Caloric restriction and aging (WP4191)

Caloric restriction leads to a decrease in the ATP/AMP ratio, thereby activating the key nutrient sensor of the body: AMPK. AMPK then blocks mTOR function, as mTOR has an important role in regulating the balance between cell growth and autophagy, nutrient decrease leads to the induction of autophagy. AMPK stimulates NAMPT function and PGC-1a release. NAMPT converts nicotinamide to nicotinamide mononucleotide for NAD+ synthesis. PGC-1a is the regulator of mitochondrial biosynthesis (increasing mitochondrial cell mass to produce more ATP) which thus will increase if more PGC-1a is released. Levels of NAD rise during caloric restriction leading to increased SIRT1 activity. SIRT1 blocks the Insulin/IGF-1 pathway. This is a very complex and paradoxal tissue, which need further investigation/research. Increased SIRT1 activity leads to activation of FOXO/p53 genes. FOXOs become phosphorylated by AKT and this may attenuate apoptotic stimuli and reduce antioxidative stress expression. In the end these effects result in increased stress resistance and improved lifespan and health span. Proteins on this pathway have targeted assays available via the [https://assays.cancer.gov/available_assays?wp_id=WP4191 CPTAC Assay Portal]

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