18 November 2005
Anti-Aging Finding Turned On Its Head
by Kate Melville

It's been well established with previous research that an extra copy of the SIR2 gene can promote longevity in yeast, worms and fruit flies. But a counterintuitive experiment that deleted the gene entirely has resulted in one of the longest recorded life-span extensions in any organism. The new study, by scientists at the University of Southern California, suggests that SIR2 promotes, rather than retards, aging. The findings may throw a spanner into the works of biotech companies and their anti-aging drug development programs.

Author of the study, Valter Longo, said deleting the gene altogether in yeast resulted in a dramatically extended life span - up to six times longer than normal - when combined with caloric restriction and/or a mutation in one or two genes, RAS2 and SCH9, that control the storage of nutrients and resistance to cell damage. Longo added that human cells with reduced SIR2 activity also appeared to confirm that SIR2 has a pro-aging effect, but these results were not included in the Cell paper.

Longo believes that SIR2 (and possibly its counterpart in mammals, SIRT1) may stop an organism from entering an extreme survival mode characterized by the absence of reproduction, improved DNA repair and increased protection against cell damage. Organisms usually enter this mode in response to starvation. According to Longo, the SIR2 deletion made the yeast extraordinarily resilient under stress. "We hit them with oxidants, we hit them with heat. They are highly resistant to everything. What they're doing is basically saying, 'I cannot afford to age. I still have to generate offspring, but I don't have enough food to do it now', he remarked."

While any kind of anti-aging treatment for humans is still a long way off, Longo is excited about the possible implications for another area of research. "Cells may be able to speed up their DNA repair efforts. All organisms have the ability to repair harmful mutations in their DNA, whether caused by age, radiation, diet or other environmental factors," said Longo. And while many researchers believe DNA repair systems are already running flat out, the organisms in Longo's experiment suggest otherwise.

Longo's group began studying SIR2 in 2000, just after a well-known set of experiments by Leonard Guarente at MIT showed that over-expression of the SIR2 gene could extend life span beyond its natural limit. But Longo went in the opposite direction. "We were convinced that SIR2 had the potential to be a more potent pro-aging than an anti-aging gene. And the reason was in part because of the similarity with this other gene, called HST1, which negatively regulated so-called protective genes. So we set out to test whether SIR2 could do the opposite of what everybody said it does," he explained. Longo doesn't question Guarente's finding of a moderate increase in life span when SIR2 is over-expressed, but he believes his work shows that much greater potential gains may lie in the opposite direction.

Source: University of Southern California