Reduced ISW2 Expression Extends Life in Yeast and Nematodes

Researchers uncover a novel alteration of cellular metabolism that extends life in yeast and worms, and has similar effects in human cells as it does in nematode cells:

Epigenetics comprises multiple regulatory layers, including chromatin packaging - the orderly wrapping of DNA around histone proteins in the cell nucleus. By altering this DNA packaging, cells can control when and how genes are expressed. "Aging is, in part, the accumulation of cellular stress. If you can better respond to these stresses, this ameliorates the damage it can cause."

[Researchers] 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. [The] team asked whether the gene ISW2 is part of previously identified longevity pathways, especially those associated with caloric restriction, a well-known strategy for extending lifespan. But pathways involving a form of chromatin modification (histone acetylation) came up empty, as did an alternate pathway involving growth control, suggesting ISW2 functions through a never-before-seen mechanism.

The team then looked for answers in the function of the ISW2 protein, and found that its absence alters the expression of genes involved in protecting cells from such stresses as DNA damage. Deletion of ISW2 increases the expression and activity of genes in DNA-damage repair pathways - an effect also seen during calorie restriction. 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. 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 [the 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.

Link: http://www.eurekalert.org/pub_releases/2014-05/uops-pys050614.php


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