Longevity quest moves slowly from lab to life

Tinkering with growth pathways in cells
Scientists also have experimented with altering the pathways that regulate growth and nutrition in cells. Two promising options appear to be the insulin/insulin-like growth factor 1 pathway, known as IGF1, and the mammalian target of rapamycin pathway, known as mTOR.

IGF1 governs a series of hormonal signals that trigger growth in childhood, and, to a lesser extent, throughout life. Mutations that decrease insulin/IGF1 signaling and impair growth have been shown to increase significantly the lifespan of worms, flies and mice. It was information about the levels of insulin/IGF1 in Sadie Kaplan and her daughters that contributed to Barzilai’s recent findings that such mutations may link shorter stature and increased longevity in humans as well.

The mTOR is a protein involved in the signaling responses of cells and its activity may account for the lifespan extension found in CR. “By tinkering with those pathways, it’s possible we can alter the cells’ aging processes,” Kennedy says.

Research on mTOR by Kennedy and Kaeberlein was recently boosted by the discovery of 25 shared genes that regulate aging in yeast and worms, organisms separated by 1.5 billion years of evolution. Equally remarkable, researchers found that 15 of those genes are present in humans.

“It’s exciting because there are human diseases we can model in worms,” Kennedy says. “If we intervene with aging, we can affect the disease.”

Altering mTOR activity has been found to slow aging in yeast, worms and flies, but Kennedy acknowledges that it’s still a long way from the lab to practical therapies in humans.

Telomeres, antioxidants and stem cells
The same might be said of other scientific research touted as potential routes to longevity. Take telomeres, the chemical caps of DNA that keep our strands of chromosomes from fraying. Like a string of beads losing a pearl at a time, telomeres shorten with aging. When the telomere caps become too short, cells die. Researchers have experimented with an enzyme called telomerase that aims to preserve or lengthen the strand, but the results remain preliminary, Hadley and other scientists say. 

It’s a similar story with antioxidants, natural substances regarded as antidotes to the damage that occurs as tissue ages. Vitamins E and C, zinc, selenium, manganese and certain foods all have been thought to buffer or reverse harm caused by so-called “free radical” molecules that contribute to disrepair.

“Most results with antioxidants have been negative,” Hadley says.

Stem cell transplants, frequently mentioned as a possible aging therapy, are in that category, too, researchers say. Restrictions on and controversy over the use of embryonic stem cells are one problem. But much work remains before it's clear how stem cells might renew aging tissues and extend life, scientists say.

"We're far away on telomeres, and in stem cells, we're even farther away than that," Barzilai says.

Despite the hopes of an aging world, the prospect of extending longevity — or even adding a few extra years to lifespan — remains elusive, scientists say. People have to keep in mind that human longevity is increasing, but incrementally. In the U.S., average life expectancy has inched up during recent decades, from less than 60 years in 1930 and nearly 71 years in 1970 to nearly 78 years in 2005.

“Scientists and people in general want single answers, but biology is complicated and aging is complicated,” Kaeberlein says. “I don’t think there’s anything that’s going to revolutionize medicine in the next five years, unless resveratrol turns out to be a miracle.”

Until then, the scientists remind us, the best hopes for promoting a long life aren’t found in the lab at all. Not everyone can be like Sadie Kaplan, who was always active but never a health nut, and who has avoided most medical care because she's a little wary of doctors, her daughter says.

"Her hearing is impaired, but she refuses to get a hearing aid," says Fran Marton. "She's only had one mammogram in her life."

Clearly, something in Kaplan's make-up has allowed her to live so long, says Marton, who expects to celebrate her mother's 105th birthday on June 18. Part of it might be a certain spirit — "She has lived life as if she were not going to die," Marton says. But the Longevity Genes Project has shown there's almost certainly a genetic basis as well.  

Until scientists tease out the mysteries of longevity genes, or until they mimic the effects with drugs, most people need to rely on practical — albeit boring — interventions like regular exercise, avoiding obesity and limiting dangerous habits, experts insist.

Marton says she tries to eat right and stay fit because she doesn't know whether she takes after her mother or her father, who died at the more typical age of 80. She's not even sure she'd want to live to be older than 100, given the losses of family and friends and no guarantee of good health.

"It's mixed, certainly," Marton says. "But it's nice to feel you have an option."

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