The modulation of key signaling pathways, such as AMPK–PGC-1α–SIRT1, PPARs, and NF-κB, has direct implications for the prevention and management of age-related metabolic disorders in physical activity-restricted individuals, and particularly with comorbidity presence such as T2DM, obesity and insulin resistance, sarcopenia, or cardiometabolic syndrome. Here, NFKB1 is linked to obesity due to melanocortin 4 receptor deficiency.