Yeast study holds clue to longevity

Researchers are now looking for clues to longevity by studying yeast.

These single-celled microbes have long served as model systems for the puzzle that is the aging process.

The study, led by researchers at the University of Pennsylvania, identifies a new molecular circuit that controls longevity in yeast and more complex organisms and suggests a therapeutic intervention that could mimic the lifespan-enhancing effect of caloric restriction, no dietary restrictions necessary. After all, senior author Shelley Berger, PhD, said "who wants to live on 500 calories a day?"

Berger, a Penn Integrates Knowledge Professor in the departments of Genetics and Cell and Developmental Biology at the Perelman School of Medicine and the department of Biology in the School of Arts and Sciences, and her team looked for chromatin-associated genes that could influence longevity by searching for genes that already were implicated in epigenetic regulation that might extend lifespan when deleted in the yeast, Saccharomyces cerevisiae.

One such gene improved lifespan by about 25 percent - this would correspond to an increased lifespan in humans from 75 years to about 95 years - a substantial benefit to longevity, notes Berger.

The research, conducted by postdoctoral fellow Weiwei Dang, PhD, aimed to unravel how this increase in longevity was achieved and if it was related to cellular stress.

The gene ISW2, it turns out, is involved in chromatin remodeling-it controls the spacing and distribution of the histone "spools" around which DNA wraps.

Normally, ISW2 dampens stress-response pathways, possibly because overactivation of these pathways is deleterious early in life, Berger speculates. Deletion or inactivation of the ISW2 gene activates those pathways, priming the cells to more effectively handle stress-associated genetic scars as cells age.

This effect is not limited to yeast. When Berger's team reduced the levels of a related gene in the nematode worm, Caenorhabditis elegans, they observed a 15 percent improvement in longevity, which is similar in magnitude to the lifespan extension observed in other worm longevity pathways.

Similarly, knocking down expression of a human homolog in cultured human cells boosted the expression of stress-response genes that, again, like yeast, occur in DNA-damage repair pathways.

These findings suggest a pathway analogous to the one identified in yeast performs a similar function in humans, keeping stress-response genes in check - and if inhibited, could boost these pathways.

The study is published in the journal Cell Metabolism.