PRKAG1 encodes the gamma-1 regulatory subunit of AMP-activated protein kinase (AMPK), a critical cellular energy sensor 12. As the nucleotide-binding component of the AMPK heterotrimer, PRKAG1 mediates allosteric activation by AMP and ADP while sensing inhibitory ATP levels, thereby controlling whether AMPK phosphorylates metabolic substrates 12. Upon energy stress, AMPK activation inhibits biosynthetic pathways and cell growth while promoting catabolic processes 12. PRKAG1 also regulates cellular polarity through actin cytoskeleton remodeling 12. Beyond metabolic homeostasis, PRKAG1 functions in autophagy regulation through DNA-dependent protein kinase-mediated phosphorylation at Ser192 and Thr284, promoting lysosomal AMPK localization and starvation-induced autophagy 3. PRKAG1 expression declines with aging, and sustained AMPKγ1 activation prevents metabolic dysfunction and supports longevity in aging models 4. Clinically, rare PRKAG1 variants associate with complex regional pain syndrome type 1 5, and transcriptome-wide association studies identify PRKAG1 as a novel cortical brain gene influencing Alzheimer's disease risk 6.