# Lifespan‐Extending Endogenous Metabolites **Authors:** Yizhou Jiang, Jing‐Dong J. Han PMC · DOI: 10.1111/acel.70371 · Aging Cell · 2026-01-12 ## TL;DR This paper reviews how certain natural metabolites in the body can extend lifespan by influencing aging-related processes and metabolic pathways. ## Contribution The paper provides a comprehensive review of how endogenous metabolites influence aging and healthspan across species. ## Key findings - Endogenous metabolites modulate conserved cellular pathways to influence longevity. - Metabolites integrate into networks affecting multiple aging-related pathways. - Metabolite-based interventions show promise for extending healthspan with minimal adverse effects. ## Abstract Aging is a multifactorial process influenced by genetic, environmental, and metabolic factors. Dysregulated nutrient sensing and metabolic dysfunction are hallmarks of aging, and reduction of insulin/IGF‐1 signaling or metabolic interventions such as caloric restriction extend lifespan across species. Endogenous metabolites reflect and mediate these metabolic cues, linking nutrient status to epigenetic and transcriptional programs by serving as cofactors for chromatin‐modifying enzymes or as allosteric modulators of transcription factors. Some metabolites have emerged as key regulators of longevity, integrating into networks to concurrently influence multiple aging‐related pathways. In this review, we summarize evidence supporting the lifespan‐extending effects of key endogenous metabolites across diverse model organisms and discuss their mechanisms of action. These insights underscore the potential of targeting metabolic networks as a multifaceted strategy to delay aging. Finally, we consider the translational promise of metabolite‐based interventions to extend healthspan while minimizing adverse effects, and we note remaining challenges such as optimal dosing, context‐specific effects, and demonstrating efficacy in humans. Endogenous metabolites act as mediators of longevity by modulating conserved cellular pathways. We summarize mechanistic evidence linking specific metabolites to lifespan and healthspan benefits across model systems, with discussion of clinical evidence, translational opportunities, and remaining knowledge gaps. ## Full-text entities - **Genes:** Ern2 (endoplasmic reticulum to nucleus signalling 2) [NCBI Gene 26918] {aka Ern1, Ire1, Ire1b, ire1-beta, mIre1}, gsy-1 (Glycogen) [NCBI Gene 174924], FAHD1 (FAH domain containing oxaloacetate decarboxylase 1) [NCBI Gene 81889] {aka C16orf36, ODx, YISKL}, sams-1 (putative S-adenosylmethionine synthase 1) [NCBI Gene 181370], HCAR1 (hydroxycarboxylic acid receptor 1) [NCBI Gene 27198] {aka FKSG80, GPR104, GPR81, HCA1, LACR1, TA-GPCR}, Sst (somatostatin) [NCBI Gene 20604] {aka SOM, SRIF, SS, Smst}, Il10 (interleukin 10) [NCBI Gene 16153] {aka CSIF, If2a, Il-10}, daf-2 (Insulin-like receptor subunit beta;Protein kinase domain-containing protein;receptor protein-tyrosine kinase) [NCBI Gene 175410], PDE4C (phosphodiesterase 4C) [NCBI Gene 5143] {aka DPDE1, PDE21}, ASPA (aspartoacylase) [NCBI Gene 443] {aka ACY2, ASP}, MTR (5-methyltetrahydrofolate-homocysteine methyltransferase) [NCBI Gene 4548] {aka HMAG, MS, cblG}, SUCNR1 (succinate receptor 1) [NCBI Gene 56670] {aka GPR91}, Mss51 (MSS51 mitochondrial translational activator) [NCBI Gene 74843] {aka 4833444M15Rik, Zmynd17}, Skn1 (skin antigen 1) [NCBI Gene 103985] {aka Sk-1, Skn-1}, Cd55b (CD55 molecule, decay accelerating factor for complement B) [NCBI Gene 13137] {aka Daf, Daf-TM, Daf2, TM-DAF}, cth-1 (cystathionine gamma-lyase) [NCBI Gene 180079], tps-2 (Alpha,alpha-trehalose-phosphate synthase;Trehalose-6-phosphate phosphatase C-terminal domain-containing protein) [NCBI Gene 3565050], ATG8 (ubiquitin-like protein ATG8) [NCBI Gene 852200] {aka APG8, AUT7, CVT5}, Atg7 (autophagy related 7) [NCBI Gene 74244] {aka 1810013K23Rik, Agp7, Apg7l, Atg7l, Gm21553}, Irs2 (insulin receptor substrate 2) [NCBI Gene 384783] {aka Irs-2}, Eif4g2 (eukaryotic translation initiation factor 4, gamma 2) [NCBI Gene 13690] {aka DAP-5, E130105L11Rik, Nat1, Natm1, p97}, GPBAR1 (G protein-coupled bile acid receptor 1) [NCBI Gene 151306] {aka BG37, GPCR19, GPR131, M-BAR, TGR5}, Mtor (mechanistic target of rapamycin kinase) [NCBI Gene 56717] {aka 2610315D21Rik, FRAP, FRAP2, Frap1, RAFT1, RAPT1}, Nfkb1 (nuclear factor of kappa light polypeptide gene enhancer in B cells 1, p105) [NCBI Gene 18033] {aka NF-KB1, NF-kappaB, NF-kappaB1, p105, p50, p50/p105}, Pten (phosphatase and tensin homolog) [NCBI Gene 19211] {aka 2310035O07Rik, A130070J02Rik, B430203M17Rik, MMAC1, PTENbeta, TEP1}, cbs-1 (Cystathionine beta-synthase cbs-1) [NCBI Gene 181215], Tbk1 (TANK-binding kinase 1) [NCBI Gene 56480] {aka 1200008B05Rik}, Ppargc1a (peroxisome proliferative activated receptor, gamma, coactivator 1 alpha) [NCBI Gene 19017] {aka A830037N07Rik, Gm11133, PGC-1, PPARGC-1-alpha, Pgc-1alpha, Pgc1}, Gimap5 (GTPase, IMAP family member 5) [NCBI Gene 317757] {aka D630024P16, E230026N22Rik}, Fgf2 (fibroblast growth factor 2) [NCBI Gene 14173] {aka Fgf-2, Fgf2a, Fgfb, bFGF}, Nfe2l2 (nuclear factor, erythroid derived 2, like 2) [NCBI Gene 18024] {aka Nrf2}, Becn1 (beclin 1, autophagy related) [NCBI Gene 56208] {aka Atg6}, Abcc9 (ATP-binding cassette, sub-family C member 9) [NCBI Gene 20928] {aka SUR2A, SUR2B, Sur2}, ATG7 (Atg7p) [NCBI Gene 856576] {aka APG11, APG7, CVT2}, ATG5 (Atg5p) [NCBI Gene 855954] {aka APG5}, Casp1 (caspase 1) [NCBI Gene 12362] {aka ICE, Il1bc}, Eif5a (eukaryotic translation initiation factor 5A) [NCBI Gene 276770] {aka D19Wsu54e, Eif4d, Eif5a1, eIF-4D, eIF-5A, eIF-5A-1}, Atp5f1b (ATP synthase F1 subunit beta) [NCBI Gene 11947] {aka Atp5b}, tor (tortured) [NCBI Gene 21977], H3c7 (H3 clustered histone 7) [NCBI Gene 260423] {aka H3.2-221, H3c13, H3c14, H3c15, H3c2, H3c3}, BHMT (betaine--homocysteine S-methyltransferase) [NCBI Gene 635] {aka BHMT1, HEL-S-61p}, Mettl21c (methyltransferase 21C, AARS1 lysine) [NCBI Gene 433294] {aka A530098C11Rik}, Vdr (vitamin D (1,25-dihydroxyvitamin D3) receptor) [NCBI Gene 22337] {aka Nr1i1}, Rps6kb1 (ribosomal protein S6 kinase B1) [NCBI Gene 72508] {aka 2610318I15Rik, P70S6K1, S6K, S6K-beta-1, S6K1, p70 S6K-alpha}, SCH9 (serine/threonine protein kinase SCH9) [NCBI Gene 856612] {aka HRM2, KOM1}, INS (insulin) [NCBI Gene 3630] {aka IDDM, IDDM1, IDDM2, ILPR, IRDN, MODY10}, Map1s (microtubule-associated protein 1S) [NCBI Gene 270058] {aka 6430517J16Rik, Bpy2ip1, Map8, Mtap1s, VCY2IP1}, Nlrp3 (NLR family, pyrin domain containing 3) [NCBI Gene 216799] {aka AGTAVPRL, AII/AVP, Cias1, FCAS, FCU, MWS}, IGF1 (insulin like growth factor 1) [NCBI Gene 3479] {aka IGF, IGF-I, IGFI, MGF}, Akt1 (Akt serine/threonine kinase 1) [NCBI Gene 11651] {aka Akt, LTR-akt, PKB, PKB/Akt, PKBalpha, Rac}, Xbp1 (X-box binding protein 1) [NCBI Gene 22433] {aka D11Ertd39e, TREB-5, TREB5, XBP-1}, sir-2.1 (NAD-dependent protein deacetylase sir-2.1) [NCBI Gene 177924], Igf1 (insulin-like growth factor 1) [NCBI Gene 16000] {aka C730016P09Rik, Igf-1, Igf-I}, Msra (methionine sulfoxide reductase A) [NCBI Gene 110265] {aka 2310045J23Rik, 6530413P12Rik, MSR-A}, Atg5 (autophagy related 5) [NCBI Gene 11793] {aka 2010107M05Rik, 3110067M24Rik, Apg5l, Atg5l, Paddy}, Gulo (gulonolactone (L-) oxidase) [NCBI Gene 268756] {aka 5730581M22, GLO, LGO, sfx, unh, unhip}, Tgfb1 (transforming growth factor, beta 1) [NCBI Gene 21803] {aka TGF-beta1, TGFbeta1, Tgfb, Tgfb-1}, Yy1 (YY1 transcription factor) [NCBI Gene 22632] {aka NF-E1, YY-1}, Insr (insulin receptor) [NCBI Gene 16337] {aka 4932439J01Rik, CD220, D630014A15Rik, IR, IR-A, IR-B}, Gsk3b (glycogen synthase kinase 3 beta) [NCBI Gene 56637] {aka 7330414F15Rik, 8430431H08Rik, GSK-3, GSK-3beta, GSK3} - **Diseases:** neurodegeneration (MESH:D019636), hypertension (MESH:D006973), neuroinflammation (MESH:D000090862), mitochondrial dysfunction (MESH:D028361), paralysis (MESH:D010243), VB12 deficiency (MESH:D014806), frailty (MESH:D000073496), obese (MESH:D009765), muscle loss (MESH:D009135), osteoporosis (MESH:D010024), toxicity (MESH:D064420), liver fibrosis (MESH:D008103), CR (MESH:D002313), cancer (MESH:D009369), hepatocellular carcinoma (MESH:D006528), IIS (MESH:C564816), neurotoxic (MESH:D020258), tumorigenic (MESH:D002471), endogenous ketogenesis deficiency (MESH:D011017), type 2 diabetes (MESH:D003924), peripheral artery disease (MESH:D058729), overweight (MESH:D050177), prediabetic (MESH:D011236), heart failure (MESH:D006333), cardiovascular disease (MESH:D002318), cognitive decline (MESH:D003072), AD (MESH:D000544), memory deficits (MESH:D008569), glucose intolerance (MESH:D018149), metabolic syndrome (MESH:D024821), non-alcoholic fatty liver disease (MESH:D065626), Insulin Resistance (MESH:D007333), diabetes (MESH:D003920), metabolic dysfunction (MESH:D008659), inflammation (MESH:D007249), ALS (MESH:D000690), cardiac dysfunction (MESH:D006331), chronic kidney disease (MESH:D051436), adiposity (MESH:D018205), Trehalose (MESH:C562603), temporomandibular joint osteoarthritis (MESH:D013706) - **Chemicals:** glucose (MESH:D005947), sugar (MESH:D000073893), leucine (MESH:D007930), VD3 (MESH:D002762), minocycline (MESH:D008911), amino acid (MESH:D000596), phosphatidylinositol (MESH:D010716), S-adenosylhomocysteine (MESH:D012435), Betaine (MESH:D001622), polyamine (MESH:D011073), trehalose-6-phosphate (MESH:C082722), Lipid (MESH:D008055), glutamate (MESH:D018698), fatty acids (MESH:D005227), VB12 (MESH:D014805), S-adenosylmethionine (MESH:D012436), calcium (MESH:D002118), choline (MESH:D002794), valine (MESH:D014633), guanine (MESH:D006147), MI (MESH:D007294), beta-hydroxybutyrate (MESH:D020155), VC (MESH:D001205), lactate (MESH:D019344), Ceramides (MESH:D002518), sulfur- (MESH:D013455), D-galactose (MESH:D005690), glucose-6-phosphate (MESH:D019298), Ketone (MESH:D007659), succinyl-CoA (MESH:C012046), glyoxylate (MESH:C031150), BCAA (MESH:D000597), TMAO (MESH:C005855), citrate (MESH:D019343), glycine (MESH:D005998), Ca-AKG (MESH:D007656), putrescine (MESH:D011700), L-Ile (-), Metformin (MESH:D008687), Methionine (MESH:D008715), Ginsenosides (MESH:D036145), H2S (MESH:D006862), sodium (MESH:D012964), cysteine (MESH:D003545), sphingolipid (MESH:D013107), dcSAM (MESH:C012702), NR (MESH:C018613), GABA (MESH:D005680), oxygen (MESH:D010100), carbohydrate (MESH:D002241), Taurine (MESH:D013654), 7-dehydrocholesterol (MESH:C016705), PC (MESH:D010713), ROS (MESH:D017382), homocysteine (MESH:D006710), acetic acid (MESH:D019342), ATP (MESH:D000255), succinate (MESH:D019802), oligomycin (MESH:D009840), NaHS (MESH:C025451) - **Species:** Panax ginseng (Asiatic ginseng, species) [taxon 4054], C. elegans [taxon 328850], Mus musculus (house mouse, species) [taxon 10090], Caenorhabditis elegans (species) [taxon 6239], Saccharomyces cerevisiae (baker's yeast, species) [taxon 4932], Rattus norvegicus (brown rat, species) [taxon 10116], Cercopithecidae (monkey, family) [taxon 9527], Drosophila melanogaster (fruit fly, species) [taxon 7227], Schizosaccharomyces pombe (fission yeast, species) [taxon 4896], Diptera (flies, order) [taxon 7147], Homo sapiens (human, species) [taxon 9606] - **Mutations:** G93A ## Full text _Full body text omitted from this summary view._ Fetch the complete paper as Markdown: https://tomesphere.com/paper/PMC12796513/full.md ## Figures 1 figure with captions in the complete paper: https://tomesphere.com/paper/PMC12796513/full.md ## References 204 references — full list in the complete paper: https://tomesphere.com/paper/PMC12796513/full.md --- Source: https://tomesphere.com/paper/PMC12796513