DNA genetik evolution kunstner koncept

Genregulering kan være nøglen til længere levetid

Forskere opdagede, at langlivede organismer ofte har høj ekspression af gener involveret i DNA-reparation, RNA-transport og cytoskeletorganisering og lav ekspression af gener involveret i inflammation og energiforbrug.

University of Rochester forskere, der er interesseret i genetik for lang levetid, foreslår nye mål for at bekæmpe aldring og aldersrelaterede lidelser.

Pattedyr, som ældes med meget forskellige hastigheder, blev skabt gennem naturlig udvælgelse. For eksempel kan nøgne muldvarperotter blive op til 41 år, hvilket er over 10 gange længere end mus og andre gnavere af sammenlignelig størrelse.

Hvad forårsager en længere levetid? Ifølge en nylig undersøgelse foretaget af biologer fra University of Rochester ligger en afgørende brik i puslespillet i de mekanismer, der styrer genekspression.

Vera Gorbunova, Doris Johns Cherry-professor i biologi og medicin, Andrei Seluanov, papirets første forfatter, Jinlong Lu, en postdoktor i Gorbunovas laboratorium, og andre forskere undersøgte gener forbundet med lang levetid i en nylig artikel i cellulær metabolisme.

Deres resultater viste, at to regulatoriske mekanismer, der kontrollerer genekspression, kendt som døgnrytme og pluripotente netværk, er afgørende for levetiden. Opdagelserne er vigtige for at forstå, hvordan lang levetid opstår, og for at skabe nye mål for at bekæmpe aldring og aldersrelaterede lidelser.

Langlivede vs. kortlivede arter grafik

Når man sammenlignede genekspressionsmønstrene for 26 arter med forskellige levetider, fandt biologer fra University of Rochester ud af, at egenskaberne af de forskellige gener styres af døgnrytme eller pluripotente netværk. Fotokredit: University of Rochester illustration / Julia Joshpe

Sammenlign gener med lang levetid

Med en maksimal levetid på to år (spidsmus) til 41 år (nakkede mole-rotter) analyserede forskerne genekspressionsmønstrene for 26 pattedyrarter. De opdagede tusindvis af gener, der enten var positivt eller negativt korreleret med levetid og knyttet til en arts maksimale levetid.

De fandt ud af, at langlivede arter har en tendens til at have lav ekspression af gener involveret i energimetabolisme og inflammation; og høj ekspression af involverede gener[{” 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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