A Collection of Sirtuin Research Results

Sirtuin research is probably the most overhyped area of present day research into the mechanistic interactions between metabolism, health, and aging - certainly more so than for the calorie restriction studies that it branched from. This is the somewhat inevitable result of more than a billion dollars of capital going into research and development, as funding at that level always generates a bright public relations aura, plus the shills of the "anti-aging" marketplace latching on to something they can use to push new products to the gullible. The bottom line for research into sirtuins is this: (a) it's relevant if you want to learn more about the detailed operation of metabolism, and (b) it's near completely irrelevant if your goal is to live longer in good health.

The press has reacted in their normal clueless way to a recent piece of news from the researchers that first popularized SIRT1; it is essentially a defense of earlier work against the proposition that there were significant artifacts in the data caused by some of the experimental protocol details. There's nothing in this new release to change the overall story, however - that despite a decade and a billion dollars, there's nothing much to see here other than increased understanding of a narrow slice of metabolism. Little in the way of meaningful extension of life in normal rodents, no therapies to even slightly slow aging in humans, considerable dispute over the basic science, etc, etc. Give that much money to SENS research and it'd be a very different story.

New Study Validates Longevity Pathway: Findings Identify Universal Mechanism for Activating Anti-Aging Pathway

The team tested approximately 2,000 mutants of the SIRT1 gene, eventually identifying one mutant that completely blocked resveratrol's effect. The particular mutation resulted in the substitution of a single amino acid residue, out of the 747 that make up SIRT1. The researchers also tested hundreds of other molecules from the Sirtris library, many of which are far more powerful than resveratrol, against this mutant SIRT1. All failed to activate it.

The authors propose a model for how resveratrol works: When the molecule binds, a hinge flips, and SIRT1 becomes hyperactive.

Although these experiments occurred in a test tube, once the researchers identified the precise location of the accelerator pedal on SIRT1 - and how to break it - they could test their ideas in a cell. They replaced the normal SIRT1 gene in muscle and skin cells with the accelerator-dead mutant. Now they could test precisely whether resveratrol and the drugs in development work by tweaking SIRT1 (in which case they would not work) or one of the thousands of other proteins in a cell (in which they would work). While resveratrol and the drugs tested revved up mitochondria in normal cells (an effect caused activating by SIRT1), the mutant cells were completely immune.

This is plain old metabolic science - interesting stuff if you're in that line of work, but not the road to greatly enhanced human longevity. Calorie restriction has a far greater effect on human metabolism, and it's generally accepted by the research community that it only grants a marginal improvement to human life span, even while producing tremendous benefits to health. If it did more we'd certainly know about it; there are plenty of human communities that undertake calorie restriction to various degrees.

The only way that large enhancements to human longevity will happen in our lifetimes is through biotechnologies designed and targeted to repair specific forms of cellular and molecular damage that cause aging. Conveniently, this is a path that is considerably better known and less costly than even marginal attempts to change a very narrow set of mechanisms in the operation of metabolism. Consider that for the money and time spent so far on sirtuins - with no signs of coming to any sort of meaningful result any time soon - most or all of the SENS program to build rejuvenation therapies could be implemented in laboratory mice.

From where I stand, metabolic manipulation of the sort exemplified by sirtuin research is a gargantuan false path for medicine and the biotechnologies of human health. Its chief output is to steer resources away from where they might produce meaningful results in a short enough time frame to matter to those of us reading this now. Even if fabulously successful beyond the wildest dreams of the researchers involved, sirtuin research would do no more than recapitulate some of the effects of calorie restriction - that wouldn't help the old, as slowing aging doesn't help those already harmed by aging, it wouldn't reverse or repair the effects of aging, it wouldn't even be as effective as actual calorie restriction. In no way would any of this add decades of healthy years to life; there is simply no path to that end goal via the likes of Sirtris and similar groups working on sirtuins or other calorie restriction mimetic mechanisms.

While we're on the subject, here are two more recent research publications on the topic of sirtuins; all quite interesting, all of little value when it comes to the only metric that really matters, which is the ability to revert the course of degenerative aging.

The sirtuins, oxidative stress and aging: an emerging link

Reactive oxygen species (ROS) are a family of compounds that can oxidatively damage cellular macromolecules and may influence lifespan. Sirtuins are a conserved family of nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylases that regulate lifespan in many model organisms including yeast and mice.

Recent work suggests that sirtuins can modulate ROS levels notably during a dietary regimen known as calorie restriction which enhances lifespan for several organisms. Although both sirtuins and ROS have been implicated in the aging process, their precise roles remain unknown. In this review, we summarize current thinking about the oxidative stress theory of aging, discuss some of the compelling data linking the sirtuins to ROS and aging, and propose a conceptual model placing the sirtuins into an ROS-driven mitochondria-mediated hormetic response.

While considerable more investigations are required, a causative role for oxidative stress in aging remains one of the most solid aging theories [and] sirtuins are intimately linked to the cellular response to oxidative stress. Moving forward, it will be important to develop experimental models in which the levels of oxidative stress and the activities of sirtuins can be precisely modulated to determine if sirtuins have a causative role in lifespan extension. Does mitochondrial sirtuin overexpression in mice extend lifespan? Do long-lived animals exhibit chronic low levels of oxidative stress? From a more practical standpoint, is it possible to rejuvenate tissue function by targeted overexpression of sirtuins to reduce oxidative stress? We look forward to future studies that will undoubtedly address many of these important questions.

Sirt1 activation by resveratrol is substrate sequence-selective

Sirtuins are protein deacetylases used as therapeutic targets. Pharmacological Sirt1 activation has been questioned since the in vitro activator resveratrol failed to stimulate deacetylation of several physiological substrates. We tested the influence of substrate sequence by analyzing resveratrol effects on Sirt1-dependent deacetylation of 6802 physiological acetylation sites using peptide microarrays.

Resveratrol stimulated deacetylation of a small set of sites and inhibited deacetylation of another set, whereas most substrates were hardly affected. Solution assays confirmed these substrate categories, and statistical analysis revealed their sequence features. Our results reveal substrate sequence dependence for Sirt1 modulation and suggest substrates contributing to resveratrol effects.

The substrate sequence-dependent effect would explain why resveratrol has Sir2-dependent effects in C. elegans overlapping with, but not identical to, the effects of Sir2 overexpression, and why resveratrol failed to stimulate Sirt1 against some substrates.

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