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. The gene discussed is NFKB1; the disease is Insulin resistance.