Sirtuins

a family of seven highly conserved proteins found in virtually every organism from yeast to humans.
named after Sir2 (Silent Information Regulator 2) - the yeast gene whose discovery launched the entire field when researchers found that extra copies of Sir2 extended yeast replicative lifespan.

sirtuins are proteins your body already makes. the question is how to activate and maintain them because they decline with age.

sirtuins attracted researcher attention when inducing sirtuin action was presumed responsible for lifespan-extending effects of caloric restriction (fasting).
perhaps that's why eugenia c looks so young.
intermittent fasting is effectively a sirtuin activation protocol.

sirtuins are NAD-dependent proteins that function as cellular guardians regulating DNA repair, metabolism, and inflammation. these longevity proteins require NAD as fuel and become less active with age contributing to cellular dysfunction.

the seven sirtuins - locations and roles:
nuclear sirtuins: SIRT1, SIRT6, SIRT7 - protect DNA and regulate gene expression. mitochondrial sirtuins: SIRT3, SIRT4, SIRT5 - control energy production and metabolism. cytoplasmic sirtuin: SIRT2 - manages cell division and cellular processes.

SIRT1 overexpression or pharmacological SIRT1 activation in mice has been shown to prevent metabolic and age-related disease including insulin resistance, obesity and liver steatosis.

SIRT1 is the caloric restriction mediator. activated by fasting, it deacetylates and activates FOXO transcription factors (driving stress resistance and longevity genes), PGC-1α (mitochondrial biogenesis), NF-κB suppression (anti-inflammatory), p53 deacetylation (cancer suppression), and PPAR-γ deacetylation (fat metabolism). resveratrol's primary mechanism (the most famous longevity molecule) is SIRT1 activation.

SIRT3 mitochondrial deficits associated with aging and neurodegeneration might be slowed or prevented by SIRT3 activation. emerging data supports neuroprotective action of SIRT3 against Alzheimer's disease, Huntington's disease, Parkinson's disease, and ALS.

SIRT3 deacetylates and activates the mitochondrial antioxidant enzyme manganese superoxide dismutase (MnSOD) - the primary defense against mitochondrial free radical damage. it also activates ATP synthase subunits improving mitochondrial energy efficiency. declining SIRT3 activity with age is a primary driver of the mitochondrial dysfunction that underlies neurodegeneration.

SIRT6 is the telomere maintenance sirtuin. it deacetylates histone H3K9 at telomeric chromatin, preventing telomere dysfunction. mammals lacking SIRT6 develop accelerated aging with metabolic defects, genomic instability, and shortened lifespan. SIRT6 also suppresses cancer by maintaining genome stability and controlling the Warburg effect — it deacetylates histone H3K9 at glycolytic gene promoters, reducing the excessive glucose consumption that characterizes cancer cells.

in response to caloric restriction there is increased SIRT1 activity.

NAD+ boosters confer pan-sirtuin activation with protective cardiometabolic effects: they improve endothelial dysfunction, protect from experimental heart failure, hypertension, and decrease progression of liver steatosis.

phytochemicals such as berberine, curcumin, fisetin, kaempferol, quercetin, and resveratrol can support sirtuin activity mainly through SIRT1.

honokiol (from magnolia bark), potent SIRT3 and SIRT5 activator, neuroprotective. one of the strongest natural mitochondrial sirtuin activators identified.

spermidine, polyamine found in fermented foods, wheat germ, and aged cheese. activates autophagy and SIRT1 simultaneously. one of the best-evidenced longevity compounds from food.

pterostilbene, the methylated form of resveratrol with 4x greater bioavailability. present in blueberries. more potent SIRT1 activation per dose than resveratrol.

NAD+ levels in human tissue decline approximately 50% between age 40 and 60.

Sirtuins = proteins that maintain cellular health and slow aging while cells are still functional, they're the prevention side.