Pathway

Longevity gene

SIRT1

The Longevity Switch

17 blends on this site modulate it.

Also searched as SIRT1.

You want it active: it is the switch fasting, exercise and resveratrol-class compounds reach for.

In depth

A sirtuin enzyme that tunes metabolism, DNA repair and mitochondrial health toward the state linked with longer healthspan.

What drives it

Fasting response increases it.

Cohen 2004, Science 305:390 — expression of the SIRT1 deacetylase is induced by caloric restriction; CR could extend lifespan by inducing SIRT1. PMID 15205477. Verified: across modalities CR and intermittent fasting consistently activate AMPK and sirtuins, inhibit mTOR and enhance autophagy, aligning with improved insulin sensitivity, lipid profile, low-grade inflammation and selected epigenetic aging measures in humans. CR-mimetics (metformin, resveratrol, rapamycin, spermidine) only partially reproduce these effects and their long-term safety and efficacy in healthy populations remain incompletely defined. PMID 15205477

Energy sensing increases it.

Cantó 2009, Nature 458:1056 — AMPK raises cellular NAD+, activating SIRT1. PMID 19262508. Mouse skeletal muscle. The route is disputed: one group proposes NAMPT upregulation as the AMPK-SIRT1 linkage, while Canto found AMPK alters NAD+/NADH and activates SIRT1 apparently independently of NAMPT (PMC2853213). The link holds; the mechanism between them does not have one settled account. PMID 19262508 · PMC2853213

Cellular fuel increases it.

Cantó 2009, Nature 458:1056 — NAD+ is the obligate co-substrate that activates the SIRT1 deacetylase. PMID 19262508. Mouse skeletal muscle. SIRT1 is NAD+-dependent by definition; the NAMPT-dependent vs NAMPT-independent route is disputed (PMC2853213). NAD+ is the substrate, not a modulator — sirtuins consume it to deacetylate, so the arrow is stoichiometric: it is described as indispensable for sirtuin activity. Human randomized evidence: in a double-blind, randomized, crossover trial a salvage-pathway-targeting supplement raised whole-blood NAD+, and that rise was accompanied by increased SIRT1 and increased NAMPT in peripheral blood mononuclear cells, alongside lower plasma IL-2, reduced glycated serum protein, and an IgG glycosylation shift toward a younger biological age. measured in blood, not in the tissues where the aging phenotype lives — and Nat Metab 2025 reviews NAD+ precursor trials specifically to flag the crucial knowledge gaps that remain. PMID 19262508 · PMC2853213

Alcohol metabolism reduces it.

SIRT1 is an NAD-dependent deacetylase, so the same redox shift that blocks fat oxidation also represses SIRT1 activity (PMC4941543). This is why alcohol metabolically mimics the fed state even in the absence of food. PMC4941543

Central fuel molecule reduces it.

Acetyl-CoA availability sets histone acetylation, which sirtuins oppose - the two are in direct opposition on the same substrate. Carried by the intermediary-metabolism and clinical reviews. doi 10.1016/j.molmet.2023.101755 · PMC9967593

Ketone fuel increases it.

Verbatim: 'BHBA significantly improved water maze performance; increased the ACh content, SOD activity, and SIRT1 expression; and decreased AChE and LDH activity, ROS, MDA, IL-1β, TNF-α contents, and NLRP3 expression.' (DOI 10.3389/fphar.2021.751028). What was measured: SIRT1 expression in hippocampus / HT22 cells (measured alongside water maze performance, ACh, SOD, AChE, LDH, ROS, MDA, IL-1β, TNF-α, NLRP3), in D-galactose-injured mice. doi 10.3389/fphar.2021.751028

Calms inflammation reduces it.

NF-kB signaling down-regulates SIRT1 activity through the expression of miR-34a, IFN-gamma and reactive oxygen species; SIRT1 inhibits NF-kB directly by deacetylating the p65 subunit. doi 10.1016/j.cellsig.2013.06.007 · PMC6770793

Spares NAD⁺ during DNA repair reduces it.

PARP1 hyperactivation consumes the NAD+ pool that SIRT1 requires as its cosubstrate. PMID 21459330

Curbs the main NAD⁺ consumer reduces it.

CD38 is the dominant NAD+ consumer limiting sirtuin cosubstrate availability with age. PMID 16935261

What it drives

It increases Heat shock master switch.

Westerheide 2009, Science 323:1063 — SIRT1 deacetylates HSF1, sustaining its DNA-binding and prolonging the heat-shock response; links the SIRT1 longevity factor to proteostasis. PMID 19229036

It reduces Blocks new fat cells.

Picard 2004, Nature 429:771 — SIRT1 binds and represses PPAR-γ (docking with NCoR/SMRT corepressors), promoting fat mobilization in white adipocytes. PMID 15175761

It increases Protects DNA caps.

Palacios 2010, J Cell Biol 191:1299 — SIRT1 positively regulates telomere length in vivo and blunts age-related telomere shortening. PMID 21187328

It reduces Calms inflammation.

Yeung 2004, EMBO J 23:2369 — SIRT1 deacetylates RelA/p65 at Lys310, inhibiting NF-κB transcription. PMID 15152190. Mechanism: SIRT1 is the primary deacetylase of the NF-kappa-B p65 subunit at lysine 310. Bidirectional evidence, which is rare and strong: SIRT1 overexpression attenuated TNF-alpha-induced p65 acetylation, while SIRT1 inhibition by EX-527 increased it. Small-molecule SIRT1 activators suppressed TNF-alpha-induced NF-kappa-B transcriptional activation and reduced LPS-stimulated TNF-alpha secretion in A SIRT1-dependent manner, and in an acute mouse LPS model the STAC SRTCX1003 decreased TNF-alpha and IL-12 production in vivo. Additional routes: SIRT1 inhibits IkB degradation, and resveratrol blocks nuclear aggregation of p65 and its DNA binding. SIRT1 suppresses NF-kappa-B activity while NF-kappa-B induces SIRT1 expression: a negative feedback loop. PMID 15152190

It increases Builds mitochondria.

Cantó 2009, Nature 458:1056 — SIRT1 deacetylates and activates PGC-1α. PMID 19262508. Mouse skeletal muscle. SIRT1 also deacetylates FOXO1 and FOXO3a in the same paper -- PGC-1a is one target among several, not the sole one. SIRT1 deacetylates PGC-1-alpha, and the effect is both post-translational and transcriptional: SIRT1 positively regulated the level of Pgc-1-alpha transcription, likely because a deacetylated PGC-1-alpha coactivates FOXO more strongly at its own promoter — a self-amplifying loop. In the SCN, neuronal SIRT1 and PGC-1-alpha bind cooperatively and in close proximity at the Bmal1 promoter. SIRT1 is NAD+-DEPENDENT, so this arrow only carries flux when NAD+ is available — see the NAD⁺ → SIRT1 link. PMID 19262508

It increases Cellular cleanup.

Lee 2008, pnas 105:3374 — SIRT1 deacetylates Atg5/7/8, required for autophagy induction. DOI 10.1073/pnas.0712145105. Mechanism is direct deacetylation of the autophagy machinery itself: SIRT1 deacetylates FOXO3, beclin 1, atg proteins and LC3. Loss-of-function: SIRT1-silenced cells showed down-regulated autophagy in both parental and chemoresistant lines. demonstrated in HepG2 and Huh-7 hepatocellular carcinoma cell lines in a sorafenib-resistance model — a cancer-drug-resistance context, not normal tissue physiology, and SIRT1 in that setting was elevated alongside activated nf-kappa-B, which runs opposite to the suppressive relationship above. Context decides. Essential, not merely contributory: deacetylation of FOXO by SIRT1 plays an essential role in mediating starvation-induced autophagy in cardiac myocytes (Hariharan 2010, Circ Res 107:1470). But the linear model is complicated by its own opposite: the perception of a linear SIRT1-FOXO axis is complicated by findings that acetylated FoxO1 — the UNdeacetylated form — binds ATG7 in the cytoplasm and drives autophagy directly, under prolonged stress when FoxO1 dissociates from cytoplasmic SIRT2 and becomes hyperacetylated. Both acetylation states can reach autophagy by different routes. doi 10.1073/pnas.0712145105.

It increases Brain adaptability.

Tested in both directions in the same work: SIRT1-knockout mice showed impaired immediate memory, classical conditioning and spatial learning, and the deficits were associated with defects in synaptic plasticity — with basal synaptic transmission and NMDA-receptor function unchanged, which localises the effect to plasticity itself; mice overexpressing SIRT1 in brain had normal plasticity and memory. The authors conclude SIRT1 is indispensable for normal learning, memory and synaptic plasticity (PMC2921958). Mechanism: a SIRT1/YY1 repressor complex regulates miR-134, which in turn regulates CREB and BDNF, and SIRT1-null mice show decreased long-term potentiation in hippocampal CA1 (PMC4040287). Hippocampal SIRT1 knockdown damages plasticity in healthy animals and re-expression rescues it (PMC10848102). Note this runs through BDNF rather than around it. PMC2921958

It increases Body clock.

SIRT1 is a circadian deacetylase acting on core clock components, and hypothalamic functions including circadian rhythmicity are regulated by SIRT1 (PMC4040287, reviewing Asher 2008, Nakahata 2008 and Belden & Dunlap, Cell 2008;134:212). This is the metabolic arm of the clock: the same NAD-dependent enzyme that reads energy status also sets time. The literature contradicts itself on this edge's sign and both sides ARE recorded here. Activator: SIRT1 in the brain governs central circadian control by activating the transcription of the two major circadian regulators, BMAL1 and clock, forming an amplifying loop with PGC-1-alpha and Nampt (Cell 2013). Repressor: SIRT1 acts as a negative regulator by deacetylating BMAL1 and histones at circadian gene promoters to promote repression by the inhibitory limb of the oscillator, and separately deacetylates PER2 to facilitate its ubiquitination and degradation. The aging evidence is the strongest part and is not disputed: in aged wild-type mice SCN SIRT1 falls, BMAL1 and PER2 fall with it, and the animals show a longer intrinsic period, a more disrupted activity pattern, and an inability to adapt to changes in light entrainment. Aging lowers NAD+, which lowers SIRT1, which reduces circadian amplitude and desynchronises peripheral clocks. PMC4040287

It increases Supports BDNF signaling.

Gating the two drivers of neuroplasticity revealed they are one pathway, not two — but the note filed at the time was explicit: search it on its own evidence, do not assume it from the neuroplasticity work. It was searched separately. It clears the bar. The mechanism is measured at the promoter, not inferred from behavior: in SIRT1-deficient mice, BDNF and CREB ARE downregulated while miR-134 is up-regulated — shown as BDNF mRNA and Western blot, with chromatin immunoprecipitation using an anti-CREB antibody followed by qPCR for BDNF promoters 1, 2 and 4. The transcription factor was caught at the gene. The route is named: SIRT1 functions to limit expression of miR-134 via a repressor complex containing the transcription factor YY1, and unchecked miR-134 expression following SIRT1 deficiency results in the downregulated expression of CREB and BDNF. And it is confirmed pharmacologically by a different group using a different tool: resveratrol treatment increases SIRT1, p-CREB, CREB and BDNF expression and decreases miR-134 levels in hippocampus, and the authors conclude the effects of resveratrol ARE mediated by activating the SIRT1/miR-134 pathway. Genetic deletion and pharmacological activation, opposite directions, same axis. A second independent route is also reported: resveratrol via SIRT1 directly deacetylates MeCP2 and promotes BDNF transcription — MeCP2 being a known repressor at the BDNF locus. Two mechanisms, one direction. And miR-134 inhibition alone restores CREB and BDNF in an amyloid model of Alzheimer’s, which isolates the microRNA step from SIRT1 entirely. What this fixes: the SIRT1 → Synaptic Plasticity link and the BDNF → Synaptic Plasticity link were drawn as independent parallel inputs, which made SIRT1 and BDNF look like two separate levers when one is upstream of the other. They are now correctly ordered. rodent hippocampus and cell culture throughout. A ResearchGate mirror appeared and the primary sources were used. doi 10.1016/j.bbr.2018.04.052 · PMC2928875

It reduces Cellular aging.

Named across five inflammaging and hallmarks-of-aging reviews as part of the shared mechanism set that links molecular damage to organ decline: nutritional perception dysregulation and inflammatory aging ARE the core key elements linking upstream molecular damage to downstream organ function decline. doi 10.1016/j.molmet.2023.101755 · PMC11233824