Rescuing Healthspan in Obese, Aged Mice: A Comparison between Multi-Ingredient Nutraceuticals and Senolytic Interventions

Nutraceuticals, bioactive compounds derived from foods, are increasingly investigated as interventions to promote healthy ageing. Multi-ingredient formulations may offer additive or synergistic benefits by targeting multiple ageing pathways while using low doses of each component for improved safety. However, their efficacy in mammals remains poorly understood. Here, we compared the effects of a continuous multi-ingredient nutraceutical intervention with two short-courses of senolytic regimen in naturally aged male C57Bl/6J mice. Importantly, these mice were overweight following a switch to soaked food at 20 months, a protocol that increased caloric intake and likely induced metabolic stress. This context frames the study as a model of ‘rescue’ from premature ageing rather than extension of maximum lifespan. Mice were assigned to either control, nutraceutical (12 pro-longevity natural compounds), or senolytic (Navitoclax plus BAM15) groups at 20 months of age. Lifespan and healthspan indicators were assessed longitudinally. Both interventions improved survival compared to controls (median lifespan +18–21%) and mitigated frailty progression, but with distinct patterns: nutraceutical benefits accumulated gradually, whereas senolytic effects were transient. Cognitive performance was preserved in nutraceutical-treated mice and improved shortly after senolytic treatment. In vitro, the nutraceutical lacked senolytic activity but exhibited senostatic effects, reducing nuclear size, ROS release, and IL-6 secretion in senescent fibroblasts. These findings suggest that multi-ingredient nutraceuticals can restore healthspan compromised by metabolic stress and deliver benefits comparable to senolytics when administered continuously, potentially through senostatic mechanisms. Combining senolytics to reduce senescent burden with long-term nutraceutical treatment may offer a safe, accessible strategy to optimise healthspan, particularly in the context of modern human ageing, which often occurs under conditions of caloric excess and metabolic syndrome.