Semaglutide Extends Lifespan and Ameliorates Aging in Female Mice, Study Shows

A recent scientific investigation has shed light on how semaglutide, a medication widely utilized for managing diabetes and obesity, impacts the aging process and extends longevity in elderly female mice. This late-life intervention demonstrated significant positive effects on age-related physiological and molecular pathways, presenting both similarities and distinctions when compared to the effects of calorie restriction.

Glucagon-like peptide-1 (GLP-1), a naturally occurring gut hormone, plays a crucial role in the body's response to food intake by stimulating insulin secretion and reducing appetite. Pharmaceutical agents that activate the GLP-1 receptor, such as semaglutide, are highly effective treatments for type 2 diabetes and obesity. Beyond their primary functions of regulating blood glucose and body weight, these GLP-1R agonists have been observed to offer broader health benefits, including improvements in cardiovascular, kidney, and liver health, as well as potential advantages in neurodegenerative conditions. The underlying mechanisms responsible for these diverse benefits, however, have largely remained elusive.

Calorie restriction, defined as a reduced caloric intake without compromising essential nutrition, has been proven to decelerate aging and prolong the lifespan across various species. Similar to the actions of GLP-1R agonists, calorie restriction has shown efficacy in mitigating a range of seemingly unrelated diseases. Mechanistic studies suggest that calorie restriction exerts its beneficial effects through several signaling pathways, notably involving sirtuins and insulin-like growth factor 1 (IGF-1) signaling. Despite the well-documented metabolic and longevity benefits, consistent long-term adherence to calorie restriction presents considerable challenges. This underscores the importance of identifying pharmacological interventions that can mimic the effects of calorie restriction and are suitable for human application.

Researchers at the University of California, Berkeley, initiated the current study to explore whether semaglutide could serve as a mimetic for calorie restriction, offering similar health and longevity advantages. Given that GLP-1R agonists suppress food intake through receptor activation, the scientists hypothesized that semaglutide might replicate the effects of calorie restriction. The study focused on 20-month-old female mice, examining the impact of late-life semaglutide administration on aging and longevity.

The investigation comprised three distinct experimental phases, designed to analyze the physiological, molecular, and cellular alterations induced by semaglutide, its role in lifespan extension, and its comparative effects against calorie restriction. In the lifespan study, the treatment was administered throughout the animals' lives. For physiological, molecular, and cellular analyses, the treatment lasted three months, while a five-month comparative longitudinal study directly contrasted semaglutide's effects with those of calorie restriction. The findings indicated that semaglutide treatment led to a 24% reduction in food intake and a decrease in body weight, primarily due to a reduction in fat mass. Critically, the treatment significantly extended the median lifespan of the mice, increasing it from 742 days in control subjects to 834 days in the semaglutide-treated group.

Aging is commonly associated with a spectrum of physical and neurological impairments, including diminished movement, compromised muscle function, poor motor coordination, metabolic dysregulation, and cognitive decline. The semaglutide treatment demonstrated remarkable efficacy in reversing these age-associated changes. Specifically, older mice treated with semaglutide exhibited enhanced locomotor and exploratory behaviors in novel environments, alongside improvements in motor coordination, muscle function, cognitive abilities, glycemic regulation, and insulin sensitivity.

Well-recognized hallmarks of aging include the depletion and dysfunction of stem cells, cellular senescence, inflammation, mitochondrial dysfunction, and genomic instability. Semaglutide treatment was found to improve indicators of hematopoietic stem-cell function and regenerative capacity. The drug also mitigated the aging of neural stem cells, promoting neurogenesis in the hippocampus and consequently enhancing cognitive performance. Furthermore, semaglutide reduced age-related inflammation and cellular senescence, bolstered mitochondrial function, improved the oxidative stress response, and enhanced genomic stability.

At the molecular level, RNA-sequencing analyses of liver tissues revealed that semaglutide downregulated processes related to lipid metabolism and inflammatory responses, while simultaneously upregulating adaptive immune responses, insulin responses, and protein homeostasis. A comparative analysis of semaglutide's effects with calorie restriction highlighted a shared impact. In the liver, genes suppressed by both treatments were enriched in pathways associated with inflammation and lipid metabolism, whereas genes induced by both treatments were enriched in adaptive immune response, glucose and insulin response, and protein homeostasis. Further examination revealed that late-life semaglutide treatment successfully replicated several functional benefits of calorie restriction, such as reducing age-related decline, and provided additional advantages in exploratory drive, spatial memory, and glycemic control, suggesting effects beyond merely reduced caloric intake.

This study underscores that GLP-1R agonists, like semaglutide, can alleviate age-related physiological deterioration and extend the longevity of aged female mice, in addition to their established benefits in glycemic control and body weight management. The research particularly emphasizes semaglutide's role as a calorie-restriction mimetic that modulates nutrient sensors and genetic regulators of aging, though it also identified distinct mechanistic and functional differences. For instance, calorie restriction typically leads to hunger-driven behavioral and metabolic adaptations, whereas semaglutide treatment inhibits food intake without triggering the same compensatory feeding-related metabolic rhythms. While calorie restriction generally maintained exploratory drive, spatial memory, and glucose control at near-baseline levels, semaglutide treatment significantly improved these outcomes beyond baseline levels. These findings collectively imply that GLP-1R agonists could potentially slow down and even reverse some aspects of age-related functional decline. However, since the study was conducted on aged female mice, it remains to be seen whether semaglutide or other GLP-1 medications can influence aging trajectories or lifespan in humans. Researchers suggest that long-term clinical trials in older human populations would be necessary to ascertain these effects.