By David N. Leff

Women in the United States are 4.7 times more likely than men to reach the triple-digit age of 100. U.S. Census figures for 1990, the latest count available, estimate the total American population of centenarians at 37,306. Of this number, 7,901 are males and 29,405 are females.

And there's no stopping at that 100-year ceiling. What's the limit?

Four years ago, on August 4, 1997, the world's oldest known human being, a French woman named Jeanne Calment, born February 21, 1875, died at the age of 122. A decade earlier, in 1986, a man in Japan, Shirechiyo Izumi by name, succumbed to pneumonia at the age of 120 years, 237 days.

"Our best estimate," demographer James Vaupel told BioWorld Today, "is that 100,000 centenarians the world over celebrated the dawn of the millennium on Jan. 1, 2000." Vaupel is founding director of the Max Planck Institute for Demographic Research in Rostock, Germany.

"This number is doubling approximately every decade," he pointed out. "It's the fastest growing segment of the global population by far. Researchers in aging," he observed, "are beginning to understand the genetics of longevity, in models from yeast cells to fruit flies to roundworms to mice. It's potentially very important for humans as well. Many of the genes found in these lower species," he noted, "have homologues in humans.

"So there's quite a lot of work being done now," Vaupel added, "looking at the genetic makeup of very old people - nonogenarians, octogenerians - compared with younger people. It would be very interesting if the genes from other species could be looked at in humans, to try to uncover genetic factors that may enhance human longevity."

Juvenile Hormone Arrests Aging Process

Today's issue of Science, dated April 6, 2001, carries an article titled: "A mutant Drosophila insulin receptor analog that extends life span and impairs neuroendocrine function." Its senior author is evolutionary geneticist Marc Tatar, at Brown University in Providence, R.I.

"This work reports two advances of general importance," Tatar told BioWorld Today. "The first shows that the insulin-like receptor [InR], for which we studied the gene, modulates aging in nematodes - roundworms - so it's got taxonomic generality, suggesting that we'd be able to find similar things in vertebrates and mammals.

"The second point," Tatar continued, "is that our paper was able to prove the hypothesis that secondary hormonal signaling is responsible for the aging effects of the insulin pathway. Studies two years back suggested that the insulin mutants in nematodes were affecting just a few cells in the brain, the central nervous system, and therefore there had to be some other hormone downstream of that, which was systemic. We were able to identify it as the juvenile hormone [JH], and show how it triggers reproduction and rapid aging in flies."

The co-authors bred fruit flies with mutant InR, aiming to suppress the release of juvenile hormone, thus arresting the aging process. This experiment yielded dwarf females with life spans lengthened from a normal 32 days to 60 days. When they then administered JH to those long-lived insects, these recovered normal life expectancy.

"We concluded," Tatar said, "that JH deficiency is sufficient to extend life span."

Can current discoveries of aging processes in lower forms of life be extrapolated to humans? "We cannot experiment with people," Tatar granted. "We'll have to do them in nonhuman primates. Actually," he allowed, "I have an interest in baboons, but I'm only beginning to develop a system for doing that research. I think we could nail down the genetics of aging in baboons within 10 years."

Back to back with the Brown University paper in the same issue of Science is a related article: "Extension of life span by loss of CHICO, a Drosophila insulin receptor substrate protein." Its corresponding author is geneticist David Gems, a senior research fellow at University College, London.

"The essence of our experiments," Gems told BioWorld Today, "was duplicating those previously done in nematodes - Caenorhabditis elegans - but this time using fruit flies - Drosophila melanogaster. Those roundworms age and die after two to three weeks. Defects in two of C. elegans' genes, daf-2 and age-1, can double, even triple, worm life span.

"We also tested a third insulin/insulin growth-factor gene, called chico," Gems continued. "Our results showed that both chico and Drosophila daf-2 regulate aging. Chico mutant flies lived up to 48 percent longer than normal.

"In humans," Gems recalled, "you have the insulin receptor and the insulin-like growth factor with very similar signaling machinery. Why do all these animal models have this similar gene that seems to extend their life span? The best hypothesis is they're part of the caloric restriction response.

"What our results suggest," Gems concluded, "is the possibility that these are the genes of caloric restrictions. That looks like a universal system in all animals. If so, it's a target for therapies, because that's what people want - to retard aging."

Cut Calories, Add Years

Molecular biologist Leonard Guarente, at the Massachusetts Institute of Technology, is a pioneer researcher of the aging process, particularly in the nematode. He recently discovered a gene called Sir2 (Silent Information Regulator) in the worms, in mice and in yeast cells. (See BioWorld Today, Feb. 17, 2000, p. 1.)

"Now, with the same gene working here with worms and flies," Guarente pointed out, "there's an expectation that a few fundamental processes will be conserved in aging - with the caveat that this has to be demonstrated experimentally in mammals."

He sees "the ultimate goal of the current wave of aging research would be not so much to create more centenarians, but to slow down the degenerative processes that are linked to advanced aging. I think they should understand," he observed, "that aging is regulated. There are going to be targets out there for therapeutic intervention.

"Rodents that are calorie-restricted live a long time," Guarente pointed out, "and they're very healthy. The same is true in humans," he concluded. "Centenarians tend to be healthy, relatively disease-free. The question is: Have they inherited the right gene, or one of these genes we're talking about? That remains to be seen." n

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