Moderate dose of new form of stress promotes longevity

A recently described form of stress called chromatin architectural defect, or chromatin stress, triggers a response in cells that leads to a longer life span. Researchers from Baylor College of Medicine and the Houston Methodist Research Institute report in the newspaper Progress of science that moderate levels of chromatin stress trigger a stress response in yeast, the tiny laboratory worm C. elegans, embryonic stem cells of fruit and mouse flies, as well as in yeast and C. elegans the answer promotes longevity. The results suggest that the response to chromatin stress and the longevity that it mediates could be conserved in other organisms, opening the possibility of new ways to intervene in human aging and promote the longevity.

"Chromatin-induced stress refers to disturbances in the way DNA is packaged into the nucleus of the cell," said Dr. Weiwei Dang, corresponding author, assistant professor of human and molecular genetics at Huffington Center on Aging and a member of Dan L Duncan Comprehensive Cancer. Center in Baylor. "One of the factors that influences the structure of chromatin are proteins called histones."

In the nucleus of cells, DNA wraps around histone proteins forming a "string-on-chain" structure called chromatin. Other proteins bind along the chromatin and the structure bends further into more complicated configurations. Everything about DNA should deal with this chromatin structure, explained Dang. For example, when a particular gene is expressed, some enzymes interact with the chromatin structure to negotiate access to the gene and translate it into proteins. When chromatin stress occurs, a disruption of the chromatin structure can result in unwanted changes in gene expression, such as gene expression when they are not supposed to occur. be or the lack of gene expression when this should occur.

In this study, Dang and his colleagues worked in the laboratory with the yeast Saccharomyces cerevisiae to study the effects of histone gene dosing on longevity.

They expected genetically modified yeast to contain fewer copies of certain histone genes than normal yeast or control yeast, which would lead to changes in chromatin that would make yeast less alive than witnesses.

"Unexpectedly, we found that yeasts containing fewer copies of histone genes lived longer than controls," said first author, Ruofan Yu, research assistant in molecular and human genetics at the Dang Lab .

Yeasts with a moderately low dose of histone genes showed a moderate reduction in histone gene expression and significant stress to chromatin. Their response to chromatin disruption was changes in the activation of a number of genes that ultimately promoted longevity.

In previous work, Dang and his colleagues had shown that in aging cells the chromatin structure gradually disintegrated. Histone alterations, such as lowering their protein levels, are characteristic of the aging process, but researchers have shown that, if they offset this decline related to aging histone levels by overexpressing certain genes in the histone In histones, they prolonged the lifespan of aging yeast cells. . In this study, they discovered that the moderate reduction in the number of histone gene copies in young yeast also promoted longevity.

"We have identified an unexpected and previously unrecognized form of stress that triggers a beneficial reaction for the body," said Yu. "The mechanism underlying the chromatin stress response generated by a moderate reduction in the dosage of histone is different from that triggered by the overexpression of histone that we had previously described, as shown by their different profile of protein expression responses. "

Dang, Yu, and their colleagues discovered that chromatin-induced stress also occurs in other organisms such as the laboratory worm. C. elegans, embryonic stem cells of fruit and mouse flies, as well as in yeast and C. elegans the chromatin response to stress promotes longevity.

"Our results suggest that the response to chromatin-induced stress may also be present in other organisms, and if present in humans it will provide new opportunities to intervene in the aging process," he says. said Dang.