Looking Back, Looking Forward

In 2003, gerontologists inched toward finding antiaging pills--and a comprehensive theory of aging itself. 2004 could bring them even closer, in the process igniting a race for drugs to keep us young.

You won't find a crystal ball among the standard equipment in any molecular biology lab. And scientists, as a breed, tend to be leery of predictions: "We are not soothsayers," says Rajindar Sohal, a molecular pharmacologist at the University of Southern California in Los Angeles. Still, in response to a December SAGE Crossroads survey that asked prominent gerontologists about the hottest studies of 2003 and their broader implications, a handful of scientists stuck out their necks and ventured some guesses about where they see research on aging headed in the future.

First, some scientists now seem more confident that someday we will be able to manipulate the process of aging in humans. "This is the first time in 30 years I have been in aging that I truly feel there is a chance that we might be able to develop an antiaging pill," wrote gerontologist Arlan Richardson of the University of Texas Health Science Center in San Antonio. Although such a drug is still at least a decade away, 2004 could see a race between rival biotech companies hoping to find it.

At the same time, some scientists say that research in 2003 provided a blueprint for a possible grand theory of aging--one powerful enough to tie together a multitude of different findings. "We don't have it yet," says David Sinclair, a pathologist at Harvard Medical School in Boston. "But it's getting very close."

Raging Hormones

The scientists' optimism stems in large part from studies that bolster the notion that a few fundamental molecules and pathways influence aging in a variety of animals. One such discovery that rocked the field in 2003 was published online by Nature in December 2002. In that study, molecular biologist Martin Holzenberger and his colleagues at INSERM, the French biomedical research agency, genetically engineered mice to respond poorly to insulin-like growth factor-1 (IGF-1), a hormone that normally regulates cell growth and division. These IGF-1 impaired mice lived 26% longer than their non-engineered cousins did (see "All Together Now.").

The finding is exciting because it dovetails with prior discoveries. Ten years ago, Cynthia Kenyon of the University of California, San Francisco, demonstrated that manipulating an evolutionary analog of the IGF-1 pathway in worms doubled their life span. Other scientists have lengthened the lives of fruit flies by similar means. Now mice, too, appear to have joined the party. "A continuing question in the genetics of aging is whether the studies on invertebrates extend into mammals," wrote behavioral geneticist Thomas Johnson of the University of Colorado, Boulder. "The paper showed that [they do]."

Other results published in 2003 bolster this conclusion. The pathway explored by Kenyon in worms split over evolutionary time into two different, but related, pathways in mice--one dedicated to IGF-1 signaling and the other involved in the cellular response to the hormone insulin. In a study that appeared in Science in early January, Ronald Kahn of Boston's Joslin Diabetes Center and colleagues genetically engineered mice that would respond poorly to insulin in liver, brain, and fat. The animals whose fat was insulin-deficient lived 18% longer than normal mice do.

Combined with the Holzenberger study, this work strongly implies that the same endocrine systems control aging in worms, fruit flies, and mice, wrote gerontologist David Gems of the University College London, U.K. If so, they could also regulate aging in humans. The mouse studies, says Johnson, thus suggest bona fide pharmaceutical targets for drug discovery efforts. The fact that drug companies have already done a great deal of research on the insulin pathway in search of diabetes drugs could provide researchers with a head start in developing novel antiaging compounds.

The next step will be for scientists to confirm the findings from the Holzenberger and Kahn studies and to further explore the roles of insulin and IGF-1 signaling in mammalian aging, says Richardson. Unfortunately, no such results in mice will likely appear in 2004, for a simple biological reason: "It would take 3 to 4 years before the mouse studies would be completed even if they were initiated this year." Nevertheless, Richardson says that extending these studies, and proving them robust and repeatable, would constitute "the big breakthrough" because "that would suggest to me that it would be very likely that [similar effects] would occur in humans. In 4 or 5 years, I think that we're going to know how important the insulin/IGF-1 pathway is."

What's more, additional studies should reveal whether certain tissues are better targets than others for antiaging therapies. "I think it could well turn out that the action in a particular cell type is really causally connected to aging," says Andrzej Bartke, a physiologist at Southern Illinois University in Springfield. Bartke noted that the results of Kahn's study should focus future attention on insulin action in fat cells, which "really narrows it down a lot."

Raise Your Glass

Another exciting avenue that opened up in 2003, according to some of the scientists canvassed, concerned recent findings in the humble brewer's yeast. In a study whose publication garnered Section A national coverage in The New York Times and The Washington Post, Sinclair and colleagues unveiled a group of chemicals--including one found in red wine--that can extend longevity in yeast. The results suggest a possible solution to what's often called the "French paradox": Although the French enjoy wine and eat plenty of fatty foods, this apparently unhealthy behavior doesn't seem to shorten their lives.

The superstar compound, resveratrol, mimics the longevity-boosting effect of calorie restriction (CR), a strict diet that extends life span in a variety of organisms, including yeast. In Sinclair's hands, resveratrol kept these simple unicellular organisms reproducing--a measure of longevity in yeast--80% longer than untreated cells. And it did so by spurring the activity of "sirtuins," a group of enzymes whose most famed member, encoded by the gene Sir2, was first linked to longevity by Leonard Guarente of the Massachusetts Institute of Technology in Cambridge in the mid-1990s. Guarente has shown that enhancing Sir2 activity--in yeast and in worms--provides these organisms with a longer lease on life. And CR, he found, lengthens yeast longevity by activating Sir2p, the sirtuin enzyme encoded by Sir2.

Resveratrol, Sinclair finds, also activates the human analog of Sir2p, known as SIRT1, when tested on cultured human cells in the laboratory. The central question now, wrote Sinclair, is, "Do sirtuin activators extend life span in higher organisms?"

Sinclair says he thinks the answer might be yes. What's more, he says that soon-to-be-published research will describe a previously unknown connection between the IGF-1/insulin and Sir2 pathways. At several meetings in 2003, researchers in the United States and the Netherlands reported that SIRT1 controls the activity of a set of specialized proteins in the insulin/IGF-1 signaling pathways that control gene activity. These proteins, in turn, appear to turn on genes that defend cells against so-called oxidative damage, which occurs when the chemically unstable byproducts of metabolism relentlessly assault our DNA and cellular machinery. This finding is particularly exciting because many scientists believe that oxidative damage fuels cell deterioration and thus aging.

Given the hint of such linkages, and looking ahead to 2004, Sinclair says we might be reaching a point of convergence between a body of research concerning genes that control longevity and an even more vast body of research on calorie restriction. "Things are pointing towards a day, maybe not too far in the future, where we would have final proof that these two fields have merged," he says.

The Drug War

At the same time, the future could also hold some heated competition among biotech companies hoping to capitalize on findings such as Sinclair's. Sinclair has founded a biotech firm called Sirtris to hunt for drugs that target SIRT1. But Sirtris is not alone. BioMarker Pharmaceuticals in Campbell, California, and the Baltimore, Maryland-based company GeroTech are also working to derive CR mimetics. And Ed Cannon, the CEO of Elixir Pharmaceuticals in Cambridge, Massachusetts--a company founded by MIT's Guarente--has said that Elixir has discovered compounds that mimic the effects of CR.

"The race is certainly on," says Sinclair, who trained with Guarente at MIT. "At this stage, we're just going as fast as we can, and they're going as fast as they can, and down the line we'll see who's got what, when we reveal our cards." Perhaps Elixir and Sirtris will even join forces and collaborate at some point in the future, he says. In any event, we can expect competition between these companies to heat up in 2004.

Sinclair predicts that more than one antiaging drug will make its way to the market within 10 or 20 years and that such products could do more than extend life span. They might also prevent the onset of diseases of aging. Animals altered to live longer--through genetic or dietary interventions--also resist a broad spectrum of age-related conditions: cancer, diabetes, and cognitive decline. If any of these companies succeed in creating such drugs, health agencies such as the U.S. Food and Drug Administration (FDA) would have to determine whether the products require any special regulation. But Sinclair argues that the FDA should eschew unique regulatory steps for antiaging medicines and evaluate them based on their safety and efficacy in battling individual aging-related diseases.

Looking Forward

Gazing further into the future, gerontologists outlined other possible developments that could have a dramatic impact on the field of aging. Although many lines of research might be converging, some gerontologists predict that the biggest breakthroughs in the future could come from findings that fall further from the beaten path. For example, although research in 2003 revealed evolutionary connections between mammals and invertebrates, Johnson suggests that the field could ultimately see the direct identification of longevity genes specific to mammals--genes that invertebrates don't share.

On a similar note, Bartke says a future research breakthrough in gerontology could come with the discovery of key physiological or genetic characteristics that promote long life in humans. Studies of centenarians have turned up evidence suggesting a genetic underpinning to extreme longevity. But Bartke says that current research has been limited to isolated human populations. Future studies could be more broadly applicable.

Meanwhile, if even half of these promises and predictions come true, policymakers will have to react. For example, the notion that slowing aging could help ameliorate its attendant diseases has implications for future funding allocation, wrote Gems. Medical research agencies such as the National Institutes of Health should more heavily fund basic research on aging, added Gems. Such an approach might furnish a more effective way to treat a broad variety of diseases at once. Thus, studying aging itself should be a better way for funding agencies "to invest their money for the maximum good."

In the future, researchers studying the biology of aging might also benefit from grants from organizations such as the Ellison Medical Foundation, which supports SAGE KE, SAGE Crossroads' sister site. Gerontologists have already seen a "huge increase" in such funding, says Johnson. "I think private investments are probably up 10- or 20-fold."

Some ethicists, however, dispute that aging is something we should be tampering with. This debate heated up in 2003 with the publication of a chapter on antiaging interventions by the President's Council on Bioethics, which took a largely disapproving view of such potential advances, and it is likely to escalate further in 2004. At the same time, scientists will continue to probe mechanisms of aging. If mice and yeast show us the way to longer human lives, society will have to decide whether that path--or pathway--is worth following.

Chris Mooney, a freelance writer living in New Orleans, Louisiana, is testing the crystal ball he got for Christmas.