Fight Aging!

Without careful study design, studies in which the use of GLP-1 receptor agonists such as semaglutide lowered calorie intake significantly via suppression of appetite might be expected to teach us little that we did not already know. Reducing calorie intake without compromising minimum necessary levels of essential nutrients slows aging and extends life, whether achieved via limiting food availability or by limiting appetite. Researchers know this, and they know a great deal about the fine details of the metabolic response to reduced nutrient availability. The effects of reduced calorie intake readily overpowers the effects of other mechanisms that may or may not be operating as a result of GLP-1 receptor agonism, particularly in short-lived species. One has to look more carefully to see any more interesting outcomes that lie outside the normal effects of calorie restriction.

Reported in today's open access paper, researchers conducted a study in mice in which (a) GLP-1 receptor agonism reduced calorie intake by a quarter when started in late life, and (b) the mice lived ~15% longer. That falls in line with the results of many calorie restriction studies conducted in aged mice over the past twenty years. Indeed, the researchers conducted their own calorie restriction study with a reduced calorie intake matched to the results of their GLP-1 receptor agonist study, and found the outcomes in health to be very similar. There are a few differences, however. Why do those differences exist? GLP-1 receptor agonism affects some aspects of metabolism that calorie restriction does not, and vice versa. Most notably, calorie restricted mice are hungry for much of the time, while mice treated with GLP-1 receptor agonists are not. The signaling associated with the hunger response has its own effects on metabolism distinct from those resulting directly from sensing of nutrient levels in cells.

Late-life semaglutide treatment slows ageing and extends lifespan in female mice

Preclinical studies in disease mouse models and clinical studies have revealed pleiotropic beneficial effects of GLP-1R activation, including improved glucose and weight control, and reduced cardiovascular, renal, hepatic, and neurodegenerative disease burden. We found that GLP-1R activation late in life improved physiological function and extended lifespan in an ageing mouse model (20-month-old female C57BL/6) treated with a defined semaglutide regimen that reduced food intake by 24%. Female mice were selected to minimize confounding effects of male aggression and injury, consistent with previous long-term ageing studies. Within the end points monitored in the study, we did not observe adverse effects attributable to semaglutide. While GLP-1 medicines are widely used clinically, whether GLP-1R activation modulates ageing trajectories and lifespan in humans will require long-term clinical studies designed to evaluate ageing-related outcomes in older populations.

Our findings establish that GLP-1R activation late in life alleviates broadly ageing-associated decline and phenocopies the molecular and physiological benefits of calorie restriction. In aged female C57BL/6 mice, semaglutide treatment extended lifespan, improved physiological function, reduced hallmarks of ageing (such as stem cell attrition, inflammation, cellular senescence, genomic instability, mitochondrial dysfunction, and loss of proteostasis) and modulated the genetic regulators of ageing and nutrient sensors in the same manner as calorie restriction. The restoration of neural stem cells and neurogenesis in aged mice was particularly marked, considering the emerging evidence that GLP-1 medicines have beneficial effects on neurodegeneration.

Direct comparison of semaglutide treatment with matched calorie restriction further showed comparable effects across several aspects of ageing-associated physiological decline, consistent with the idea that GLP-1 medicines can act as calorie restriction mimetics. As ageing is the biggest risk factor for numerous chronic diseases and calorie restriction slows ageing and ameliorates a broad spectrum of ageing-associated diseases, our findings raise the possibility that GLP-1 medicines may influence a wide array of seemingly unrelated diseases by slowing ageing.