Sirtuins (SIRT1–7)
The longevity enzymes that depend on NAD+ to function
Definition
Sirtuins are a family of 7 deacylase proteins (SIRT1–7) that regulate cellular processes fundamental to longevity: DNA repair, genome stability, energy metabolism, stress response, inflammation, and the circadian clock. They were discovered in yeast (Sir2), where their overexpression extended lifespan by 30%. All sirtuins require NAD+ as a catalytic cofactor — without NAD+, sirtuins cannot function.
Detailed explanation
Each sirtuin has a specific localisation and function:
SIRT1 (nucleus/cytoplasm): the most studied. Deacetylates p53, NF-κB, FOXO. Regulates autophagy, inflammation, glucose and lipid metabolism. Activated by resveratrol, NAD+, and exercise.
SIRT3 (mitochondria): regulates mitochondrial metabolism, activates SOD2 (mitochondrial antioxidant). High levels correlate with longevity in centenarians.
SIRT6 (nucleus): repairs double-strand DNA breaks. Its overexpression extends lifespan in male mice by 15%.
SIRT7 (nucleolus): stabilises pericentromeric heterochromatin. Its dysfunction accelerates ageing.
David Sinclair (Harvard) proposes that the age-related decline in NAD+ 'starves' the sirtuins, making this a primary driver of ageing. NAD+ IV therapy aims to restore NAD+ levels to reactivate the sirtuins.
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