Gene regulation could be the key to a longer life

The researchers found that long-lived organisms often exhibit high expression of genes involved in DNA repair, RNA transport, and cell skeleton organization and low expression of genes involved in inflammation and energy consumption.

University of Rochester researchers interested in the genetics of longevity propose new targets to combat aging and age-related disorders.

Mammals that age at very different rates have been created through natural selection. 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 causes a longer shelf life? A crucial component of the puzzle, according to a recent study by biologists at the University of Rochester, it is found in the mechanisms that control gene expression.

Vera Gorbunova, the Doris Johns Cherry Professor of Biology and Medicine, Andrei Seluanov, the publication’s first author, Jinlong Lu, a postdoctoral researcher in Gorbunova’s lab, and other researchers looked at genes linked to longevity in a recent paper published in Cellular metabolism.

Their findings indicated that two regulatory mechanisms that govern gene expression, known as circadian and pluripotential networks, are crucial for longevity. The discoveries are important for understanding how longevity arises, as well as providing new targets for combating aging and age-related disorders.

By comparing the gene expression patterns of 26 species with various lifespans, biologists at the University of Rochester found that the characteristics of the different genes were controlled by circadian or pluripotency networks. Credit: University of Rochester Illustration / Julia Joshpe

Comparing Longevity Genes

With a maximum life expectancy ranging from two years (shrews) to 41 years (naked mole rats), the researchers analyzed the gene expression patterns of 26 mammalian species. They discovered thousands of genes that correlated positively or negatively with longevity and were linked to 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; and high expression of genes involved in[{” 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.