Gene editing may be the key to a longer lifespan

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The researchers discovered that long-lived organisms generally exhibit high expression of genes involved in DNA repair, RNA transport and cellular skeletal organization, and low expression of genes involved in inflammation and energy expenditure.

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

Mammals that age at very different rates were created through natural selection. For example, naked mole rats can live up to 41 years; this is 10 times longer than mice and other rodents of similar size.

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

Vera Gorbunova, Doris Johns Cherry professor of biology and medicine, Andrei Seluanov, first author of the publication, Jinlong Lu, a postdoctoral research associate in Gorbunova’s lab, and other researchers examined genes related to longevity in a recently published paper. Cell Metabolism.

Their findings showed that two regulatory mechanisms that govern gene expression, known as circadian and pluripotency networks, are crucial for longevity. In addition to providing new targets for tackling aging and age-related disorders, the discoveries are also important for understanding how longevity emerges.

Long-lived vs. Short-lived Species Chart

When comparing the gene expression patterns of 26 species with different life spans, University of Rochester biologists found that the traits of different genes are controlled by circadian or pluripotency networks. Credit: University of Rochester illustration / Julia Joshpe

Comparison of longevity genes

With maximum lifespans 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 were positively or negatively correlated with longevity and linked to a species’ maximum lifespan.

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