The field has reached its prime. Data on everything from the physiology of long-lived lab animals to the genes of centenarians are pouring in. Scientists now have a pretty good idea why we age and are testing a slew of hypotheses to explain how. By altering genes, diet or other factors, they can make a menagerie of lab organisms live longer. And serious researchers, not crackpots, are talking about ways to extend the human life span — or at least spare the elderly from many of the trials of old age.

Why get old?

At first glance, aging appears to defy natural selection. In a Darwinian world, offspring are what counts. Because aging curtails reproduction, you’d think that natural selection would stave off senescence. More than 40 years ago, three researchers — evolutionary biologists George Williams, PhD, and William Hamilton, PhD, and immunologist Peter Medawar — pieced together an explanation for why it doesn’t.

The key insight is that natural selection can weed out a gene that sickens young organisms because death at that age terminates reproduction. But a gene that makes trouble late in life can escape from natural selection’s oversight because it has little impact on how many offspring an organism produces. In other words, we grow old because natural selection’s power over our bodies wanes with age. This explanation has reached middle age, but it remains healthy, says evolutionary biologist Steve Austad, PhD, of the University of Texas Health Science Center in San Antonio.

The enemy within

Figuring out why we age has been easier than nailing down how. Over the decades, researchers have proposed numerous potential mechanisms, from accumulated DNA damage to hormone deficiencies to parasite infestations. The leading candidate blames life itself — or more specifically, living things’ ceaseless need for energy. As mitochondria use food molecules and oxygen to meet this need, they emit noxious waste products called reactive oxygen species, or free radicals. The name is apt — the molecules react with and erode proteins, DNA and lipids, causing an assortment of nasty effects. Reactive oxygen species can mutate a gene. They can make proteins overactive or sluggish, or spur them to adhere into abnormal clumps. If reactive oxygen species attack lipids in a cell’s membrane, it can spring a leak.

The first person to blame these marauding molecules for aging was Denham Harman, MD (Stanford ’54), PhD, now an emeritus professor at the University of Nebraska Medical School in Omaha. At age 92, he has given up lab work but continues to write and think about the hypothesis he dreamed up in November 1954. After his post-med school internship, Harman became a research associate at UC-Berkeley. The job demanded minimal clinical duties, so he had plenty of time to think big. He decided to tackle a gigantic question: What makes us grow old? “It sounds naïve today,” he admits. But after four months of puzzling, he recalls, one day the phrase “free radicals” popped into his mind. He knew these molecules well. Before med school, he’d worked for seven years in a Shell Oil company lab that studied the molecules’ chemistry. They were the only explanation that fit the data, he says.

The modern version of Harman’s idea, the oxidative stress hypothesis, ascribes aging to cells’ losing battle against reactive oxygen species, such as superoxide and hydrogen peroxide. Cells defuse some of the ruinous molecules with enzymes, but these countermeasures can only slow the destruction. The older we get, the more molecular injuries we amass, with mitochondria — the major source of free radicals — taking the brunt of the damage. As Harman explains, the side effects of metabolism are inescapable. “We live on oxygen, and oxygen generates free radicals.” In effect, we all have a bunch of filthy power plants inside our bodies. We need their energy, but eventually the pollution gets us.

The oxidative stress hypothesis has kept vitamin C and other antioxidants flying off the shelves. But lately it’s taken a few hits, particularly from research on genetically modified rodents with impaired or enhanced antioxidant defenses. In 2003, physiologist Arlan Richardson, PhD, of the University of Texas Health Science Center in San Antonio and colleagues performed one of the most telling studies, tracking mice that pumped out half the normal amount of an antioxidant enzyme. Although their DNA took a beating from free radicals, the animals had normal life spans. “I’m not willing to say that oxidative stress has nothing to do with aging,” says Richardson. However, it might cause aging only in certain species or environments, he says.

Beyond oxidative stress

Free radicals aren’t the only metabolic rogues lurking in our tissues. Sweet glucose is another. The sugar is sticky, and it sometimes gloms onto proteins or DNA and then undergoes a series of reactions to form a tough attachment called an advanced glycation end product, or AGE. AGEs accrue rapidly in diabetics, who often have high blood sugar, but they also build up as everyone ages. Cooked foods, such as meat and bread, also harbor AGEs. At least in mice, a diet rich in AGEs shortens life, as Helen Vlassara of the Mount Sinai School of Medicine and colleagues showed last year.

AGEs are like abnormal growths on a molecule, and they can cause it to malfunction. They can obstruct the active site of an enzyme, for instance, and prevent it from doing its job. Sticky AGEs can also fasten neighboring proteins together, and these crosslinks might account for the stiffening of arteries with age. Older folks often show signs of chronic, bodywide inflammation, and AGEs might trigger this problem as well, according to cell biologist Ann Marie Schmidt, MD, of Columbia University. As with free radicals, however, the evidence that AGEs cause us to grow old remains circumstantial. They might only be signs of aging, not culprits.

Cancer is one of the scourges of old age, but ironically, one of our defenses against rampant cell division might help make us old. That idea got started at the Wistar Institute in Philadelphia in the early 1960s when Leonard Hayflick, PhD, later a Stanford medical school professor and now an emeritus at the UC-San Francisco, and Paul Moorehead noted that cells growing in culture dishes could divide only a set number of times. Once they reach the limit, cells switch into a semi-quiescent state called replicative senescence.

Scientists later found that cells carry built-in division counters: telomeres. They are structures on the tips of chromosomes that shrink every time a cell splits. Worn-out telomeres can lead to cancer by allowing DNA to break or rearrange. Hence, the argument goes, cells enter replicative senescence after a certain number of divisions so they don’t become cancerous.

Potential troublemakers are forced to retire before they can act up — sounds great. However, the body depends on continued division by stem cells to replace damaged or worn-out cells in the blood, skin, digestive system and elsewhere. But if stem cells can’t perform their task because they’ve entered replicative senescence, our tissues could begin to break down. The hitch in this explanation is that, so far, researchers haven’t shown that replicative senescence stops stem cells from refurbishing tissues.

Stayin’ alive

By far the biggest revelation from recent research is how easy aging is to manipulate — at least in lab organisms. Cut a mouse’s food intake to just above starvation level — a regimen known as calorie restriction or dietary restriction — and it could live more than 30 percent longer than normal [See “On the fast track,” page 38]. Mutations can double the life spans of nematode worms. Moderate doses of radiation or toxic chemicals also boost longevity.

Researchers are convinced that these disparate hardships activate the same fundamental response. At least some organisms adjust their life span according to the quality of their environment. When food is plentiful and the environment congenial, they age normally. But when times get tough, they flip on defenses (against stresses such as heat and free radicals) that extend their lives. “Longevity is clearly a result of an enhanced ability to cope with stress,” says molecular geneticist Gordon Lithgow, PhD, of the Buck Institute for Age Research in Novato, Calif.

One way that organisms key on stress is through a biochemical pathway that centers on insulin and related hormones. A key participant in the pathway, which researchers have studied intensively in roundworms, is the protein FOXO, the specialty of molecular geneticist Anne Brunet, PhD, of Stanford. FOXO is a DNA manager that switches genes on and off. Its nemesis is insulin. When insulin is abundant, an indication of ample food, FOXO gets evicted from the cell nucleus. When food is scarce, FOXO re-enters the nucleus and flips on genes that boost resistance to free radicals, speed up DNA repair and generally toughen the organism. Last fall, Brunet, assistant professor of genetics, and colleagues reported that FOXO also takes its cues from a cellular “fuel gauge” that reflects nutritional status. Moreover, they found that the protein allows worms to reap the life-extending benefits of one calorie-restriction regimen. FOXO appears to integrate various indicators of the organism’s status to help set life span, she says. “It’s important for triggering programs of genes that have long-term consequences for longevity.”

A second stress-sensing system involves a family of proteins called the sirtuins. Molecular biologist Leonard Guarente, PhD, of the Massachusetts Institute of Technology and colleagues rescued sirtuins from obscurity in the late 1990s, showing that they extend the lives of lab denizens and enable creatures to respond to the stress of calorie restriction. The proteins uncorked even more excitement when molecular geneticist David Sinclair, PhD, of Harvard Medical School and colleagues found that a component of red wine called resveratrol not only switches on sirtuins, it increases longevity. Sinclair’s team recently demonstrated that resveratrol prolongs survival in mice that, like many Americans, eat a high-fat diet.

Can researchers replicate their lab successes on us, perhaps tricking our cells into deciding they are under stress so we can live longer? Such an approach could bring huge medical benefits, says Lithgow. Instead of individually treating the diseases that tarnish our golden years — from osteoarthritis and macular degeneration to atherosclerosis — we could prevent them all simultaneously by attacking their underlying cause. However, researchers hasten to add that we don’t yet know how to alter human aging. All of the so-called anti-aging products now on the market are snake oil, says Austad. “Growth hormone and so-called secretagogues, DHEA, melatonin and supplementation with antioxidant vitamins are a few of the products I would put into this category,” he says.

But if researchers do devise ways to intervene in human aging, the biggest benefits won’t come from adding time to the tail end of our lives, says Brunet. Rather, we’d gain most if we could stretch our “health span,” or how long we live before disability strikes. “The end of life would still be the end of life,” she says, “but people could live it in better condition.”