Epigenetics has numerous connections to the process of aging, research hinting at the association between longevity and factors such as transcriptome length and DNA methylation patterns. Clearly, understanding the molecular controls of aging proves to be an intriguing endeavor as we try to interpret the clues of how we might slow down and perhaps even reverse aging. Although research has a long way to go before we can expect anything akin to a fountain of youth, studies are offering new insight into the epigenetic mechanisms of growing old.
Results from a recent study conducted by researchers at the University of Pennsylvania show that yeast could help advance our progress in extending life in human cells. The team of researchers included Shelley Berger, PhD, professor in Cell & Developmental Biology and Biology & Genetics departments at the Perelman School of Medicine, Weiwei Dang, PhD, assistant professor at Baylor College of Medicine and former postdoc fellow at Penn, and Payel Sen, PhD, a current postdoc fellow in Berger’s lab. The study was published in Genes & Development and focused on how a certain epigenetic histone modification could extend yeast’s lifespan.
Chemical tags on chromatin are known to alter its structure and regulate gene expression. Chromatin is a complex of protein and DNA, consisting of histones around which DNA is wound. Various epigenetic mechanisms can affect whether the chromatin is highly condensed and inaccessible to gene transcription, known as heterochromatin, or loosely organized and highly accessible, known as euchromatin. The altered chromatin structure as a result of various histone modifications ultimately impacts the production of proteins.
“Researchers have just started to appreciate how these epigenetic histone modifications may be playing essential roles in determining lifespan,” said Berger. She has conducted studies on epigenetic marks for more than 20 years and was one of the first to identify particular histone modifications that are altered during aging and directly impact longevity.
Dang explained that their study pinpointed a type of abnormal transcription that is significantly increased in older cells and, if reduced, can lengthen lifespan in yeast. He started the research when he was working in Berger’s lab.
He explained that “this longevity effect is mediated through an evolutionarily conserved chemical modification on histones [and] this is the first demonstration that such a mechanism exists to regulate aging.”
Although measuring aging in yeast is quite different from measuring human aging, Sen noted that using a budding yeast single-cell organism model turned out to be surprisingly powerful in their study of aging and epigenetic regulation.
Because age-associated phenotypes are difficult to quantify in yeast, longevity can be measured by budding lifespan, or the number of cell divisions of mother cells into daughter cells. The researchers discovered that the number of divisions – an average of 25 – is strictly controlled and can be decreased or increased as a result of changing histone modifications, specifically histone methylation.
The researchers discovered that the less histone H3K36 methylation there was, the more abnormal transcription they saw in a subset of genes and the shorter the yeast’s lifespan. Deletion of a particular enzyme called K36me2/3 demethylase Rph1, in contrast, was shown to increase H3K36me3 within these genes, reduce the abnormal transcription, and extend lifespan by approximately 30%.
Because of these results, the researchers propose that “epigenetic misregulation in aging cells leads to loss of transcriptional precision that is detrimental to lifespan, and, importantly, this acceleration in aging can be reversed by restoring transcriptional fidelity.” Although these results were found in yeast, the concept of epigenetic misregulation and effects on lifespan may apply to more complex mammalian cells, too.
“We have started investigating whether such a longevity pathway can also be demonstrated in mammalian cells,” Berger said. “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.”
Source: Sen, P., Dang, W., Donahue, G., Dai, J., Dorsey, J., Cao, X., Liu, W., Cao, K., Perry, R., Lee, J.Y., Wasko B.M., Carr, D.T., He, C., Robison, B., Wagner, J., Gregory, B.D., Kaeberlein, M., Kennedy, B.K., Boeke J.D., and Berger, S.L. (2015). H3K36 Methylation Promotes Longevity by Enhancing Transcriptional Fidelity. Genes & Dev. 29: 1362-1376.
Reference: Penn Medicine. Cell Aging Slowed by Putting Brakes on Noisy Transcription. 30 Jul 2015. Web.