Chromatin Stress Promotes Longevity in Yeast. Flies, and Nematodes

Researchers here report on the finding that modest impairment of the histones responsible for packaging nuclear DNA into chromatin leads to slowed aging in short-lived laboratory species. This adds to the sizable number of existing forms of stress that can somewhat slow aging via hormetic processes, such as heat, lack of nutrients, and so forth. A little damage induces greater cellular maintenance activities, which on balance leads to more efficient, less damaged cells and tissues over the long term. Unfortunately, effects on life span are very much smaller in long-lived species such as our own, when compared with effects in short-lived species such as flies, worms, and mice.

In the nucleus of cells, DNA wraps itself around histone proteins forming a 'beads-on-a-string' structure called chromatin. Other proteins bind along chromatin and the structure folds further into more complicated configurations. Everything involving DNA would have to deal with this chromatin structure. For example, when a particular gene is expressed, certain enzymes interact with the chromatin structure to negotiate access to the gene and translate it into proteins. When chromatin stress happens, disruption of the chromatin structure can lead to unwanted changes in gene expression, such as expression of genes when they are not supposed to or lack of gene expression when it should occur.

In this study, researchers worked in the lab with the yeast Saccharomyces cerevisiae to investigate how the dosage of histone genes would affect longevity. They expected that yeast genetically engineered to carry fewer copies of certain histone genes than normal or control yeast would have chromatin changes that would result in the yeast living less than controls. "Unexpectedly, we found that yeast with fewer copies of histone genes lived longer than the controls." Yeast with a moderately low dose of histone genes showed a moderate reduction of histone gene expression and significant chromatin stress. Their response to chromatin disruption was changes in the activation of a number of genes that eventually promoted longevity.

"We have identified a previously unrecognized and unexpected form of stress that triggers a response that benefits the organism. The mechanism underlying the chromatin stress response generated by moderate reduction of histone dosage is different from the one triggered by histone overexpression we had previously described, as shown by their different profiles of protein expression responses." The researchers found that chromatin stress also occurs in other organisms such as the laboratory worm C. elegans, the fruit fly, and mouse embryonic stem cells, and in yeast and C. elegans the chromatin stress response promotes longevity. "Our findings suggest that the chromatin stress response may also be present in other organisms. If present in humans, it would offer new possibilities to intervene in the aging process."



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