Gene regulation may be the key to longer life

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

Mammals aging at vastly different rates were created by natural selection. For example, naked mole rats may live up to 41 years, which is 10 times the lifespan of rats and other rodents of similar size.

What causes longevity? A crucial element of the puzzle, according to a recent study by biologists at University of Rochester, It is found in the mechanisms that control gene expression.

Vera Gorbunova, Doris Jones Cherry Professor of Biology and Medicine, Andrei Siluanov, first author of the publication, Jane Long Lu, a postdoctoral research fellow in Gorbunova’s lab, and other researchers looked at genes related to longevity in a recent paper published in cell metabolism.

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

When comparing the gene expression patterns of 26 species with varied ages, the University of Rochester biologists found that the properties of different genes were controlled by circadian networks, or pluripotency networks. Credit: University of Rochester illustration / Julia Joshby

Comparing longevity genes

With maximum lifespans ranging from 2 years (shrews) to 41 years (naked mole rats), the researchers analyzed the gene expression patterns of 26 mammal species. They discovered thousands of genes that were positively or negatively associated with longevity and were linked to the species’ maximum lifespan.

They found that long-lived species tended to have lower expression of genes involved in energy metabolism and inflammation. and 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.