Gut microbiota-derived caproic acid attenuates aging-associated arteriosclerosis

Abstract

Aim: Aging is an irreversible primary risk factor for arteriosclerosis, causing high cardiovascular morbidity-mortality in the elderly via vascular remodeling and cellular senescence. Gut microbiota-derived short-chain fatty acids (SCFAs) exert cardiovascular protective effects, yet cross-species functional SCFAs counteracting age-related arteriosclerosis remain unclear. This study aimed to identify conserved SCFAs linked to vascular aging and validate caproic acid’s protective function against AngII-induced arteriosclerosis.

Methods: We assessed vascular aging phenotypes in young (8-week) and aged (24-month) mice and a human cohort (97 young < 65 years, 30 old ≥ 65 years). Serum SCFAs were quantified by targeted GC-MS. Correlation and mediation analyses evaluated relationships between caproic acid, pulse pressure (PP), and pulse wave velocity (PWV). Caproic acid protection was validated in AngII-induced arteriosclerosis mice and MOVAS cells.

Results: Circulating SCFAs declined with aging in humans and mice. Caproic acid and butyric acid were the two shared significantly down-regulated SCFAs. Serum caproic acid negatively correlated with human PP, and with both PP and aortic PWV in mice. Mediation analysis showed caproic acid directly ameliorated age-related vascular dysfunction. In AngII-treated mice, caproic acid reduced systolic blood pressure, PP and aortic PWV, mitigated aortic remodeling and elastic fiber damage, and suppressed vascular senescence protein upregulation. Gpr41 knockdown in MOVAS cells eliminated caproic acid’s anti-senescence effect, confirming GPR41-dependent protection.

Conclusion: Caproic acid acts as a conserved metabolite against age-related arteriosclerosis by inhibiting vascular cell senescence and improving hemodynamics, representing a promising therapeutic target for arteriosclerosis.

Keywords

Gut microbiota / caproic acid / sodium caproate / arteriosclerosis / vascular aging

References

[1] Sun Z.Aging, arterial stiffness, and hypertension.Hypertension2015;65:252-6

[2] Minamino T,Tateno K.Ras induces vascular smooth muscle cell senescence and inflammation in human atherosclerosis.Circulation2003;108:2264-9

[3] Libby P.Inflammation in atherosclerosis.Nature2002;420:868-74

[4] Laurent S,Asmar R.Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in hypertensive patients.Hypertension2001;37:1236-41

[5] Perler BK,Wu GD.The role of the gut microbiota in the relationship between diet and human health.Annu Rev Physiol2023;85:449-68

[6] Canfora EE,Blaak EE.Short-chain fatty acids in control of body weight and insulin sensitivity.Nat Rev Endocrinol2015;11:577-91

[7] Yang F,Gao Y.Gut microbiota-derived short-chain fatty acids and hypertension: Mechanism and treatment.Biomed Pharmacother2020;130:110503

[8] O’donnell JA,Meric G.The gut microbiome and hypertension.Nat Rev Nephrol2023;19:153-67

[9] Liu T,Yang Z.Microbiota-derived short-chain fatty acids and modulation of host-derived peptides formation: focused on host defense peptides.Biomed Pharmacother2023;162:114586

[10] Hu T,Yao Q,Yu J.Short-chain fatty acid metabolism and multiple effects on cardiovascular diseases.Ageing Res Rev2022;81:101706

[11] Verhaar BJ,Wortelboer K.Effects of oral butyrate on blood pressure in patients with hypertension: a randomized, placebo-controlled trial.Hypertension2024;81:2124-36

[12] Lakatta EG.Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part II: the aging heart in health: links to heart disease.Circulation2003;107:346-54

[13] Lakatta EG.Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part I: aging arteries: a “set up” for vascular disease.Circulation2003;107:139-46

[14] Faleeva M,Theofilatos K.Sox9 accelerates vascular aging by regulating extracellular matrix composition and stiffness.Circ Res2024;134:307-24 PMCID:PMC10826924

[15] Ungvari Z,Donato AJ,Csiszar A.Mechanisms of vascular aging.Circ Res2018;123:849-67 PMCID:PMC6248882

[16] Ji Y,Chen S,Bai J.Evening home pulse pressure predicted cardiovascular events and mortality in older adults with hypertension: findings based on the STEP trial.Hypertens Res2025;48:2801-10 PMCID:PMC12586171

[17] Pucci G,Avolio AP.Age-specific acute changes in carotid-femoral pulse wave velocity with head-up tilt.Am J Hypertens2020;33:1112-8 PMCID:PMC7814224

[18] Tsimploulis A,Lam PH.Systolic-diastolic hypertension versus isolated systolic hypertension and incident heart failure in older adults: insights from the Cardiovascular Health Study.Int J Cardiol2017;235:11-6 PMCID:PMC6454896

[19] Saeedi Saravi SS,Constancias F.Gut microbiota-dependent increase in phenylacetic acid induces endothelial cell senescence during aging.Nat Aging2025;5:1025-45 PMCID:PMC12176623

[20] Gan L,Liu J.CD38 deficiency alleviates Ang II-induced vascular remodeling by inhibiting small extracellular vesicle-mediated vascular smooth muscle cell senescence in mice.Sig Transduct Target Ther2021;6:223 PMCID:PMC8192533

[21] Liu S,Zhang Y.Targeting gut microbiota in aging-related cardiovascular dysfunction: focus on the mechanisms.Gut Microbes2023;15:2290331 PMCID:PMC10730151

[22] Xu J,Pluznick JL.Short-chain fatty acid receptors and blood pressure regulation: council on hypertension mid-career award for research excellence 2021.Hypertension2022;79:2127-37

[23] Tang WW,Hazen SL.Gut microbiota in cardiovascular health and disease.Circ Res2017;120:1183-96 PMCID:PMC5390330

[24] Zhang D,Zhang Y.Short-chain fatty acids in diseases.Cell Commun Signal2023;21:212 PMCID:PMC10436623

[25] Weiss D,Taylor WR.Angiotensin II-induced hypertension accelerates the development of atherosclerosis in ApoE-deficient mice.Circulation2001;103:448-54

[26] Yin L,Yu W,Li H.Blocking VCAM-1 prevents angiotensin II-induced hypertension and vascular remodeling in mice.Front Pharmacol2022;13:825459 PMCID:PMC8866968

[27] Trejo-Moreno C,Castro-Martínez G.Characterization of a murine model of endothelial dysfunction induced by chronic intraperitoneal administration of angiotensin II.Sci Rep2021;11:21193 PMCID:PMC8551243

[28] Zhang W,Yan P.A single-cell transcriptomic landscape of primate arterial aging.Nat Commun2020;11:2202 PMCID:PMC7200799

[29] Pang J,Shen W.Endothelial LRRC8A delays vascular ageing in natural and accelerated ageing mouse models.Cardiovasc Res2025;121:2549-64

[30] Muralitharan RR,Snelson M.Influence of angiotensin II on the gut microbiome: modest effects in comparison to experimental factors.Cardiovasc Res2024;120:1155-63 PMCID:PMC11368123

[31] Kimura I,Ohue-Kitano R.Free fatty acid receptors in health and disease.Physiol Rev2020;100:171-210

[32] Brown AJ,Barnes AA.The orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids.J Biol Chem2003;278:11312-9

[33] Pham QH,Sim W.Daily oral administration of probiotics engineered to constantly secrete short-chain fatty acids effectively prevents myocardial injury from subsequent ischaemic heart disease.Cardiovasc Res2024;120:1737-51 PMCID:PMC11587561

[34] Bellet MM,Frati L,Romani L.The gut microbiome as a possible mediator in autoimmunity and cardiovascular disease: shared pathways and therapeutic implications.Am J Pathol2025;195:2288-302

[35] Fitzgerald BG,Firth IJ.Members of Lachnospiraceae produce valerate and caproate in response to short-chain fatty acids.Microbiome2025;13:201 PMCID:PMC12505567

[36] Wei G,Shen F.Polystyrene microplastics exposure increases the disruption of intestinal barrier integrity and gut microbiota homeostasis during obesity and aging.J Environ Sci2026;162:430-43

[37] Melgarejo JD,Wei D.Relative and absolute risk to guide the management of pulse pressure, an age-related cardiovascular risk factor.Am J Hypertens2021;34:929-38 PMCID:PMC8457427

[38] Safar ME.Arterial aging—hemodynamic changes and therapeutic options.Nat Rev Cardiol2010;7:442-9

[39] Wang H,Brady T.Sex differences and role of lysyl oxidase-like 2 in angiotensin II-induced hypertension in mice.Am J Physiol Heart Circ Physiol2024;327:H642-59 PMCID:PMC11427116

[40] Muralitharan RR,Dinakis E.Gut microbiota metabolites sensed by host GPR41/43 protect against hypertension.Circ Res2025;136:e20-33