Gene regulation may be the key to longevity

The researchers found that long-lived organisms often showed higher expression of genes involved in DNA repair, RNA transport and cytoskeleton organization, and lower expression of genes involved in inflammation and energy consumption.

University of Rochester researchers interested in the genetics of longevity are proposing new targets for fighting aging and age-related diseases.

Natural selection has produced mammals that age at very different rates. For example, naked mole rats can live up to 41 years, which is 10 times longer than mice and other rodents.

What causes longevity? According to recent research by biologists at the University of Rochester, an important piece of the puzzle is found in the mechanisms that control gene expression.

Vera Gorbunova, the Doris Jones Cherry Professor of Biology and Medicine, the paper’s first author Andrei Seluanov, Jinglong Lu, a postdoctoral researcher in Gorbunova’s lab, and other researchers studied genes associated with longevity in a recently published paper. Cell metabolism.

Their findings show that two regulatory mechanisms that control gene expression, called the circadian and pluripotential networks, are critical to longevity. The findings have implications for understanding how longevity occurs, as well as providing new targets for combating aging and age-related diseases.

Graphic of Long-Lived vs Short-Lived Species

Biologists at the University of Rochester compared gene expression in 26 different species and found that the characteristics of different genes are controlled by circadian or pluripotency networks. Credit: University of Rochester Illustration / Julia Joshpe

Comparison of longevity genes

With maximum life spans ranging from two to 41 years (naked mole rats), the researchers analyzed the gene expression patterns of 26 species of mammals. They found thousands of genes that were either positively or negatively associated with longevity and associated with the species’ maximum lifespan.

They found that long-lived species tend to have lower expression of genes involved in energy metabolism and inflammation; and high expression of the genes involved[{” attribute=””>DNA repair,

Two pillars of longevity

When the researchers analyzed the mechanisms that regulate the expression of these genes, they found two major systems at play. The negative lifespan genes—those involved in energy metabolism and inflammation—are controlled by circadian networks. That is, their expression is limited to a particular time of day, which may help limit the overall expression of the genes in long-lived species.

This means we can exercise at least some control over the negative lifespan genes.

“To live longer, we have to maintain healthy sleep schedules and avoid exposure to light at night as it may increase the expression of the negative lifespan genes,” Gorbunova says.

On the other hand, positive lifespan genes—those involved in DNA repair, RNA transport, and microtubules—are controlled by what is called the pluripotency network. The pluripotency network is involved in reprogramming somatic cells—any cells that are not reproductive cells—into embryonic cells, which can more readily rejuvenate and regenerate, by repackaging DNA that becomes disorganized as we age.

“We discovered that evolution has activated the pluripotency network to achieve a longer lifespan,” Gorbunova says.

The pluripotency network and its relationship to positive lifespan genes is, therefore “an important finding for understanding how longevity evolves,” Seluanov says. “Furthermore, it can pave the way for new antiaging interventions that activate the key positive lifespan genes. We would expect that successful antiaging interventions would include increasing the expression of the positive lifespan genes and decreasing the expression of negative lifespan genes.”

Reference: “Comparative transcriptomics reveals circadian and pluripotency networks as two pillars of longevity regulation” by J. Yuyang Lu, Matthew Simon, Yang Zhao, Julia Ablaeva, Nancy Corson, Yongwook Choi, KayLene Y.H. Yamada, Nicholas J. Schork, Wendy R. Hood, Geoffrey E. Hill, Richard A. Miller, Andrei Seluanov and Vera Gorbunova, 16 May 2022, Cell Metabolism.
DOI: 10.1016/j.cmet.2022.04.011

The study was funded by the National Institute on Aging. 

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