Sarcopenia, or age-associated muscle atrophy, is a progressive condition which affects ~10-30% of the human geriatric population (1, 2). A number of contributors to sarcopenia have been proposed, including the progressive loss of muscle stem cells (MuSCs) with age. However, studies in mice have provided evidence that MuSC depletion is not sufficient to induce sarcopenia (3, 4). We recently showed that in response to age-associated mitochondrial damage, MuSCs self-remove by fusing with neighboring myofibers, which depletes the stem cell population of damaged progenitors (5). Here, we show that MuSC-myofiber fusion is sufficient to initiate myofiber atrophy in mice, which limits their motor function and lifespan. Conversely, inhibition of MuSC-myofiber fusion blocks myofiber atrophy with age, with a concomitant increase in the maximum lifespan of animals. These findings suggest a model where the accumulation fusion of damaged MuSCs with adult myofibers is a key driving feature of sarcopenia, and resolves the findings that MuSC depletion on its own does not initiate myofiber atrophy.