Background

Semaglutide, a glucagon-like peptide-1 receptor (GLP-1R) agonist, suppresses appetite and regulates blood glucose and is used in the treatment of type 2 diabetes and obesity. Clinical studies have reported reduced risks of cardiovascular, renal, and hepatic diseases, but it remains unclear whether the benefits observed in different organs are a result of weight loss or reflect intrinsic changes in aging biology.

Caloric restriction, a well-established anti-aging intervention, extends the lifespan of various animals by reducing caloric intake without malnutrition. It modulates evolutionarily conserved pathways such as sirtuins and insulin–insulin-like growth factor-1 (IGF1) signaling. However, it is difficult to maintain over the long term and is often accompanied by behavioral and metabolic changes due to hunger. Researchers at the University of California, Berkeley, investigated whether semaglutide could mimic caloric restriction and whether its administration in old age could alter healthspan and lifespan.

Key Findings

Researchers administered semaglutide at 10 nmol/kg daily via subcutaneous injection to 20-month-old female C57BL/6 mice. The lifespan analysis included 39 control mice and 40 treated mice. Semaglutide reduced food intake by 24% and decreased body weight, primarily through fat loss. The median lifespan of the treated group was 834 days, compared to 742 days in the control group, an increase of 92 days, or approximately 12.4%. The distribution of causes of death did not significantly differ between the two groups.

In a separate group treated for 3 months, the drug improved exercise and exploratory behavior, balance on a rotating rod, climbing strength, treadmill endurance, and glucose tolerance. These improvements remained significant even after adjusting for body weight as a covariate. In the Barnes maze, the treated mice showed increased target zone exploration and reduced time to locate the escape hole, indicating improved spatial memory.

Molecular and cellular changes were also widespread. In the bone marrow, the accumulation of phenotypically aged hematopoietic stem cells and myeloid bias decreased. In the hippocampal dentate gyrus, BrdU-positive cells and doublecortin (DCX)-positive newborn neurons increased. Inflammatory cytokines, p16, p21, senescence-associated β-galactosidase, and DNA damage marker γ-H2AX were reduced. Mitochondrial-related genes and ATP levels increased, while reactive oxygen species decreased.

Transcriptomic analysis of the liver revealed suppressed inflammatory and lipid metabolism genes, and activated adaptive immunity, insulin response, and protein homeostasis pathways. Nicotinamide adenine dinucleotide (NAD+) and several sirtuin expressions increased, while circulating IGF1 levels decreased. Researchers interpreted these findings as evidence that semaglutide modulates aging-related circuits overlapping with caloric restriction.

Implications and Outlook

When semaglutide-treated mice were directly compared with a caloric restriction group with 24% reduced food intake over 5 months, both interventions showed similar trajectories in weight and fat reduction and maintenance of physical function. However, the caloric restriction group exhibited behaviors such as rapid food consumption followed by prolonged fasting and waiting for the next feeding. The semaglutide group distributed food intake more evenly throughout the day without such rhythmic changes. Exploration desire, spatial memory, and glucose regulation improved beyond baseline in the drug-treated group, whereas the caloric restriction group remained near baseline. These effects suggest more than just reduced intake.

Nevertheless, it is premature to interpret these findings as a direct anti-aging drug for humans. The study was limited to a single strain of female mice, and the sample size for lifespan analysis was 79. It remains unknown whether the same results would be observed in male mice, different genetic backgrounds, or non-obese humans. Clinical administration methods and dosages differ, and long-term safety in the elderly, including muscle loss and gastrointestinal disturbances, must be evaluated separately. This study provides preclinical evidence that initiating GLP-1R stimulation in old age can simultaneously alter multiple aging axes and survival in mice, but it is not clinical proof of reversing aging.