Tuesday, March 29, 2011

Diets, Drugs, and How to Live Forever Without Resorting to Vampirism

For a long time the only reliable way to extend lifespan was to eat less. Much less. In experiment after experiment, caloric restriction (CR) increased longevity in everything from yeast to primates. I would call this a fine tradeoff were it not for my deeply held conviction that a life without candy corn is not worth living. Not that I’m advocating industrialized civilization’s current level of run-amok gluttony, but really, a person needs a few empty calories to cope with the tedium of an average workday. Fascinating though the idea sounded, for me, and for most others of my species, caloric restriction was off the table. Then somewhere around 2006 I began reading about a molecule called resveratrol that was found in red wine and had demonstrated health benefits in laboratory animals similar to those provided by CR. But five years have passed and I’m still impatiently awaiting my life-extending miracle drug. What’s taking so long?

Less is More
The study of caloric restriction dates back to the Great Depression, when animal experiments were designed to examine whether prolonged food scarcity might damage longevity in mammals (humans, of course, being the real interest). But lab rats subjected to Depression-esque chronic hunger surprised scientists by living longer than control groups. Further experiments would show the same trend in other animals. Not only did CR extend lifespan, but it also extended health by delaying many diseases associated with aging.

Initially, such benefits were believed to result from a reduction in metabolic strain that causes cellular damage over time (free radical and all that business). But more recent experiments suggest that CR affects regulating pathways that govern gene expression. When the body’s sensors perceive food as being plentiful, resources are allotted to growth and reproduction.* When food is scarce, such expansions are put on hold in favor of damage control. The organism now focuses on cell protection and preservation (life-extended processes) while awaiting the next period of abundance. It’s no great stretch to wonder if one couldn’t somehow trick the body into believing feast was famine, and thus reap the rewards of CR without all the dreary dieting. Enter resveratrol.

Wining and Dining
In 2003 David Sinclair and Konrad Howitz published a paper in Nature asserting that lifespan (in yeast) could be extended by 70% through the activation of a class of proteins called sirtuins by the molecule resveratrol. Resveratrol, a naturally occurring polyphenol, is found in red grape skins and therefore eventually makes its way into red wine. It was an excellent candidate for life/health extension, since Americans had been scratching their heads for decades over how the French could eat meat and dairy-rich foods and still be reasonably slim and healthy (um, smaller portions perhaps?) The answer was clearly red wine. Never mind that the dosage of resveratrol fed to various model organisms was far higher than a human could obtain from wine, even if they had the most formidable of drinking problems.

Sinclair started the biotech company Sirtris to further research sirtuins and resveratrol, and went on to show that resveratrol improved health and reduced mortality in mice fed a high fat, high calorie diet. Videos of the fat-but-fit resveratrol-enhanced rodents outpacing ordinary obese mice on treadmills assured lazy humans everywhere that society was on the verge of having its cake and eating it too. Despite two separate papers that found flaws in the original research demonstrating resveratrol’s sirtuin-activating abilities, in 2008 Sinclair and his partners sold Sirtris to the pharmaceutical behemoth GlaxoSmithKline (GSK) for a whopping US$720 Million.

And the Rest is History
Commercially, resveratrol is a pretty worthless molecule. As a natural substance it can’t even be patented. Additionally, it was often uncooperative in the lab, with difficulty maintaining consistent levels in blood sited as one significant issue. As a result, Sirtris’ research has focused more on creating and testing new drugs that mimic resveratrol’s (somewhat disputed) activation of sirtuins. Additionally, the goal shifted away from increasing lifespan overall and instead toward treating the diseases of aging, such as type 2 diabetes and certain cancers. Partly this is because Sirtris is an FDA approval company, and the FDA does not consider aging to be a disease per se. But it’s worth noting that, while resveratrol did well for mice subjected to the unhealthy diet, it demonstrated no increase in longevity for normal mice, casting doubt on whether it actually functions by the same mechanism as CR.§

SRT501 was among the first of Sirtris’ drugs to be unleashed in human clinical trials, and in early 2008 it was holding its own in a phase 1 trial for use as a diabetes medication. It continued to climb the ranks of trial phases and to branch out into other disease trials. But in Spring of 2010 a trial testing SRT501 on multiple myeloma patients was called off early after several people developed kidney failure.** Sirtris halted the last of its remaining resveratrol mimic trials later that year. Results from the debacle won’t be released until next year, and nobody seems anxious to divulge much until then. I’m curious to get a look at their findings, but for the moment things aren’t looking good for resveratrol and friends.

In the meantime, you might want to give caloric restriction another thought. While scientists struggle to figure out how caloric restriction works and how to replicate its effects using drugs, in CR we already have a well-demonstrated method of extending lifespan in a wide range of organisms. The technology is ready, and yet not many people want in on the opportunity of a lifetime. It’s hardly shocking. CR requires a 25-30% reduction in daily caloric intake. And since you’d be living off substantially fewer calories and still trying to meet crucial nutritional requirements, every calorie counts. The idea is to craft meals from calorie-sparse, nutrient dense foods, like vegetables. Say goodbye to cookies, ice cream, ice cream made out of cookies, etc. And don’t even think about sugary beverages. Ironically, you probably won't be able to spare enough calories to consume red wine. But on the bright side you’ll have a chance at living long enough to witness the discovery of age-thwarting remedies that will finally allow you to eat a well-deserved cupcake in the year 2100 or so. I think I’ll just go ahead and have mine now.

* Does this mean that CR affects fertility? Yes, it’s certainly a possibility. Think of it as another tradeoff. Who wants kids anyway.

A fluorescent tag was used in the initial study to gauge the activity of a particular sirtuin – SIRT 1. When similar experiments were conducted using a different measuring tool (and no fluorescent tag), nothing happened. So either resveratrol bypassed its intended target (SIRT 1) and acted directly on the fluorescent tag, or (as the original authors prefer to conclude) the tag mimics some sort of natural cofactor – in other words, that it’s no big deal and we’ll sort out the details later.

Some of these are remodeled forms of resveratrol, whereas others are completely new compounds designed to activate sirtuins.

§ This isn’t the only flaw in the model, and addition concerns have been voiced over whether sirtuins are even that important in controlling aging.

** This problem may have been caused by the disease itself, rather than the drug. Stay tuned for trial results in 2011? 2012?

Who told you this?

Wade, N. “Doubt on Anti-Aging Molecule as Drug Trial Stops.” The New York Times, 10 January 2011.

Fontana, L., et al. 2010. “Extending Healthy Life Span – From Yeast to Humans.” Science 328: 321-326.

Kenyon, C. 2010. “The genetics of ageing.” Nature 464: 504-511.

Lebford, H. 2010. “Much ado about ageing.” Nature 464: 480-481.

Callaway, E. “GlaxoSmithKline strikes back over anti-ageing pills.” Nature, published online 16 August 2010.

Garber, K. 2008. “A mid-life crisis for aging theory.” Nature Biotechnology 26: 371-374.

No comments:

Post a Comment