Happy 120th? Science Pushes Human Longevity

How long can humans conceivably live? In most developed countries, life expectancy has grown steadily to an average of 75 years.

But scientists are exploring ways to extend lifespan to lengths that seem inconceivable now—perhaps 120 years and beyond.

Ideally, future centenarians who avail themselves to life-prolonging advances won't suffer the familiar frailties of old age. The goal is for them to retain their youthful vitality, rather than add extra years of decline.

Genetic Insights

Several studies show lifespans can be stretched far beyond normal limits. In one example, Cynthia Kenyon, a professor at the University of California in San Francisco, has doubled the lifespans of simple roundworms from two weeks to a month by altering the function of a single gene, known as daf-2.

Even near death, these mutated worms look better than normal worms half their age. Their bodies are smooth and plump, and they wriggle along like much younger worms.

"It's amazing that they look so healthy," Kenyon said.

The daf-2 gene has two counterparts in mammals, both conserved during evolution. One is the insulin receptor, or tiny cell structure, that controls levels of blood sugar. By inactivating this receptor in mouse fat cells, scientists can increase the rodents' lifespans by up to 18 percent.

Even longer lifespans are achieved by changing the daf-2 genes's other mammalian counterpart, known as insulin-like growth factor, or IGF-1. Reduce this gene's function and mice can live up to 33 percent longer than average.

Why? Preliminary evidence suggests the mice suffer less cell and organ damage from naturally corrosive oxidants, which play a role in aging. What's more, the animals are less susceptible to age-related diseases, including cancer.

"They're more youthful, and so naturally more resistant to these diseases," Kenyon said.

Diets and Aging

Insulin signaling ties into the best-known method for increasing lifespan—caloric restriction.

For more than 70 years, scientists have known that animal lifespans can be lengthened proportionately to their decreased caloric intake.

In other words, mice fed 40 percent fewer calories will live, on average, 40 percent longer than mice fed normal diets, and look better besides.

Ingested calories trigger the release of insulin, which stimulates the IGF-1 pathway that seems to promote aging.

Peter DiStefano, chief science officer with Elixir, a Cambridge, Massachusetts-based drug company, cautions that reduced IGF-1 and calorie restriction probably affect aging in different ways.

Nevertheless, both approaches—at least in rodents—increase lifespans, he says.

Might humans respond the same way? Scientists don't know.

UCLA evolutionary biologist John Phelan suggests calorie-reduced diets could increase human lifespans, but not substantially.

In Phelan's view, lean diets extend longevity in mice and other experimental animals chiefly by diminishing their sexual activity. Mice devote tremendous amounts of energy toward reproduction.

But when fed calorie-restricted diets they mate less—liberating energy that allows them to live longer, he says.

Humans, on the other hand, invest less in reproduction, and won't likely achieve the same longevity benefit.

"Our message is that suffering years of misery to remain super-skinny is not going to have a big payoff in terms of a longer life," Phelan said in a recent press statement.

Other researchers aren't so sure. They caution that more data in larger animals are needed.

Donald Ingram, acting chief of the Laboratory for Experimental Gerontology at the National Institute of Aging, investigates the effects of a 30 percent calorie-reduced diet in monkeys, which share many metabolic similarities with humans.

It's too soon to tell if the animals will live longer. (The study began in 1987, and the monkeys' typical lifespan is 40 years). But preliminary indicators show risk factors for age-related disease are reduced among these animals.

"But we just don't know enough yet about how much longer large animals might live on a calorie-restricted diet," Ingram said.

In the meantime, researchers are combing metabolic pathways for drug targets that might prolong human life.

Elixir's DiStefano says the insulin-signaling pathway is especially promising.

The holy grail is a drug that tricks cells into thinking they've been deprived of calories when they haven't. These cells might activate mysterious processes that prolong life, without the need for extreme dieting or its side effects, DiStefano says.

Evolutionary biologist Michael Rose, from the University of California, Irvine, was among the first scientists to postpone aging in animals.

He accomplished this in 1980 by forcing fruit flies to mate only at advanced ages. By selectively breeding the progeny, he produced flies that live twice as long as normal.

When asked about the most plausible methods for prolonging human life, Rose said, "First drugs and then organs cultured using stem cells from your own tissues."

"It's just like cars are better now than they were at the turn of the century," he added. "We'll be able to give you a new body, bit by bit, and pathway by pathway."

"I don't necessarily think anyone should feel they need to live longer, nor do I see life extension as a moral virtue or a societal goal. But I am saying that if it's something you want to do, then we can offer the technical possibilities."


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