PI3K / AKT Signalling

•Mechanistic— One of the most-studied signalling cascades in biology

What it is

Phosphatidylinositol 3-kinase (PI3K) is activated when receptor tyrosine kinases (insulin/IGF-1 receptor, EGFR, others) engage their ligands. PI3K phosphorylates PIP₂ → PIP₃, recruiting AKT (also called PKB) to the membrane where PDK1 and mTORC2 fully activate it. AKT then phosphorylates dozens of substrates that drive:

• Cell growth and survival.
• Glucose uptake (GLUT4 translocation).
• Lipid and protein synthesis (via mTORC1).
• FOXO inactivation (suppresses stress-response genes).

Why it matters in aging

Persistent activation of PI3K–AKT is a hallmark of both cancer and metabolic disease. Reduced signalling through this axis (heterozygous IGF1R mutations, PI3K hypomorphs, FOXO3 longevity variants) is consistently associated with extended lifespan and reduced cancer in model organisms and centenarian cohorts.

Cross-talk

• mTORC1 is downstream — AKT inhibits TSC1/2, releasing Rheb to activate mTORC1.
• FOXO transcription factors are phosphorylated and excluded from the nucleus by AKT, blunting the longevity-protective FOXO programme.
• GSK-3 is inhibited by AKT, with effects on glycogen synthesis and Wnt signalling.
• NF-κB is potentiated by AKT, linking growth signalling to inflammation.

Pharmacology

Pan-PI3K and isoform-selective inhibitors (alpelisib, copanlisib) are approved in oncology with significant metabolic side effects (hyperglycaemia). AKT inhibitors (capivasertib) are emerging. Direct longevity application is mostly limited to indirect modulation via diet, exercise, metformin, and mTOR inhibitors.

Related entries

mTOR, Insulin / IGF-1, FOXO, Cancer.