Gene Regulation May Be Key to Longer Life

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

Researchers from the University of Rochester interested in longevity genetics propose new targets to fight aging and age-related disorders.

Mammals that age at very different rates have been created through natural selection. The naked mole rat, for example, can live up to 41 years, which is 10 times longer than rats and other rodents of comparable size.

What causes longer life? An important component of the puzzle, according to a recent study by biologists at the University of Rochester, is found in the mechanisms that control gene expression.

Vera Gorbunova, 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 examined genes associated with longevity in a recent paper published in Cell Metabolism.

Their findings suggest that two regulatory mechanisms that regulate gene expression, known as circadian networks and pluripotency, are critical for longevity. This discovery is important for understanding how longevity came about as well as for providing new targets for fighting aging and age-related disorders.

In comparing gene expression patterns of 26 species with diverse life spans, University of Rochester biologists found that different gene characteristics are controlled by circadian or pluripotent networks. Credit: University of Rochester Illustration / Julia Joshpe

Comparing longevity genes

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

They found that long-lived species tended to have low expression of genes involved in energy metabolism and inflammation; and high expression of genes involved in

DNA

DNA, or deoxyribonucleic acid, is a molecule made up of two long strands of nucleotides wrapped around each other to form a double helix. It is the hereditary material in humans and almost all other organisms that carry the genetic instructions for development, function, growth, and reproduction. Almost every cell in a person’s body has the same DNA. Most DNA is located in the cell nucleus (called nuclear DNA), but small amounts of DNA can also be found in the mitochondria (called mitochondrial DNA or mtDNA).

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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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