Deregulated Nutrient-Sensing

What it is

Cells sense nutrient availability through four interlocking pathways: insulin/IGF-1 signalling (IIS), mTOR, AMPK, and sirtuins. Together they decide whether to grow and divide, or to conserve and repair. With age and especially with chronic over-nutrition, signalling through the “abundance” arms (IIS, mTOR) stays high, while the “scarcity” arms (AMPK, sirtuins) attenuate.

Why it matters in aging

The clearest cross-species lifespan-extension data come from reducing nutrient-sensing tone: dietary restriction extends lifespan in yeast, worms, flies, mice, and (with caveats) rhesus monkeys. Heterozygous IGF-1 receptor knockout extends female mouse lifespan; mTOR inhibition extends lifespan in mice of both sexes.

Mechanisms

• mTORC1 drives protein synthesis, lipid synthesis, and suppresses autophagy.
• Insulin/IGF-1 drives the FOXO transcription factor family (longevity-protective when activated).
• AMPK is activated by low ATP and promotes catabolism + autophagy.
• Sirtuins are NAD⁺-dependent deacetylases linking metabolism to chromatin.

What’s being studied

Caloric restriction, time-restricted eating, rapamycin, and metformin all act on this axis. NAD+ precursors target the sirtuin arm.

Related entries

See also: Disabled macroautophagy, Mitochondrial dysfunction.