Researchers have found that a number of antidiabetic drugs act to modestly slow aging in mice, albeit often differently by sex, while some effects are more reliable than others. Insulin metabolism was one of the first aspects of cell biochemistry to be well studied in the context of effects on aging, and drugs that affect insulin metabolism in the environment of the dysfunction of type 2 diabetes were thus thought likely to have at least some small effect on aging. The effect is indeed small and unreliable in some of the more studied drugs, such as metformin. Here, researchers assess the outcome of treatment with the antidiabetic drug canagliflozin in a mouse model of Alzheimer's disease, focusing on measures of brain aging and pathology, finding it to produce useful benefits in male mice only.
Aging is the strongest risk factor for cognitive decline and Alzheimer's disease (AD), yet the mechanisms underlying brain aging and their modulation by pharmacological interventions remain poorly defined. The hippocampus, essential for learning and memory, is particularly vulnerable to metabolic stress and inflammation. Canagliflozin (Cana), an FDA-approved sodium-glucose co-transporter 2 inhibitor (SGLT2i) for type 2 diabetes, extends lifespan in male but not female mice, but its impact on brain aging is unknown. Here, we used a multi-omics strategy integrating transcriptomics, proteomics, and metabolomics to investigate how chronic Cana treatment reprograms brain aging in genetically diverse UM-HET3 mice.
In males, Cana induced mitochondrial function, insulin and cGMP-PKG signaling, and suppressed neuroinflammatory networks across all molecular layers, resulting in improved hippocampal-dependent learning and memory. In females, transcriptional activation of neuroprotective pathways did not translate to protein or metabolite-level changes and failed to rescue cognition. In the 5xFAD AD model, Cana reduced amyloid plaque burden, microgliosis, and memory deficits in males only, despite comparable peripheral glucose control improvements in both sexes. Our study reveals sex-specific remodeling of hippocampal aging by a clinically available SGLT2i, with implications for AD pathology and lifespan extension, and highlights Cana's potential to combat brain aging and AD through sex-specific mechanisms.
Link: https://doi.org/10.1111/acel.70255
View the full article at FightAging
