Not very long ago at all, slowing aging was considered a fool's errand. In fact, by many people, it still is. Sure, online ads may show you Photoshopped, or at the very least Photoshopped-looking, pictures of men with wrinkled faces on top of impossibly muscular bodies. But in real life, aging was thought to be inevitable – too complex, and too random, to be significantly stalled by anything as simple as a pill.

But in the past decade, research has shown that targeting single proteins such as IGF-1, SIRT1, and most recently, mTOR, can increase the lifespan of animals including worms, flies and mice.

In a recent white paper, the Alliance for Aging Research made the case that advances in aging science could lead to the development of drugs that add an average of seven healthy years to average lifespan – and that going directly after aging itself is by far the cheapest way to increase lifespan. According to a 2005 analysis by the RAND Corp., cited in the report, a drug that added 10 healthy years to life expectancy would cost an estimated $8,790 "1999 dollars" per year. A drug that could reduce Alzheimer's prevalence by one-third cost 10 times as much, slightly more than $80,000 per year added – and even that looked cheap compared to certain cardiac devices that came in above $1 million.

Drugs manipulating the genes implicated in aging are in clinical trials for various indications – indeed, the mTOR inhibitor rapamycin is an FDA-approved drug to prevent transplant rejection. So far, though, there is no way to develop an anti-aging drug. The FDA does not consider aging to be a disease. Neither does the Alliance for Aging Research, for that matter; it describes aging as "a gradual process of decline that, while not caused by disease, increases the odds of grave illness."

And that's not about to change, Alliance for Aging Research CEO Dan Perry told BioWorld Insight.

"The political reality is that it's not on the agenda today," he said.

One Piece at a Time

For now, Perry said, companies are approaching the issue piecemeal. "At this point, a company that may have a compound that is effectively acting as a rheostat, decelerating the rate of aging . . . [will] go to the FDA and seek approval for one indication that it can make the strongest case for."

Perhaps ironically, the leader of the company that is most strongly associated with anti-aging drugs is one of the continuing skeptics of the aging field. George Vlasuk is the CEO of Sirtris Inc., now part of GlaxoSmithKline plc, which develops sirtuin activators and has become linked, at least in the public mind, with resveratrol, a sirtuin activator that appears to have general anti-aging effects.

Personally, Vlasuk appears to have no use for the anti-aging moniker. "We get put into that category all the time," he told BioWorld Insight. "But I'm still not sure what that means . . . I don't believe that aging is anything other than the body and its tissues progressing towards disease." Sirtris is in clinical development with three sirtuin-targeting drugs, targeting, for the time being, inflammation, cardiovascular disease and metabolic disorders.

If there is any one indication that is associated with diseases of aging, at this point it is chronic inflammation. IGF-1, sirtuin, and mTOR signaling all affect inflammation, and it has been linked to just about every disease where anyone has cared to look. (See BioWorld Insight, Nov. 1, 2010.)

Some people use the term "inflammaging" to describe inflammation's reach – a concept that Robert Hughes, an associate professor at the Buck Institute for Aging Research, called "not a totally proven concept, but certainly an intriguing one that's worth investigating."

Once a drug is approved in one aging-related indication, such as inflammation, it can be tested for others, like cardiovascular disease or metabolic disorders – exactly the path Sirtris is treading. In other cases, epidemiological studies may turn up other indications that the drug appears to be protective against. This approach is still being applied to some of the oldest drugs around – aspirin has cardioprotective effects and is emerging as useful against at least some types of cancer, as well.

Endpoint Debate

For now, that piecemeal approach will have to suffice. Even if the FDA were to decide tomorrow that it would review drugs developed to combat aging, at this point there would be no realistic endpoints to look at for such trials. Overall survival is becoming problematic even in cancer trials as patients live longer – the necessary lifespan of lifespan trials makes them pretty much out of the question.

As a result, the first thing that would need to be done is to develop biomarkers. "In a perfect world," Perry said, "we would be developing biomarkers" by looking at large-scale databases to determine markers that can give a clue how far along the aging trajectory a person is, independently of their chronological age.

Many such biomarkers, such as wound healing speed, would also be markers of disease, of course. But they wouldn't have to be – Perry named walking speed as another possible marker.

It will take time to develop and validate aging-related biomarkers, and to figure out how to incorporate them into clinical trial design. But, Perry said, even if aging drugs today are approved for one indication at a time, "there is no question that we are going to see compounds that work because they are slowing the rate of aging."

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