Gene regulation may be key to longer lifespan


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Researchers have found that long-lived organisms often have high expression of genes involved in DNA repair, RNA transport, and skeletal organization, and low expression of genes involved in inflammation and energy consumption.

Researchers at the University of Rochester with an interest in the genetics of longevity propose new targets to combat aging and age-related disorders.

As a result of natural selection, mammals have been created that age at completely different rates. Naked mole rats, for example, can live up to 41 years, more than 10 times longer than mice and other rodents of comparable size.

What increases life expectancy? According to a recent study by biologists at the University of Rochester, a key piece of the puzzle lies in the mechanisms that control gene expression.

Vera Gorbunova, professor of biology and medicine, Doris Jones Cherry, Andrey Seluanov, first author of the publication, Jinlong Lu, researcher in Gorbunova’s laboratory, and other researchers studied genes associated with longevity in a recent article published in Cellular metabolism.

Their results showed that two regulatory mechanisms that govern gene expression, known as circadian networks and pluripotency networks, are critical to longevity. The findings have implications for understanding how longevity occurs, as well as providing new targets to combat aging and age-related disorders.

Graph of long-lived and short-lived species

Comparing the gene expression patterns of 26 species with different lifespans, biologists at the University of Rochester found that the characteristics of different genes are controlled by circadian or pluripotent networks. Credit: University of Rochester Illustration/Julia Joshp.

Comparison of longevity genes

With a maximum lifespan of two years (shrews) to 41 years (naked mole rats), the researchers analyzed gene expression patterns in 26 mammalian species. They found thousands of genes that were positively or negatively correlated with longevity and were associated with the maximum lifespan of a species.

They found that long-lived species tend to have low expression of genes involved in energy metabolism and inflammation; high expression of genes involved in[{” attribute=””>DNA repair, RNA transport, and organization of cellular skeleton (or microtubules). Previous research by Gorbunova and Seluanov has shown that features such as more efficient DNA repair and a weaker inflammatory response are characteristic of mammals with long lifespans.

The opposite was true for short-lived species, which tended to have high expression of genes involved in energy metabolism and inflammation and low expression of genes involved in DNA repair, RNA transport, and microtubule organization.

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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