Altogether, these results suggest that the naturally occurring functional MOTS-c deficiency increases the risk of sarcopenia and T2D by interacting with age and physical activity levels, and high physical activity levels, ≥150 min of MVPA per week, can alleviate the increased risk of sarcopenia and T2D in elderly men with MOTS-c deficiency by activating muscle CK2. Here, MT-RNR1 is linked to sarcopenia.