There is some debate over whether GLP-1 receptor agonist drugs such as semaglutide can affect mechanisms relevant to aging independently of weight loss. GLP-1 receptors are present in many organs, including the brain, so it is not unreasonable to think that other outcomes may result from GLP-1 receptor agonism over and above reduced appetite and calorie intake. But do those outcomes slow aging to a meaningful degree in comparison to the effects of weight loss? That is where we should be appropriately skeptical.
Compelling mechanistic and epidemiological data indicates that excess visceral fat tissue accelerates aging, such as via the increased accumulation of senescent cells and the induction of a harmful diabetic metabolism. The effect size is fairly large. Losing weight should reduce biological age, so any data on GLP-1 receptor agonist drug use and biological age in overweight populations, as is the case in today’s open access paper, cannot be used to argue that there is something other than weight loss going on – the weight loss effects get in the way.
The most compelling evidence for GLP-1 receptor agonists to affect pace of aging independently of loss of visceral fat tissue comes from a study in mice using low doses of the drug exenatide, too low to cause weight loss. The researchers nonetheless noted effects on aging, and their evidence suggests that this is specifically due to GLP-1 receptor agonism in the hypothalamus, and downstream effects from there. Recall that the hypothalamus is influential on many aspects of metabolism, and research has suggested that changes in hypothalamic function do affect pace of aging.
People with HIV (PWH) represent a unique population exhibiting accelerated biological aging, characterized by premature onset of age-related conditions, persistent low-grade inflammation, and metabolic dysfunction, even when HIV replication is effectively suppressed by antiretroviral therapy. A common metabolic complication in this population is HIV-associated lipohypertrophy, defined by excessive accumulation of visceral and ectopic adipose tissue, which further exacerbates aging processes. Within the geroscience framework, the accelerated-aging phenotype in PWH provides an ideal clinical model to evaluate candidate geroprotective therapies.
In a completed phase 2b, randomised, double-blind, placebo-controlled trial (semaglutide n = 45; placebo n = 39), we tested whether once-weekly semaglutide can slow epigenetic aging in people with HIV-associated lipohypertrophy, a population marked by visceral adiposity (average BMI = 32.86) and accelerated epigenetic age. Using paired peripheral-blood methylomes collected at baseline and 32 weeks, we conducted a post-hoc analysis spanning 17 DNA-methylation clocks.
After adjustment for sex, BMI, hsCRP, and sCD163, semaglutide significantly decreased epigenetic aging: PCGrimAge (-3.1 years), GrimAge V1 (-1.4 years), GrimAge V2 (-2.3 years), PhenoAge (-4.9 years), and DunedinPACE (-0.09 units, ≈9 % slower pace). Semaglutide also lowered the multi-omic OMICmAge clock (-2.2 years) and the transposable element-focused RetroAge clock (-2.2 years). Eleven organ-system clocks showed concordant decreased with semaglutide, most prominently inflammation, brain and heart, whereas an Intrinsic Capacity epigenetic clock was unchanged. These findings provide, to our knowledge, the first clinical-trial evidence that semaglutide modulates validated epigenetic biomarkers of aging, justifying further evaluation of GLP-1 receptor agonists for health-span extension.
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