Sirtuin activators as anti-diabetes drugs, and beyond

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”?)