Caloric restriction and aging (WP4191)

Homo sapiens

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 [ CPTAC Assay Portal]


Denise Slenter , Egon Willighagen , and Kristina Hanspers


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Homo sapiens



Pathway Ontology

aging pathway autophagy pathway oxidative stress response pathway


Label Type Compact URI Comment
ATP Metabolite chebi:15422
AMP Metabolite chebi:16027
NAD Metabolite chebi:13389
mTOR GeneProduct ensembl:ENSG00000198793
NAMPT GeneProduct ensembl:ENSG00000105835
AMPK GeneProduct ensembl:ENSG00000131791
SIRT1 GeneProduct ensembl:ENSG00000096717
insulin/IGF1 GeneProduct ensembl:ENSG00000017427
PGC-1a GeneProduct ensembl:ENSG00000109819
FOXO GeneProduct ensembl:ENSG00000214295
AKT GeneProduct ensembl:ENSG00000142208
p53 GeneProduct ensembl:ENSG00000141510


  1. The hallmarks of aging. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Cell. 2013 Jun 6;153(6):1194–217. PubMed Europe PMC Scholia