Semaglutide extended lifespan in older female mice, but that was not the only finding

A late-life experiment reveals how a widely used metabolic drug reshapes age-related physiology and molecular pathways, with effects that both resemble and differ from calorie restriction.

Study: Late-life semaglutide treatment slows ageing and extends lifespan in female mice. Image Credit: Edugrafo / Shutterstock

Late-life treatment with the diabetes and obesity drug semaglutide slowed age-related decline and extended lifespan in aged female mice, according to a new study published in the journal Nature.

Background

Glucagon-like peptide-1 (GLP-1), a natural gut hormone secreted in response to food ingestion, triggers glucose-dependent insulin secretion and inhibits food intake. Activation of the GLP-1 receptor (GLP-1R) with pharmaceuticals like semaglutide is an effective treatment for type 2 diabetes and obesity.

In addition to controlling blood glucose and body weight, these GLP-1R agonists have shown benefits beyond glucose and weight control, including reduced cardiovascular, kidney, and liver disease burden and beneficial effects in neurodegenerative disease. However, the mechanisms driving these additional benefits remain largely unknown.

Calorie restriction, characterized by reduced calorie intake without malnutrition, can slow aging and extend lifespan across species. Similar to GLP-1R agonist-based treatment, calorie restriction ameliorates a variety of apparently unrelated diseases.

Mechanistic evidence indicates that calorie restriction exerts beneficial effects through various signaling pathways, including sirtuins and insulin-like growth factor 1 (IGF-1) signaling.

Despite well-established metabolic and longevity benefits, long-term adherence to calorie restriction remains challenging. This highlights the need to identify calorie restriction mimetics suitable for human application.

The current study, led by researchers at the University of California, Berkeley, was designed to investigate whether semaglutide could act as a calorie-restriction mimetic with health and longevity benefits. Since GLP-1R agonists inhibit food intake via receptor activation, the researchers hypothesized that semaglutide might act as a mimetic of calorie restriction. Using 20-month-old female mice, they investigated how late-life semaglutide treatment affects aging and longevity.

Key findings

The researchers conducted three separate sets of experiments to explore semaglutide-mediated physiological, molecular, and cellular changes, lifespan expansion, and its effects compared with calorie restriction. For the lifespan study, the treatment continued throughout the lifespan of experimental mice. For physiological, molecular, and cellular experiments, treatment continued for three months, while a five-month longitudinal study directly compared semaglutide with matched calorie restriction.

The findings revealed that semaglutide treatment reduced food intake by 24% and body weight, primarily by reducing fat mass. The treatment significantly increased lifespan, with median lifespan rising from 742 days in control mice to 834 days in semaglutide-treated mice.

Age-related changes

Aging is associated with a range of physical and neurological disabilities, including reduced movement, impaired muscle function, poor motor coordination, metabolic dysregulation, and cognitive decline. The semaglutide treatment showed potency in ameliorating these age-related changes.

Specifically, semaglutide-treated aged mice showed greater locomotor and exploratory activity in novel-environment tests, along with improved motor coordination, muscle function, cognition, glycemic control, and insulin sensitivity.

Aging hallmarks

Stem cell attrition and dysfunction, cellular senescence, inflammation, mitochondrial dysfunction, and genetic instability are well-established hallmarks of aging.

Semaglutide treatment improved indicators of hematopoietic stem-cell function and regenerative capacity. The treatment also ameliorated neural stem cell aging and increased neurogenesis in the hippocampus, as well as improved cognitive performance.

The drug also reduced age-related inflammation and cellular senescence, improved mitochondrial function and oxidative stress response, and improved genomic stability.

At the molecular level, liver RNA-sequencing analyses showed that semaglutide downregulated lipid metabolism and inflammatory responses and upregulated adaptive immune responses, insulin responses, and protein homeostasis.

The comparison of semaglutide’s effects with calorie restriction revealed a shared impact. In the liver, genes suppressed by both treatments were enriched for inflammation and lipid metabolism, while genes induced by both treatments were enriched for adaptive immune response, glucose and insulin response, and protein homeostasis.

Further analysis revealed that semaglutide treatment later in life successfully recapitulated several functional benefits of calorie restriction by reducing age-related decline and providing additional benefits in exploratory drive, spatial memory, and glycemic control, suggesting effects beyond reduced calorie intake alone.

Study significance

The study reveals that semaglutide, a GLP-1R agonist, can improve age-related physiological decline and extend longevity in aged female mice, in addition to providing well-established glycemic control and body weight management benefits.

Notably, the study highlights that semaglutide treatment late in life acts as a calorie-restriction mimetic that modulates nutrient sensors and genetic regulators of aging. However, the researchers have identified mechanistic and functional differences.

As observed in the study, calorie restriction is associated with hunger-driven behavioral and metabolic adaptations, whereas semaglutide treatment is associated with inhibition of food intake without eliciting the same compensatory feeding-related metabolic rhythms.

While calorie restriction generally maintained exploratory drive, spatial memory, and glucose control near baseline levels, semaglutide treatment significantly improved these outcomes above baseline.

Taken together, these findings suggest that GLP-1R agonists like semaglutide may be capable of slowing and potentially reversing some aspects of age-associated functional decline.

However, the study was conducted in aged female mice, and whether semaglutide or other GLP-1 medicines can alter aging trajectories or lifespan in humans remains unknown. The researchers note that this would require long-term clinical studies in older populations.