Metformin promotes healthspan by attenuating frailty and preserving musculoskeletal function-structure in middle-aged mice.

As global life expectancy rises, age-related musculoskeletal decline poses a growing public health challenge-impairing mobility, increasing frailty, and diminishing quality of life for billions worldwide. Functional deterioration often begins in midlife, yet effective early interventions remain limited. Metformin, a widely prescribed antidiabetic drug, has shown geroprotective potential. However, its capacity to preserve musculoskeletal health during early aging remains poorly defined. Addressing this gap is critical to developing scalable, cost-effective strategies to extend healthspan. Here, we investigated the effects of midlife metformin treatment in male C57BL/6 J mice by comparing young, untreated middle-aged, and metformin-treated middle-aged groups. Metformin treatment was initiated at 30 weeks of age and continued through 53 weeks. Frailty was evaluated using composite clinical and functional indices, while musculoskeletal health was assessed through motor tests and detailed histological analyses of muscle, bone, and joint tissues. Metformin-treated middle-aged mice maintained body weight comparable to that of young adult controls, preventing excessive age-associated weight gain. Both clinical and performance-based frailty scores were significantly attenuated. Muscle strength, endurance, and mass were preserved, alongside increased muscle fiber size, enhanced capillary density, and reduced fibrotic remodeling. Bone integrity was similarly maintained, evidenced by preserved trabecular architecture, osteoblast abundance, and collagen organization. Additionally, metformin supported locomotor function by preserving gait parameters and knee joint structure, including articular cartilage thickness and chondrocyte integrity. Collectively, these findings demonstrate that metformin administration supports healthspan by attenuating frailty and preserving musculoskeletal integrity in middle-aged mice, reinforcing its potential as a scalable geroprotective intervention targeting early aging.