Calpain activation has been postulated as a potential contributor to the loss of muscle mass and function associated with both aging and disease but limitations of previous experimental approaches have failed to completely examine this issue. We hypothesized that mice overexpressing calpastatin, an endogenous inhibitor of calpain (CalpOX), solely in skeletal muscle would show an amelioration of the aging muscle phenotype. We assessed 4 groups of mice (age in months): (1) young wild type (5.71±0.43) (WT); (2) young CalpOX (5.6±0.5); (3) old WT (25.81±0.56); and (4) old CalpOX (25.91±0.60) for diaphragm and limb muscle (extensor digitorum longus, EDL) force frequency relations. Aging significantly reduced diaphragm and EDL peak force in old WT mice, and decreased the force-time integral during a fatiguing protocol by 48% and 23% in aged WT diaphragm and EDL, respectively. In contrast, we found that CalpOX mice had significantly increased diaphragm and EDL peak force in old mice, similar to that observed in young mice. The impact of aging on the force-time integral during a fatiguing protocol was abolished in the diaphragm and EDL of old CalpOX animals. Surprisingly, we found that CalpOX had a significant impact on longevity, increasing median survival from 20.55 months in WT mice to 24 months in CalpOX mice (p = 0.0006).