Resveratrol


After a great deal of early promise, resveratrol has been on the ropes for a while, most prominently as a result of studies questioning whether it can directly activate sirtuins — this against a backdrop of growing skepticism that sirtuin activation can extend mammalian lifespan in any case.

Now, another (possible) black eye: GlaxoSmithKline (the company that purchased Sirtris, a pharmaceutical company co-founded by sirtuin/resveratrol pioneer David Sinclair) has suspended a trial of a resveratrol formulation, SRT501 in multiple myeloma patients, because several of the study’s subjects developed kidney failure.

GSK emphasizes that the trial has not been cancelled, but they are observing a moratorium on recruiting new patients until they determine whether the resveratrol was responsible for the subjects’ kidney problems. Nephropathy is a frequent complication in myeloma; one hypothesis being entertained is that the very high doses of resveratrol used in the trial caused vomiting, which in turn resulted in dehydration and tipped the balance in kidneys already close to failure due to the underlying cancer.

More elsewhere:

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An overwhelming number of natural products and nutraceuticals vie for our attention. Each is associated with a variety of claims of health benefits, often without any reference to the experimental evidence (if any) supporting those claims – or with reference only to dubious, poorly controlled studies in backwater journals. I don’t spend a lot of time following these compounds, but occasionally one gets mentioned often enough that is breaks through into the literature (e.g., resveratrol, green tea, carnitine/lipoate, or other supplements) and I discuss it here.

If only because of the size of the heap, I nonetheless still suspect that there’s a pony in there somewhere; I’ve often wished I had the time to do a comprehensive literature review of my own, so that I could identify the compounds whose associated claims are supported by the best evidence. Now it looks like I can start wishing for something else, because someone did it for me.

At the (amazing) blog Information is Beautiful, David McCandless and Andy Perkins have assembled a “generative data-visualisation of all the scientific evidence for popular health supplements“. In David’s words:

I’m a bit of a health nut. Keeping fit. Streamlining my diet. I plan to live to the age of 150 in fact. But I get frustrated by constant, conflicting reports and studies about health supplements.

Is Vitamin C worth taking or not? Does Echinacea kill colds? Am I missing out not drinking litres of Goji juice, wheatgrass extract and flaxseed oil every day?

In an effort to give myself a quick reference guide, I dove into the scientific evidence and created a visualization for my book. And then worked with the awesome Andy Perkins on a further interactive, generative “living image”.

The image itself is dynamic with respect to both user input about what information is desired, and introduction of new data – it is based on the information in a spreadsheet, which can be updated (new compounds, or information about compounds already mentioned), altering the visual rendering the dynamic image. You can play with the image here; I’ve attached a still snapshot below.

The rendering is imperfect (as also discussed elsewhere): More reliable claims are near the top, and more dubious claims are near the bottom, but this positioning is the result of a single variable, “evidence,” which may the based largely on a citation count. This is a problem because not all citations that mention a compound should be weighted equally; furthermore, it’s not clear how conflicting claims end up getting counted. The abstraction of a complex body of data into a single number unquestionably involves some judgment calls that could be made differently – that’s not necessarily a lethal criticism, but the process should be as transparent as possible.

On a visual level, the image is attractive, but color is mostly a wasted variable: position along the color spectrum is synonymous with height — except in the case of orange, which indicates a compound with “low evidence, promising results”. The orange compounds are still assigned an evidentiary weight, according to an algorithm I can’t fathom; this is particularly confusing at both ends: beta-glucan is in the “high evidence” position, which seems to contradict the label’s definition (“low evidence”); whereas noni and astragalus are in the “no evidence” position, raising questions about how there could be “promising results”.

The strength of the project, however, is that it can evolve; the creators are already enthusiastically updating it. So far the changes (as detailed in this log) are content-oriented; one hopes that the methodology of generative data visualization will also enjoy improvements as time goes by.

(For another example of user-driven visualization, see the Timeline of Discoveries in the Science of aging, which we discussed here previously (1 2). That piece hasn’t been updated in a while – perhaps it could use some new contributors.)

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A review I should have cited yesterday addresses the promise and challenges of the two most prominent natural-product candidates for longevity-enhancing therapeutics. The author is prominent biogerontologist and all-around bright feller Matt Kaeberlein (see here for earlier posts on his group’s work).

Resveratrol and rapamycin: are they anti-aging drugs?

Studies of the basic biology of aging have advanced to the point where anti-aging interventions, identified from experiments in model organisms, are beginning to be tested in people. Resveratrol and rapamycin, two compounds that target conserved longevity pathways and may mimic some aspects of dietary restriction, represent the first such interventions. Both compounds have been reported to slow aging in yeast and invertebrate species, and rapamycin has also recently been found to increase life span in rodents. In addition, both compounds also show impressive effects in rodent models of age-associated diseases. Clinical trials are underway to assess whether resveratrol is useful as an anti-cancer treatment, and rapamycin is already approved for use in human patients. Compounds such as these, identified from longevity studies in model organisms, hold great promise as therapies to target multiple age-related diseases by modulating the molecular causes of aging.

Note that resveratrol has been taking a bit of a thrashing of late, with recently released studies calling into question its ability to directly activate sirtuins. Briefly, the critics posit that the early data may have been misinterpreted due to artifacts in a fluorescence-based system used to detect protein-drug interactions — but check comment #32 on that post for David Sinclair’s personal response on this issue.

ResearchBlogging.orgKaeberlein, M. (2010). Resveratrol and rapamycin: are they anti-aging drugs? BioEssays, 32 (2), 96-99 DOI: 10.1002/bies.200900171

Here’s the latest in our (infrequent and irregular) series of “review roundups” — links, without extensive further comment, to the reviews I found most intriguing over the past few weeks. For the previous foray into the secondary literature, see here.

Remember, each Review Roundup is guaranteed to contain at least one link to a review you will find highly educational, or your money back.

Autophagy:

Chaperones:

Evolution:

Glycation:

Immunology:

Mitochondria:

Neurodegeneration:

Resveratrol:

Senescence:

Longevity is correlated with stress resistance. This makes abundant sense: Aging is (among other things) the decreasing ability to maintain cellular homeostasis over time. Cellular stress responses, broadly speaking, detect suboptimal conditions and activation of gene expression aimed at correcting the problem — a fairly reasonably definition of maintaining homeostasis. So it seems reasonable that more robust stress responses (or high basal expression of stress response target genes) would be associated with delayed aging and extended lifespan; indeed, this relationship has been used more than once to screen for long-lived mutants.

The heat shock proteins (HSPs), originally characterized (and therefore named) in the context of cellular responses to high-temperature stress, appear to play a critical role in regulation of lifespan, as illustrated by two examples from C. elegans: Expression levels of hsp-16.2, which vary stochastically even within clonal populations, are correlated with lifespan. Consistent with this, heat shock factor (HSF), the transcription factor that governs the heat shock response, is required for the lifespan extension caused by daf-2 mutations. (Mechanistically, HSF may serve this function by activating target genes that drive disaggregation and degradation of malfolded proteins.)

The heat shock response has now been connected to another major player in lifespan regulation: SIRT1, the most well-studied member of the sirtuin family. In mammals, HSF is subject to acetylation, which diminishes its ability to bind DNA and activate transcription – but this modification can be removed by the longevity assurance factor SIRT1, which is a protein deacetylase. From Westerheide et al. (see also the Perspectives piece in the same issue of Science):

Stress-Inducible Regulation of Heat Shock Factor 1 by the Deacetylase SIRT1

Heat shock factor 1 (HSF1) is essential for protecting cells from protein-damaging stress associated with misfolded proteins and regulates the insulin-signaling pathway and aging. Here, we show that human HSF1 is inducibly acetylated at a critical residue that negatively regulates DNA binding activity. Activation of the deacetylase and longevity factor SIRT1 prolonged HSF1 binding to the heat shock promoter Hsp70 by maintaining HSF1 in a deacetylated, DNA–binding competent state. Conversely, down-regulation of SIRT1 accelerated the attenuation of the heat shock response (HSR) and release of HSF1 from its cognate promoter elements. These results provide a mechanistic basis for the requirement of HSF1 in the regulation of life span and establish a role for SIRT1 in protein homeostasis and the HSR.

The relationship between a master regulator of aging (SIRT1) and an effector pathway (HSF and its target genes) is another example of an emerging trend in the biogerontological literature: the unification of separate longevity control mechanisms. (By “unification”, I don’t mean that these separate mechanisms are shown to be literally equivalent; I simply mean that our increasing knowledge of the connections between genes and their functions has revealed that many phenomena previously thought to act independently are in fact coordinated by regulatory factors).

These findings may also give mechanistic insight into a curious observation from a couple of years ago: resveratrol, an activator of SIRT1, induces the heat shock response. (When we discussed that study, I lamented that the authors hadn’t determined whether SIRT1 was required for the effect — in light of this paper, it does seem that they missed a pretty big boat.) It now seems reasonable to explain those data as follows: resveratrol activates SIRT1, which deacetylates HSF, which in turn binds DNA more efficiently and increases transcription of heat shock response genes. A strong prediction of this model is that HSF should be necessary for any lifespan extension resulting from resveratrol treatment.

Resveratrol is probably good for you on balance, but the high doses used in some studies, the ongoing debate about mechanism of action, and mixed results of studies to date (follow-ups to the study discussed in the linked post have suggested no positive effects on longevity) have made the compound’s efficacy as a lifespan extension drug somewhat controversial.

It’s almost as if the drug were doing something good and something bad simultaneously, and that either or both of these consequences depended sensitively on dose and other experimental variables (like strain background). Then nearly identical studies might give very different results, making it hard to determine whether the compound is having a positive or negative effect.

Like if the drug were decreasing oxidative damage in key tissues (as one might expect) but at the same time wrecking the kidneys — which would be an especially serious issue at higher doses.

Resveratrol, a compound found in red grape skins and other plant sources, can increase exercise tolerance — but only at rather high levels: veritable torrents of red wine would be required for a human to achieve comparable doses. In the Shouts and Murmurs column of the most recent New Yorker, Noah Baumbach explores a humorous corollary of this idea (emphasis mine)

Red wine may be much more potent than was thought in extending human lifespan, researchers say in a new report that is likely to give impetus to the rapidly growing search for longevity drugs. The study is based on dosing mice with resveratrol, an ingredient of some red wines. . . . [In a related study] scientists used a dose on mice equivalent to just 35 bottles a day.

—The Times.

The complete account of a scientist’s descent into (happy) madness can be found here.

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