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levels decline 21% in 70-81 year olds vs 18-30 year olds Mechanisms of action •AMPK pathway activation: directly activates AMP-activated protein kinase in skeletal muscle, triggering metabolic adaptations and glucose uptake •NAD+/SIRT1 activation: elevates NAD+ levels and activates sirtuins (particularly SIRT1), critical metabolic cofactors for cell survival •Nuclear translocation: unique ability to travel to nucleus and influence gene expression related to metabolism via ARE/TFAM pathways •Glucose metabolism: enhances glucose uptake in muscle and adipose tissue, improving whole-body glucose homeostasis •Fatty acid oxidation: promotes lipid catabolism and reduces fat accumulation through metabolic gene activation •Methionine restriction mimetic: promotes methionine restriction effects (which extends mouse lifespan by 45% and reduces age-related diseases) •Most data from rodent models—human translation not established •Endogenous production declines with age, complicating supplementation logic •Optimal dosing and administration routes for research not standardized •Long-term effects of exogenous MOTS-c administration unknown •Not FDA approved for any therapeutic use Lee C, et al