berger et al., 2008 – although longevity was not probed specifically), suggesting that combinations of partial CR agents may get closer to a full calorie restriction effect than a single compound.  Given the potential impact that a full calorie restriction mimetic could have on aging and the diseases of aging (particularly the potential extension of ‘health span’), there is remarkably little research into this area, relative to its potential biologic promise. Large pharmaceutical firms have just recently begun to pay more attention to this area (see the recent GSK acquisition of Sirtuis), http://www.gsk.com/media/pressreleases/2008/2008_us_pressrelease_10038.htm).

 

 

Calorie Restriction Mutants

There are many ways to generate calorie restriction effects, beyond classic calorie restriction approaches.  One of the most basic of these is simply intermittent fasting (which may not result in nearly as much weight loss as full calorie restriction), and additionally, methionine restriction (as noted above).  In addition there is manipulation of growth hormone (such as growth hormone knockout), and IGF-1 and insulin signaling manipulations (consistent with overwhelming evidence that insulin signaling pathways are primary targets for calorie restriction effects – see graphics below).  A dwarf mouse implementing a growth hormone knockout shows a roughly 60% life extension (and won a recent Methuselah prize – Bartke and Brown-Borg, 2004).  This animal showed reduced hepatic synthesis of IGF-1, reduced secretion of insulin, increased sensitivity to insulin actions, reduced plasma glucose, reduced generation of reactive oxygen species markers, upregulated antioxidant defenses, increased resistance to oxidative stress, and reduced oxidative damage, all quite consistent with calorie restriction physiology.

 

 

Glycation, Advanced Glycation End Products and AGE Receptors (rAGE)

 

Glycation of proteins is a fundamental mechanism in aging and in the deterioration of both organ structure and function, and is probably neglected in many treatments of aging relative to its importance (Semba et al., 2010; Bengmark, 2007).  Glycation appears implicated in almost every disease of aging, and not simply diabetes.  Additionally, advanced glycation end products (acronym: ‘AGE’) interact with receptors (acronym rAGE) to up-regulate inflammation, another primary factor in the biology of aging (see section on inflammation), potentially contributing to another critical dimension to aging.  The creation of AGEs involves bonding two or more proteins together, a process known as ‘crosslinking’ by the creation of sugar-protein bonds.  While some AGEs are relatively short-lived and fluctuate in response to diet and metabolic state, other advanced glycation end products are long-lived and virtually impossible for the body to break down.  The creation and accumulation of these AGEs, particularly in essential tissues such as coronary arteries and the brain, can have serious effects on function and constitute a major risk factor for a disease of aging in those organs (Semba et al., 2010).  Areas for example of arterial glycation are much more likely to eventually become regions of atherosclerosis and plaque accumulation, while glycation of CNS tissue is associated with increasing inflammation and the classic plaque and tangle pathology of Alzheimer’s disease (Srikanth et al., 2009; Lue et al., 2010), with advanced glycation end products a major facilitating co-factor in the creation of both amyloid oligomers and tangles (Gella & Durany, 2009).

 

Glycation of tendons and other connective tissue may form important foundations for loss of flexibility in aging (refs).  Obviously, diabetes provides a classic model for the acceleration of glycation, and generates a more rapid accumulation of AGEs, with hemoglobin A1C a direct measure of glycation of hemoglobin molecules (an example of a relatively short-lived form of glycation).  rAGE receptors are also implicated in Alzheimer’s disease, as a channel for amyloid oligomers to enter cells where the oligomers potentially wreak havoc with multiple cellular compartments, particularly mitochondria and lysosomes (LeFerla, 2008).  Glycation can be inhibited by AGE breakers, which includes the amino acid l-carnosine, and also blocked by multiple polyphenols.  Green tea extract (Babu et al., 2008), curcumin (Pari & Murugan, 2007), and many flavonoids (Urios, et al., 2007) have shown at least some anti-glycation functionality, along with alpha lipoic acid (Thirunavukkarasu et al., 2005).  This suggests that a diet high in polyphenols and relatively low in free sugars might prevent or reduce long-term glycation of tissues (although this is never been proven in a human clinical assay to our knowledge).

 

 

Inflammation

 

Increasing evidence argues that aging centrally involves changes in both innate and adaptive immunity (in the direction of declining adaptive immunity and compensatory upregulation of innate immunity), combined with increasing systemic inflammation, recently dubbed ‘inflammaging’ (Franceschi, et al, 2007) – even in the absence of obvious pathological consequences or lesions.  While traditional perspectives on inflammation emphasize acute and local inflammatory processes and the classic cardinal signs of localized inflammation (‘rubor et tumor cum calor et dolore’ – redness and swelling with heat and pain) involving many ‘acute phase’ proteins, recent work on ‘inflammaging’ emphasizes a different side of inflammation that is more systemic, chronic, and oftentimes (at least initially if not over the long term) asymptomatic.

 

Of course, inflammation is also a highly adaptive and selected process, central to both organism defense and tissue repair, and without which we could not survive long at all, and operates at virtually all levels of biological organization, from the small molecular level all the way to the level of behavioral organization (see chapter on depression and its connection to inflammatory signaling).  And yet it is centrally implicated in many if not virtually all of the major diseases of aging, particularly atherosclerosis (see section on this), Alzheimer’s disease, Parkinson’s disease, most cancers, arthritis, type II diabetes, etc (see Finch, 2011 for detailed review).  This profoundly Janus-faced nature of inflammation may be one of the most striking examples of ‘antagonistic pleiotropy’, suggesting that aging and its acceleration may be at least partially one of the ‘wages’ of successful organism defense and tissue repair.

 

Blood levels of pro-inflammatory cytokines (such as C reactive protein and interleukin-6) are now widely understood to be primary risk factors for vascular disease and predictors of mortality/morbidity in cardiovascular events.  Underlining intimate relationships between pro-inflammatory and anti-inflammatory signaling, the adaptive upregulation of IL-6 due to exercise appears critical to the anti-inflammatory production of IL-10 (refs), and IL-1ra while inhibiting production of a cardinal proinflammatory cytokine TNF-ά.  IL-6 was suggested to be a ‘myokine’, defined as a cytokine that is produced and released by contracting skeletal muscle fibers, and responsible for the anti-inflammatory effects of exercise, part of increasing evidence that systemic inflammatory signaling and ‘tone’ are highly plastic and perhaps highly responsive to diet and lifestyle issues (see last sections).  Indeed many important lifestyle variables appear to modulate systemic inflammatory tone directly, including classic dietary factors such as fiber consumption (Galland, 2010), omega-3 intake (Mittal, Ranganath, and Nichani, 2010), and polyphenol intake (Zhou, Beevers, & Huang, 2011), sleep quality versus sleep deprivation (Motivala, 2011) aerobic exercise (Walsh et al 2011), and even social stress (social isolation versus social comfort) (Slavich et al., 2010).  This suggests that Western lifestyles (sedentary and with typical Western diet patterns) may be – in toto – seriously pro-inflammatory and significantly increase the risk of the diseases of aging most related to chronic inflammation (many cancers, cardiovascular disease, Alzheimer’s and Parkinson’s disease, diabetes, and arthritis).

 

 

Autophagy

 

Autophagy is an essential catabolic process through which existing proteins and other cellular components are degraded and recycled, supporting the adaptive function of removal and potential repair of damaged, dysfunctional or even toxic proteins and cellular organelles.  This function is dependent on ‘autophagosomes’, (an intracytoplasmic vacuole containing elements of a cell’s own cytoplasm) typically fused with lysosomes to facilitate digestion of target proteins by lysosomal proteases.  Autophagy, like glycation, is perhaps one of the more neglected critical ‘story lines’ in aging in many popular treatments of the subject, but its importance in aging appears central.  Indeed, it would appear that aging can be slowed down significantly by simply improving this critical process, or alternatively, perhaps aging itself causes degradation of this process (Madeo et al, 2010).  Anti-aging effects from improved autophagy are robust (Petrovski & Das, 2010).  Severe dysfunction in the various autophagy pathways (typically caused by mutations) can generate severe pathology, affecting multiple organ systems including muscle, liver, the immune system, and the brain.  Defects in autophagy have shown accelerated aging phenotypes in classic yeast, worm and fly model organisms (in which aging is typically studied and modeled in terms of its basic cellular and molecular mechanisms).  In mammals, autophagy appears essential to life and survival, as genetic knock-out of proteins required for the process are lethal, suggesting a basic role in homeostasis and development.  More limited knock-out of genes involved in autophagy in mice result in accelerated aging phenotypes. While the precise underlying mechanisms driving autophagy-related pathology remain obscure, the study of Finkel and colleagues (Wu et al., 2009) suggests that mitochondrial dysfunction is likely a critical factor.  Underscoring important reciprocal relationships between the many phenotypes of aging, recent work suggests that disruption of autophagy may manifest itself physiologically in terms of mitochondrial dysfunction and increased oxidative stress (Wu et al., 2009)

 

Growing evidence links declining autophagy to all the neurodegenerative disorders, with their characteristic protein aggregations (oftentimes ubiquitinated suggesting that they are being tagged for removal) although pathological changes can result from excessive or disinhibited as well as deficient autophagy (Cherra and Chu, 2008).  Experimental animals genetically defective in autophagy develop neurodegeneration accompanied by ubiquitinated protein aggregates, demonstrating that basic autophagy function is essential for long terms neuronal health.  Additionally, both age- and disease- associated reductions in the autophagy regulatory protein beclin 1 have been found in patient brain samples (Cherra and Chu, 2008), while treatments which promote autophagy have been shown to reduce levels of pathological proteins in several in vivo and in vitro models of neurodegeneration.  Rapamycin, lithium and several polyphenols have been show to enhance degradation and also possibly reduce synthesis of proteins which may contribute to toxic oligomers formation as well as larger aggregates of toxic protein seen in several neurodegenerative diseases. Quercetin, several other polyphenols, as well as vitamin D, all appear to increase autophagy, suggesting important but incompletely mapped roles for diet and lifestyle in modulating this critical aging-related process (Wang et al, 2011; Wu et al 2011).

 

 

Apoptosis

 

Apoptosis, originally thought to be a deleterious and primarily negative process, now is appreciated to have a critical role in adaptation and longevity.  Apoptosis must balance regulation the potential benefits of eliminating damaged cells against the pathogenic impact of more maladaptive forms of cell death (such as progressive cell loss in post-mitotic tissues, a major mechanism driving atrophy in neurodegenerative disorders).  Thus, a delicate balance must be struck, and dysfunction in the regulation of programmed cell death can mean that apoptosis on the one hand potentially contributes to atrophy and a senescent cell phenotype, while on the other, its failure potentially leads to neoplastic cell proliferation.  Apoptosis is thus an important cellular defense for maintaining both genetic stability and physiological function.  Data points supporting an assumption of the centrality of apoptosis in longevity include the central finding that centenarians are more prone to apoptosis (refs), suggesting that longevity may slightly favor an excessive trimming of still possibly viable cells over allowing an increased percentage of potentially rogue cells to survive.  Additional data points underscoring the importance of a finely tuned apoptosis equation include that cells which avoid apoptosis, particularly proliferating vascular smooth muscle cells, participate centrally in atherosclerosis.  Cancer could be thought of as the paradigmatic failure of apoptosis, and several lines of evidence suggest that cellular senescence and apoptosis (both of which contribute to aging) are defenses against cancer.

 

 

Sarcopenia

 

Sarcopenia, the loss of both muscle mass and function, is a universal feature of aging has major impact on individual health and quality of life, predisposing to falls and eventual frailty.  Given the critical contribution of frailty to disability and mortality and geriatric populations, Sarcopenia is a critical aging phenotype.  All elderly show evidence of it particularly after the seventh decade with a roughly 40% decline in muscle mass by the age of 80 (Evans, 1995).  Mechanisms leading to this are multifactorial, and include mitochondrial dysfunction and decline, altered apoptotic and autophagic processes, and, even altered trace metal homeostasis (Marzetti et al., 2009).  Like virtually every other aspect of aging, calorie restriction mitigates this process in a variety of species studied, again via pleiotropic effects of CR, including mitochondrial biogenesis, reduction of oxidative stress, and improved apoptotic regulation and autophagic processing.  To our knowledge, reduction of sarcopenia has not been demonstrated in humans with CR mimetics, but the prediction would be that rapamycin might be more successful in preventing and slowing this than resveratrol – (again an untested prediction to our knowledge).  Similar but not identical challenges are faced by cardiac muscle in aging, where

 

 

Lifestyle and Dietary Factors

 

There is increasing if not collectively convincing evidence that core lifestyle factors such as exercise and diet (as well as sleep quality and social stress vs social comfort) might potentially influence some aspects of aging, and may constitute a complex collection of negative and positive risk factors for all the diseases of aging, but presumably interactive with a small group of known and a likely much larger group of unmapped polymorphisms that collectively may have a large effect on longevity (Yashin et al, 2010) and risk for diseases of aging.  Future mapping of those polymorphisms (and their likely complex interactions) may allow much better prediction of risk, and early intervention to reduce specific risk for a particular disease of aging.

 

 

Exercise

 

Regular aerobic exercise is widely recognized as an essential component of a healthy lifestyle, and yet less than 15% of individuals living in the United States engage in adequate amounts of aerobic exercise, and a majority of people in the USA are almost completely sedentary (Roberts and Barnard, 2005), with sedentary lifestyles though to contribute to risk for all diseases of aging, particularly CV disease, metabolic syndrome and type II diabetes, particularly when combined with a Western diet.  Exercise has an extremely complex biological footprint, but among its many effects, exercise offers protection against all-cause mortality, particularly against atherosclerosis, DMII, and several but perhaps not all cancers, particularly colon and breast cancer (7).  It also significantly reduces frailty and sarcopenia.  Regular exercise appears specifically protective against diseases associated with chronic low-grade systemic inflammation (Peterson and Peterson, 2005), perhaps due the anti-inflammatory response elicited by an acute bout of exercise, largely mediated by muscle-derived IL-6. IL-6 stimulates production of anti-inflammatory cytokines (such as IL-1ra and IL-10) and inhibits subsequent (post-exercise) production of the key proinflammatory cytokine TNF-α.  In addition, IL-6 stimulates lipolysis and fat oxidation and metabolism (see Peterson and Peterson, 2005 for detailed review). These anti-inflammatory effects also inhibit insulin resistance, which is in part modulated by TNF-α and by NFκ-B, a transcription factor involved in inflammatory signaling.

 

Exercise may also upregulate anti-oxidant defenses (Kaliman et al, 2011), while oxidative stress actually initially increases during a bout of exercise, with subsequent upregulation of endogenous defenses (referred to as mitochondrial hormesis or ‘mitohormesis’).  Some work on effects of exercise calls into question the conventional wisdom of blocking oxidative stress, as evidence suggests that this actually impairs exercise benefit, and even may prevent beneficial effects of CR (Ristow & Schmeisser, 2011).  Exercise may also increase neurotrophins, improve stress resistance, improve mood and emotional and stress resilience, and enhance cognitive function and learning (Ratey, 2009)

 

Obesity

 

One of if not the most worrisome public health trend over the last 20 years has been a steady and dramatic increase in the prevalence of overweight and obese individuals, with current statistics suggesting that now roughly 1/3 of the United States is obese (BMI greater than 30), and another 1/3 is overweight (BMI over 25 but less than 30) (Wang et al., 2007), meaning that basically two thirds of United States adults are overweight.  Even more worrisome is the emerging evidence that the rates of obesity in the United States are now actually higher in children than in adults, perhaps due to a highly undesirable combination of increasingly sedentary gameplay (in which video games have largely supplanted more physical activity), increasing fast food consumption, and overconsumption of sugary beverages.  Obesity is increasingly appreciated as a risk factor for virtually every disease of aging, beyond its popular linkage to risk for cardiovascular disease.  Obesity contributes significantly to risk for hypertension, dyslipidemia, insulin resistance and type II diabetes, multiple cancers and even Alzheimer’s disease.  Evidence suggests that increased abdominal fat (versus subcutaneous fat) is a more significant risk factor than generalized obesity, and this relationship is potentiated, curiously enough, in otherwise leaner subjects (Pischon et al., 2008), as abdominal fat may have a particularly potent effect on dysregulation of inflammation (Fontana et al. 2007) via promotion of pro-inflammatory cytokines, such as interleukin-6.  Aging itself decreases subcutaneous fat while increasing abdominal fat, and simply reducing abdominal fat surgically has a pro-longevity effect in animal models.  Increased visceral fat is independently associated with all cause-mortality, insulin resistance and diabetes, cardiovascular disease, cerebrovascular disease, Alzheimer’s disease, and disability in the elderly (Florido et al. 2011).  Additionally, there is evidence for intrinsic relationships between obesity and upregulated inflammation (in part as compensatory and a way of using more energy), and, on the other hand, calorie restriction and reduced inflammation Ye and Keller, 2010).

 

 

Polyphenols

 

Although conventionally regarded as ‘antioxidants’, polyphenols are an enormous class of substances (constituting perhaps as many as 6000 distinct compounds) found in plants, principally fruits and vegetables, that have enormously pleiotropic effects on human and mammalian physiology.  Some of these effects may be more biologically significant than any direct ‘free radical scavenging’ done by a polyphenol, and include many effects on cell signaling, the regulation of growth factors and apoptosis, the regulation of cell cycling, the regulation of inflammation, the modulation of many of not most cellular stress pathways, impact on multiple transcription factors including those involved in energy homeostasis, and (consistent with their conventional designation), the management of oxidative stress (Virgili & Marino, 2008).  Many of these effects on aspects of cell signaling require much lower levels of polyphenol than any direct ‘free radical scavenging’ in serum or tissues.  Indeed, from this perspective, polyphenols look less like ‘antioxidants’ and more like complex cell physiology and cell signaling modulators, but it is seems unlikely that such a designation is going to replace the catchy title of ‘antioxidant’, even in the context of increasing evidence that such a title may be fundamentally misleading.  Many if not most of the phenotypes of aging (oxidative stress, mitochondrial dysfunction, inflammation, and declining autophagy among others), appear to be partially modulated by various polyphenols.

 

Polyphenols consist of several classes of chemical substances, including non-flavonoid compounds (such as resveratrol, other stilbenes and curcuminoids), and classic flavonoids (consisting of two large classes, anthocyanins (colorful and pigmented), and anthoxantins (colorless).  Resveratrol and its first cousin pterostilbene are both naturally-occurring phytoalexins produced by plants in response to fungal infection (phytoalexins are all ‘plant defense’ compounds).  Of the anthoxantin family, quercetin is one of the best known and studied members, along with EGCG (a member of the catechins family, with catechins constituting a large group of polyphenols in tea and wine).  Dietary sources for polyphenols include many foods that have been ancient components of the human diet for many hundreds and even thousands of years: fruits and their juices (typically containing both anthocyanins and anthoxantins), tea (catechins), coffee (chlorogenic, caffeic and ferulic acids), red wine (anthocyanins, resveratrol, and quercetin), vegetables (many anthoxantins and anthocyanins), some cereals, chocolate (multiple flavonoids including catechins and proanthocyanidins), and various legumes, particularly soy (isoflavones) and peanuts.

 

This context, there are multiple challenges to any emerging science that might explain the roles polyphenols could play in health maintenance and the slowing of at least some aspects of aging.  First of all, there are many thousands of different bioflavonoids in toto, but only a handful with much in vivo research (resveratrol, curcumin, green tea extract, and quercetin).  Most of the studies of polyphenols use in vitro approaches, although there are increasing numbers of in vivo studies in animal models, but very few if any clinical studies in humans.  An additional major challenge to potential therapeutic use, virtually all bioflavonoids have relatively poor bioavailability, which may be part of their extraordinarily non-toxic biologic footprint.  Most polyphenols are rapidly conjugated (oftentimes sulfated and glucuronided), and variably metabolized, oftentimes with an uncertain biological status of their multiple metabolites.  The proper study of any polyphenol in potentially slowing or preventing any disease of aging is methodologically challenging, and also expensive (long time frames needed, difficulty in controlling for many other positive and negative lifestyle risk factors that are potential confounds).  With all these challenges, there is little financial incentive to study polyphenols in humans in relationship to the diseases of aging or aging itself, given the poor return on investment in relationship to inexpensive agents that cannot be patented.  This collection of factors has generated the current situation in which there is oftentimes promising animal model data for multiple polyphenols in relationship to a disease of aging, but a dearth of good human clinical studies.  This is changing slowly, and several polyphenols are in clinical trails in relationship to several diseases of aging.

 

One of the few completed studies of a polyphenol in a human clinical population demonstrated that resveratrol is in fact effective at higher doses (3 to 5 g a day) in treating diabetes (Patel, 2011) and clinical studies are underway in relationship to cancer, Alzheimer’s disease, and heart disease.  Curcumin is also being increasingly studied for its anti-inflammatory, anti-proliferative, and anti-aging effects.  It is thought to affect many dozens of cellular pathways, particularly NF kappa-B, a transcription factor involved in the regulation and activation of inflammatory responses (Aggarwal, 2010).  Curcumin is one of several polyphenolic inhibitors of target of rapamycin (mTOR), a critical nutrient-sensing and growth factor integrative pathway increasingly implicated as a molecular target of calorie restriction, and which if inhibited, may slow down aging and may also inhibit or delay diseases of aging (Beevers et al., 2009), but curcumin has notoriously poor bioavailability.

 

 

Diseases of Aging (with particular relevance to Neurology)

 

Cardiovascular Disease

 

Although technically ‘cardiovascular disease’ refers to any disease that affects the heart or blood vessels, the term has become over the last 20 years increasingly synonymous with atherosclerosis.  This disease of aging is responsible directly for more deaths than any other in Western societies, killing twice as many individuals as all cancers combined and more than all the other diseases of aging put together (Minino et al., 2006; ) and thus clearly merits a summary review.  Atherogenesis is a complex and long-term process involving many players, including endothelial cells, immune cells, growth factors, extracellular matrix molecules, lipids, and with a primary role for oxidative stress and inflammation.  Atherogenesis requires a cascade of processes starting with a maladaptive pro-inflammatory reaction to oxidized lipid deposition in the arterial wall.  The initiating event appears to be the deposition of Apo-B containing lipids, typically oxidized low density lipoproteins.  Oxidation of these lipids dramatically increases the chances that the deposition process will irritate the vessel, promoting increased proinflammatory cytokine release, suggesting that plasma redox balance may also be a critical variable (Maharjan et al., 2008).  Hyperlipidemia is also associated with declining eNOS (endothelial nitric oxide synthase) and increasing nitroxidative stress in the endothelium (Heeba et al. 2009).  These inflammatory cascades lead to accumulation and swelling in arterial structures, mostly from macrophage cells combined with lipids (principally oxidized LDL, VLDL and other fatty acids), calcium (particularly in advanced lesions), and a certain amount of fibrous connective tissue.  Glycation of proteins (an intrinsic component or phenotype of aging) as well as foreign antigens also promote these fundamental inflammatory changes (Milioti et al. 2008), with regions of more glycated tissue and advanced glycation end products promoting and accelerating the formation of these plaque structures (Kim et al. 2010).

 

These slowly developing structures (‘atheromatous plaques’) are found at least to some degree in most individuals in Western societies, and early asymptomatic stages of this process are found in many young adults, but are rare in hunter-gatherers (Eaton et al, 1988).  LDL is the most common Apo-B plasma lipoprotein, but Apo B-containing VLDL, remnant VLDL (depleted of trigycerides), intermediate-density lipoprotein (IDL), and LP(a) have also been shown to be atherogenic, as well as Apo B from chylomicron remnants, suggesting that many forms of lipid contribute to risk.  These lesions actually begin in childhood and develop slowly over many, many decades.  While the early stages of deposition are called ‘fatty streaks’, these are not composed of adipose cells, but instead of white cells, especially macrophages, that have taken up oxidized low-density lipoprotein (LDL).  After these cells accumulate large amounts of cytoplasmic membranes (and high cholesterol content) they become ‘foam cells’.  When foam cells die, these contents are deposited into the surrounding tissue, attracting more macrophages and inflammation, and causing a positive and self-sustaining feedback loop.  Upon activation by pro-inflammatory stimuli, macrophages and lymphocytes in turn release proinflammatory cytokines which stimulate migration of smooth muscle cells (SMCs) from the media of the vessel wall.  Smooth muscle cells then contribute to more foam cell and fibrous cap formation, also under the influence of pro-inflammatory cytokines (e.g., IFNγ and TNFα secreted by T helper cells, IL-12 secreted by macrophages and foam cells) (Milioti et al. 2008).  Eventually foam cells die via apoptosis, dumping non-degradable cholesterol crystals forming the lipid core of the plaque structure.  Plaque structures can be either stable or unstable, with vulnerable plaque tending to be faster growing, and with higher macrophage content, suggesting that auto-inflammatory processes not only contribute to the early, more silent stage of the process, they also drive the deadly late stages of the process as well.

 

Although popularly viewed as a ‘disease of cholesterol’ (a perspective that dominated the earlier conceptualizations of vascular disease in the 1960s and 70s), increasing scientific opinion favors atherosclerotic vascular disease as a disease of inflammation and oxidative stress.  Consistent with this, there is increasing evidence that statins actually impact both inflammatory and oxidative stress issues (Heeba et al., 2009), while promoting upregulation of heme oxygenase (an important antioxidant defense enzyme).  Statins appear to inhibit vascular disease through pleiotropic mechanisms, including decreasing synthesis of LDL, increasing removal of LDL (through hepatic LDL receptors), up regulation of eNOS (endothelial nitric oxide synthase), increased tissue-type plasminogen activator, and also inhibiting endothelin 1, a potent vasoconstrictor and mitogen, all of these promoting improved endothelial function.  Statins also reduce free radical release, thus inhibiting LDL-C oxidation (Liao & Laufs, 2005), while increasing endothelial progenitor cells, and reducing both number and activity of inflammatory cells and cytokines.  They also may help stabilize atherosclerotic plaques, reduce production of metalloproteinases, and inhibit platelet adhesion/aggregation (Liao & Laufs, 2005).

 

While extremely common in Western societies (at least in some stage, even if clinically silent), extensive vascular disease is virtually non-existent in hunter-gatherer groups (Eaton and Eaton, 2002), suggesting a primary role for etiology in the Western lifestyle and diet (see later sections), in which multiple if not virtually all components of the Western diet and lifestyle appear pro-inflammatory relative to hunter gatherer lifestyles (sedentary versus highly aerobically active, altered omega-6/omega-3 ratios, poorer sleep, social isolation, lower consumption of fiber, lower consumption of protective polyphenol phytochemicals, high levels of obesity).

 

In addition to atherosclerosis (which is clearly the largest problem in pathologic vascular aging in Western cultures), there is also vascular aging independent of atherogenesis, in which increasing evidence implicates angiotensin II signaling as central to this process (Wang, Khazan, and Lakatta 2010). Arterial remodeling and decline in aging (even absent atherosclerosis) is increasingly thought linked to angiotensin II signaling (Wang, Khazan, and Lakatta 2010).  Components of Ang II signaling (including several reactive oxygen species, multiple growth factors, matrix metalloproteinases, chemokines, and nicotinamide adenine dinucleotide phosphate-oxidase) are upregulated within arterial walls, in many species including humans, during aging.  In vivo studies suggest that elevation of Ang II signaling drives accumulation of AGE (advanced glycated end products – which are themselves pro-inflammatory), increased collagen, disruption of elastin, and invasive hypertrophy of both smooth muscle and endothelial cells (Wang, Khazan, and Lakatta 2010).  Obvious clinical implications are that attenuating Ang II signaling may significantly retard this age-associated arterial remodeling, suggesting important protective effects for ACE inhibitors and ARB compounds.  Intriguingly, multiple polyphenols, including those in pomegranate juice (rich in tannins and anthocyanins), appear to inhibit angiotensin signaling, (perhaps in part from nonspecific anti-oxidant effects) but also from inhibition of angiotensin-converting enzyme activity and may also reduce blood pressure (Stowe, 2011).  Angiotensin II (Ang II) also enhances ROS production, by activating NAD(P)H oxidase and uncoupling endothelial nitric oxide synthase (NOS).  Systemic inhibition of Ang II thus may potentially have CR mimetic (anti-aging) effects, due to its central role in coordination of vascular aging, oxidative stress and impact on the mitochondria (de Cavanagh, Inserra, and Ferder 2011).

 

These processes driving vascular aging and disease are of obvious primary relevance to vascular dementias, but also to commonplace findings of white matter erosion (typically referred to as ‘white matter hyperintensities’ or white matter ‘ischemic change’ on MRI and CT scans), sometimes appearing as a highly comorbid pathology with Alzheimer’s disease (Brinkman et al).

 

 

Alzheimer’s Disease

 

As the disease of aging with perhaps the greatest relevance to this textbook, there has been a paradigm shift over the last 20 years away from the original assumption that Alzheimer’s disease had nothing to do with aging.  Of course this could not possibly have been true, given the simple fact that Alzheimer’s disease roughly doubles in incidence every five years after the age of 60 to 65, and that aging remains the greatest risk factor for nonfamilial sporadic Alzheimer’s disease.  Recent research suggests that markers for oxidative stress and mitochondrial decline (Pratico, 2010; Aliev et al., 2010; Mancuso et al., 2007) are elevated even prior to the appearance of extracellular amyloid deposition, which takes place in the preclinical stages of the disease.  Indeed multiple lines of evidence link Alzheimer’s disease to many if not virtually all of the phenotypes of aging, including inflammation (Masters and O’Neill, 2011), oxidative stress, accumulation and/or clearance failure of characteristic pathogenic proteins (Barnett and Brewer, 2011), along with increasing deleterious synaptic effects from those proteins and from associated inflammation (De Strooper, 2010; Mondragon-Rodriguez et al., 2010; Palop & Mucke, 2010).  Recent work has suggested that pathogenic proteins (such as oligomeric amyloid) are not being cleared out (Mawuenyega et al., 2010), underlining an important role for declining autophagy in the etiology.

 

These considerations suggest that AD is indeed a highly pleiotropic and complex disease, and one where we may still not understand fully all the critical factors or how they interact.  What were originally adaptive mechanisms (such as inflammation, recruitment of amyloid pathways by various stresses and neuroplasticity challenge, phosphorylation, apoptosis, cell cycling, etc.) may become pathogenic in the context of chronic synergistic recruitment, biological stress and neuroplasticity challenge.  This suggests an image of Alzheimer’s disease in which a host of individually adaptive and compensatory mechanisms jointly ‘conspire’ to drive the brain into a neurodegenerative process (Mondragon-Rodriguez et al., 2010).  Given that these interactions between a host of individually adaptive processes occur well past a reproductive period, they would escape virtually any conceivable selection pressure or modification.  In this sense, the vulnerability to AD may reflect a ‘fault line’ in the human genome consistent with the evolutionary perspectives outlined earlier, although a ‘mutation accumulation’ view of AD has never been adequately probed to our knowledge.  Thus AD itself may be an expression of ‘antagonistic pleiotropy’ in which genes and molecular pathways which were adaptive during periods of youth and fecundity potentially ‘backfire’ in aging, particularly when synergistically recruited.  The table below summarizes some of the complex interactions between factors in AD, emphasizing an image of the disease as highly multifactorial, but where the primary phenotypes of aging (oxidative stress, inflammation, glycation, apoptosis, mitochondrial decline, accumulation of junk proteins and declining autophagy) all appear only contributory but also highly interactive.

 

Factors Contributing To A Neurodegenerative Matrix in AD

Biomarker	Produced By	Producing	Clinical/Other Correlates
Beta Amyloid Plaque (Extracellular Aβ )	Aging, genes, ↓ BBB fx, ↓ clearance, oxidative stress	Inflammation, (glial activation), oxidative stress	Subtle regional atrophic changes?  Second biomarker to appear after OS.
Small aggregate amyloid (Oligomeric Aβ)	β/γ secretases, inflammation, oxidative stress, ↓ clearance	synaptic loss and dysfunction, OS, INFLAM	Synaptic loss (NMDA, AMPA), Loss of LTP, increased LTD
Inflammation (INFLAM) (esp. ↑ innate immunity)	Amyloid fibrils, ↓ ACh, ↑ rAGE signaling, aging, OS	Synaptic dysfunction, ? Apoptosis, ↑ Aβ, OS	Contributes directly to cognitive dysfunction via multiple effects
Central Insulin Resistance (in CNS)	Inflammation (↑ NFk-b)	↓ Energy, HC damage, ↑ Kinases (→ tangles)	Promotes synaptic dysfunction and loss. Promotes amyloidosis
Oxidative Stress (OS), (MITO, lipid membranes)	Aging, Aβ oligomers in MITO, metal ions, INFLAM, advanced glycation end products	Synaptic & neural loss, INFLAM, Aβ, ? tangling, aberrant cell cycling	Appears before plaques/tangling. Membrane OS increases with disease; DNA OS markers don’t.
Excitotoxicity and Ca++ dysfunction	Oligomers (Aβ) in MITO, and at calcium channels	Probable synaptic dysfunction. Apoptosis	Synaptic dysfunction, eventually SL/NL
Neurotrophin and neuro-transmitter depletion	Oligomers (Aβ) → receptor internalization, tau pathology → microtubule dysfxn, INFLAM	ACh loss → ↑ Aβ, BDNF/ NGF declines, aberrant cell cycling and apoptosis	Synaptic dysfunction, promotion of both SL and apoptosis
Neurofibrillary Tangling and Tau Aggregates	Oxidative stress (OS) → ↑ kinases, ? insulin resistance	Basal forebrain (ACh) loss, SL, Apoptosis	Tracks atrophic change (SL/NL) and declining cog. fxn closely.
Atrophy HC/EC→ lateral temporal→frontal/parietal	Multifactorial – many factors listed contribute to synaptic loss and to apoptosis	Proceeds functional declines (slightly)	Major biomarker for degenerative changes in clinical stages of AD.
Cognitive loss, esp. STM, then language & exec. fxn	Synaptic loss early, SL plus NL later (apoptosis)	Declining fxn, compensatory neuroplasticity effort?	Primary functional measure, necessary for diagnosis

 

Legend: SL: synaptic loss, NL: neural loss (neuronal cell death), Aβ: beta-amyloid, BBB fx: blood brain barrier function, MITO: mitochondria, ACh: acetylcholine, NGF: nerve growth factor, BDNF: brain derived neurotrophic factor, rAGE: receptors for Advanced Glycation End products (which promote inflammation), HC: hippocampus, EC: entorhinal cortex, Apoptosis: programmed cell death, NFk-b: Nuclear Factor Kappa B (transcription factor involved in inflammatory signaling), Oligomers: several molecules of beta-amyloid stuck together, Kinases: enzymes promoting phosphorylation and tangling, NMDA/AMPA: subtypes of glutamate receptor, LTP: long-term potentiation, LTD: long-term depression, lateral temporal: lateral temporal lobe, frontal/parietal: frontal and parietal convexity.

 

 

Parkinson’s disease

 

Parkinson’s disease, and its more aggressive and malignant close relative, diffuse Lewy body disease (DLBD), are idiopathic neurodegenerative diseases characterized by intraneuronal accumulation of Lewy bodies (aggregates of alpha-synuclein), particularly in substantia nigra (midbrain dopamine producing regions) in classical PD (and much more widely in DLBD), with progressive loss of DA cell bodies, deafferentation of basal ganglia, and dysfunction in direct and indirect corticostriatal pathways, and subsequent primary symptoms of resting tremor, slowing of movement, rigidity and gait difficulties and eventual postural instability.  There is evidence of differential vulnerability to degenerative in nigral regions, with ‘ventral tier’ neurons more vulnerable than ‘dorsal tier’, and with VTA neurons least effected (Collier, Kanaan, & Kordower, 2011), despite the fact that these fields form a continuous sheet of DA neurons.  This differential vulnerability is viewed in recent work as multifactorial, and in animals models, appears linked to several markers, including the appearance of alpha-synuclein, ubiquitin (as a marker of proteasome activation), lipofuscin (as a marker of lysosome activation), 3-nitrotyrosine (as a marker for nitroxidative stress), dopamine transporter activation, and markers of astrocyte and microglial activation (inflammation markers).  Dysfunctional mitochondria are thought to be the primary intracellular source of reactive oxygen species, and lysosome mediated autophagy is the primary cellular mechanism for removing defective mitochondria.  The progressive accumulation of lipofuscin (leading to its being regarded as ‘age pigment’) is thought to reflect an index of mitochondrial damage and subsequent lysosomal degradation of defective mitochondria (Terman, Gustafsson, & Brunk, 2006).  Collier, Kanaan, & Kordower, 2011 argue that the etiology of PD, while remaining still uncertain, may reflect stochastic interactions between inflammation, oxidative stress, declining autophagy, and accumulations of pathogenic junk proteins, producing a ‘stochastic acceleration hypothesis’ graphically represented below (with permission).  These basic models may provide a template for unraveling the etiology of other neurodegenerative disorders, particularly AD, but also the FTD family, where the connections to aging are much less clear.

 

 

 

The stochastic acceleration hypothesis of Collier, Kanaan, & Kordower, 2011. A revised hypothesis of the relationship between ageing and Parkinson’s disease (PD) as they affect the biology of midbrain dopamine (DA) neurons. The hypothesis incorporates evidence that supports the involvement of common cellular mechanisms involved in dopamine neuron dysfunction in ageing, and degeneration in Parkinson’s disease. a | The effects of these altered cellular mechanisms as they accumulate during normal ageing result in par­kinsonian dopamine neuron dysfunction, either very late in life or not at all (shown by the light grey line). However, when these same cellular mechanisms are accelerated by specific, individually deter­mined factors, parkinsonism emerges earlier in the lifespan (shown by the dark grey line). b | The hypothesis contends that the cellular mechanisms that threaten dopamine neuron function are identi­cal, but not linked in an orderly cascade of cause and effect, and instead can contribute to varying degrees and combine in patient-specific patterns, thus fulfilling the definition of a stochastic interac­tion: incorporating elements of randomness with directionality towards dopamine neuron dysfunc­tion. Light grey double-ended arrows show cellular events in normal ageing. Thicker, dark grey double-ended arrows show accelerated cellular events in PD. UPS, ubiquitin–proteasome system. (with permission).

 

 

 

 

Departure from Ancient Evolutionary Environment:

Impact on Aging Processes and Promotion of Diseases of Aging

 

There is enormous evidence that Western societies involve diets and lifestyles which are radically different from hunter-gatherer lifestyles and diets, and indeed radically different from the original evolutionary environment in which the entire hominid line evolved, producing an ‘evolutionary discordance’ (Konner, 2001) that may have profound effects for human health and have a major influence on the biological trajectories of human aging.  This notion of a radical departure from an evolutionary environment, and a subsequent mismatch between our genes and our environment may provide a unifying context for connecting all increased risk factors for all the diseases of aging, as humans in modern technological societies are now living much longer (primarily due to our successful control over predation, starvation, and infection as primary causes of early mortality for children and younger adults).  Put differently, all of the so-called healthy lifestyle practices that have been piecemeal discovered through many empirical studies (such as a diet high in fruits and vegetables, healthy omega-3 omega-6 ratios, high intake of fiber, regular exercise, etc. etc.) all have as a unifying context that they are components of our original long-term biological environment as hunter-gatherers (Eaton and Eaton).  This suggests that healthy lifestyle practices reduce or perhaps even virtually eliminate chronic mismatches between a genome carved in a more ancient hunter-gatherer environment and our current technological environment.  Unfortunately, adoption of these healthy lifestyle practices is far from widespread in the United States or in other Western societies (refs), and may be relatively restricted to those better educated and also to those belonging to more fortunate socioeconomic groups.

 

The fundamental hominid diet for probably more than 2 million years (pre-agriculture) was lean game meats and fish, supplemented by significant quantities of fruits and vegetables (Cordain et al., 2005), while modern technological diets are higher in fat (particularly omega-6 fats), higher in carbohydrates (largely from grains and other agricultural products), and now contain significant trans fats (which did not exist in our original biological environment) and are deficient in fiber, in multiple protective phytochemicals (polyphenols), and low in other several critical micronutrients including choline, several B vitamins and several minerals (Eaton et al., 2007).  In addition, vitamin D deficiency is common (Hollick, 2009), which was probably very rare if not non-existent in ancient hunter gatherer societies, in which skin color seems to have evolved to match latitudes and to balance vitamin D production with skin protection.

 

The following summarizes some of these fundamental differences between an ancient and a current biological environment for humans, including work on biomarkers from studies of hunter-gatherer societies (Eaton and Eaton, 1999; Eaton, Cordain & Sebastian, 2007); Eaton et al., 1998; Cordain et al., 2005).  This evidence for huge biologic environment shifts, during a period of minimal genetic change for humans (the last 10,000 years) suggests a potential ‘unifying field theory’ for the diseases of aging (suggesting that diseases of aging are largely diseases of civilization) (refs).  Ironically, humans have never lived longer than they are living in modern technological societies, while the average life expectancy at birth within preindustrial (hunter gatherer) societies was probably roughly 30 to 35 years (Konner and Eaton, 2010).  However, this significantly extended lifespan in technological cultures is one in which penetration by a major disease of aging (excepting osteoarthritis) appears more likely, relative to the few elders who existed in hunter gatherer societies (Dunn, 1968; Konner and Eaton, 2010), although conclusive data on this question is lacking, and reconstruction of more ancient (Paleolithic) hunter gatherer lifestyles and biological state involves extrapolation from the relatively few hunter gatherer societies that survived into the 20^th century (columns extracted from Eaton and Eaton, 1999; Eaton, Cordain & Sebastian, 2007); Eaton et al., 1998; Cordain et al., 2005; Watt, 2011).

 

Original Evolutionary Environment           Modern Technological Environment

 

1) Regular aerobic exercise (2-3+ hrs/d)                1)  Minimal to no aerobic exercise (< 15 min/d)

2) 9+ hours sleep (see #1)                                      2)  7 hours or less of sleep (see #1)

3) Calorie limitations (some CR)                            3)  Unlimited calories

4) High phytochemical/polyphenol diets               4)  Low phytochemical/polyphenol diets

5) Omega-6/Omega-3 ratio 1:1 to 3:1                    5)  Omega-6/Omega-3 ratio 12:1 to 20:1

6) High intake of fiber (~50-100 gm/d)                 6)  Low intake of fiber (≤ 15 gm/d)

7) Low sugar/carbs, except fruits/veggies              7)  High sugar/carbs, not from fruits/veggies

Intake of K+ > Na+ (K+ > 4 gm/d)                    8)  Intake of Na+ > K+ (Na+ > 4 gm/d)

9) Pro-alkaline diet                                                            9)  Pro-acidic diet

10) Minimal to no glycated proteins                                  10 Common glycated protein (esp. milk products)

 

11) Social

 

 

 

 

 

 

isolation common                          11) carbs

Intimate social groups/tribes

12) Early mortality: infection, starvation,              12) Death from an advanced disease of aging:

predation, and intra-species violence:                    life expectancy 75 to 85

life expectancy 35-45

 

 

Biomarkers

 

Hunter Gatherers                         Current Technological Societies

 

1)      BMI 21-23                                           1)  ~30% BMI > 30, ~30% BMI 25-30

2)      total cholesterol under 125                  2)  Total cholesterol ~ 200 or higher

3)      blood pressure 100-110/70-75             3)  120/80 (‘normative’), w/ hypertension common

4)      VO2 max good to superior                   4)  VO2 max fair to poor (sedentary lifestyles)

5)      Homocysteine low                               5)  Homocysteine significantly higher

6)      Vitamin D ~ 50-100 ng/ml                   6)  Vitamin D deficiency common (10-30 ng/ml)

7)      High insulin sensitivity                                    7)  Variable degrees of insulin resistance

8)      Physical activity > 1000 kcal/d                        8)  Physical activity ~ 150-490 kcal/d for most.

 

Although conclusive data is still lacking, the preliminary evidence suggests that hunter gatherer societies did not appear to have nearly the incidence of cancer and heart disease (Eaton and Eaton, 2002), diabetes (Eaton, Cordain & Lindeberg, 2002) or Alzheimer’s disease (Eaton & Eaton, 1999). suffered by modern societies, even when the rarity of elder members is taken into account (Konner and Eaton, 2010).  Consistent with these findings, a paleolithic diet improved diabetic biomarkers more than the highly touted Mediterranean diet (Lindeberg et al., 2007), and improved BP and glucose tolerance, decreased insulin secretion, increased insulin sensitivity and improved lipid profiles, all without weight loss in healthy sedentary humans (Frassetto et al., 2009).

 

It is difficult to know precisely what the sum total or composite effect of such global shifts in our basic biological environment might be, and what each factor may contribute to the overall increasing burden of diseases of aging in Western societies, but the evidence favors the hypothesis that these shifts are individually deleterious, and therefore collectively, they are likely to be highly undesirable.  Indeed, there may be poorly mapped synergisms between these various factors in promoting diseases of aging, as every one of these factors – the complex and multifactorial dietary shifts, sedentary vs aerobic lifestyles, the common obesity generated by these two factors, vitamin D deficiency, low-grade sleep deprivation, and increased social isolation and stress (versus the intimate social groups of our ancestors) – all impact the regulation and management of inflammation (as even psychosocial isolation and social stress is a pro-inflammatory event).  This suggests that, collectively, Western lifestyles (when compared to the lifestyles of our hunter-gatherer ancestors) may be hugely pro-inflammatory, and there is much evidence that auto-inflammation involves increased oxidative stress (Finch, 2011), drives insulin resistance, and is also potentiated by glycation (Semba et al., 2009).  Such a global view of the biological environment also suggests strongly that single component fad-diet approaches, such as the elimination of all fructose, sugar or carbohydrates, are not likely to be successful, unless combined with a larger group of dietary and lifestyle changes (although carbohydrate reduction may help with weight loss, which is critically important for many in Western cultures).  In any case, our current penchant for single factor ‘fad diets’ is not supported by this analysis, which suggests a composite of environmental shifts relative to ancient hunter gatherer environments that collectively are biologically profound.

 

Many if not most of these lifestyle and dietary factors may also deteriorate the endogenous management of oxidative stress (Kaliman et al, 2011)), and given that auto-inflammation creates oxidative stress (OS) for ‘bystander’ tissues (Finch, 2011), these lifestyle variables may impose a double burden, of, one the one hand increased OS, while depriving us of several protective factors (found in our ancient evolutionary diet and lifestyle) that might ameliorate or protect from oxidative stress.  Oxidative stress is also believed to be a primary factor in genetic damage and genomic instability as well (refs), leading potentially into cancers and acceleration of cellular senescence (as a primary defense against cancer).  Many of these dietary and lifestyle factors also modulate the glycation of proteins and the formation of advanced glycation end products (particularly diets low in polyphenols and high in refined sugars), a primary regulator and inducer of inflammation.  Many lifestyle factors also impinge on the cell signaling related to endogenous defenses against oxidative stress, particularly exercise, polyphenol intake, inflammatory state, obesity and excessive energy, and insulin resistance.  Indeed, the typical alterations in energy homeostasis in Western diets and lifestyles, leading to an excess of energy (in turn, commonly leading to obesity), are suspected to be a primary (and undesirable) activator of mTOR (mammalian target of rapamycin, as a pathway that integrates nutrient signaling and growth factors), increasingly implicated as a central factor in the regulation of aging (Blogoslonny, 2009) while multiple polyphenols (modestly), and dietary restriction (more powerfully) inhibit mammalian target of rapamycin.  Collectively, these considerations suggest that Western lifestyles impact the biology of the diseases of aging (and aging itself) directly, and powerfully, in a multitude of undesirable ways.  Prevention of the diseases of aging therefore has to begin with appreciation for the central importance of lifestyle change, back towards at least some approximation of our evolutionary environment.

 

 

What Constitutes Optimal Prevention of the Diseases of Aging?

 

In sum, this large constellation of globally altered lifestyle variables all impact the fundamental biology of aging and also modulate the underlying mechanisms driving all the diseases of aging, directly.  Jointly these lifestyle factors, interacting with our genome (containing many currently unmapped polymorphisms which presumably directly modulate aging processes and the vulnerability to diseases of aging variably across individuals), in concert with multiple lifestyle behaviors, determine what aging trajectories our systems enter as we get older.  These basic interactions between lifestyle (which we can map out) and many polymorphisms in our genetic endowment (which we can now only map minimally) determine how much our fundamental cellular repair mechanisms and defenses against cellular damage are supported and enhanced as much as possible, versus overtaxed and overwhelmed.  The primary and multifactorial mechanisms of aging reviewed in this chapter lead invariably into the diseases of aging if given enough time and enough room to work – indeed the sum total of (presence or absence) of all of the diseases of aging may be one of the best ways to globally index aging itself (Blagosklonny, 2009) – although challenges remain in operationalizing such a definition, given that practical, cost effective (and nonintrusive) metrics in relationship to many of the diseases of aging are not yet clinically available.  Unfortunately, the conventional medical perspective on diseases of aging in this country is still largely unaware of evidence that they may reflect common mechanisms operating in different tissues and systems, and instead approaches each major disease of aging in a piecemeal and fragmented fashion.

 

Western lifestyles (consisting of a typical Western diet pattern and sedentary lifestyle with poor sleep and increased social isolation) are clearly not good for the brain, deteriorate capacity to deal with stresses, and remove us from our proper and ancient evolutionary environment.  We have changed remarkably little genetically, since our days as hunter-gatherers, but our lifestyles have changed dramatically, suggesting that much of our current difficulties with health, rather than being due to some exotic collection of esoteric biological derailments that can only be interpreted and treated by a “medical-industrial complex” and understood by someone with a doctoral degree, are due to a fundamental if not profound mismatch between our genes and our environment.  This suggests that basic health considerations should focus on approximating that ancient biological environment as much as possible: regular aerobic exercise, large amounts of fruits and vegetables, not too many calories, minimal processed food and other products of ‘food technology’ (particularly our highly addicting ‘fast food’), a better Omega-6/Omega-3 ratio (typically too high in most Western diets with significant Omega-3 deficiency), reduced social isolation, and improved sleep quality and quantity.  As noted before, all of these common recommendations place us closer to our ancient evolutionary environment, and thereby reduce this fundamental and destructive discordance between genes and environment in Western lifestyles.

 

At this point, there is no cure for virtually any disease of aging (perhaps excepting some cancers), so meaningful prevention, instead of being almost an afterthought in our healthcare system, needs to a genuine priority.  We must be willing to spend money on prevention, and to make lifestyle changes a genuine cultural priority.  It is also quite sobering to realize that even in the context of the best possible preventative efforts, all one can do is delay the onset of a major disease of aging, as eventually, we will all succumb to one or another of these manifestations of aging.  However, such delay in onset of a major disease of aging can potentially increase healthspan (even if major life span extension remains elusive), and substantially decrease the burden of diseases of aging in old age, and their often punitive impact on quality of life and personal and societal economics (see chapter on depression).

 

Prevention, in this context of the many considerations reviewed in this chapter, thus has to mean much more than “statins and beta-blockers” (controlling multiple conventional risk biomarkers which clearly have some prognostic value but may only minimally index our deceptive yet radical physiological departure from our ancestors).  Instead, real prevention must mean re-approaching, for the large majority of individuals in a culture and not simply for a fortunate few, our original evolutionary environment.  In simplest terms, as a culture, these major lifestyle changes must involve that we exercise and sleep significantly more, eat significantly less, and eat more wisely (consuming more the ‘paleolithic’ foods of our ancestors and much less the questionable products of food technology).  In addition, we need to aim more for quality of social connection than quantity of material consumption, as quality and depth of social attachment is clearly one of the best predictors of long-term health (refs).  Making these critical change in priorities and approach, both individually, and in terms of the embedded high-technological priorities of our healthcare systems, is likely to be both painful in many ways, as well as profoundly politically contentious.  However, one cannot envision any viable long term prescription or a ‘big picture’ view of biological health that does not place these simple principles first.  Additionally, this view of health (that it emerges from the basic fit between genes and environment) places health back into a proper evolutionary perspective badly lacking in many treatments of diseases of aging.  There seems to be little sense in the current healthcare environment that Darwin’s central insights (about the match between (genetic) endowment and environment determining adaptive success) has any relevance for discussions of basic health or illness.  Has modern medicine abandoned Darwin?  A central implicit myth of the ‘medical industrial complex’ (implicit in the sense that it is largely embedded in relentless advertising and never explicitly stated) may be that high tech medicine and first-line drugs are our best defense against the chronic diseases of aging, a supposition for which there is very little substantive evidence, and much counter evidence against any such assumption.

 

An additional option for the future may be the possibility of a highly effective calorie restriction mimetic, perhaps a future version of resveratrol or rapamycin, some combination of current partial calorie restriction mimetics, or perhaps even a completely new and different compound yet to be discovered.  It seems an easy prediction that a truly safe and effective calorie restriction mimetic (which by definition would give the physiology of calorie restriction without the pain of chronic hunger), which could both slow aging, and substantively delay onset of all the diseases of aging, would be a compound that almost everyone would readily consider taking and many would find highly attractive, for obvious reasons.  Indeed, if a patentable agent were to be proven highly effective and safe, one could predict that it might become the largest selling prescription medicine of all time, making Lipitor (the most successful prescription drug in commercial pharmaceutical history) appear by comparison to be a commercial bust.  However, such considerations (potential widespread use of calorie restriction mimetics) embed a major conundrum, similar to that posed by the potential creation of “an exercise pill”.  Would individuals with the option to take a safe and effective CR mimetic still be adequately motivated to modify problematic lifestyle habits, and move closer towards the original evolutionary environment of humans, which we believe promotes long term health and healthy (or at least healthier) aging?  One can readily appreciate the temptation to continue eating problematic but tasty foods, and remaining overweight and sedentary, if one’s anxiety about any potential disease of aging could be significantly ameliorated by simply taking a pill.

 

Such a dilemma in many ways goes to the heart of difficult choices confronting modern technological Homo sapiens, in relationship to both healthcare, and more fundamentally, long term health.  Do we trust first and foremost in our technology?  Do we place an exclusive faith in our technological competencies, to the exclusion of trusting in other things that are (at least in some sense) pre-technological?  Or must we place equal or even greater trust in our basic evolutionary heritage and our embeddedness in a complex biological matrix and ecology, the environment that carved our genome?  Answers to these questions may determine a great many things about our long-term health in the coming century, and our healthcare system, and these choices indeed mirror much larger and difficult choices about our basic relationship to a complex biological matrix – the extended environment – which is clearly showing the negative impact of human technologies.  A tempting hypothesis is that our disregard of the environment may be intrinsically hinged to the overvaluation of technology and the undervaluation of our biological ‘embeddedness’ and our fundamental evolutionary context.  In simplest terms, overvaluing high technology medicine over ‘low-tech’ lifestyle interventions may be a mistake we are culturally primed to make in how we construct and finance our healthcare systems.

 

Whatever answers we might construct to such questions, there seems little question that Western societies face enormous challenges in a tsunami of age-related disease, in an aging population, at a time when fundamentally unhealthy lifestyles, promoting those very same diseases of aging, are widespread within the United States and in other Western societies as well.  Healthcare professionals of virtually all disciplinary persuasions need to take responsibility for educating both patients and the general public about these issues, as a critical part of the reprioritizing of genuinely proactive and early prevention efforts and health maintenance over much later high-technology interventions which are proving to be both prohibitively costly and at the same time yield very uncertain benefits in relationship to quality of life.

 

Mike Adams Resveratrol Report

Friday, September 23rd, 2011

Introduction

Is resveratrol a breakthrough discovery that is destined to play a more vital role in the prevention and treatment of age-related disease than antibiotics or is it a momentary diversion of finite research time and money from the development of pharmaceuticals the world needs now to treat an aging population suffering near pandemic levels of obesity, diabetes, coronary disease and cancer?  Only five years ago virtually no one, including physicians, scientists and pharmaceutical companies, had even heard of this phytoalexin, and only a handful of scientists and physicians possessed any real knowledge of the molecule’s potential health and wellness effects.  A few animal studies had shown the potential for increases in life span, and a few hundred investigations, primarily by researchers at universities in Japan, India and China, elucidated resveratrol’s chemo-protective properties, particularly with respect to cancer, diabetes and the so-called life style diseases.  However the same could be said for thousands of other phytochemicals and synthetic drugs that had at one time or another shown promising results in the lab, only to die an ignoble death when scientists were unable to replicate the same effects in mammals, especially humans. Very little was known about the potential toxicity of resveratrol in humans or what might constitute an efficacious dose.   There were also serious concerns about the low bioavailability of resveratrol and questions about its possible estrogenic effects. Some scientists speculated that women who might be best advised to avoid resveratrol for this reason. We now know that precisely the opposite is true. Resveratrol has since been shown to be a powerful protectant against breast cancer.  The big missing element was published human clinical trials by major medical schools and research institutions.

As earlier studies were successfully replicated and new investigations by research teams around the world uncovered more and more transcription factors, signaling pathways and other important pharmacokinetic effects of this very small molecule, interest in resveratrol increased exponentially in Asia, the US and Europe. By late 2010 there were over 4,000 published studies on resveratrol and a remarkable consensus was developing.  Not only were scientists finding unusually consistent positive results, as one institution after the other examined the molecule using different approaches and technologies, but fundamental new effects and modes of action were being discovered at an astonishing rate.  Many of these diverse properties of resveratrol have potentially huge implications for the prevention and treatment of human disease.

Only time will tell if resveratrol manages to unseat antibiotics to take the top spot as contributor to human health but at this point in time it can not be counted out. Certainly in terms of its beneficial properties relative to chronic conditions such as diabetes, cardiovascular diseases, many cancers, and quality of life enhancement overall resveratrol is clearly a contender, and for resveratrol the race has just begun.

Resveratrol vs Penicillin

In an interview with a well known international technology magazine in March 2009 I told the journalist “In my opinion, resveratrol will, in the space of 20 or 30 years come to be regarded as a more important scientific development than penicillin. In this prediction I was referring to this small molecule’s potential to  positively impact the health, longevity, and quality of life of the human race.  Seven months after my interview a scientist researching resveratrol at Harvard University took this prediction one step further by proclaiming that resveratrol will be more important than all antibiotics.  Penicillin was discovered in 1928 and has been credited with saving many thousands, if not millions of lives.  Resveratrol was first isolated from a plant source in 1940 in the West but has been used as a traditional medicine in asia for more than 2,000 years.  In 1970 it was first characterized as a chemo-preventative, a substance which protects healthy human tissue from the disease causing effects of various agents such as poor diet, bacteria, viruses and aging.  An example of a chemoprotective would be the use of low dose aspirin to protect against heart attacks.  Both penicillin and resveratrol are derived from natural sources; penicillin comes from a common fungus, and resveratrol is found in a variety of plants including grapes, peanuts, cranberries but most importantly in the Japanese Giant Knotweed plant, also known as Polygonum-cuspidatum.  Giant Knotweed has been used in Asia as a traditional medicine to treat immune disorders, cancer, and neurological conditions.  The plant acquired a rather unsavory reputation as a foreign invader throughout Southeast Asia and Japan owing to its ability to survive in the harshest conditions and to crowd out other plants and crops.  Five years ago a Google search for giant knotweed would return hundreds of articles on how to exterminate it.  The same search today would be filled with scientific studies elucidating its astonishing medical and health applications.

The Scientific Community Agrees

In September 2010 the first international conference of resveratrol researchers was held outside of Copenhagen, Denmark.  At this milestone event over 120 of the world’s leading scientists from  prestigious institutions in the US, Asia, India, Europe and Australia met to present their findings on resveratrol.  After attending this conference and listening to the presentations of these distinguished and highly accomplished scientists I am now convinced that, if anything, my comparison of resveratrol with penicillin was extremely conservative.  Resveratrol and the drugs, treatments, supplements and functional foods, based which will contain this tiny but incredibly potent molecule will eclipse penicillin’s importance within one generation.  From 1940 until 2005 there were some 800 published studies on resveratrol’s biological properties and its health benefits.  From 2005 until the middle of 2010 there have been more than 3,000 new studies on cells, animals, and humans.  New and surprising revelations are being announced almost weekly now by the leading universities, medical schools and research organisations around the world.  All of these discoveries add to our knowledge of resveratrol’s remarkable range of health and disease prevention effects and give us new ideas on how to apply this knowledge for the good of mankind.  The reservations expressed by some physicians and science writers a few years ago about possible side effects or over estimation of the benefits of resveratrol have been almost entirely refuted,  and new earlier unimagined benefits are being revealed as more funding is devoted to animal and human clinical trials of this remarkable natural chemical.  At a time when we face multiple drug resistant bacteria, an explosion in the incidence of diabetes, pandemic levels of obesity, debilitating increases in Alzheimer’s disease and other forms of dementia, and many other diseases of aging, it is clear that Resveratrol is a  chemopreventative whose time has come.  No single molecule or drug known to medical science has shown the wide range of potential preventative, therapeutic, and quality of life enhancement properties of resveratrol.  It has been shown to inhibit cancer, kill bacteria, viruses and fungal infections, extend life span in animals, improve energy production in cells, quench damaging free radicals, increase glucose tolerance in diabetics, improve cardiac function, enhance physical and mental fitness and concentration, repair damaged DNA, prevent cell damage from nuclear radiation, and much more.  Penicillin has been shown to have one use; to combat bacterial infections.  Its effectiveness has been greatly diminished over the past twenty years as many strains of harmful bacteria have acquired resistance to it. Time will tell if resveratrol does fulfill its promise as a so-called miracle molecule, but if it only proves to possess ten percent of the health and medical benefits researchers have attributed to it so far it will in deed make a greater contribution to human health then penicillin, and perhaps even all antibiotics.

Wine Vs. Weed

Given all of the recent publicity about the health benefits of drinking wine and the so-called French Paradox one would logically assume that the principal source of resveratrol used by scientists and supplement makers is the red wine grape.  Although the skin of red grapes does contain small amounts of resveratrol, the concentration is much too low to make grapes an economical source of this compound. Another problem with the extraction of resveratrol from grapes is the difficulty in removing the residues from pesticides, fungicides, and other agricultural chemicals needed to protect the fruit while it ripens.  The application of agricultural chemicals not only poses a serious problem from contamination by toxins but also tends to reduce the natural production of resveratrol and other antioxidants by the grape.  The highest concentration of resveratrol is found in organic grapes that are stressed by fungus, unfavorable weather, too little or too much water and a lack of pesticides.  These conditions also lower the wine production levels but often result in a wine of outstanding quality.

If the amount of resveratrol in red wine is inadequate to explain the French Paradox then what is the reason the French suffer 40% less heart disease than the average westerner? As anyone who has spent time in France knows, the typical French urban diet is high in fats and salt and other less than ideal ingredients from a health standpoint, but in spite of this fact the French people tend to have far lower rates of cancer and cardiovascular disease then do Americans. Even lung cancer rates are relatively low amongst the tobacco loving French citizens. Furthermore, France has more people over the age of 100 than any other European country. Many scientists now believe that it is the full range of polyphenols, not only resveratrol, which accounts for the chemo-protective effects of drinking wine.

There is another paradox and that is the American Paradox.  The American Paradox refers to the fact that even though Americans are amongst the best fed and most affluent people in the world their rate of mortality from cancer and heart disease, and more recently, diabetes and the effects of obesity, is extraordinarily high compared to many other developed countries.  Wine consumption in the US is relatively low and the typical American and UK diet is heavy on bad fats, red meat raised on antibiotics, growth hormones and other chemicals, high fructose corn syrup, processed foods and chemical laden burgers and other fast foods.  These factors along with too little exercise, too much stress, not enough sound sleep, and a heavy reliance on pharmaceuticals to treat chronic conditions surely account for much of the incidence of serious diseases in the US. They also result in a shorter health span, the number of years a person lives free of the so-called diseases of aging. A person who dies at the age of 85 who manages to avoid cancer, diabetes, heart disease and neurological conditions such as Alzheimer’s and dementia has a far longer health span than a person who dies at the same age after many years of intensive medical treatment and a dramatically impaired quality of life due to disease and incapacity.

So, if grape skins are not the preferred source of resveratrol what is? The answer is the Japanese Giant Knotweed plant, aka Polygonum-cuspidatum. If there were a master ninja of the plant kingdom it would surely be Japanese Giant Knotweed.  This voracious predator is one of the toughest and most aggressive plants in existence.  Above the ground it appears to be much like any other relatively harmless flowering green perennial but under the surface its roots tell a different story. If you can imagine a gnarly, hard, dense, thick brown mass that resembles the roots of a mature oak tree you have a good idea of what the roots of this plant look like. It thrives just as well in high and low altitudes, and in hot and cold, and wet or arid climates. It seems to actually grow stronger in more hostile environments. It is an aggressive invader and, once established in an area, will overwhelm existing vegetation within a few years.  It is so tough it has been known to grow up through concrete building foundations.  In Japan and parts of Europe a perpetual battle is waged by farmers and local councils to eliminate or at least control it.  In mid 2010 the government of the United Kingdom took the extreme measure of approving the importation of a worm known to thrive on the roots of the Polygonum-cuspidatum plant in a rather desperate attempt to rid England and Wales of the invasive weed.  British  and Asian farmers who have tried to remove infestations of Giant Knotweed will tell you that if even one centimeter of the root of one plant is left in the ground the plant will return with a vengeance within a year or two.  This obnoxious plant is the principal source of the resveratrol used in thousands of studies on cells, animals and humans.  It is also a  2,000 year old traditional medicine in China and Tibet.   Resveratrol functions as the immune and defense systems for this plant and many others.  Although resveratrol is found in peanuts, blueberries, and many other plants, the concentration of resveratrol is highest in Knotweed.  Not only is the plant rich in resveratrol, it is also a source of other natural protective compounds with names like polydatin, pterostilbene, and emodin, which western scientists are only beginning to investigate.  Some of these compounds appear to be even more potent than resveratrol in fighting specific diseases and improving health.  Pterostilbene, for example, a compound closely related chemically to resveratrol, has been shown to reverse decline in mental function in rats even better than resveratrol  or any pharmaceutical.  It also has potent cholesterol lowering properties.  Many scientists believe that the optimum health and medical effects will follow from combining  resveratrol with other chemoprotective plant extracts such as pterostilbene, fruit-based polyphenols, and other natural compounds.  As one physician and researcher recently stated, “Antioxidants are not solo acts, they perform best as players in a diverse symphony orchestra”

That which Protects the Plant Protects He Who Consumes the plant

In 2006 scientists working at Harvard began referring to resveratrol as a hormetic.  A hormetic is a substance which is produced by a plant in response to stresses such as fungus, bacteria, insects, heat, and too much sunlight, which protects the plant against damage or infection.   The theory of zenohormesis is that these substances also provide protection and early warning of environmental threats to the animals in their vicinity who consume them, either by eating the whole plant or  in the case of humans, a concentrated form of the plant compounds, such as in a supplement. Hormetics, such as resveratrol, do not normally act directly on the illness or biological stressor as do most drugs. They do not function like conventional medicines such as antibiotics, pain killers, cancer drugs, and  blood pressure regulators; nor do they generally possess the toxicity of synthetic drugs.  These natural plant derived compounds work by kick starting processes within the animals’ own cells and organs which attack disease or protect against the stress of harmful environmental factors.  One example of a way in which resveratrol protects animals is its ability to prevent and reduce inflammation by suppressing certain proteins produced by the body in response to infection, injury, and other stresses.  It is well known that inflammation, rather then simply being a symptom of disease as once though, is itself the cause of many human adverse medical conditions.  We have very compelling evidence for example that inflammation plays a key role in auto immune diseases such as arthritis, allergies, multiple sclerosis and other illnesses including heart disease, diabetes and Alzheimer’s disease and many other maladies. When resveratrol is consumed it does not directly reduce inflammation, instead it activates systems in the body’s cells and proteins which reduce inflammation naturally. This is why resveratrol is called a regulator or a potentiator, and not a drug as such.  A regulator works by activating or deactivating various  enzymes, proteins and even genes to prevent or treat the cause of a problem, not simply mask its symptoms.  When is the last time you heard of a synthetic drug that actually cured any disease?  Resveratrol inhibits inflammation by activating many of the same processes that are activated by anti-inflammatory drugs, but in a more sophisticated and precisely targeted manner.  Comparing resveratrol with the NSAIDS, non-steroidal anti-inflammatory drugs, is analogous to comparing a scalpel to a blunt kitchen knife.  Resveratrol reduces inflammation without also interfering with the  beneficial processes that the anti-inflammatory drugs inhibit.  It also does not have the side effects of drugs such as aspirin, ibuprofen, and the more recently released next generation anti-inflammatory drugs.  The manner in which resveratrol attacks cancer is another example of its selective, almost intelligent effects on cells. Resveratrol inhibits the growth of cancerous cells through a number of different actions.  It inhibits the growth of small blood vessels that feed a tumor, but does not stimulate the spread of the tumor to other areas of the body, a process referred to as metastasis, which is one side effect of the anti-cancer drugs which also inhibit the supply of blood to a cancerous tumor.  It also works by activating or deactivating certain proteins such as Tumor Necrosis Factor, TNF, an important immune system molecule that characterizes many tumors, and by suppressing a protein called NF-κB, a which is linked to almost all cancers in humans.  Many of these anti-cancer effects of resveratrol are the same effects that the pharmaceutical companies are spending billions of dollars to reproduce in new pharmaceuticals.  Unfortunately, many of the more effective drugs being used today are also highly poisonous.  Often it is a death race for the patient between the drugs’ toxic effects and the growth and spread of the cancer. One oncologist I spoke to  at M.D, Anderson Hospital in Houston said “Very few people are actually dying of cancer these days, with aggressive treatments such as chemo, radiation and surgery most die of the therapy first, or if they are lucky they survive both the cancer and the treatment.”  This is not to propose the use of resveratrol as a treatment against cancer, or any other disease for that matter.  We need much more actual human clinical data and confirmation of the results seen in the 3500 studies, trials and investigation already completed before we can say with confidence that resveratrol is as effective as the laboratory studies indicate it should be against any specific disease. It may well turn out that some combination of resveratrol and the more effective anti-cancer drugs will be the best strategy to pursue. We know for example that,  in the case of some chemo therapy agents, resveratrol improves their effectiveness and reduces the severity of their side effects.    It may also turn out that some other phytochemical, such as Pterostilbene or Picead, may be even more effective than resveratrol.  There is presently an enormous amount of research being undertaken to answer these questions.

Why Smaller is Better

The larger and more complex a molecule is the harder it is for the molecule, be it a drug or nutrient, to be taken up by the cell, and very often the less effective it is against the basic process or disease being targeted.  Larger molecules are also more likely to have unpredictable side effects.  Smaller molecules are better able to pass through the cell membranes which, act as barriers surrounding all cells. They are also better able to precisely target individual disease components at the cellular level.  The effects of large molecules, which constitute most pharmaceutical drugs on the market today, vs small molecules, such as resveratrol, is the difference between using a laser to remove a tumor versus removing the entire organ or limb surgically. The major drug companies, such as Biotica and Genentech, as well as research organizations, including the National Institutes of Health, consider small molecule drug candidates to have the greatest potential as treatments for diseases such as arthritis, Alzheimer’s disease, cancer.  In the areas of gene therapy, and neurological diseases such as Alzheimer’s disease, larger molecules are essentially ineffective due to their inability to pass through the blood brain barrier, the protective barrier which prevents potentially damaging chemicals from entering the brain.  Only small molecules can pass through this protective filter. Resveratrol is an exceptionally small molecule that has shown astonishing effects in thousands of animal and laboratory studies.  In the past few years many of the health and longevity effects seen in the laboratory have also been confirmed in human clinical trials.  We now know in much finer detail how resveratrol operates at the cellular level to affect the body’s systems and functions. Going forward the emphasis of researchers will shift from cell and animal trials to clinical trials on humans. Results from these limited human studies so far have been nothing short of astonishing. It is expected that progress in discovering new medical and health enhancement applications for resveratrol over the coming decade will be rapid and dramatic.

Resveratrol and Aging, Life span versus health span.

Increases in the maximum and average life span of humans from the beginning of the 20th century until now have not been particularly impressive compared to the advances made in other areas of science and technology; and some countries, such as Russia,  life spans have actually declined.  Predictions by demographers of a drop in US life span in this century are based upon compelling evidence of declining health amongst the present generation of teens and twenty somethings.  Our poor record in extending maximum life span is attributable to the fact that medical technologies and  pharmaceutical research have focused more on keeping sick people alive rather than on preventing the diseases and disabilities related to aging. Drug companies may far more money selling drugs that treat disease then they on cures to diseases. This is one reason why virtually no cures have been offered by any major pharmaceutical company in the last 25 years. One result of corporate medicine has been that the average person spends more than 90% of the his or her lifetime medical expenditures during the last five years of life.  Although average life spans have increased moderately over the past two decades, Health Span, the number of years one enjoys a healthy, independent, and productive life, has not kept pace.  In fact, Health Span appears to be decreasing in the US and the UK and in much of Asia as the citizens of these countries forsake traditional diet and remedies for the western lifestyle; and parents aged 45 to 60 may, on average, outlive their children for the first time in history. At the current rate of increase of medical costs the policy of treating disease rather then preventing disease is unsustainable. At some point during the next ten to twenty years the result will be that health care, and consequently life span, will be severely rationed, or national budgets for health care will consume more than the total government revenues for all public services.  Preventable diseases such as type 2 diabetes, many cancers, and cardiovascular diseases are increasing in incidence at unprecedented rates in the developed world.  It appears that resveratrol can play a critical strategic role in reducing run away health care costs by preventing, delaying or treating many of the health conditions associated with poor diet, lack of exercise, and obesity.

Most of what you think you know about aging is wrong. This applies whether you are a laymen, physician, political leader, science journalist, social scientist or author of books and articles on the subject.  To begin the process of dismantling the prevailing myths and misconceptions here are a few facts to consider.

•   Aging and the widely recognized diseases of aging are the inevitable consequences of living longer. False

Aging is not in itself the cause of diabetes, obesity, heart disease, cancer or Alzheimer’s. Nor does aging necessarily lead to impairment of emotional health, physical capacity, libido, cognition, memory or intelligence. Aging is merely the name given to the constellation of adverse health and medical conditions normally associated with the elapse of time since one is born. The diseases and disabilities associated with advancing age all have specific causes.  One’s age is simply a measurement of time lived, and time is not a cause of any disease.  By modifying one’s diet and daily routine, staying physically and mentally active, adopting preventative life style practices, and seeking appropriate medical  interventions to repair, replace and renovate deteriorated body parts and capabilities virtually all of the diseases normally associated with chronological aging can be either delayed, prevented or even  reversed.  The mortality rate from disease can be radically lowered by adopting preventative strategies at the individual level and one such strategy is the intelligent use of supplements such as resveratrol.  Unfortunately, the institutionalized profit motive driving the emphasis on treatment versus prevention deprives the majority of the world’s population of the benefits of increased longevity and improved health during later life. Only those individuals who take personal responsibility for their health can expect to achieve improved Health and Life spans.

• An aging population will be a drag on society, the young and the economy.
  •       False

Precisely the opposite scenario to this almost universally predicted calamity will actually ensue.

The science commentators and social scientists who contend that an increased population of older citizens will be a burden on the younger members of society fail to understand one very simple fact; many people will live longer because they are free of the disabling medical conditions which presently drain the wealth, vitality, and productivity from society.  It is foolish to presume that people will somehow magically live substantially longer without concurrent improvements in their health and vitality.  An elderly professional man of woman, for example, who is still healthy, energetic, and mentally sharp is advantaged over a younger colleague by virtue of his or her additional years of work experience, judgement, and maturity.  Think about it.  Given the choice between two surgeons, both of whom are fit and healthy, would you prefer the doctor with 40 years of experience and thousands of operations under this belt to remove your ruptured appendix or the surgeon with 5 years and only 100 operations?  Industry and the professions are already seeing a surge in demand for older workers over their less experienced colleagues in all developed countries.  As Health Span increases we will see people taking up new careers and starting university at the age of 50 and greater, professional athletes in their 40s and 50s will challenge  competitors who are decades younger, and the average retirement age will increase dramatically, which means that many more people will be paying  taxes and contributing to the GNP for five to twenty years longer during their life times. Importantly, many fewer people will be drawing retirement and disability payments or requiring costly medical treatments. If prevention and personal responsibility for health become a reality the improvements in Health Span could be the single largest contributor to the US and UK economies twenty years from now. Resveratrol and other natural compounds related to resveratrol may have the potential to add many productive years to the life of westerners by extending health span and inhibiting conditions such as dementia, diabetes, cardiovascular disease, and cancer.

• There is an intrinsic biological limit to the number of years humans can live healthy, vital, independent lives.
• False

Scientists have yet to identify a ticking “biological clock” that predetermines the maximum life span for a human.  Humans are not “programmed” to die at a certain age. We know what the principal causes of aging are, and we are rapidly closing in on solutions to these causes.  Some, such as the corruption of one’s DNA, and decreasing telemere length, which occur as cells divide and are replaced, are a bit more complex than others, but none are impossible to solve given the application of sufficient resources. A Manhattan Project styled attack on aging would probably solve all of these challenges in less than ten years. Now that the medical and research communities are beginning to treat aging as any other disease, rather then accepting it as inevitable, and simply focusing on making older people more comfortable, we can expect dramatic breakthroughs in life extension. Each new breakthrough will give humans a bit more time during which new discoveries will be made that will create stepping stones to the final goal of indefinite life span.

Resveratrol is known to be a chemo protective agent which can play a critical role in delaying or possibly even preventing the most serious causes of mortality in the developed world.  Serious consideration should be given to incorporating resveratrol and other natural chemo preventative supplements into a more rational, humane and effective national health plan in every developed country.  Unless the priority shifts from treatment to prevention the health, wealth and life span of citizens will continue to decline and national health care budgets will be unable to provide cope.

•       There is no silver bullet on the horizon that will dramatically extend human life span.
•       True

The increase will come in small steps which will turn aging from a debilitating terminal

disease into a treatable condition just as the case has been with diseases such as diabetes,

HIV-AIDS, malaria, and many others.   

Resveratrol is not a magic elixer that will prevent the diseases of aging or compensate for poor health habits. Like stem cell therapy, genetic engineering, organ replacement, natural and synthetic drugs, exercise, diet, and medical technology, it has an important part to play in any longevity program.  As we collect more data from human clinical trials we will be better able to define just what this role should be.  Resveratrol is only the first in what will likely be a long list of similar compounds with extensive health benefits.  Other compounds related to resveratrol, such as Pterostilbene, Polydatin, and various analogs of resveratrol, will be intensively investigated over the coming few years and it is almost certain that researchers will find a treasure trove of genetic and other biological effects even more impressive than those of resveratrol.  Pterostilbene, a natural compound found in blueberries, for example, has been shown in rats to actually reverse declines in decision making abilities and appears to improve intelligence. It also lower bad cholesterol more effectively than resveratrol does. Polydatin is more effective than resveratrol in preventing the damage to heart tissue which occurs when a heart attack victim is resuscitated or a heart is restarted following some types of cardiac surgery. Emodin, an antioxidant found in the Japanese Giant Knotweed plant is a potent anti-cancer agent. The more we learn about these astonishing molecules the more we are awed by their benefits to human health.  Many researchers have noted a synergistic effect when resveratrol is combined with other polyphenols such as curcumin however not all combinations of polyphenols are synergistic.  For example, a negative effect on Sirt gene activation has been observed when resveratrol is combined with the antioxidant quercetin.

Health Span and Life Span will increase at a steady but ever increasing rate as discoveries are made and knowledge is created that will lead to cures and therapies to treat the so-called diseases of aging.  Natural chemo-preventatives such as resveratrol, curcumin and a wide range of other polyphenols may take over much of the role synthetic drugs now play in treating disease after the fact rather than focusing on preventing disease naturally.

• Technology advances will lead to longer life spans and elimination of many diseases.

True

Dr. Sinclair at Harvard discovered the gene activation properties of resveratrol only because he had the help of a new computerized chemical screening system that could examine thousands of molecules for their anti-aging gene activation properties in the time it previously took to investigate only a handful of compounds.  Advances in computing power are rapidly increasing our ability to comprehend the intricacies of the metabolic process and to realistically simulate critical biological pathways. The past decade saw the development of genomics.  The coming ten years will consolidate this knowledge and move on to unraveling the role of the proteins which are encoded by our genes.  This will represent an enormous advance in our ability to design drugs that turn on beneficial genes and switch off the genes responsible for diseases such as multiple sclerosis, asthma, mental illness and hundreds of other diseases that are caused by either a specific genetic abnormality or a combination of genetic factors.  We will also begin to solve the mystery of what function the 95% of the genome which does not code for proteins plays in human development. This will lead to the design of new strategies to prevent orreverse aging and result in quantum leaps in human longevity.

By 2020 computers and other medical devices will be powerful and cheap enough to give scientists the tools they have needed to virtually stop the aging process in animals.  This goal has already been achieved in the lab.  The convergence of thousands of independent discoveries and incremental breakthroughs by dedicated professionals working in diverse fields are creating synergies and mutually reinforcing discoveries that are the key to extending life span and eventually eliminating aging altogether.  Developments in advanced prosthetics, stem cell therapy, organ replacement, and the prevention and treatment of cancer, heart disease, and neurological conditions such as Alzheimer’s and dementia will mean that those persons who are presently under 60 years of age and in excellent health will have a reasonably good chance of living indefinitely. This assumes that they are financially able to afford the treatments, drugs, and therapeutic procedures which will become available over the next 30 years.  Beyond 2040 aging will be simply a chronic condition treatable or preventable at a reasonable cost to the patient.  The timing of one’s death will become for many people a matter of individual choice.  Accidents and needless wars over resources will become the main causes of death in the developed world. Unless we stop destroying our planet through the  plundering of its resources and poisoning its air and water, climate change and scarcity of usable water and breathable air will negate any increases we make in average life spans.

It is not necessary to fully understand the cell’s incredibly complex metabolic process to develop effective drugs and other preventatives and treatments for the disease we call aging.

            True

Many of the safest and most successful drugs in use today work by targeting, unidentified biological processes they were not initially designed to target. Luck plays a part in drug discovery.  Serendipity and persistency on the part of researchers and physicians resulted in the discovery of penicillin, aspirin, pain killers and many other valuable drugs. Partial knowledge of the cellular-level biological processes being targeted coupled with the intelligent application of trial and error is an effective and rational life extension strategy. It probably offers the greatest potential to conquer aging in the near to mid term.   When Dr Sinclair discovered the ability of resveratrol to activate the so-called anti-aging genes it was due to serendipity as much as to science.  Sinclair discovered this previously unknown ability of resveratrol because he was able to quickly screen thousands of chemicals for this property due to advances which had just been made in laboratory analysis technology.  His discovery did not come about because he had some reason to believe that resveratrol might fit any receptor on a cell or it might have anti-inflammatory or antioxidant properties.

Why are we aging faster but living longer?

The decline in the health status of the average British or American citizen is not principally a   natural or inevitable consequence of human evolution nor is it due to the rise of new diseases  or the deterioration of the quality of the environment in which we live, although environmental factors do militate against increasing life spans.  The causes are simple and well known.

• Life span increases so far have come about only because advances in medical technology and  pharmaceuticals are keeping sick people alive longer, but at a very high and untenable cost; not because diseases and disabilities are being prevented or that people are staying healthy longer.  Further increases in both health span and life span must come from adopting prevention as our primary focus.  We have yet to begin to exploit the advantages of prevention at the institutional level. Resveratrol is one molecule that may play an important part in both prevention and treatment.

Obesity and life style factors, not aging, are the principal cause of diabetes, hypertension, most heart conditions, and most cancers.  Obesity is also a major causal factor for gastric reflux disease, gall bladder disease, degeneration of L-Sacral Spine and weight-bearing joints, asthma and hundreds of other adverse medical conditions.  Resveratrol was shown to increase the life span and health span in obese mammals.  In his now famous study published in the journal Nature, obese rats lived 31% longer and managed to avoid all of the diseases normally contracted by aging animals.  Their organs resembled those of young, lean, health rats.

Lack of regular exercise  compounds the  negative medical consequences of obesity, and is a risk factor for osteoporosis as well as a wide range of adverse physical, emotional and neurological conditions. Mitochondria are the cells’ energy factory. Resveratrol increases mitochondrial density and enhances mitochondrial function.  Rats fed resveratrol in the study by Dr Auwerx and published in the journal Cell, were able to run twice as far as rats not fed resveratrol. 

Probably the largest contributor to early aging and the diseases associated with aging is poor diet.  Excessive consumption of red meat, processed foods, sugars and high fructose corn syrup, as well as trans fats and the lack of omega 3 rich foods and polyphenols from fruits and green leafy vegetables, and overeating in general are all enemies of human Health Span and longevity. Resveratrol has been shown to counter many of the adverse effects of poor diet.

Chronic unresolved stress, results in endocrine imbalances, immune system dysfunction, inflammation, sleep disorders and neurological impairment. Resveratrol is a natural anti-inflammatory agent and may have important neuroprotective properties.

A prescription for longevity.

Anyone can substantially enhance both Health Span and Life Span by adopting the following measures:

• Stop using tobacco products of all types and limit alcohol use to no more then 3 glasses of wine or three ounces of spirits per day.
• Reduce, or better yet eliminate, all processed foods, fast foods, and sweetened beverages. Make green leafy vegetables your primary food group.  Reduce or eliminate red meat from your diet.
• Take a pill. Add the below supplements to your daily routine:

Biotivia or other quality Resveratrol, 250mg to 1,000mg

Pterostilbene, a molecule closely related to resveratrol, 250mg

•              Non fish oil derived Omega 3, such as Green Omega 3, with EPA and DHA, at least 1,000mg

A multi-antioxidant complex such as Bio Quench, 500mg to 1,000mg

Vitamin D, 10,000 IU

Acetyl L-Carnitine and Alpha Lipoic Acid supplements,  250mg of each Curcumin, also known as the spice tumeric, 1 to 2 grams per day Vitamin C, preferably the oil soluble form called ascorbyl palmitate There are, of course, many other supplements that may have a beneficial impact on Health Span and longevity but the published scientific evidence best supports the above nutrients. The majority of over the counter supplements are of no value whatsoever.

• Incorporate at least 30 minutes of moderate to intense exercise, at least 3 times each week, into your routine.  Get up from your computers, video games, Ipads, email, and Facebook accounts and do something physical, preferably out of doors. Even if you are overweight you can be fit. In fact, it is healthier to be fit and fat then unfit and thin.
• Meditate or at least take a one hour mental and physical break from your daily grind once each day.  Midday naps of 20 to 45 minutes are extremely beneficial.
• Maintain a healthy weight, which is best measured by dividing your height in inches by your waist circumference.  The result should be no less than 2.0.  The popular BMI measurement is basically worthless as it makes no distinction between lean and fat body mass.
• Use high quality air and water purifiers in your home and office. Lobby your political leaders to take environmental protection and clean energy seriously. At some point the limit on life span will be the determined by the ability of the Earth’s climate and resources to support life at all.
• See a physician at least once per year and repair failing parts just as you do with your automobile or any other complex machine.  If your eyesight is deteriorating consider having a corrective procedure by an eye surgeon, if you have dental or periodontal issues see your dentist.  Gum infections can cause serious heart conditions and other life threatening conditions. Do not ignore symptoms of an underlying problem. Your chances of surviving cancer, as we all know, are dramatically enhanced if you begin treatment early, the same rule applies to diabetes and most other chronic diseases.
• Drive sensibly, wear seat belts and control your anger. It would be a pity to live a healthy life and then die at the age of 40 on the motorway.  

I will expand the below summary of the more recent and interesting studies in the final document. This section will be about fifteen pages when finished.

What the Science Says

The most recent research results by scientists and physicians working at prestigious medical schools and other institutions around the world were presented in September of this year at the Resveratrol 2010, the first international science conference on resveratrol and health.  There is not enough space in this paper to discuss all of the remarkable results presented by the experts at this conference.  I have chosen to summarize the high points of some of the more interesting and authoritative studies below.  It should be noted that no study was presented in which any toxic or serious adverse effect of oral administration of resveratrol to animals was observed, and no study or trial was stopped due to the presence of such negative effects.

Resveratrol Human Clinical Trials

Over the past three years a substantial number of medical schools and research institutions have undertaken studies of resveratrol’s ability to prevent or treat disease in humans.  The number of such clinical trials is increasing weekly.  A few of the more important ones are described.

Diabetes

Albert Einstein Medical College conducted two human clinical trials in which the ability of resveratrol to enhance mitochondrial function and improve insulin sensitivity, two important functions the drug companies are attempting to target with a new generation of drugs.

The results were extremely positive and thes

The Phenomemon of Resveratrol: Redefining the Virtues of Promiscuity

John M Pezzuto

College of Pharmacy, University of Hawaii at Hilo, Hilo Hawaii

*There are presently over 3500 papers which have been published in various scientific and medical journals which concern some aspect of resveratrol.  This represents a huge and accelerating increase in the interest in this compound by the scientific community from 2000 to the present.

*Resveratrol is contained in significant amounts in the red wine grape, which may explain the so-called “French Paradox”, the low incidence of cancer and heart disease in France in spite of a diet that is high in saturated fats, salt and other dietary risk factors for heart disease.

•           Cancer chemoprotection “entails the ingestion of dietary or pharmaceutical agents that can prevent, delay or reverse the process of carcinogenesis (cancer).  Resveratrol is classified as a chemo-protective.

**The low amounts of resveratrol available in wine and foods are not likely to have a major beneficial impact on human health.  This suggests that a concentrated resveratrol supplement is required to produce the health effects of resveratrol as seen in the thousands of trials and investigations. In most of these studies the resveratrol dose used, in human equivalent values, ranged from 100mg to over 2,000mg for a 70kg person.

*Study observation

**Author’s analysis or comment

A definitive guide to selecting a quality resveratrol supplement

Since the study by Dr. David Sinclair was published in the journal Nature a plethora of New companies have sprung into existence offering resveratrol supplements. Evalualating resveratrol sellers and their products has become a confusing and frustrating process. This guide is meant to elucidate the most important factors one should use to discriminate one resveratrol supplement from another based upon their relative quality, value and likelyhood of being effective.

Unlike most dietary supplements, hundreds of well managed scientific studies and trials have upheld resveratrol’s potentially critical health properties as a treatment for diabetes, cancer, inflammatory and autoimmune diseases and neurological conditions. Without passing judgement on resveratrol’s actual efficacy or effectiveness it is clear that many people purchase resveratrol as a preventative or treatment for a serious medical condition. If the resveratrol these consumers purchase is not a high quality, properly manufactured, bio active compound they are not only wasting their money but are also failing to obtain whatever benefits resveratrol may offer for the amelioration of their condition.

The criteria below are based upon valid scientific principals and accepted standards for the evaluation of either a of a functional dietary supplement such as resveratrol. The standards can also be used in judging other supplements.

Ethical labeling is essential.  The labels of many resveratrol suppliers do not disclose the exact form of resveratrol or the quantity which is contained in their supplement. Some simply call their main ingredient “red wine complex” or a “proprietary blend”. Given that red wine contains less than 1% resveratrol it seems a bit strange that a company would use this description to label a resveratrol product unless the purpose was to conceal the actual ingredients in the product. A proprietary blend can be almost anything, but is unlikely to consist of pure resveratrol given the relatively high cost of quality resveratol versus other possible ingredients.

Resveratrol is composed of two principal isomers, trans-resveratrol and cis-resveratrol. Only the trans-isomer has been associated with health benefits. The cis isomer actually acts to nullify the effects of trans-resveratrol. Unless the seller states on the label that the product consists entirely of the trans-resveratrol form it is highly likely that it contains either some or all of cis-resveratrol, which is, by an order of magnitude, the less costly form of resveratrol.

Capsule size makes a difference. A size zero capsule is able to contain about 500mg of resveratrol, if the base material is processed using pharmaceutical technology and equipment. This is the largest size capsule that is quite easily swallowed by most people.  Sellers who use larger capsules do so to compensate for the fact that they are simply stuffing lower potency raw extract into a capsule without going through the time and expense of purifying and granulating the resveratrol extract. A larger capsule size also allows for the use of various fillers and chemicals such as silicon, magnesium sterate, cellulose, and other additives. The best quality resveratrol supplements are contained in a size zero, all vegetable capsule and contain no additives or fillers at all. There is no reason why you should have to consume sand, chemicals, and other unwanted ingredients in your supplement simply because your supplier can not be bothered with using more sophisticated processing and filling technology.

Is red wine the best source of resveratrol? Although much of the news about resveratrol mentions the red wine grape as its source, wine grapes are not a practical or desirable source of resveratrol for two important reasons. First grapes are subjected to a wide range of toxic chemicals in the cultivation process. Fungicides, pesticides, chemical fertilizers and many more chemicals are sprayed directly on wine grapes.  Since resveratrol comes from the skins it is very difficult to eliminate contamination in the resveratrol concentrate. The second reason wine grapes are not a good source of resveratrol is that it is impossible to produce a high potency supplement using grape extract. The concentration of resveratrol in grape skins is simply too low. This is why, in virtually all of the animal and tissue studies on the health benefits of resveratrol, the source of the resveratrol was the Giant Knotweed plant, which grows without fertilizers or agricultural chemicals in the wild.

Capsule ingredients and packaging The capsules themselves should be all vegetable such as Pfizer Vcaps rather than clear gelatin, which is made from an animal product. Not only is an all vegetable capsule healthier to consume than an animal by product but it is designed to better regulate the release of the active ingredients into your digestive tract when taken orally. What is the use of taking a natural supplement if the capsule it is contained in is made from the collagen inside animals’ skin and bones?

Resveratrol is highly susceptible to deterioration by oxidation and exposure to ultraviolet light. A quality supplement will be protected from oxidation during manufacture through the use of nitrogen gas filled processing lines. The bottle in which the supplement is contained should also use an inert gas to prevent oxidation during shipment. However once the bottle is opened oxygen is allowed to enter. If active packaging technology is not employed to protect against this damage the shelf life of the product will be seriously degraded. Only one company uses an oxygen absorber system to capture the oxygen which enters the bottle when a capsule is retrieved.

Dosage The appropriate dosage of trans-resveratrol is a highly contentious issue, with respect to the rhetoric of resveratrol suppliers that is. The science regarding dosage is relatively clear however. Although doses of around 100mg appear from some studies to have potentially important preventative effects, the consensus is that at least 250mg is required to reach the threshold for efficacy as demonstrated in most animal and in vitro studies undertaken to date. This equates to the human equivalent of the dosage used in the Dr. Sinclair study and many other studies. The dose recommended by most clinicians for treatment of an existing condition ranges from 1,000mg to 4,000mg. however it is recommended that one consult a physician before taking a dose over 1,000mg daily. No toxicity or serious adverse effects were observed in several animal and human studies in which up to 5,000mg was given on a daily basis for an extended period of time. In animal studies dosages up to the human equivalent of 30,000mg have been tolerated with only minor adverse effects. Products which offer less than 250mg of pure trans-resveratrol are of dubious value.

Natural versus synthetic resveratrol? Synthetic resveratrol can be produced using one of two methods, fermentation and chemical engineering. In the case of fermentation a yeast or bacteria is genetically modified to produce resveratrol. Chemically engineered resveratrol is constructed from a broth of compounds using organic chemistry to engineer the molecule. Both processes are fraught with potential pitfalls. In the case of fermentation often what occurs is that bits of the bacteria or yeast DNA used to produce the resveratrol show up in the finished material. This means that if you use this product you are consuming a novel substance, that is a compound that has never been previously consumed by a human, with potentially toxic or other other unknown effects. In the case of a chemically engineered resveratrol product the issue is contamination by small amounts of the chemicals used to produce the synthetic resveratrol. On a typical HPLC graph of a synthetic resveratrol there will almost always be spikes on the chart of what are  referred to as “unknowns”. These trace chemicals are by-products of the creation of the resveratol which are unidentified and assumed, or hoped, to be non toxic. Furthermore, naturally extracted resveratrol from the polygonum cuspidatum plant is known to be effective and non toxic. Neither properties have been definitively verified in regard to synthetic resveratrol. When a natural compound such as resveratrol is copied using chemicals, yeast or bacteria often the final product is not truly identical to the natural compound. There is only one reason why some suppliers use synthetic resveratrol in place of natural resveratrol from polygonum cuspidatum. The reason is the far lower cost of synthetic resveratrol. If a supplier does not disclose which type of resveratrol is contained in its products you can normally assume that it is the synthetic variety.

Gimmicks to avoid

Micronized Resveratrol.  There is absolutely no published scientific evidence that micronization improves the bioavailability of resveratrol.  In fact, it may have a negative effect by reducing the half life of resveratrol in blood plasma.  There is no reason to pay extra for a micronized resveratrol product, which offers no practical advantage to the user.

Resveratrol with Quercetin.   Quercetin is a potent antioxidant in its own right, however it should not be combined with resveratrol or even taken within at least 8 hours of taking a resveratrol supplement. The reason, which was only recently discovered, is that quercetin blocks the metabolites of resveratrol from entering your blood stream. Quercetin also deactivates sirtuins, precisely the opposite effect of resveratrol. Until a few years ago it was assumed that adding quercetin was a good thing since the importance of the metabolites was not understood. Before the latest studies revealed otherwise it was assumed that the metabolites were not responsible for the biological and longevity gene activation effects of resveratrol. Based upon several highly regarded studies we now know that it is very likely that the beneficial effects of resveratrol actually derive mainly from these metabolites rather then from the free resveratrol. These metabolites are bioactive products of the breakdown of resveratrol by the liver and layer of cells lining the small intestine. By blocking these sulphates and glucordinates quercetin interferes with the ability of resveratrol to activate the sirtuins, specifically Sirt-1 and 2, the so called anti aging genes, and blocks other signaling pathways through which resveratrol operates, and which are responsible for many of the desirable health effects of resveratrol. Moreover, the half life of the metabolites in human tissue is several hours whereas the half life of free resveratrol is only about 12 minutes. In a 2009 study of resveratrol’s effects on inducing the creation of hemoglobin cells in be patients’ blood it was found that quercetin totally blocked the ability of resveratrol to create the new red blood cells. Quercetin also nullified the anti inflammatory property of resveratrol in an informal trial of resveratrol’s palliative effect on arthritis. There is no scientific justification for adding quercetin to a resveratrol supplement. If one wishes to take quercetin it is readily available as a low cost supplement that may be taken by itself.

Red Wine Complex.  Some supplement makers attempt to confuse the buyer into thinking that he is buying a resveratrol product by using this misleading description.  There is no standard for “Red Wine Complex”. Red wine contains only very small amounts of resveratrol, less than 5% as a rule.

Dr. Oz or Oprah Recommended Resveratrol. Neither Dr Oz nor Oprah recommend any brand of resveratrol.  If you are interested in knowing which brand they use in their presentations on resveratrol you can find this by searching for Resveratrol on their respective web sites.

The credentials of your supplier are important. The media coverage of the studies demonstrating the potential benefits of resveratrol has attracted a flood of new and clearly disreputable resveratrol sellers to the market. These companies have no experience in producing a food or health supplement, no scientific staffs, testing labs, or other technical resources. Most have no established quality control standards and no history by which one can judge their reliability and integrity. Many of these companies use a form of the word resveratrol in their names and sell only via a web site. The lawyers for Dr. Mehmet Oz and Oprah Winfrey recently filed federal law suits against over 50 of these companies for illegally using their trademarks and making false claims that their products were endorsed by these well known personalities. A copy of the litigation can be downloaded by clicking on the below link.

Your resveratrol supplier should be a manufacturer rather than simply a reseller.  Many suppliers buy raw material from Asian sources at the lowest possible price and simply fill capsules, rather then collect the plant and process it in their own GMP certified facility.  `legitimate resveratrol supplements will have passed Consumer Lab’s recently updated evaluation of resveratrol brands, and its web site should provide easy methods to contact the company if you have any questions, complaints or a request for a refund.

Your resveratrol provider should have a history of at least ten years, preferably more, of ethical business operations with no unresolved Better Business Bureau complaints. It should offer a range of products not only one or two virtually identical products. If the company offers a monthly recurring order program a clear and convenient means of canceling your subscription should be offered. Before you give your credit card information to an on line seller be sure that the company is legitimate.  This can usually be established by contacting your local BBB and doing a bit of on line due diligence.

The company should offer its product through respected retail shops. If the company’s products are not available in brick and mortal stores such as GNC, Walgreens, The Vitamin Shop and other reputable resellers it should probably be avoided.  Anyone can sell a product over the Internet but to have one’s products accepted by major Health and Supplement stores requires liability insurance, thorough testing of the products’ quality and vetting of the company and its principals. Shops that carry supplements carry out thorough due diligence of both the product itself and the company supplying and manufacturing the product.  You have no such assurance with most on line suppliers.  This is not to say that all on line suppliers sell inferior quality supplements.  There are some very reputable and ethical Internet merchants and manufactures.  Unfortunately however, with any new supplement comes a raft of brand new suppliers with no history or experience in manufacturing advanced nutritional products who buy from lost cost, low quality brokers and whose products consistently fail independent evaluation.  These companies usually employ highly unethical business practices or compete entirely on the basis of price. More often than not their products are virtually worthless, their customer service is non existent and their lifespan is measured in months if not weeks.

The gold standard for a manufacturer is for its products to win widespread acceptance by the medical and research communities. Resveratrol used in human trials at institutions such as the Albert Einstein Medical School, Ottawa Hospital, Harvard, international institutes such as the University of Ferrara, University of Queensland in Australia and the NIH are the purest and most thoroughly tested supplements available to the general public. These institutions must put any product used in human trials through a rigorous and extensive series of tests for purity and possible toxicity.   Their endorsement is far more valuable than any test done by the manufacturer themselves or by the so-called independent labs. One company whose products satisfy all of these criteria, and which have been used in National Institutes of Health, Health Canada and other health ministry funded studies is Biotivia, who introduced the original resveratrol supplement over six years ago. The company has been in operation in the US and Europe for over 20 years.  On the opposite end of the scale are the companies who have sprung into existence to take advantage of the hundreds of news articles about resveratrol’s potential health benefits.  In mid 2010 Oprah Winfrey hosted Dr. Mehmet Oz on her program to talk about extreme life extension.  He extolled the virtues of resveratrol in his presentation and shortly thereafter literally dozens of new suppliers materialized offering free bottles of resveratrol and claiming an endorsement by Dr Oz.  Not only were they deceiving customers with their sleazy marketing schemes their product were found, in many cases, not to contain resveratrol at all. The lawyers for Dr Oz and Oprah’s production company filed suit against most of these companies, and the states attorney general in several states launched criminal investigations.