April 22, 2019
Explorers have dreamt for centuries of a Fountain of Youth,
with healing waters that rejuvenate the old and extend life
indefinitely.
Researchers
at the University of Rochester, however, have uncovered more evidence
that the key to longevity resides instead in a gene.
In a new paper published in the journal Cell, the
researchers—including Vera Gorbunova and Andrei Seluanov, professors of
biology; Dirk Bohmann, professor of biomedical genetics; and their team
of students and postdoctoral researchers—found that the gene sirtuin 6
(SIRT6) is responsible for more efficient DNA repair in species with
longer lifespans. The research illuminates new targets for anti-aging
interventions and could help prevent age-related diseases.
Inevitable double-strand breaks
As humans and other mammals grow older, their DNA is increasingly
prone to breaks, which can lead to gene rearrangements and
mutations—hallmarks of cancer and aging. For that reason, researchers
have long hypothesized that DNA repair plays an important role in
determining an organism's lifespan.
While behaviors like smoking can exacerbate double-strand breaks (DSBs)
in DNA, the breaks themselves are unavoidable. "They are always going
to be there, even if you're super healthy," says Bohmann. "One of the
main causes of DSBs is oxidative damage and, since we need oxygen to breathe, the breaks are inevitable."
Organisms like mice have a smaller chance of accumulating
double-strand breaks in their comparatively short lives, versus
organisms with longer lifespans, Bohmann says. "But, if you want to live
for 50 years or so, there's more of a need to put a system into place
to fix these breaks."
The longevity gene
SIRT6 is often called the "longevity gene" because of its important
role in organizing proteins and recruiting enzymes that repair broken
DNA; additionally, mice without the gene age prematurely, while mice
with extra copies live longer. The researchers hypothesized that if more
efficient DNA repair is required for a longer lifespan, organisms with
longer lifespans may have evolved more efficient DNA repair regulators.
Is SIRT6 activity therefore enhanced in longer-lived species?
To test this theory, the researchers analyzed DNA repair in 18 rodent species
with lifespans ranging from 3 years (mice) to 32 years (naked mole rats
and beavers). They found that the rodents with longer lifespans also
experience more efficient DNA repair because the products of their SIRT6
genes—the SIRT6 proteins—are more potent. That is, SIRT6 is not the
same in every species. Instead, the gene has co-evolved with longevity,
becoming more efficient so that species with a stronger SIRT6 live
longer. "The SIRT6 protein seems to be the dominant determinant of
lifespan," Bohmann says. "We show that at the cell level, the DNA repair works better, and at the organism level, there is an extended lifespan."
The researchers then analyzed the molecular differences between the
weaker SIRT6 protein found in mice versus the stronger SIRT6 found in
beavers. They identified five amino acids responsible for making the
stronger SIRT6 protein "more active in repairing DNA and better at
enzyme functions," Gorbunova says. When the researchers inserted beaver
and mouse SIRT6 into human cells,
the beaver SIRT6 better reduced stress-induced DNA damage compared to
when researchers inserted the mouse SIRT6. The beaver SIRT6 also better
increased the lifespan of fruit flies versus fruit flies with mouse
SIRT6.
Species with even more robust SIRT6?
Although it appears that human SIRT6 is already optimized to
function, "we have other species that are even longer lived than
humans," Seluanov says. Next steps in the research involve analyzing
whether species
that have longer lifespans than humans—like the bowhead whale, which
can live more than 200 years—have evolved even more robust SIRT6 genes.
The ultimate goal is to prevent age-related diseases
in humans, Gorbunova says. "If diseases happen because of DNA that
becomes disorganized with age, we can use research like this to target
interventions that can delay cancer and other degenerative diseases."
Explore further:
Scientists identify protein that improves DNA repair under stress
