Resveratrol


Resveratrol decreases tobacco-induced inflammation in the lungs of smokers, suggesting that SIRT1 is involved in regulating the inflammatory response to cigarette smoke. Further evidence for a role for sirtuins in this process comes from Rajendrasozhan et al., in a study that confirms and extends the results of previous work.

The authors show once again that SIRT1 levels are low in the lungs of smokers, and that these levels diminish further in response to cigarette smoke. Smoke-exposed lung cells and macrophages exhibited increased inflammatory signaling (assayed primarily by looking at IL-8), as do cells in which SIRT1 has been artificially knocked out. Consistent with this, the RelA subunit of the master inflammation regulator NF-κB is hyperacetylated — recall that SIRT1 is a deacetylase — and consequently more active. Conversely, overexpression of SIRT1 decreases inflammatory cytokine production, echoing earlier results that described SIRT1 activation by resveratrol treatment.

Thus, a key longevity-assurance gene is also involved in restricting inflammation, which is a risk factor for some of smoking’s worst complications — chronic obstructive pulmonary disease (COPD) — as well as tumorigenesis. Tobacco is a major public health issue, so it’s not surprising that SIRT1 is getting attention in this context, but there is reason to believe that the phenomenon is general to organs other than the lung — e.g., see this review from Salminen et al., which describes how signaling from SIRT1 and FoxO transcription factors (mammalian homologs of the worm longevity gene DAF-16) can inhibit NF-κB signaling in a variety of systems. The authors close the circle by discussing the connection between longevity assurance and the mitigation of one specific age-related phenotype, inflammaging.

COPD is a leading cause of death worldwide, and it arises not only in smokers but in members of their households, as well as people exposed to environmental pollutants. A host of other inflammatory diseases, such as arthritis, beset the elderly and decrease quality of life. Increasing evidence that SIRT1 activity could mitigate the health harms of runaway inflammation point to even more potential uses for the new class of sirtuin-activating drugs that are currently under consideration as therapies against diabetes and metabolic syndrome.

We know that resveratrol, an activator of SIRT1, boosts exercise tolerance and performance in mice (see Resveratrol: Breakfast of champions). Now it appears that the converse is also true: exercise increases SIRT1 activity in aged rats. From Ferrara et al.:

Exercise Training Promotes SIRT1 Activity in Aged Rats

The objective of this study was to determine the effects of aging and exercise training on SIRT1 activity and to identify a pathway linking SIRT1 to antioxidant response and cell cycle regulation in rats. SIRT1 is a NAD+-dependent deacetylase involved in the oxidative stress response and aging. The effects of aging and of moderate and prolonged exercise training in rats are unknown. We measured SIRT1 activity in heart and adipose tissue of young (6 months old), sedentary old (24 months), and trained old (24 months) rats using an assay kit. … Aging significantly reduced SIRT1 activity in heart, but not in adipose tissue, increased TBARS and 4-HNE and decreased Mn-SOD and catalase expression in both heart and adipose tissue. Aging did not affect FOXO3a protein expression in the heart or FOXO3a mRNA in adipose tissue. Exercise training significantly increased FOXO3a protein in the heart and FOXO3a mRNA in adipose tissue of aged rats. It also significantly increased Mn-SOD and catalase levels in both heart and adipose tissue. … We concluded that exercise training, which significantly increases SIRT1 activity, could counteract age-related systems impairment.

Note that the effects are observed both in cardiac tissue, where SIRT1 levels decrease with age, and in adipose, where SIRT1 activity remains constant throughout the lifespan.

These findings are consistent with recent observations that resveratrol induces the heat shock response, leading some to speculate that the compound exerts some of its positive effects via hormesis. Exercise is the quintessential example of beneficial hormesis: stress the body acutely now to make it more resistant to chronic stress later. Could resveratrol and exercise (and for that matter, calorie restriction) converge on a common pathway that confers stress resistance?

For those of you who lack the hepatic fortitude to consume 1000 bottles of red wine, I’m betting that New Year’s resolution to get off your duff and hit the gym is looking a lot more appealing.

Last year, we learned that the sirtuin activator resveratrol extends the healthspan of mice and increases exercise tolerance. Resveratrol occurs naturally in several plants, most famously the skins of red grapes; unfortunately for the would be life-extensionist, a human would have to consume upwards of 1000 bottles of red wine in order to approach the dose of resveratrol used in the rodent studies. What we needed was an orally bioavailable, clinically useful drug with the same specificity but much higher activity.

One year later, a collaboration between the pharmaceutical company Sirtris and the research group of David Sinclair (who co-founded Sirtris, and whose lab was responsible for the observation that resveratrol extends the lifespan of mice eating an unhealthy diet) has resulted in the development of sirtuin activators that are a thousand times more efficacious than resveratrol (link). While longevity data is not yet forthcoming, the compounds do have a significant influence on glucose homeostasis, and are being touted as a potential prophylactic or therapy against type II diabetes:

Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes

Calorie restriction extends lifespan and produces a metabolic profile desirable for treating diseases of ageing such as type 2 diabetes. SIRT1, an NAD+-dependent deacetylase, is a principal modulator of pathways downstream of calorie restriction that produce beneficial effects on glucose homeostasis and insulin sensitivity. Resveratrol, a polyphenolic SIRT1 activator, mimics the anti-ageing effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance, increases mitochondrial content, and prolongs survival. Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol. These compounds bind to the SIRT1 enzyme–peptide substrate complex at an allosteric site amino-terminal to the catalytic domain and lower the Michaelis constant for acetylated substrates. In diet-induced obese and genetically obese mice, these compounds improve insulin sensitivity, lower plasma glucose, and increase mitochondrial capacity. In Zucker fa/fa rats, hyperinsulinaemic-euglycaemic clamp studies demonstrate that SIRT1 activators improve whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle and liver. Thus, SIRT1 activation is a promising new therapeutic approach for treating diseases of ageing such as type 2 diabetes.

Standard qualifications: humans and mice have quite different metabolic needs, and it remains to be seen whether the drugs will work in humans. Even in the rodent, I’ll want to see next year’s paper (by that time, there should be lifespan curves available for animals that have taken the compounds for a long periods of time) before getting too terribly excited about the prospects of the first longevity drugs. It’s also important to keep in mind that the effect of long-term systemic sirtuin activation is unknown, and may even be harmful in certain key tissues (like the brain). In other words: I retain my skepticism; nonetheless, for the rest of this post I’m going to take these results at face value and look toward the future.

The work represents the culmination of a huge amount of progress in a relatively short time: in less than 15 years, the sirtuin story has evolved from basic biology in the simplest model organisms, through exhaustive (though essential) testing in larger animals, into a source of potential therapies for a major human disease.

Furthermore, for the first time we have a clearly defined path toward the regulatory approval and widespread use of a compound that could be used as a frank anti-aging drug. There are significant practical barriers to testing a longevity-enhancement therapy, not least of which is the timescale of the necessary studies. There are also institutional barriers: despite the inefficiency of treating every disease of aging separately, there’s still major reluctance on the part of funding and regulatory agencies to see aging as a disease per se (though even over my relatively short career in biogerontology, I have seen this changing for the better).

But a drug for which a clear clinical indication existed, shown to be efficacious against a widely acknowledged disease, could pass over regulatory hurdles and enter the clinic much more smoothly. Since clinicians could point to a specific short-term benefit of the drug, public acceptance (sometimes curiously hard to achieve in discussions of explicit longevity enhancement) might also come more readily. (One question: in advertisements, would the manufacturer have to warn patients that the drugs “may slow aging and extend the lifespan”?)

Following up on our recent discussions of hormesis, in which mild acute stress protects against severe or chronic stress, here’s a review by Suresh Rattan that discusses the phenomenon in light of aging. Stress resistance and longevity, after all, go hand in hand.

Hormesis in aging is represented by mild stress-induced stimulation of protective mechanisms in cells and organisms resulting in biologically beneficial effects. Single or multiple exposure to low doses of otherwise harmful agents, such as irradiation, food limitation, heat stress, hypergravity, reactive oxygen species and other free radicals have a variety of anti-aging and longevity-extending hormetic effects. Detailed molecular mechanisms that bring about the hormetic effects are being increasingly understood, and comprise a cascade of stress response and other pathways of maintenance and repair. Although the extent of immediate hormetic effects after exposure to a particular stress may only be moderate, the chain of events following initial hormesis leads to biologically amplified effects that are much larger, synergistic and pleiotropic. … Healthy aging may be achieved by hormesis through mild and periodic, but not severe or chronic, physical and mental challenges, and by the use of nutritional hormesis incorporating mild stress-inducing molecules called hormetins. The established scientific foundations of hormesis are ready to pave the way for new and effective approaches in aging research and intervention.

The discussion is quite broad, with appropriate emphasis given to classical examples of hormesis (radiation, thermal stress, and the emerging idea that calorie restriction is a form of hormetic stress) as well as forays into unusual stresses such as hypergravity.

At the end of the abstract he mentions “hormetins” — this is a fairly new term that has yet to gain substantial traction in the field, referring to compounds that confer stress resistance and possibly increased longevity by inducing low levels of stress themselves. As we learned recently, resveratrol may be among them.

How might hormesis — the protective effect of low-dose or acute stress against higher-dose or chronic stress — work at the molecular level? One possibility is that the mild “priming” stress tones up the protective actions of stress responses: a hit of peroxide, for example, might accelerate expression of antioxidant enzymes like superoxide dismutase, protecting the cell against a future oxidative wallop. To the extent that chronic stresses can be risk factors for age-related decline in cellular function, hormetic stress might protect the cell against such long-term grinding damage, and ultimately against aging itself.

Compounds that protect against stress and aging might therefore function in a hormetic manner — either by literally stressing cells or by “simulating” stress, i.e., inducing protective stress responses without actually causing even short-term acute damage. Consistent with this idea are some recent findings on resveratrol, a compound found in red wine grapes that has been implicated in extending lifespan, improving exercise tolerance, and as an antioxidant.

Putics et al. have demonstrated that resveratrol induces the heat shock response (HSR), a well-studied and canonical stress response that results in higher expression of protein chaperones. The effect is not due to the compound’s antioxidant activity, and is distinct from endoplasmic reticulum folding stress pathways such as the unfolded protein response. For reasons that escape me, the authors did not attempt to determine whether the known resveratrol target proteins, the sirtuins, play a role in the induction of the HSR.

Furthermore, treatment with resveratrol protect cells against severe heat shock, a hallmark of hormesis. The authors suggest in the final sentence of the abstract that

Our results reveal resveratrol as a chaperone inducer that may contribute to its pleiotropic effects in ameliorating stress and promoting longevity.

This is a long way from having been proven — future work will need to uncover the mechanism by which resveratrol induces the HSR, and manipulate the genetics of both the resveratrol-heat shock connection and the heat shock response itself in a system suitable for the study of longevity — but it’s a promising start.

One wonders whether heating the resveratrol might have a synergistic effect. Glögg, anyone?

The family of proteins called sirtuins (named after the founding member, the yeast gene Silent Information Repressor-2) are intimately connected with the history of modern biogerontology. Originally identified as key players in the determination of yeast replicative lifespan, these proteins were subsequently shown to play essential roles in life-extension pathways in worms. More recent findings suggest that sirtuins are also important in regulation of mammalian aging — though the story there is more complex, with seven SIR2 homologs in the human and mouse genomes, each with its own tissue specificity and subcellular localizations.

Small-molecule sirtuin activators such as resveratrol have been shown to promote longevity in specific animal models (see our earlier articles, Resveratrol, lifespan and an unhealthy diet and Resveratrol: Breakfast of champions), raising the hope that such compounds could be developed as a means of therapeutically intervening in the natural aging process or as a prophylactic against age-related diseases (see Toward sirtuin activators in the clinic).

Where questions are asked about diseases of aging, the discussion will eventually turn toward the great scourge of age-related neurodegenerative disease. Given that sirtuins have already demonstrated potential to positively impact the aging process in a wide range of animals, it seems logical to ask whether they might also have therapeutic or prophylactic potential against neurodegeneration.

The answer may end up being murky, and rely on the specific details of the specific illness and sirtuin family member in question. Two recent papers have studied the effect of sirtuin expression (and pharmaceutical modulation of sirtuin activity) on neurodegenerative disease — and come up with two diametrically opposing answers.

The first study yielded result that one might expect, given the well-documented pro-longevity effects of sirtuins discussed above. Kim et al. showed that both overexpression of SIRT1 and administration of the activator resveratrol had a salutary effect in models of two kinds of neurodegeneration, Alzheimer’s disease (AD) and ALS:

SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer’s disease and amyotrophic lateral sclerosis

A progressive loss of neurons with age underlies a variety of debilitating neurological disorders, including Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS), yet few effective treatments are currently available. The SIR2 gene promotes longevity in a variety of organisms and may underlie the health benefits of caloric restriction, a diet that delays aging and neurodegeneration in mammals. Here, we report that a human homologue of SIR2, SIRT1, is upregulated in mouse models for AD, ALS and in primary neurons challenged with neurotoxic insults. In cell-based models for AD/tauopathies and ALS, SIRT1 and resveratrol, a SIRT1-activating molecule, both promote neuronal survival. In the inducible p25 transgenic mouse, a model of AD and tauopathies, resveratrol reduced neurodegeneration in the hippocampus, prevented learning impairment, and decreased the acetylation of the known SIRT1 substrates PGC-1alpha and p53. Furthermore, injection of SIRT1 lentivirus in the hippocampus of p25 transgenic mice conferred significant protection against neurodegeneration. Thus, SIRT1 constitutes a unique molecular link between aging and human neurodegenerative disorders and provides a promising avenue for therapeutic intervention.

In contrast, Outeiro et al. found that inhibition of another sirtuin, SIRT2, was neuroprotective in a model of Parkinson’s disease:

Sirtuin 2 Inhibitors Rescue alpha-Synuclein-Mediated Toxicity in Models of Parkinson’s Disease

The sirtuins are members of the histone deacetylase family of proteins that participate in a variety of cellular functions and play a role in aging. Here, we identified a potent inhibitor of sirtuin 2 (SIRT2), and found that inhibition of SIRT2 rescued alpha-synuclein toxicity and modified inclusion morphology in a cellular model of Parkinson’s disease. Genetic inhibition of SIRT2 via siRNA similarly rescued alpha-synuclein toxicity. Furthermore, the inhibitors protected against dopaminergic cell death both in vitro and in a Drosophila model of Parkinson’s disease. The results suggest a link between neurodegeneration and aging.

Why the dramatic difference in results? The answer could lie either in differences between the diseases studied or in the functions of the sirtuin family members that were targeted.

AD and Parkinson’s are both characterized by protein misfolding and amyloid aggregation of specific proteins (Aß and alpha-synuclein, respectively), but there are distinct differences at the cellular level: Aß plaques tend to be extensively deposited outside the cell, whereas alpha-synuclein inclusion bodies are almost entirely intracellular. Although both diseases result in neuronal cell death, they affect cells in different parts of the brain, and consequently have very different clinical presentations and symptomatology. My expertise in the specifics of neurodegenerative disease is rather limited, so I’ll close this thought by merely pointing out the formal possibility that despite some superficial similarities in cellular etiology, idiosyncrasies of AD or Parkinson’s might be sufficient to explain the seemingly contradictory findings.

It is also possible that SIRT1 (expressed/activated in the AD paper) and SIRT2 (inhibited in the Parkinson’s paper) have very different biochemical functions, and that this difference explains their opposing influences on neurodegeneration. We already know from the work of Matt Kaeberlein and colleagues that resveratrol potently stimulates SIRT1 but not SIRT2, suggesting that despite their homology and conserved deacetylase activities, these proteins differ substantially in molecular detail. We also know that the preferred substrates of the two proteins differ: SIRT1 acts primarily on histones, and thereby influences chromatin state and transcription; in contrast, SIRT2 targets tubulin and appears to play a role in the control of differentiation and mitosis.

It is therefore tempting to speculate that SIRT1 activity either triggers expression of neuroprotective genes or represses genes actively involved in cell death; stimulation of this protein, either by ectopic overexpression or the administration of an activator, would delay the progress of Alzheimer’s pathology. In contrast, SIRT2 lacks the gene-regulatory activity of SIRT1, and thus inhibiting it should have no preventive effect on cell death.

It remains a mystery how tubulin acetylation might influence the life-or-death outcome of protein aggregation in neurons. Certainly, tubulin is an essential component of the complex neuronal cytoskeleton and the transport machinery that delivers critical materials back and forth along the axons and dendrites. Hence, it’s not too much of a stretch to imagine that alterations in tubulin acetylation could dramatically impact a cell already under stress due to protein aggregation toxicity.

Taken together, these two studies underscore the importance of understanding the detailed molecular mechanism of drug action. While resveratrol appears to be selective for SIRT1 vs SIRT2, it is not necessary for all chemical modulators of sirtuin activity to observe the same preference. A hypothetical broad-spectrum sirtuin activator might end up doing more harm than good — regardless of its pharmacokinetics, bioavailability, or for that matter patentability/profitability — if it delayed Alzheimer’s (via SIRT1) only to speed the progress of Parkinson’s (via SIRT2). As we develop more compounds to target sirtuins, then, it will be critical not only to monitor efficacy in limited contexts, but also to carefully enumerate off-target effects on proteins within the same family.

Steve Austad’s review in Aging Cell summarizes the progress reported last year:

This Hot Topics review, the first in a projected annual series, discusses those articles, published in the last year, which seem likely to have a major impact on our understanding of the aging process in mammals and the links between aging and late-life illnesses. The year’s highlights include studies of oxidation damage in the very-long-lived naked mole-rat, and of caloric restriction in monkeys, humans, and growth hormone-unresponsive mice. Two studies of resveratrol, one showing its ability to extend lifespan in a short-lived fish, the other demonstrating beneficial effects in mice subjected to a diet high in fat, may well be harbingers of a parade of intervention studies in the coming decade.

Recently we’ve discussed the flurry of attention being paid to resveratrol, a natural product derived from grape skins. Several current papers have demonstrated that the compound extends lifespan, increases exercise tolerance, and decreases some types of inflammation — at least, when administered in very high doses to rodents.

Most of the excitement has focused on resveratrol’s role as an activator of the sirtuins, proteins that have been implicated in lifespan regulation across evolution, in organisms ranging from yeast to worms to mammals. Perhaps as a consequence, one of the molecule’s other properties has gotten short shrift: thanks to the central olefin bond joining the two hydroxyphenyl rings, resveratrol is a potent antioxidant:

resveratrol

The ability to efficiently scavenge reactive oxygen species such as peroxide makes resveratrol protective against oxidative stress, specifically in the vascular endothelia. From Ungvari et al.:

Epidemiological studies suggest that Mediterranean diets rich in resveratrol are associated with reduced risk of coronary artery disease. However, the mechanisms by which resveratrol exerts its vasculoprotective effects are not completely understood. Because oxidative stress and endothelial cell injury play a critical role in vascular aging and atherogenesis, we evaluated whether resveratrol inhibits oxidative stress-induced endothelial apoptosis. We found that oxidized LDL (ox-LDL) and TNF{alpha} elicited significant increases in caspase 3/7 activity in cultured endothelial cells, which were prevented by resveratrol pre-treatment (10-6 to 10-4 mol/). The protective effect of resveratrol was partially reversed by glutathione peroxidase inhibitor mercaptosuccinate suggesting a role for antioxidant systems in the anti-apoptotic action of resveratrol. Indeed, resveratrol treatment protected cultured aortic segments and/or endothelial cells against increases in intracellular H2O2 levels and H2O2-mediated apoptotic cell death induced by oxidative stressors (exogenous H2O2, paraquat, ultraviolet light). Resveratrol treatment up-regulated the expression of glutathione peroxidase and catalase in cultured arteries, whereas it had no significant effect on expression of SOD isoforms. Resveratrol also effectively scavenged H2O2 in vitro. Thus, resveratrol seems to increase vascular oxidative stress resistance by scavenging H2O2 and preventing oxidative stress-induced endothelial cell death. We propose that the anti-oxidant and anti-apoptotic effects of resveratrol, together with its previously described anti-inflammatory actions, are responsible, at least in part, for its cardioprotective effects.

While the authors didn’t investigate the role of sirtuins in this protective effect, so it’s possible that activation of sirtuins result in upregulation of cellular antioxidant defenses — but that adds an extra step to the story, one that the in vitro radical scavenging experiment demonstrates isn’t essential to explain the phenomenon. (Likewise, the anti-apoptotic activity discussed early in the abstract could be the result of sirtuin activation, but that is a less parsimonious explanation than that oxidized proteins trigger caspase activity and resveratrol decreases protein oxidation, thereby down-modulating apoptosis).

Thus the cardioprotective effects of resveratrol (or, if you prefer, the wine in a Mediterranean diet) could be mediated not by the regulatory-biological output of a ligand-receptor interaction but rather by an unassisted chemical reaction between small molecules.

Why the fuss?

Because (as I’ve argued before with respect to the catechins in green tea) in order for scientists to make the best choices about how to spend our time, it’s important to know how a beneficial molecule is exerting its effects. If it’s the receptor-mediated outcome that is most desirable, then we should be working on better ligands: molecules that bind more tightly to the proteins that actually generate the relevant output. On the other hand, if the growing family of salubrious natural products turn out to be valuable primarily for their antioxidant activity, then we should be focusing on generating highly effecting antioxidant compounds that can target every tissue and subcellular structure in the body.

Of course, the answer could be “both,” in which case either path could bear fruit, but before a huge amount of effort is invested in drug development, it would be nice to know for sure.

Smoking is bad for you.

Sometimes the sheer scope of its badness takes my breath away, no pun intended: The tars damage DNA directly, and are thus carcinogenic; each puff is loaded with carbon monoxide and trillions of oxidative radicals; and the lung reacts to the smoke by releasing pro-inflammatory cytokines that cause fibrotic changes in that tissue, changes that in the long run can be every bit as lethal as cancer. We know this, yet many of us who know better still smoke: evidence not of ignorance or failed willpower but of the pernicious addictiveness of nicotine.

Smoking is bad for you.

But a protein that is positively involved in lifespan determination may also protect the body by decreasing the harmful inflammatory response to tobacco. SIRT1, one of the sirtuins, downregulates the release of pro-inflammatory cytokines by lung cells exposed to cigarette smoke — specifically, inhibitors of SIRT1 aggravate the inflammation while the now-famous natural product activator resveratrol decreases it. From Yang et al. (emphasis mine):

The Silent information regulator2 (Sir2) family of proteins (sirtuins or SIRT) which belong to class III histone/protein deacetylases, have been implicated in calorie restriction, aging and inflammation. We hypothesized that cigarette smoke-mediated pro-inflammatory cytokine release is regulated by SIRT1 by its interaction with NF-{kappa}B in the monocyte-macrophage cell line (MonoMac6) and in inflammatory cells of rat lungs. Cigarette smoke extract (CSE) exposure to MonoMac6 cells caused dose- and time-dependent decrease in SIRT1 activity and levels, that was concomitant to increased NF-{kappa}B-dependent pro-inflammatory mediators release. Similar decrements in SIRT1 were also observed in inflammatory cells in the lungs of rats exposed to cigarette smoke as well as with increased levels of several NF-{kappa}B-dependent pro-inflammatory mediators in bronchoalveolar lavage fluid and in lungs. Sirtinol, an inhibitor of SIRT1, augmented whereas resveratrol, an activator of SIRT1, inhibited CSE-mediated pro-inflammatory cytokine release. CSE-mediated inhibition of SIRT1 was associated with increased NF-{kappa}B levels. Furthermore, we showed that SIRT1 interacts with RelA/p65 subunit of NF-{kappa}B, which was disrupted by cigarette smoke, leading to increased acetylation RelA/p65 in MonoMac6 cells. Thus, our data show that SIRT1 regulates cigarette smoke-mediated pro-inflammatory mediator release via NF-{kappa}B implicating a role of SIRT1 in sustained inflammation and aging of the lungs.

The logic of the gene regulation here is a bit twisted and surprising: The drug studies indicate the direction of SIRT1′s influence: increasing sirtuin activity decreases inflammation. But — counter-intuitively for a stress response, where one expects protective proteins to be expressed at higher levels in the presence of the stressor — SIRT1 activity is downregulated by cigarette smoke. So even though SIRT1 is protective, in that it decreases the body’s harmful inflammatory response to smoke, its efficacy is diminished by the very toxins it would protect us against.

It’s yet another way in which smoking is bad — it locally accelerates the aging process.

But the sirtinol/resveratrol results give hope to the idea of using sirtuin activators (which are likely to have anti-aging effects) to address specific, clearly defined clinical issues. Comparable to the idea of using sirtuin activators to combat metabolic syndrome, one could imagine administering resveratrol or its derivatives to nicotine addicts who are having a hard time kicking the habit. It wouldn’t make smoking safe, but it would help prevent the fibrotic changes that smoking causes in the lung, so that after patients attain their goal of full abstinence, they can look forward to a healthier life — with younger lungs than they might otherwise have.

Such an approach provides another path to regulatory approval of sirtuin activators, whose off-label uses (for those patients not lucky enough to be at risk for metabolic syndrome, type II diabetes or pulmonary fibrosis) might include treatment of the long-term time-dependent deterioration of tissue function that is the major risk factor for most life-threatening diseases — i.e., aging itself.

As I implied in an earlier discussion of resveratrol, the increasingly compelling data on this compound has encouraged me to do a little bit of research about taking it myself, as a dietary supplement (supplementary, that is, to what I already get as part of a wine-rich lifestyle).

I’m currently in the homework/due diligence phase, considering issues of price and purity as I look around for a source that I can (a) afford and (b) have some objective reason to trust.

As a pure compound, resveratrol is prohibitively expensive. As an unregulated “nutraceutical,” however, it’s still costly (~$450 per annum), but of uncertain potency. None of the commercial suppliers I can find are straightforward about how many mg of resveratrol their products contain. Even among the more reputable-seeming and less fly-by-night vendors, there tends to be a lot of misleading indirection on the labels — take, for instance, the label for Revatrol:

revatrol label

How much resveratrol is in one caplet? Not 400 mg, to be sure, but that’s not very helpful, and it seems like the vendor is taking pains to avoid making a statement that they can be held to (e.g., the knotweed extract might be 15% resveratrol, but it’s not clear what proportion of the proprietary mix is knotweed extract, so what looks deceptively like data is really just a meaningless number).

Several of the other plant-derived compounds quoted on the label are also potent anti-oxidants, but it’s becoming increasingly clear that a big part of resveratrol’s activity is via activation of sirtuins, and that the antioxidant properties are either significantly less important or a complete red herring — so I’m not terribly impressed by those.

Given that the current literature is focusing on resveratrol explicitly, I’d like to see a commercial supplier take the plunge and do some analytical chemistry on their own product, establishing once and for all how much resveratrol is contained in each dose — and then standing by it for all time, ideally with the assay results for each lot to be shipped along with every bottle.

Because I’m willing to make myself a guinea pig, but not a chump.

Has anyone else looked into these supplements? I looked at four or five different suppliers; while I liked Revatrol the most, I still wasn’t sold. If you have done any thinking or research about this, please leave a comment. Let us know how you evaluated different products and (if you got that far) how you made your choice. (If you’re affiliated with or are taking money from a supplier, please opt yourself out. I’ll just expose and mock you, and no one wants that.)

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