Fight Aging!

For those who haven't yet got the message, the article linked here points out just how little came of resveratrol as a drug candidate and sirtuin research as a whole from the past decade. Resveratrol and the study of sirtuins were hyped up at the time, as I'm sure many of you recall, and yet nothing came of it beyond a little more knowledge of cellular metabolism. Sirtuins do not have any meaningful influence on aging from the perspective of producing therapies and neither does resveratrol. The hype resulted from a confluence of the tendency for venture investment to talk up a position (in the company Sirtris, acquired for more than $700 million in the end, money written off by the acquirer since nothing of practical use ever came from it), and the "anti-aging" marketplace finding yet another set of potions its members could market to the gullible. A lot of resveratrol was sold, and many people who really should have known better bought some.

Whenever a new drug candidate emerges with claims that it allegedly slightly slows the aging process, the first thing you should think of is resveratrol, and be wary of hype driven by the profit motive. Resveratrol was just the latest in a line of hyped products allegedly providing benefits to health in aging, and in fact doing nothing of any significance other than helping some people to find profits. Mining the natural world for compounds that can alter the operation of metabolism has shown itself incapable of reliably producing results that matter when it comes to aging: decades of work on this and nothing to show for it but the continued ability to sell useless products to people who hope for something that works.

There is only one useful road ahead here when it comes to aging and health. It is the construction of new biotechnologies that deliberately and usefully repair the cellular damage that causes aging. Don't alter metabolism, instead fix it by removing the dysfunction that causes it to run awry in a careful, targeted way. The future is clearance of damaged cells, gene therapies to repair mitochondrial DNA, manufactured enzymes that break down specific forms of persistent metabolic waste, and so on - a world away from screening random compounds from plants in the hope that they will do more good than harm.

Resveratrol is a compound that gained a lot of notoriety in the mid-2000's as sort of a multipurpose pro-health molecule. In its heyday, it spawned companies and a plethora of enthusiastic articles that recommended binging on resveratrol-containing foods as an all-purpose health enhancement. Interest has since waned on this compound, but it's worth revisiting the story to see how an exciting, trendy scientific discovery can lose steam when scientists better understand its limitations. A first hint of Resveratrol's pro-health effects came in 2003 out of the lab of David Sinclair, a young investigator at Harvard. Sinclair's lab found that resveratrol could extend lifespan in yeast. The extension was thought to be dependent on the protein Sir2, the founding member of a family of related proteins called sirtuins. The idea that small molecules could be used to extend healthspan was gaining excitement and attracting funding. A year later, Sirtris went public, eventually being bought up by pharma giant GlaxoSmithKline. The resveratrol supplement industry grew.

However, later reports led to questioning resveratrol's benefits. Work out of the lab of Linda Partridge, a well-respected Drosophila researcher, was unable to reproduce earlier findings of lifespan extension in Drosophila and produced only variable effects in C. elegans. There has also been a broader controversy over the role of resveratrol's reported target SIRT1. A major stain on the field came in 2012, when resveratrol researcher Dipak Das was fired from UConn for allegedly committing 145 instances of scientific fraud including "fabrication and falsification of data". Much of Das' work formed the basis for supposed cardioprotective benefits of resveratrol. As a result, resveratrol's efficacy for this application is now in serious doubt.

But even before the Das controversy, there were indications that people in the know had cooled on resveratrol related formulations as therapeutics, possibly due to inherent limitations with the compound. One of the co-founders of Sirtris left the company in 2011, and GlaxoSmithKline eventually shut down Sirtris and folded it into its broader business. This diminished industry interest in resveratrol may stem from two unfortunate issues: 1) research suggesting resveratrol does not act via SIRT1 makes it difficult to develop resveratrol into a drug; and 2) resveratrol is rapidly degraded by the liver after ingestion, making it naturally a poor drug. The first is an even bigger problem than it seems because FDA approval of new drugs requires knowing their mechanism of action. The second is a problem because it means it's difficult to increase the levels of resveratrol in the body by taking a pill, and medicines usually need to be administered by pill for average patients to be able to use them.

Link: http://sage.buckinstitute.org/resveratrol-placebo-or-youth-in-a-pill/