September 26, 2011

Is the Fountain of Youth Spouting Contaminated Water?

A few days ago, the prestigious biomedical journal Nature reported that the water in the Fountain of Youth was contaminated. While the article’s title didn’t exactly have the ring of a call to battle, “Absence of effects of Sir2 overexpression on lifespan in C elegans and drosophila,” (AKA roundworms and fruit flies) it raised the hackles of pro-longevity scientists. What’s the fuss about and what are the prospects for improving the health of older people through gene manipulation?

Back in the early 1990s, Leonard Guarente of MIT began doing innovative research on genes coding for a protein called Sir2 in species such as roundworms and yeast. The analog of these proteins in mammals is a family of 7 proteins, SIRT1 through SIRT7, collectively known as “sirtuins.” One of Guarante’s early findings was that stimulating production of SIRT1 induced changes in mammals comparable to the life-prolonging effects of calorie restriction. But while decreasing food intake to starvation levels may lengthen life in rats and mice, it hasn’t yet been shown to have the same effects in primates and, more importantly, its prospects as a panacea against aging seem dim in an era when obesity is epidemic. The sirtuins turned out to have a variety of anti-inflammatory and anti-metabolic effects, reportedly protecting against cancer, diabetes, heart disease, and dementia. While it’s wise to be suspicious of any substance that claims to produce such a wide array of benefits, conjuring up the patent medicines of the nineteenth century, Guarante has soberly spelled out many of the discoveries about the sirtuins, writing in a recent review in the New England Journal of Medicine (June, 2011).

Seeking to translate his research findings into drugs that might prevent many of the diseases of old age, Guarente founded Elixir Pharmaceuticals in 1999, partnering with other researchers in the aging field, including centenarian specialist, Tom Perls of Boston Medical Center. Elixir has raised roughly $43 million in venture capital and has 9 drugs in various stages of testing, but as yet no FDA-approved product.

One of Guarante’s postdocs, David Sinclair, made a splash in 2003 when he discovered that resveratrol, a chemical in red wine, could mimic the life-prolonging effects of calorie restriction. Building on this work, he founded a second pro-longevity company in 2004 together with entrepreneur Christoph Westphal, a company that he called Sirtris. According to its website, Sirtris has 7 drugs in the pipeline, all in the earliest stages of testing. The company was purchased by GlaxoSmithKline in 2008 for $720 million. Since that time, Sinclair has become a full professor at Harvard; Westphal resigned as CEO after he was noted to have developed a nonprofit venture called the Health Lifespan Institute, which was selling a year’s worth of resveratrol to customers for $540. In late 2010, GSK halted a trial of resveratrol, a naturally available (read: unpatentable) substance and is focusing exclusively on the synthesis of small molecules that activate sirtuin proteins.

The new article in Nature challenges some of the early studies purporting to demonstrate that Sirtuins mediated the effects of calorie restriction in mammals. It does not undercut the now extensive body of work demonstrating the multiple roles of sirtuins. It does not diminish the appeal of the sirtuin approach, which targets the biochemical process underlying the development of degenerative diseases such as cancer, diabetes, heart disease, and dementia in the first place.

What remains to be seen is whether any of the elaborate studies in molecular biology will in fact produce drugs that prevent disease in people—without adversely affecting other important cellular processes. It’s worth a try. It’s also a good test case for whether collaboration between university-based, NIH and philanthropically funded science (Guarente at the Glenn Laboratory for the Science of Aging at MIT and Sinclair at the Paul Glenn Laboratory for the Molecular Biology of Aging at Harvard) Medical School, and profit-driven drug companies (Elixir Pharmaceuticals and Sirtris of GlaxoSmithKline, both in Cambridge, Massachusetts) will help aging Americans.