The results of a new study, recently published in Nature, have some scientists cautiously suggesting that GLP-1 drugs might affect biological ageing.
When researchers injected 20-month-old female mice with semaglutide for the rest of their little lives, they found the mice lived an extra 92 days. That’s a 12 per cent increase, compared with their typical median lifespan of 742 days.
Biological ageing is the “gradual wear and tear that happens inside your cells and tissues over time,” says HIV researcher Dr Grace McComsey, who recently co-authored a separate analysis on GLP-1s and their ability to reduce hallmarks of ageing in adults with HIV.
It’s different from how old you are in years or how many birthdays you’ve had – your chronological age.
“Someone can be chronologically 60 and be younger in biological age because they are healthy and take care of themself,” said McComsey. “The opposite is true too.”
As well as living longer, the injected mice showed markers of healthier ageing at a cellular level. This included reduced inflammation, fewer senescent cells, better-functioning mitochondria (structures inside cells that help turn nutrients and oxygen into energy) and the growth of more new cells in regions of the brain involved in learning and memory.
Prof Richard Faragher, who specialises in biological gerontology at the University of Brighton, described senescent cells as intentional drivers of inflammation, and said their reduction in the study was significant.
“It’s like that scene from Lord of the Rings where Gandalf says to Bilbo: ‘Remember Bilbo, the ring wants to be found,’” said Faragher when explaining the concept of senescent cells.
“They are making a nuisance of themselves to attract immune cells to kill them. The problem is that your immune system is also made of cells, and it’s ageing.”
He explained: “When you are a teenager, as soon as you make a senescent cell, it is clobbered. By the time you are my age it’s more like one of those calls you make to the dentist: ‘we are experiencing an extremely high call volume, please stand by’.”
The result? Damage accumulates: in the skin this causes wrinkles, in blood vessels it causes cardiovascular disease, and in the brain it causes cognitive impairment.
But semaglutide is used to reduce appetite, so these effects could have simply been a result of the mice eating less.
That’s why the researchers later ran a separate five-month study using a new group of mice. Semaglutide made the initial group of mice eat about 24 per cent less food, so the researchers restricted the comparison group’s calorie intake by 24 per cent.
Both groups of mice lost a comparable amount of body weight and fat mass, and performed similarly on their treadmills. But the mice on semaglutide pulled ahead on spatial memory, glucose control and exploratory behaviours.
“What is becoming increasingly clear is that GLP-1 receptor agonists have effects on life expectancy that are independent of their effects on body mass,” said Faragher.
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A human equivalent
Earlier this year, researchers including McComsey published an analysis that is perhaps the closest thing to a human version of the recent mouse study.
They analysed data from a 32-week randomised, double-blind, placebo-controlled trial involving 84 adults living with HIV, who tend to age faster biologically than most adults.
The participants had HIV-associated lipohypertrophy – an abnormal accumulation of fat – and they received either weekly semaglutide or a placebo for 32 weeks.
The original trial tested whether semaglutide reduced the fat accumulation in HIV-associated lipohypertrophy. But researchers went back afterward and ran an ageing analysis on the data.
“The drug not only improved metabolic health,” said McComsey, “but also reduced the accumulation of age-related changes in DNA, suggesting it may affect underlying ageing biology rather than simply treating disease.”
Compared with the placebo group, the semaglutide group had a nine per cent slower pace of biological ageing, as well as significant changes in markers associated with all-cause mortality risk, and positive signals in blood-based measures of inflammation and brain and heart ageing.
McComsey said the recent findings in mice mirrored several of the observations in the study in adults with HIV.
“Improved cognition, decreased inflammation and reduced ageing biomarkers” were noted across the board, she said.
But she cautioned that GLP-1s are not miracle drugs.
“Some people (in our study, about a third of participants) did not lose the prespecified threshold of at least five per cent weight loss,” she said. “We need to understand why.”
There was also the possibility of rare side effects such as optic neuropathy (damage or disease affecting the optic nerve) and inflammation or swelling of the brain (encephalitis).
“One side effect that is common and not at all rare is significant loss of muscle,” she added. “I urge people to exercise with the GLP-1s so they do not end up with large muscle loss that may not be easily reversible.”
There’s still a long way to go, then, before we can herald semaglutide or other GLP-1s as a fountain of youth.
One group of female mice given lifelong injections, and one relatively small post-hoc analysis of humans with a disease known to speed up ageing, are not enough to draw firm conclusions. More testing needs to be done in more varied ageing populations.
There are also wider questions about what changes in life expectancy could mean for wider society, from pension ages to healthcare systems, across the world.
Governments need to take GLP-1s seriously, said Faragher, so they can prepare.
“All the stuff people worry about, ageing of the population because of ill health, it’s going to start to disappear,” he said.
“We are living through the greatest change in human population health since penicillin. And it's happening right now.”
On a more personal level, even the hope of an extra two weeks of life is meaningful for some.
Faragher, for instance, lost his dad a few years ago. His dad had always wanted to go on a cruise to Egypt but the first time, a terrorist attack cancelled all the cruises; the second time, his mum was hospitalised.
“It’s only a ten-day trip. Two weeks extra healthy life expectancy would have been enough for my dad to tick off the one thing on his bucket list.”
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