In a new study, semaglutide given late in life increased median lifespan in female mice by more than 12% and improved various health markers. Semaglutide’s effect possibly went beyond caloric restriction [1].
Old mice, new drugs
GLP-1 receptor agonists, which act on a hormone that regulates insulin secretion and appetite, have revolutionized obesity treatment, showing benefits across several seemingly unrelated diseases. This raised the question whether the drugs’ effect goes beyond caloric restriction, which itself is a potent anti-aging intervention that has produced robust healthspan and lifespan extensions in animal models [2]. So far, human studies have not yielded conclusive results [3], so there is value in going back to animal studies, where interventions can be investigated across the model’s entire lifespan.
A new study, led by scientists from UC Berkeley and published in Nature, features a fairly straightforward design: take female mice, start giving them GLP-1 receptor agonists late in life, and see what happens. The researchers began daily semaglutide treatment in 20-month-old, non-obese, non-diabetic, female mice that ate standard lab chow, and continued it for the rest of their lives. Forty mice received semaglutide, and 39 received saline injections.
Median lifespan extended
Semaglutide reduced food intake by approximately 24% and lowered body weight. Body composition shifted toward a lower fat percentage and a higher lean-mass percentage. This, however, does not mean that overall lean mass increased – just that the animals lost more fat than muscle. There was no significant change in energy expenditure, suggesting that weight loss was mainly due to reduced calorie intake.
In the central result, median lifespan increased from 742 to 834 days: a gain of 92 days, or approximately 12.4%. The controls’ median lifespan amounted to 24.4 months, which means that although the treatment period was fairly short, it nevertheless produced a significant increase in lifespan. 742 days is also on the lower end of female C57BL/6 mice’s lifespan in previous studies, so replicating the results in longer-lived cohorts would be valuable. Mortality was delayed across several non-tumor categories, which is consistent with benefits extending beyond one particular terminal condition.
Live long – but how about prospering?
To determine if the longer-lived animals were also functioning better, the researchers treated old mice in a separate cohort for three months, testing movement, exploration, memory, physical performance, and glucose regulation. Most functional comparisons involved ten mice per group.
Semaglutide-treated mice moved more and explored exposed areas more readily in unfamiliar environments. They also performed better in a spatial memory test. Motor coordination, hanging performance, and treadmill endurance all improved, as did glucose tolerance.
The researchers then analyzed various aging-related cellular processes. Hematopoietic stem cells (HSCs) age somewhat paradoxically: they can become more numerous even as their regenerative performance deteriorates. They also increasingly favor the myeloid lineage, which includes monocytes and granulocytes, over the lymphoid lineage, which includes B and T cells. Semaglutide treatment partially reversed these aspects of HSC aging.
In the dentate gyrus, a region of the hippocampus involved in learning and memory, semaglutide increased the number of both dividing cells and immature neurons, suggesting improved neurogenesis and providing a plausible biological link to the uptick in memory performance.
Inflammation is a major hallmark of aging. Semaglutide reduced inflammatory gene expression in liver and muscle tissues and reduced inflammatory immune-cell signals in the liver. This included fewer macrophages expressing high levels of the inflammatory cytokine IL-6.
Several markers associated with cellular senescence also decreased after treatment, including expression of p16 and p21 in the liver, visceral fat, and spleen along with senescence-associated β-galactosidase staining in the kidney and spleen. However, this does not establish that semaglutide has a senolytic effect.
In the liver and spleen, semaglutide reduced the proportion of cells that bear γ-H2AX, a marker associated with DNA damage. It also increased mitochondrial gene expression and ATP content in muscle and reduced mitochondrial oxidant signaling in blood stem cells. On top of that, the treatment seemed to improve some markers of cellular stress triggered by misfolded proteins.
More than eating less?
To understand how much of the effect could be explained simply by mice eating less, the team compared semaglutide directly with a 24% reduction in food intake in another cohort of old female mice. In an experiment that lasted for five months, ten animals per group received saline, semaglutide, or caloric restriction.
The two interventions resulted in similar total food intake and comparable weight and fat loss, but the mice exhibited different eating patterns: mice under caloric restriction finished their daily rations quickly and then fasted for a prolonged period. Semaglutide-treated mice ate more gradually throughout the day, consistent with a suppressed appetite rather than enforced restriction.
Both treatments broadly preserved physical function, while untreated animals declined. The similarities spanned movement in unfamiliar evironments, rotarod and hanging performance, and treadmill endurance.
However, semaglutide-fed mice fared better than calorically restricted ones in spatial memory and glucose tolerance. Here, semaglutide improved performance above baseline, while caloric restriction generally maintained it near baseline. However, there was no caloric-restricted lifespan group, so this study did not answer the question of whether semaglutide extended life more than an equivalent reduction in food intake would have done.
Literature
[1] Feng, Y., Barthez, M., Wang, Y., Chen, Y., Qiu, H., Wang, C. L., … & Chen, D. (2026). Late-life semaglutide treatment slows ageing and extends lifespan in female mice Nature, 1-8.
[2] Mattison, J. A., Colman, R. J., Beasley, T. M., Allison, D. B., Kemnitz, J. W., Roth, G. S., … & Anderson, R. M. (2017). Caloric restriction improves health and survival of rhesus monkeys. Nature communications, 8(1), 14063.
[3] Newsome, P., Francque, S., Harrison, S., Ratziu, V., Van Gaal, L., Calanna, S., … & Sanyal, A. (2019). Effect of semaglutide on liver enzymes and markers of inflammation in subjects with type 2 diabetes and/or obesity. Alimentary pharmacology & therapeutics, 50(2), 193-203.
