Slowing Aging By Restricting Cryptic Transcription

Researchers have demonstrated slower aging in yeast by increasing H3K36 methylation, which has the effect of restricting certain forms of transcription, the first step in the process of gene expression whereby proteins are generated from their genetic blueprints. It is worth noting that many ways to slow aging in laboratory species, including calorie restriction, have broad effects on observed patterns of transcription, and there is a still a long way to go towards a complete understanding of everything that is taking place in these portions of cellular biochemistry.

Gene expression is regulated by chemical modifications on chromatin - histone proteins tightly associated with DNA. Certain chemical groups on histones allow DNA to open up, and others to tighten it. These groups alter how compact DNA is in certain regions of the genome, which in turn, affect which genes are available to be made into RNA (a process called transcription) and eventually proteins. Researchers have pinpointed specific histone modifications that not only are altered during aging, but also directly determine longevity. "In this study, we found that a type of abnormal transcription dramatically increases in aged cells and that its reduction can prolong lifespan. This longevity effect is mediated through an evolutionarily conserved chemical modification on histones. This is the first demonstration that such a mechanism exists to regulate aging."

In yeast, aging is measured by the number of times a mother cell divides to form daughters before it stops. This number - a mean of 25 divisions - is under tight control and can be either reduced or increased by altering histone modifications, as the researchers found. They showed that when fewer chemical groups of a certain type attach to yeast histones, the abnormal transcription greatly increases in old cells. In contrast, the team found that in yeast strains with a certain enzyme deletion, this abnormal transcription is reduced and lifespan is extended by about 30 percent.

The results reveal that lack of sustained histone H3K36 methylation is commensurate with increased cryptic transcription in a subset of genes in old cells and with shorter life span. In contrast, deletion of the K36me2/3 demethylase Rph1 increases H3K36me3 within these genes, suppresses cryptic transcript initiation, and extends life span. "We show that this aging phenomenon is conserved, as cryptic transcription also increases in old worms. We propose that epigenetic misregulation in aging cells leads to loss of transcriptional precision that is detrimental to life span, and, importantly, this acceleration in aging can be reversed by restoring transcriptional fidelity. We have started investigating whether such a longevity pathway can also be demonstrated in mammalian cells. However, these investigations are confounded by the complexity of the genome in more advanced organisms. One of our long-term goals is to design drugs that can help retain these beneficial histone modifications and extend healthy lifespan in humans."

Link: http://www.uphs.upenn.edu/news/News_Releases/2015/07/berger/

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