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Metformin is the main first-line drug used to treat type 2 diabetes, but a new study on monkeys suggests it could one day be used to slow brain aging, too.
Hints of the drug's anti-aging affects have been seen previously in retrospective studies on people who take the drug for diabetes, and also in worm, fly and rodent studies.
But metformin's anti-aging effects were yet to be tested in primates, so biologist Yuanhan Yang and colleagues from the Chinese Academy of Sciences spent 40 months studying the effects of metformin on crab-eating macaques (Macaca fascicularis), one of our closest relatives.
The monkeys in this experiment were all males aged 13-16 years old, which is the equivalent of ages 40-50 in human development.
A selection of the macaques were given a daily dose of metformin for a little over three years continuously, roughly equating a standard treatment for humans who are managing their type 2 diabetes.
Others of the same age were given similar treatments containing no drug. Control groups of six young (3-5 years old) and three middle-aged (10-12 years old) male monkeys were also tracked to specifically account for age effects.
"These findings suggest metformin's potential in slowing brain aging and possibly treating neurodegenerative and other chronic conditions," the researchers write.
They assessed the monkeys' aging in terms of physiology, memory, learning, and cognitive flexibility, and brain morphology.
"Specifically, we leveraged pan-tissue transcriptomics, DNA methylomics, plasma proteomics, and metabolomics to develop innovative monkey aging clocks and applied these to gauge metformin's effects on aging," the authors write.
The drug reduced the fluctuations in gene transcription associated with aging in multiple different tissues, affecting pathways associated with aging like cell death and fibrosis and reactivating aging-repressed pathways involved in development, like DNA repair and lipid metabolism.
It decreased the old monkeys' biological age by several measures, slowed liver aging and enhanced production of chemicals that protect the liver. But most importantly, the study found that metformin does indeed delay brain aging, and provides neuroprotection in elderly monkeys, "rescuing" their frontal lobe by an average of nearly six years.
"Conclusive evidence of functional rejuvenation is sparse, and a full understanding of its side effects in humans remains elusive," the authors write.
They note the study didn't assess mortality, or follow the long-term effects after the macaques were no longer given the drug.
Experts from the United States were impressed at the rigor of this experiment, which molecular geneticist Alex Soukas from Massachusetts General Hospital described to Nature's Max Kozlov as the "most quantitative, thorough examination of metformin action that I've seen beyond mice."
But Rafael de Cabo, a translational geroscientist from the National Institute on Aging in Baltimore, pointed out that with only a few monkeys given the drug, and the high cost of long-term primate experiment like this, it was concerning that the sample didn't include female monkeys.
"While the comprehensive impact and mechanisms of metformin in primates are yet to be fully charted, our findings indicate significant delays in the aging process," the authors conclude.
"This insight is a critical step forward, guiding the advancement of clinical strategies to mitigate aging impacts and its associated health issues."
But ultimately, it seems this animal experiment is just one step in the researchers' ambitions to test in humans. And it seems to have impressed some key stakeholders.
Members of the Chinese research team have already launched a 120-person phase II clinical trial testing similar effects in humans, in collaboration with a pharmaceutical company that manufactures metformin.
"Our research pioneers the systemic reduction of multidimensional biological age in primates through metformin, paving the way for advancing pharmaceutical strategies against human aging," the team writes.
This research is published in Cell.
