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 1. nature
 2. news
 3. article

 * NEWS
 * 12 September 2024


THE BRAIN AGED MORE SLOWLY IN MONKEYS GIVEN A CHEAP DIABETES DRUG

Daily dose of the common medication metformin preserved cognition and delayed
decline of some tissues.
   By
 * Max Kozlov

 1. Max Kozlov
    View author publications
    
    You can also search for this author in PubMed  Google Scholar

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Cellular measures of ageing changed more slowly in the liver, brain and other
tissues of monkeys taking the drug metformin.Credit: Vachira
Vachira/NurPhoto/Getty

A low-cost diabetes drug slows ageing in male monkeys and is particularly
effective at delaying the effects of ageing on the brain, finds a small study
that tracked the animals for more than three years1. The results raise the
possibility that the widely used medication, metformin, could one day be used to
postpone ageing in humans.

Monkeys that received metformin daily showed slower age-associated brain decline
than did those not given the drug. Furthermore, their neuronal activity
resembled that of monkeys about six years younger (equivalent to around 18 human
years) and the animals had enhanced cognition and preserved liver function.

This study, published in Cell on 12 September, helps to suggest that, although
dying is inevitable, “ageing, the way we know it, is not”, says Nir Barzilai, a
geroscientist at the Albert Einstein College of Medicine in New York City, who
was not involved in the study.


MEDICINE-CABINET STAPLE

Metformin has been used for more than 60 years to lower blood-sugar levels in
people with type 2 diabetes — and is the second most-prescribed medication in
the United States. The drug has long been known to have effects beyond treating
diabetes, leading researchers to study it against conditions such as cancer,
cardiovascular disease and ageing.



Reversal of biological clock restores vision in old mice



Data from worms, rodents, flies and people who have taken the drug for diabetes
suggest the drug might have anti-ageing effects. But its effectiveness against
ageing had not been tested directly in primates, and it is unclear whether its
potential anti-ageing effects are achieved by lowering blood sugar or through a
separate mechanism.

This led Guanghui Liu, a biologist who studies ageing at the Chinese Academy of
Sciences in Beijing, and his colleagues to test the drug on 12 elderly male
cynomolgus macaques (Macaca fasciucularis); another 16 elderly monkeys and 18
young or middle-aged animals served as a control group. Every day, treated
monkeys received the standard dose of metformin that is used to control diabetes
in humans. The animals took the drug for 40 months, which is equivalent to about
13 years for humans.

Over the course of the study, Liu and his colleagues took samples from 79 types
of the monkeys’ tissues and organs, imaged the animals’ brains and performed
routine physical examinations. By analysing the cellular activity in the
samples, the researchers were able to create a computational model to determine
the tissues’ ‘biological age’, which can lag behind or exceed the animals’ age
in years since birth.


SLOWING THE CLOCK

The researchers observed that the drug slowed the biological ageing of many
tissues, including from the lung, kidney, liver, skin and the brain’s frontal
lobe. They also found that it curbed chronic inflammation, a key hallmark of
ageing. The study was not intended to see whether the drug extended the animals’
lifespans; previous research has not established an impact on lifespan2 but has
shown lengthened healthspan3 — the number of years an organism lives in good
health.

This means that metformin can “effectively rewind organ age” in monkeys, Liu
says. The authors also identified a potential pathway by which the drug protects
the brain: it activates a protein called NRF2, which safeguards against cellular
damage triggered by injury and inflammation.

This study is the “most quantitative, thorough examination of metformin action
that I’ve seen beyond mice”, says Alex Soukas, a molecular geneticist at
Massachusetts General Hospital in Boston. “It was a surprise to see how
comprehensive [the drug’s] effects were across tissue types.”


LOW-COST DRUG, HIGH-COST TRIAL

Although these results are encouraging, much more research will be necessary to
study the drug before it’s validated as an anti-ageing compound in humans, Liu
says.



The fraught quest to account for sex in biology research



For one, only 12 monkeys received the drug. Soukas says he would therefore like
to see a replication of this effort or a study that includes more animals.
Furthermore, the researchers tested only male animals, which Rafael de Cabo, a
translational geroscientist at the National Institute on Aging in Baltimore,
Maryland, says is concerning. He acknowledges that it is extremely expensive to
run this type of long-term experiment, but adds that it is crucial to understand
ageing in females as well, given that there are often large differences between
the sexes.

In the meantime, Liu and his colleagues have launched a 120-person trial in
collaboration with the biopharmaceutical company Merck in Darmstadt, Germany,
which developed and manufactures metformin, to test whether the drug delays
ageing in humans.

Barzilai has even bigger ambitions: he and his colleagues have been spearheading
an effort to raise US$50 million to study the drug in a trial of 3,000 people
aged 65–79 over 6 years. Research into metformin and other anti-ageing
candidates could one day mean that doctors will be able to focus more on keeping
people healthy for as long as possible rather than on treating diseases, he
says.

doi: https://doi.org/10.1038/d41586-024-02938-w


REFERENCES

 1. Yang, Y. et al. Cell https://doi.org/10.1016/j.cell.2024.08.021 (2024).
    
    Article  Google Scholar 

 2. Mohammed, I., Hollenberg, M. D., Ding, H. & Triggle, C. R. Front.
    Endocrinol. 12, 718942 (2021).
    
    Article  Google Scholar 

 3. Martin-Montalvo, A. et al. Nature Commun. 4, 2192 (2013).
    
    Article  PubMed  Google Scholar 

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