Gut microbiota: an ideal biomarker and intervention strategy for aging

Abstract

Population aging is a substantial challenge for the global sanitation framework. Unhealthy aging tends to be accompanied by chronic diseases such as cardiovascular disease, diabetes, and cancer, which undermine the welfare of the elderly. Based on the fact that aging is inevitable but retarding aging is attainable, flexible aging characterization and efficient anti-aging become imperative for healthy aging. The gut microbiome, as the most dynamic component interacting with the organism, can affect the aging process through its own structure and metabolites, thus holding the potential to become both an ideal aging-related biomarker and an intervention strategy. This review summarizes the value of applying gut microbiota as aging-related microbial biomarkers in diagnosing aging state and monitoring the effect of anti-aging interventions, ultimately pointing to the future prospects of microbial intervention strategies in maintaining healthy aging.

Keywords

Aging / gut microbiota / microbial biomarker / anti-aging intervention

References

[1] Bautmans I,Amuthavalli Thiyagarajan J.WHO Working Group on Vitality CapacityWHO working definition of vitality capacity for healthy longevity monitoring.Lancet Healthy Longev2022;3:e789-96 PMCID:PMC9640935

[2] DeJong EN,Bowdish DME.The gut microbiota and unhealthy aging: disentangling cause from consequence.Cell Host Microbe2020;28:180-9

[3] Moskalev A,Lopes IA.Targeting aging mechanisms: pharmacological perspectives.Trends Endocrinol Metab2022;33:266-80

[4] Chen M,Zhao J,Xu H.Immune regulation in the aging retina.Prog Retin Eye Res2019;69:159-72 PMCID:PMC6373845

[5] López-Otín C,Roiz-Valle D,Kroemer G.Meta-hallmarks of aging and cancer.Cell Metab2023;35:12-35

[6] Burtscher J,Burtscher M.Hypoxia and brain aging: neurodegeneration or neuroprotection?.Ageing Res Rev2021;68:101343

[7] Rutledge J,Wyss-Coray T.Measuring biological age using omics data.Nat Rev Genet2022;23:715-27 PMCID:PMC10048602

[8] Wu L,Liang T.Integrated multi-omics for novel aging biomarkers and antiaging targets.Biomolecules2021;12:39 PMCID:PMC8773837

[9] Zeng X,Li X.Fecal microbiota transplantation from young mice rejuvenates aged hematopoietic stem cells by suppressing inflammation.Blood2023;141:1691-707 PMCID:PMC10646769

[10] Sharma R.Probiotic bacteria as modulators of cellular senescence: emerging concepts and opportunities.Gut Microbes2020;11:335-49 PMCID:PMC7524351

[11] Zhang L,Yousefzadeh MJ,Robbins PD.Cellular senescence: a key therapeutic target in aging and diseases.J Clin Invest2022;132:e158450 PMCID:PMC9337830

[12] López-Otín C,Partridge L,Kroemer G.Hallmarks of aging: an expanding universe.Cell2023;186:243-78

[13] Halim M.The effects of inflammation, aging and oxidative stress on the pathogenesis of diabetes mellitus (type 2 diabetes).Diabetes Metab Syndr2019;13:1165-72

[14] Triposkiadis F,Butler J.Cardiovascular aging and heart failure: JACC review topic of the week.J Am Coll Cardiol2019;74:804-13

[15] Pérez RF,Fernández AF.Aging and cancer epigenetics: where do the paths fork?.Aging Cell2022;21:e13709 PMCID:PMC9577950

[16] Culig L,Bohr VA.Neurogenesis in aging and age-related neurodegenerative diseases.Ageing Res Rev2022;78:101636 PMCID:PMC9168971

[17] Yousefzadeh MJ,McGowan SJ.Fisetin is a senotherapeutic that extends health and lifespan.EBioMedicine2018;36:18-28 PMCID:PMC6197652

[18] Xu R,Li S.Surrounding greenness and biological aging based on DNA methylation: a twin and family study in Australia.Environ Health Perspect2021;129:87007 PMCID:PMC8404778

[19] Ansary TM,Kamiya K,Ohtsuki M.Inflammatory molecules associated with ultraviolet radiation-mediated skin aging.Int J Mol Sci2021;22:3974 PMCID:PMC8069861

[20] Ji Z,Qu J.Mitochondrial sirtuins, metabolism, and aging.J Genet Genomics2022;49:287-98

[21] Chen F,Ghosh A,Wang B.Clusterin secreted from astrocyte promotes excitatory synaptic transmission and ameliorates Alzheimer’s disease neuropathology.Mol Neurodegener2021;16:5 PMCID:PMC7849119

[22] Budden KF,Rehman SF.Functional effects of the microbiota in chronic respiratory disease.Lancet Respir Med2019;7:907-20

[23] Della Bella C,Puccio S.The Helicobacter pylori CagY protein drives gastric Th1 and Th17 inflammation and B cell proliferation in gastric MALT lymphoma.Int J Mol Sci2021;22:9459 PMCID:PMC8431018

[24] Chen S,Li M.Fusobacterium nucleatum reduces METTL3-mediated m⁶A modification and contributes to colorectal cancer metastasis.Nat Commun2022;13:1248 PMCID:PMC8913623

[25] Wang J,Zhu D.The landscape in the gut microbiome of long-lived families reveals new insights on longevity and aging - relevant neural and immune function.Gut Microbes2022;14:2107288 PMCID:PMC9361766

[26] Kim S.The gut microbiota and healthy aging: a mini-review.Gerontology2018;64:513-20 PMCID:PMC6191326

[27] Singh H,Moncera KJ.Gastro-intestinal and oral microbiome signatures associated with healthy aging.Geroscience2019;41:907-21 PMCID:PMC6925087

[28] Xiong X,Yan X.Gut microbiome and serum metabolome analyses identify biomarkers associated with sexual maturity in quails.Poult Sci2023;102:102762 PMCID:PMC10208887

[29] Connell E,Pontifex MG.Microbial-derived metabolites as a risk factor of age-related cognitive decline and dementia.Mol Neurodegener2022;17:43 PMCID:PMC9204954

[30] Flanagan EW,Mey JT.Calorie restriction and aging in humans.Annu Rev Nutr2020;40:105-33 PMCID:PMC9042193

[31] de Cabo R, Mattson MP. Effects of intermittent fasting on health, aging, and disease.N Engl J Med2019;381:2541-51

[32] Badal VD,Murray ER.The gut microbiome, aging, and longevity: a systematic review.Nutrients2020;12:3759 PMCID:PMC7762384

[33] Liu C,Li J.Understanding the gut microbiota and sarcopenia: a systematic review.J Cachexia Sarcopenia Muscle2021;12:1393-407 PMCID:PMC8718038

[34] Selvarani R,Richardson A.Effect of rapamycin on aging and age-related diseases - past and future.GeroScience2021;43:1135-58 PMCID:PMC8190242

[35] Pyo IS,Yoon YE,Lee SJ.Mechanisms of aging and the preventive effects of resveratrol on age-related diseases.Molecules2020;25:4649 PMCID:PMC7587336

[36] Luo D,Li J.Gut microbiota combined with metabolomics reveals the metabolic profile of the normal aging process and the anti-aging effect of FuFang Zhenshu TiaoZhi(FTZ) in mice.Biomed Pharmacother2020;121:109550

[37] Jasper H.Intestinal stem cell aging: origins and interventions.Annu Rev Physiol2020;82:203-26

[38] Zhang P,Sun Y,Dang T.Metagenomic analysis explores the interaction of aged microplastics and roxithromycin on gut microbiota and antibiotic resistance genes of Carassius auratus.J Hazard Mater2022;425:127773

[39] Zhu Y,Zheng X.Aspirin positively contributes to Drosophila intestinal homeostasis and delays aging through targeting imd.Aging Dis2021;12:1821-34 PMCID:PMC8460307

[40] Paone P.Mucus barrier, mucins and gut microbiota: the expected slimy partners?.Gut2020;69:2232-43 PMCID:PMC7677487

[41] Mogilenko DA,Andhey PS.Comprehensive profiling of an aging immune system reveals clonal GZMK⁺ CD8⁺ T cells as conserved hallmark of inflammaging.Immunity2021;54:99-115.e12

[42] Arias-Rojas A,Hurwitz R,Iatsenko I.Resistance to host antimicrobial peptides mediates resilience of gut commensals during infection and aging in Drosophila.Proc Natl Acad Sci U S A2023;120:e2305649120 PMCID:PMC10483595

[43] Longo VD.Nutrition, longevity and disease: from molecular mechanisms to interventions.Cell2022;185:1455-70 PMCID:PMC9089818

[44] Froidurot A.Cellulolytic bacteria in the large intestine of mammals.Gut Microbes2022;14:2031694 PMCID:PMC8865330

[45] Wang B,Mao B.Anti-aging effects and mechanisms of anthocyanins and their intestinal microflora metabolites.Crit Rev Food Sci Nutr2022;1-17

[46] Varadé J,González-Fernández Á.Human immunology and immunotherapy: main achievements and challenges.Cell Mol Immunol2021;18:805-28 PMCID:PMC7463107

[47] Gao Y,Wu Y.Bacillus coagulans (Weizmannia coagulans) XY2 attenuates Cu-induced oxidative stress via DAF-16/FoxO and SKN-1/Nrf2 pathways and gut microbiota regulation.J Hazard Mater2023;457:131741

[48] Kundu P,Garcia-Perez I.Neurogenesis and prolongevity signaling in young germ-free mice transplanted with the gut microbiota of old mice.Sci Transl Med2019;11:eaau4760

[49] Shin MG,Han JS.Bacteria-derived metabolite, methylglyoxal, modulates the longevity of C. elegans through TORC2/SGK-1/DAF-16 signaling.Proc Natl Acad Sci U S A2020;117:17142-50 PMCID:PMC7382248

[50] Trist BG,Double KL.Oxidative stress in the aging substantia nigra and the etiology of Parkinson’s disease.Aging Cell2019;18:e13031 PMCID:PMC6826160

[51] Hou Y,Babbar M.Ageing as a risk factor for neurodegenerative disease.Nat Rev Neurol2019;15:565-81

[52] Cryan JF,Cowan CSM.The microbiota-gut-brain axis.Physiol Rev2019;99:1877-2013

[53] Shabbir U,Sameen A.Crosstalk between gut and brain in Alzheimer’s disease: the role of gut microbiota modulation strategies.Nutrients2021;13:690 PMCID:PMC7924846

[54] Faits T,Rodriguez-Morato J.Exploring changes in the human gut microbiota and microbial-derived metabolites in response to diets enriched in simple, refined, or unrefined carbohydrate-containing foods: a post hoc analysis of a randomized clinical trial.Am J Clin Nutr2020;112:1631-41 PMCID:PMC7727488

[55] Heyck M.Microbiota and memory: a symbiotic therapy to counter cognitive decline?.Brain Circ2019;5:124-9 PMCID:PMC6785944

[56] Khoruts A,Sadowsky MJ.Faecal microbiota transplantation for Clostridioides difficile: mechanisms and pharmacology.Nat Rev Gastroenterol Hepatol2021;18:67-80

[57] Bárcena C,Mayoral P.Healthspan and lifespan extension by fecal microbiota transplantation into progeroid mice.Nat Med2019;25:1234-42

[58] Boehme M,Bastiaanssen TFS.Microbiota from young mice counteracts selective age-associated behavioral deficits.Nat Aging2021;1:666-76

[59] Parker A,Ansorge R.Fecal microbiota transfer between young and aged mice reverses hallmarks of the aging gut, eye, and brain.Microbiome2022;10:68

[60] D’Amato A,Lucarini E.Faecal microbiota transplant from aged donor mice affects spatial learning and memory via modulating hippocampal synaptic plasticity- and neurotransmission-related proteins in young recipients.Microbiome2020;8:140 PMCID:PMC7532115

[61] Zhang H,Tang M.Association between skeletal muscle strength and dysphagia among Chinese community-dwelling elderly adults.J Nutr Health Aging2020;24:642-9

[62] Ma S,Zhang P,Fu L.Fecal microbiota transplantation mitigates bone loss by improving gut microbiome composition and gut barrier function in aged rats.PeerJ2021;9:e12293 PMCID:PMC8542369

[63] Shi X,Sakandar HA,Sun Z.Gut microbiome and aging nexus and underlying mechanism.Appl Microbiol Biotechnol2022;106:5349-58

[64] Khoruts A.Understanding the mechanisms of faecal microbiota transplantation.Nat Rev Gastroenterol Hepatol2016;13:508-16 PMCID:PMC5909819

[65] Quigley EMM.Prebiotics and probiotics in digestive health.Clin Gastroenterol Hepatol2019;17:333-44

[66] Boyajian JL,Schaly S,Prakash S.Microbiome and human aging: probiotic and prebiotic potentials in longevity, skin health and cellular senescence.Nutrients2021;13:4550 PMCID:PMC8705837

[67] Kumar A,Das S,Mukherjee AK.A potential probiotic Lactobacillus plantarum JBC5 improves longevity and healthy aging by modulating antioxidative, innate immunity and serotonin-signaling pathways in Caenorhabditis elegans.Antioxidants2022;11:268 PMCID:PMC8868178

[68] Chen S,Qi Y.Bifidobacterium adolescentis regulates catalase activity and host metabolism and improves healthspan and lifespan in multiple species.Nat Aging2021;1:991-1001

[69] Zhang J,Sun Z.Lacticaseibacillus rhamnosus probio-M9 extends the lifespan of Caenorhabditis elegans.Commun Biol2022;5:1139 PMCID:PMC9613993

[70] Lee J,Atadja L.Gut microbiota-derived short-chain fatty acids promote poststroke recovery in aged mice.Circ Res2020;127:453-65 PMCID:PMC7415518

[71] Zeng SY,Liu JH,Xie H.Potential effects of Akkermansia muciniphila in aging and aging-related diseases: current evidence and perspectives.Aging Dis2023;14:2015-27 PMCID:PMC10676789

[72] Ma J,Gao X.Gut microbiota remodeling improves natural aging-related disorders through Akkermansia muciniphila and its derived acetic acid.Pharmacol Res2023;189:106687

[73] Fu X,Zhu C,Kong Q.Nondigestible carbohydrates, butyrate, and butyrate-producing bacteria.Crit Rev Food Sci Nutr2019;59:S130-52

[74] Lordan C,Ross RP.Potential for enriching next-generation health-promoting gut bacteria through prebiotics and other dietary components.Gut Microbes2020;11:1-20 PMCID:PMC6973326

[75] Lin CW,Ho HH.Impact of the food grade heat-killed probiotic and postbiotic oral lozenges in oral hygiene.Aging2022;14:2221-38 PMCID:PMC8954981

[76] Ağagündüz D,Bozkurt O.Microbiota alteration and modulation in Alzheimer’s disease by gerobiotics: the gut-health axis for a good mind.Biomed Pharmacother2022;153:113430

[77] Machado-Fragua MD,Yerramalla MS.Association of metabolic syndrome with incident dementia: role of number and age at measurement of components in a 28-year follow-up of the whitehall II cohort study.Diabetes Care2022;45:2127-35 PMCID:PMC9472484

[78] Ham DJ,Chojnowska K.Distinct and additive effects of calorie restriction and rapamycin in aging skeletal muscle.Nat Commun2022;13:2025 PMCID:PMC9018781

[79] Kim DH,Jung HJ.Anti-aging effects of calorie restriction (CR) and CR mimetics based on the senoinflammation concept.Nutrients2020;12:422 PMCID:PMC7071238

[80] Ghosh TS,O’Toole PW.The gut microbiome as a modulator of healthy ageing.Nat Rev Gastroenterol Hepatol2022;19:565-84 PMCID:PMC9035980

[81] Partridge L,Slagboom PE.Facing up to the global challenges of ageing.Nature2018;561:45-56

[82] Asadi Shahmirzadi A,Liao CY.Alpha-ketoglutarate, an endogenous metabolite, extends lifespan and compresses morbidity in aging mice.Cell Metab2020;32:447-56.e6 PMCID:PMC8508957

[83] Zhang H,Ren J.Single-nucleus transcriptomic landscape of primate hippocampal aging.Protein Cell2021;12:695-716 PMCID:PMC8403220