The cross-talk between neurodegeneration and metabolic disorders

Abstract

Despite substantial advances extending human lifespan, the gap between healthspan and lifespan continues to widen, with neurodegenerative diseases (NDDs) and metabolic disorders representing major contributors to this disparity. Growing epidemiological and genetic evidence indicates a bidirectional relationship between NDDs and metabolic disorders, suggesting shared pathophysiological mechanisms that transcend organ-specific boundaries. In this narrative review, we sought to explore the interconnections between neurodegeneration and metabolic dysfunction through the lens of the twelve established hallmarks of aging. We conducted a comprehensive literature search across multiple databases (PubMed, Google Scholar, Scopus, ScienceDirect) from January 2013 to April 2025, focusing on studies examining aging hallmarks in both NDDs (particularly Alzheimer’s disease and Parkinson’s disease) and metabolic disorders (obesity, type 2 diabetes mellitus, and metabolic dysfunction-associated steatotic liver disease). Our analysis reveals that all twelve hallmarks - i.e., genome instability, telomere attrition, epigenetic alterations, loss of proteostasis, impaired autophagy, dysregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation, and dysbiosis - may serve as convergence points linking these seemingly disparate conditions. These findings support an integrated pathophysiological model wherein aging-related processes simultaneously promote neurodegeneration and metabolic dysfunction through shared molecular pathways. Understanding these mechanistic intersections offers promising opportunities for developing therapeutic interventions that could simultaneously target both neurodegenerative and metabolic diseases, potentially helping to close the healthspan-lifespan gap.

Keywords

Neurodegeneration / metabolic disorders / hallmarks of aging / Alzheimer’s disease / Parkinson’s disease / type 2 diabetes / obesity / metabolic dysfunction-associated steatotic liver disease

References

[1] Crimmins EM.Lifespan and healthspan: past, present, and promise.Gerontologist2015;55:901-11 PMCID:PMC4861644

[2] Garmany A.Global healthspan-lifespan gaps among 183 World Health Organization member states.JAMA Netw Open2024;7:e2450241 PMCID:PMC11635540

[3] Su B,Zhong P.Long-term trends in healthy and unhealthy life expectancy among adults aged 60 - a global perspective, 1990-2019.China CDC Wkly2023;5:877-83 PMCID:PMC10560388

[4] Wang S,Yang A,Zhang J.The expanding burden of neurodegenerative diseases: an unmet medical and social need.Aging Dis2024;16:2937-52 PMCID:PMC12339136

[5] Noor A,Zerr I.Neurodegenerative proteinopathies in the proteoform spectrum-tools and challenges.Int J Mol Sci2021;22:1085 PMCID:PMC7865347

[6] Yilmaz Y.The heated debate over NAFLD renaming: an ongoing saga.Hepatol Forum2023;4:89-91 PMCID:PMC10564248

[7] Stranahan AM.Bidirectional metabolic regulation of neurocognitive function.Neurobiol Learn Mem2011;96:507-16 PMCID:PMC3084367

[8] Procaccini C,Faicchia D.Role of metabolism in neurodegenerative disorders.Metabolism2016;65:1376-90

[9] Shinohara M.Bidirectional interactions between diabetes and Alzheimer’ disease.Neurochem Int2017;108:296-302

[10] Muddapu VR,Chakravarthy VS.Neurodegenerative diseases - is metabolic deficiency the root cause?.Front Neurosci2020;14:213 PMCID:PMC7137637

[11] Song D,Yang LL,Yao XQ.Bridging systemic metabolic dysfunction and Alzheimer’s disease: the liver interface.Mol Neurodegener2025;20:61 PMCID:PMC12121119

[12] Kaya E.Association of metabolic dysfunction-associated fatty liver disease with cognitive impairment and all-cause dementia: a comprehensive review.Turk J Gastroenterol2024;35:76-82 PMCID:PMC10895887

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

[14] Palmer AK.Metabolic changes in aging humans: current evidence and therapeutic strategies.J Clin Invest2022;132:e158451 PMCID:PMC9374375

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

[16] López-Otín C,Partridge L,Kroemer G.The hallmarks of aging.Cell2013;153:1194-217 PMCID:PMC3836174

[17] Niedernhofer LJ,Wang Y,Hoeijmakers JHJ.Nuclear genomic instability and aging.Annu Rev Biochem2018;87:295-322

[18] Shadfar S,Atkin JD.The complex mechanisms by which neurons die following DNA damage in neurodegenerative diseases.Int J Mol Sci2022;23:2484 PMCID:PMC8910227

[19] Welch G.Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease.EMBO Rep2022;23:e54217 PMCID:PMC9171412

[20] Wang J,Xie C,Lovell MA.Increased oxidative damage in nuclear and mitochondrial DNA in Alzheimer’s disease.J Neurochem2005;93:953-62

[21] Markesbery WR.DNA oxidation in Alzheimer’s disease.Antioxid Redox Signal2006;8:2039-45

[22] Bradley-Whitman MA,Beckett TL,Lynn BC.Nucleic acid oxidation: an early feature of Alzheimer’s disease.J Neurochem2014;128:294-304 PMCID:PMC3947319

[23] Santos RX,Zhu X.Nuclear and mitochondrial DNA oxidation in Alzheimer’s disease.Free Radic Res2012;46:565-76

[24] Fukae J,Kubo S.Expression of 8-oxoguanine DNA glycosylase (OGG1) in Parkinson’s disease and related neurodegenerative disorders.Acta Neuropathol2005;109:256-62

[25] Shimizu I,Suda M.DNA damage response and metabolic disease.Cell Metab2014;20:967-77

[26] Włodarczyk M.Obesity, DNA damage, and development of obesity-related diseases.Int J Mol Sci2019;20:1146 PMCID:PMC6429223

[27] Włodarczyk M,Olejarz W.Anthropometric and dietary factors as predictors of DNA damage in obese women.Nutrients2018;10:578 PMCID:PMC5986458

[28] Scarpato R,Fabiani B,Saggese G.Nuclear damage in peripheral lymphocytes of obese and overweight Italian children as evaluated by the gamma-H2AX focus assay and micronucleus test.FASEB J2011;25:685-93

[29] Zhong A,Yu T.Aberrant DNA damage response and DNA repair pathway in high glucose conditions.J Can Res Updates2018;7:64-74 PMCID:PMC6258084

[30] Khalid M,Adem A.Advanced glycation end products and diabetes mellitus: mechanisms and perspectives.Biomolecules2022;12:542 PMCID:PMC9030615

[31] Stopper H,Sebekova K.Genotoxicity of advanced glycation end products in mammalian cells.Cancer Lett2003;190:151-6

[32] Bhattacharya R,Kamal MA,Singh LR.AGE-RAGE axis culminates into multiple pathogenic processes: a central road to neurodegeneration.Front Mol Neurosci2023;16:1155175 PMCID:PMC10230046

[33] Alanazi AFR,Haider S.Structural motifs at the telomeres and their role in regulatory pathways.Biochemistry2024;63:827-42 PMCID:PMC10993422

[34] Harman A.Telomere maintenance and the DNA damage response: a paradoxical alliance.Front Cell Dev Biol2024;12:1472906 PMCID:PMC11524846

[35] Vaiserman A.Telomere length as a marker of biological age: state-of-the-art, open issues, and future perspectives.Front Genet2020;11:630186 PMCID:PMC7859450

[36] Levstek T,Dolžan V.Telomere attrition in neurodegenerative disorders.Front Cell Neurosci2020;14:219 PMCID:PMC7373805

[37] Forero DA,López-Quintero C,Barreto GE.Meta-analysis of telomere length in Alzheimer’s disease.J Gerontol A Biol Sci Med Sci2016;71:1069-73 PMCID:PMC4945891

[38] Hackenhaar FS,Adolfsson AN.Short leukocyte telomeres predict 25-year Alzheimer’s disease incidence in non-APOE ε4-carriers.Alzheimers Res Ther2021;13:130

[39] Cui Y,Cai Q.Associations of leukocyte telomere length with body anthropometric indices and weight change in Chinese women.Obesity2013;21:2582-8 PMCID:PMC3676725

[40] Gielen M, Hageman GJ, Antoniou EE, et al; TELOMAAS group. Body mass index is negatively associated with telomere length: a collaborative cross-sectional meta-analysis of 87 observational studies. Am J Clin Nutr. 2018;108:453-75. PMCID:PMC6454526

[41] Xia J,Yu Y.Associations between weight-adjusted-waist index and telomere length: results from NHANES: an observational study.Medicine2024;103:e37905 PMCID:PMC11049720

[42] Batsis JA,Vasquez E.Association of adiposity, telomere length and mortality: data from the NHANES 1999-2002.Int J Obes2018;42:198-204 PMCID:PMC5858938

[43] Tzanetakou IP,Benetos A,Perrea DN.“Is obesity linked to aging?.Ageing Res Rev2012;11:220-9

[44] He X,Fu X.The association between telomere length and diabetes mellitus: accumulated evidence from observational studies.J Clin Endocrinol Metab2024;110:e177-85

[45] Zhang L,Chang C.Epigenetics in health and disease.Adv Exp Med Biol2020;1253:3-55

[46] Słowikowski B,Jeske J.Epigenetics and the neurodegenerative process.Epigenomics2024;16:473-91

[47] Liu Y,Marcora EM,Goate AM.Promoter DNA hypermethylation - implications for Alzheimer’s disease.Neurosci Lett2019;711:134403 PMCID:PMC6759378

[48] Yu CC,Yang AF,Wu M.Epigenetic modulation on Tau phosphorylation in Alzheimer’s disease.Neural Plast2019;2019:6856327 PMCID:PMC6481020

[49] Ma Y,Liu S.Epigenetic regulation of neuroinflammation in Alzheimer’s disease.Cells2023;13:79 PMCID:PMC10778497

[50] Park J,Kim K.The role of histone modifications: from neurodevelopment to neurodiseases.Signal Transduct Target Ther2022;7:217 PMCID:PMC9259618

[51] Balmik AA.Methylation as a key regulator of Tau aggregation and neuronal health in Alzheimer’s disease.Cell Commun Signal2021;19:51 PMCID:PMC8103764

[52] Jung BC.Epigenetic regulation of inflammatory factors in adipose tissue.Biochim Biophys Acta Mol Cell Biol Lipids2021;1866:159019 PMCID:PMC8719460

[53] Ling C,Rönn T.Epigenetics of type 2 diabetes mellitus and weight change - a tool for precision medicine?.Nat Rev Endocrinol2022;18:433-48

[54] Franzago M,Di Rado S,Stuppia L.The epigenetic aging, obesity, and lifestyle.Front Cell Dev Biol2022;10:985274 PMCID:PMC9514048

[55] Meyers AK.The NLRP3 inflammasome: metabolic regulation and contribution to inflammaging.Cells2020;9:1808 PMCID:PMC7463618

[56] La Rosa F,Agostini S.Pharmacological and epigenetic regulators of NLRP3 inflammasome activation in Alzheimer’s disease.Pharmaceuticals2021;14:1187 PMCID:PMC8623160

[57] Lu S,Qian Z.Role of the inflammasome in insulin resistance and type 2 diabetes mellitus.Front Immunol2023;14:1052756 PMCID:PMC10040598

[58] Heneka MT,Latz E.Inflammasome signalling in brain function and neurodegenerative disease.Nat Rev Neurosci2018;19:610-21

[59] Coppedè F.Mitochondrial DNA methylation and mitochondria-related epigenetics in neurodegeneration.Neural Regen Res2024;19:405-6 PMCID:PMC10503600

[60] Low HC,Ratnam W.Changes in mitochondrial epigenome in type 2 diabetes mellitus.Br J Biomed Sci2023;80:10884 PMCID:PMC9970885

[61] Maldonado-Lasuncion I,Sanchez-Espinosa MP.Aging-related changes in cognition and cortical integrity are associated with serum expression of candidate microRNAs for Alzheimer disease.Cereb Cortex2019;29:4426-37

[62] Shen Y,Pan X.miR-34a and miR-125b are upregulated in peripheral blood mononuclear cells from patients with type 2 diabetes mellitus.Exp Ther Med2017;14:5589-96 PMCID:PMC5740513

[63] Hipp MS,Hartl FU.The proteostasis network and its decline in ageing.Nat Rev Mol Cell Biol2019;20:421-35

[64] Klaips CL,Hartl FU.Pathways of cellular proteostasis in aging and disease.J Cell Biol2018;217:51-63 PMCID:PMC5748993

[65] Kurtishi A,Patil KS,Møller SG.Cellular proteostasis in neurodegeneration.Mol Neurobiol2019;56:3676-89

[66] Rao G,Teng C.Ubiquitin-proteasome system in neurodegenerative disorders.J Drug Metab Toxicol2015;6:187 PMCID:PMC6370320

[67] Ottens F,Hoppe T.Build-UPS and break-downs: metabolism impacts on proteostasis and aging.Cell Death Differ2021;28:505-21 PMCID:PMC7862225

[68] Queisser MA,Geisler S.Hyperglycemia impairs proteasome function by methylglyoxal.Diabetes2010;59:670-8 PMCID:PMC2828656

[69] James HA,Nair KS.Insulin regulation of proteostasis and clinical implications.Cell Metab2017;26:310-23 PMCID:PMC8020859

[70] Santiago-Lopez AJ,Gross RE.Kinetic monitoring of neuronal stress response to proteostasis dysfunction.Mol Cell Neurosci2022;118:103682 PMCID:PMC8770608

[71] Moll L,Reuveni H.The inhibition of IGF-1 signaling promotes proteostasis by enhancing protein aggregation and deposition.FASEB J2016;30:1656-69

[72] Höhn A,Cascella R.Proteostasis failure in neurodegenerative diseases: focus on oxidative stress.Oxid Med Cell Longev2020;2020:5497046 PMCID:PMC7140146

[73] Ross JM,Coppotelli G.Mitochondrial and ubiquitin proteasome system dysfunction in ageing and disease: two sides of the same coin?.Int J Mol Sci2015;16:19458-76 PMCID:PMC4581307

[74] Ahmed T,Arguelles S.Map kinase signaling as therapeutic target for neurodegeneration.Pharmacol Res2020;160:105090

[75] Sonninen TM,Laham-Karam N,Lehtonen Š.Proteostasis disturbances and inflammation in neurodegenerative diseases.Cells2020;9:2183 PMCID:PMC7601929

[76] Chen Y,Zhao W.Carnosol reduced pathogenic protein aggregation and cognitive impairment in neurodegenerative diseases models via improving proteostasis and ameliorating mitochondrial disorders.J Agric Food Chem2022;70:10490-505

[77] Saha S,Patil S.Autophagy in health and disease: a comprehensive review.Biomed Pharmacother2018;104:485-95

[78] Mokarram P.Autophagy unveiled: new horizons in health and disease.Biochim Biophys Acta Mol Basis Dis2024;1870:167289

[79] Ryter SW,Choi AM.Autophagy: a critical regulator of cellular metabolism and homeostasis.Mol Cells2013;36:7-16 PMCID:PMC3887921

[80] Guo F,Cai H.Autophagy in neurodegenerative diseases: pathogenesis and therapy.Brain Pathol2018;28:3-13 PMCID:PMC5739982

[81] Park H,Lee S.Autophagy in neurodegenerative diseases: a hunter for aggregates.Int J Mol Sci2020;21:3369 PMCID:PMC7247013

[82] Long Z,Zhao Y.Dynamic changes of autophagic flux induced by Abeta in the brain of postmortem Alzheimer’s disease patients, animal models and cell models.Aging2020;12:10912-30 PMCID:PMC7346050

[83] Jiang S.Degradation and transmission of tau by autophagic-endolysosomal networks and potential therapeutic targets for tauopathy.Front Mol Neurosci2020;13:586731 PMCID:PMC7596180

[84] Palmer JE,Son SM.Autophagy, aging, and age-related neurodegeneration.Neuron2025;113:29-48

[85] Rabinowitz JD.Autophagy and metabolism.Science2010;330:1344-8 PMCID:PMC3010857

[86] Menikdiwela KR,Rasha F.Autophagy in metabolic syndrome: breaking the wheel by targeting the renin-angiotensin system.Cell Death Dis2020;11:87 PMCID:PMC6997396

[87] Namkoong S,Semple I.Autophagy dysregulation and obesity-associated pathologies.Mol Cells2018;41:3-10 PMCID:PMC5792710

[88] Zhao X,Tan X.Advanced glycation end-products suppress autophagic flux in podocytes by activating mammalian target of rapamycin and inhibiting nuclear translocation of transcription factor EB.J Pathol2018;245:235-48 PMCID:PMC5969319

[89] de Mello NP, Orellana AM, Mazucanti CH, de Morais Lima G, Scavone C, Kawamoto EM. Insulin and autophagy in neurodegeneration.Front Neurosci2019;13:491 PMCID:PMC6558407

[90] Lan ZQ,Lv SK,Li CX.The regulatory role of lipophagy in central nervous system diseases.Cell Death Discov2023;9:229 PMCID:PMC10326259

[91] Haidar M,Bogie JFJ.Lipophagy: a new player in CNS disorders.Trends Endocrinol Metab2021;32:941-51

[92] Park K.Current status of autophagy enhancers in metabolic disorders and other diseases.Front Cell Dev Biol2022;10:811701 PMCID:PMC8882819

[93] Rahman MA.Therapeutic implication of autophagy in neurodegenerative diseases.BMB Rep2017;50:345-54 PMCID:PMC5584741

[94] Venugopal A.Nutrient sensing.Curr Opin Gastroenterol2021;37:114-20

[95] Sung Y,Han JM.Nutrient sensors and their crosstalk.Exp Mol Med2023;55:1076-89 PMCID:PMC10318010

[96] Carroll B.Nutrient sensing, growth and senescence.FEBS J2018;285:1948-58 PMCID:PMC6001427

[97] Talbot K,Kazi H.Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline.J Clin Invest2012;122:1316-38 PMCID:PMC3314463

[98] de la Monte SM, Tong M. Dysregulated mTOR networks in experimental sporadic Alzheimer’s disease.Front Cell Neurosci2024;18:1432359 PMCID:PMC11461251

[99] Fernandez F,Sutherland HG.Sirtuin proteins and memory: a promising target in Alzheimer’s disease therapy?.Nutrients2024;16:4088 PMCID:PMC11644011

[100] Kahn BB.Obesity and insulin resistance.J Clin Invest2000;106:473-81 PMCID:PMC380258

[101] Maldonado-Rojas ADC,Uribe M.Insulin resistance and metabolic dysfunction-associated steatotic liver disease (MASLD): pathways of action of hypoglycemic agents.Ann Hepatol2024;29:101182

[102] Mao Z.Role of mTOR in glucose and lipid metabolism.Int J Mol Sci2018;19:2043 PMCID:PMC6073766

[103] Arab Sadeghabadi Z,Pasalar P.Reduced gene expression of sirtuins and active AMPK levels in children and adolescents with obesity and insulin resistance.Obes Res Clin Pract2018;12:167-73

[104] Folch J,Ettcheto M.The involvement of peripheral and brain insulin resistance in late onset Alzheimer’s dementia.Front Aging Neurosci2019;11:236 PMCID:PMC6743006

[105] Davoody S,Khodabakhsh P.mTOR signaling and Alzheimer’s disease: what we know and where we are?.CNS Neurosci Ther2024;30:e14463 PMCID:PMC11017461

[106] Marinangeli C,Vingtdeux V.AMPK in neurodegenerative diseases: implications and therapeutic perspectives.Curr Drug Targets2016;17:890-907

[107] Johnson ML,Lanza IR.Mechanism by which caloric restriction improves insulin sensitivity in sedentary obese adults.Diabetes2016;65:74-84 PMCID:PMC4686951

[108] Ma L,Wang R.Effect of caloric restriction on the SIRT1/mTOR signaling pathways in senile mice.Brain Res Bull2015;116:67-72

[109] Cantó C.Calorie restriction: is AMPK a key sensor and effector?.Physiology2011;26:214-24 PMCID:PMC3627048

[110] Dos Santos C,Shrestha S.Calorie restriction increases insulin sensitivity to promote beta cell homeostasis and longevity in mice.Nat Commun2024;15:9063 PMCID:PMC11493975

[111] Hansen B,Ebid H.Perspective: the impact of fasting and caloric restriction on neurodegenerative diseases in humans.Adv Nutr2024;15:100197 PMCID:PMC10997874

[112] Annesley SJ.Mitochondria in health and disease.Cells2019;8:680 PMCID:PMC6678092

[113] Srivastava S.The mitochondrial basis of aging and age-related disorders.Genes2017;8:398 PMCID:PMC5748716

[114] Ashleigh T,Beal MF.The role of mitochondrial dysfunction in Alzheimer’s disease pathogenesis.Alzheimers Dement2023;19:333-42

[115] Bhatia S,Sharma P,Singh M.Mitochondrial dysfunction in Alzheimer’s disease: opportunities for drug development.Curr Neuropharmacol2022;20:675-92 PMCID:PMC9878959

[116] Højlund K,Sahlin K.Mitochondrial dysfunction in type 2 diabetes and obesity.Endocrinol Metab Clin North Am2008;37:713-31, x

[117] Bournat JC.Mitochondrial dysfunction in obesity.Curr Opin Endocrinol Diabetes Obes2010;17:446-52 PMCID:PMC5001554

[118] Yoon Y,Jhun BS.Mitochondrial dynamics in diabetes.Antioxid Redox Signal2011;14:439-57 PMCID:PMC3025181

[119] Lin J,Sun Y.Exercise ameliorates muscular excessive mitochondrial fission, insulin resistance and inflammation in diabetic rats via irisin/AMPK activation.Sci Rep2024;14:10658 PMCID:PMC11082241

[120] Sridharan PS,Miller E.Acutely blocking excessive mitochondrial fission prevents chronic neurodegeneration after traumatic brain injury.Cell Rep Med2024;5:101715 PMCID:PMC11525032

[121] Belosludtsev KN,Dubinin MV.Diabetes mellitus, mitochondrial dysfunction and Ca²⁺-dependent permeability transition pore.Int J Mol Sci2020;21:6559 PMCID:PMC7555889

[122] Kalani K,Yan SS.Mitochondrial permeability transition pore: a potential drug target for neurodegeneration.Drug Discov Today2018;23:1983-9 PMCID:PMC6449145

[123] Gurung P,Kanneganti TD.Mitochondria: diversity in the regulation of the NLRP3 inflammasome.Trends Mol Med2015;21:193-201 PMCID:PMC4352396

[124] Rovira-Llopis S,Bañuls C,Rocha M.Mitochondria, the NLRP3 inflammasome, and sirtuins in type 2 diabetes: new therapeutic targets.Antioxid Redox Signal2018;29:749-91

[125] Litwiniuk A,Domańska A,Bik W.Contribution of mitochondrial dysfunction combined with NLRP3 inflammasome activation in selected neurodegenerative diseases.Pharmaceuticals2021;14:1221 PMCID:PMC8703835

[126] Zong Y,Liao P.Mitochondrial dysfunction: mechanisms and advances in therapy.Signal Transduct Target Ther2024;9:124 PMCID:PMC11094169

[127] Cortés-Rojo C.Don’t give up on mitochondria as a target for the treatment of diabetes and its complications.World J Diabetes2024;15:2015-21 PMCID:PMC11525734

[128] Fields M,Gonelli A,Maximova N.Mitochondria-targeted antioxidants, an innovative class of antioxidant compounds for neurodegenerative diseases: perspectives and limitations.Int J Mol Sci2023;24:3739 PMCID:PMC9960436

[129] Ding W,Lai K,Liu Y.The potential of therapeutic strategies targeting mitochondrial biogenesis for the treatment of insulin resistance and type 2 diabetes mellitus.Arch Pharm Res2024;47:219-48

[130] Uittenbogaard M.Mitochondrial biogenesis: a therapeutic target for neurodevelopmental disorders and neurodegenerative diseases.Curr Pharm Des2014;20:5574-93 PMCID:PMC4823001

[131] Gorgoulis V,Alimonti A.Cellular senescence: defining a path forward.Cell2019;179:813-27

[132] Di Micco R, Krizhanovsky V, Baker D, d’Adda di Fagagna F. Cellular senescence in ageing: from mechanisms to therapeutic opportunities.Nat Rev Mol Cell Biol2021;22:75-95 PMCID:PMC8344376

[133] Wang B,Elisseeff JH.The senescence-associated secretory phenotype and its physiological and pathological implications.Nat Rev Mol Cell Biol2024;25:958-78

[134] Mijit M,Melillo A,Giordano A.Role of p53 in the regulation of cellular senescence.Biomolecules2020;10:420 PMCID:PMC7175209

[135] Alshaebi F,Kayed R.The role of glial cell senescence in Alzheimer’s disease.J Neurochem2025;169:e70051 PMCID:PMC11934031

[136] Zhu J,Yang L.Cellular senescence in Alzheimer’s disease: from physiology to pathology.Transl Neurodegener2024;13:55 PMCID:PMC11577763

[137] Shen QQ,Ma XZ.Cell senescence induced by toxic interaction between α-synuclein and iron precedes nigral dopaminergic neuron loss in a mouse model of Parkinson’s disease.Acta Pharmacol Sin2024;45:268-81 PMCID:PMC10789811

[138] Lee S,Steinberg AB,Chinta SJ.A guide to senolytic intervention in neurodegenerative disease.Mech Ageing Dev2021;200:111585 PMCID:PMC8627445

[139] Zhang H,Shen X.The role of cellular senescence in metabolic diseases and the potential for senotherapeutic interventions.Front Cell Dev Biol2023;11:1276707 PMCID:PMC10587568

[140] Arias C,Cifuentes M,Kerr B.Enhancing adipose tissue functionality in obesity: senotherapeutics, autophagy and cellular senescence as a target.Biol Res2024;57:51 PMCID:PMC11312694

[141] Palmer AK,Zhu Y.Targeting senescent cells alleviates obesity-induced metabolic dysfunction.Aging Cell2019;18:e12950 PMCID:PMC6516193

[142] Narasimhan A,Robbins PD.Role of cellular senescence in type II diabetes.Endocrinology2021;162:bqab136 PMCID:PMC8386762

[143] Murakami T,Kondoh H.Cellular senescence in diabetes mellitus: distinct senotherapeutic strategies for adipose tissue and pancreatic β cells.Front Endocrinol2022;13:869414 PMCID:PMC9009089

[144] Ghosh P,Scisciola L.Obesity-induced neuronal senescence: unraveling the pathophysiological links.Ageing Res Rev2024;101:102533

[145] Cleland NRW,Dobrinskikh E.Altered substrate metabolism in neurodegenerative disease: new insights from metabolic imaging.J Neuroinflammation2021;18:248 PMCID:PMC8555332

[146] Han X,Xie J.Potential regulators of the senescence-associated secretory phenotype during senescence and aging.J Gerontol A Biol Sci Med Sci2022;77:2207-18

[147] Rando TA.Regeneration, rejuvenation, and replacement: turning back the clock on tissue aging.Cold Spring Harb Perspect Biol2021;13:a040907 PMCID:PMC8411956

[148] Rezazadeh S.Editorial: stem cell exhaustion in aging.Front Aging2024;5:1433702 PMCID:PMC11177088

[149] Brunet A,Rando TA.Ageing and rejuvenation of tissue stem cells and their niches.Nat Rev Mol Cell Biol2023;24:45-62 PMCID:PMC9879573

[150] Iqbal MA,Liu Y.The integrated stress response promotes neural stem cell survival under conditions of mitochondrial dysfunction in neurodegeneration.Aging Cell2024;23:e14165 PMCID:PMC11258489

[151] Scopa C,Latina V.Impaired adult neurogenesis is an early event in Alzheimer’s disease neurodegeneration, mediated by intracellular Aβ oligomers.Cell Death Differ2020;27:934-48 PMCID:PMC7206128

[152] Al-Regaiey K.Crosstalk between adipogenesis and aging: role of polyphenols in combating adipogenic-associated aging.Immun Ageing2024;21:76 PMCID:PMC11542427

[153] Chen X,Yang P,Sun W.High glucose inhibits neural stem cell differentiation through oxidative stress and endoplasmic reticulum stress.Stem Cells Dev2018;27:745-55 PMCID:PMC5985912

[154] Hidaka R,Fujimaki S,Asashima M.Monitoring neurodegeneration in diabetes using adult neural stem cells derived from the olfactory bulb.Stem Cell Res Ther2013;4:51 PMCID:PMC3707061

[155] Geroldi D,Emanuele E.Brain-derived neurotrophic factor and the metabolic syndrome: more than just a hypothesis.Med Hypotheses2006;67:195-6

[156] Motamedi S,Jafari F.The interrelationship of metabolic syndrome and neurodegenerative diseases with focus on brain-derived neurotrophic factor (BDNF): kill two birds with one stone.Metab Brain Dis2017;32:651-65

[157] Islam O,Heese K.Brain-derived neurotrophic factor (BDNF) has proliferative effects on neural stem cells through the truncated TRK-B receptor, MAP kinase, AKT, and STAT-3 signaling pathways.Curr Neurovasc Res2009;6:42-53

[158] Navarro Negredo P, Yeo RW, Brunet A. Aging and rejuvenation of neural stem cells and their niches.Cell Stem Cell2020;27:202-23 PMCID:PMC7415725

[159] Marsh SE.Neural stem cell therapy for neurodegenerative disorders: the role of neurotrophic support.Neurochem Int2017;106:94-100 PMCID:PMC5446923

[160] Zomer HD,Gonçalves NN.Mesenchymal and induced pluripotent stem cells: general insights and clinical perspectives.Stem Cells Cloning2015;8:125-34 PMCID:PMC4592031

[161] Sun H,Ma S,Li Y.Intercellular communication is crucial in the regulation of healthy aging via exosomes.Pharmacol Res2025;212:107591

[162] Fafián-Labora JA.Classical and nonclassical intercellular communication in senescence and ageing.Trends Cell Biol2020;30:628-39

[163] Sigdel S,Wang J.Extracellular vesicles in neurodegenerative diseases: an update.Int J Mol Sci2023;24:13161 PMCID:PMC10487947

[164] Aas V,Brusletto BS.Distinct microRNA and protein profiles of extracellular vesicles secreted from myotubes from morbidly obese donors with type 2 diabetes in response to electrical pulse stimulation.Front Physiol2023;14:1143966 PMCID:PMC10098097

[165] Liu W,Zhao Q,Jiang J.Adipose tissue-derived extracellular vesicles: a promising biomarker and therapeutic strategy for metabolic disorders.Stem Cells Int2023;2023:9517826 PMCID:PMC10761228

[166] Park KJ.Gut-brain axis and neurodegeneration: mechanisms and therapeutic potentials.Front Neurosci2024;18:1481390 PMCID:PMC11541110

[167] Liu X,Wan M,Wang Z.Peripheral extracellular vesicles in neurodegeneration: pathogenic influencers and therapeutic vehicles.J Nanobiotechnology2024;22:170 PMCID:PMC11015679

[168] Kumar MA,Sadida HQ.Extracellular vesicles as tools and targets in therapy for diseases.Signal Transduct Target Ther2024;9:27 PMCID:PMC10838959

[169] Shive C.Inflammation, immune senescence, and dysregulated immune regulation in the elderly.Front Aging2022;3:840827 PMCID:PMC9261323

[170] Zhang W,Mao Q.Role of neuroinflammation in neurodegeneration development.Signal Transduct Target Ther2023;8:267 PMCID:PMC10336149

[171] Adamu A,Gao F.The role of neuroinflammation in neurodegenerative diseases: current understanding and future therapeutic targets.Front Aging Neurosci2024;16:1347987 PMCID:PMC11045904

[172] Lista S,Grasso M.Tracking neuroinflammatory biomarkers in Alzheimer’s disease: a strategy for individualized therapeutic approaches?.J Neuroinflammation2024;21:187 PMCID:PMC11289964

[173] Singh J,Panicker N.Inflammasome assembly in neurodegenerative diseases.Trends Neurosci2023;46:814-31 PMCID:PMC10530301

[174] Welikovitch LA,Maglóczky Z.Early intraneuronal amyloid triggers neuron-derived inflammatory signaling in APP transgenic rats and human brain.Proc Natl Acad Sci U S A2020;117:6844-54 PMCID:PMC7104377

[175] Kawai T,Scalia R.Adipose tissue inflammation and metabolic dysfunction in obesity.Am J Physiol Cell Physiol2021;320:C375-91 PMCID:PMC8294624

[176] Li H,He S.Macrophages, chronic inflammation, and insulin resistance.Cells2022;11:3001 PMCID:PMC9562180

[177] Mirabelli M,Sicilia L.Hypoxia in human obesity: new insights from inflammation towards insulin resistance-a narrative review.Int J Mol Sci2024;25:9802 PMCID:PMC11432683

[178] Ertunc ME.Lipid signaling and lipotoxicity in metaflammation: indications for metabolic disease pathogenesis and treatment.J Lipid Res2016;57:2099-114 PMCID:PMC5321214

[179] Cao SS,Shi L.Endoplasmic reticulum stress interacts with inflammation in human diseases.J Cell Physiol2016;231:288-94 PMCID:PMC4659393

[180] Gkrinia EMM.The mechanisms of chronic inflammation in obesity and potential therapeutic strategies: a narrative review.Curr Issues Mol Biol2025;47:357 PMCID:PMC12110701

[181] Elwood E,Naveed H.The effect of systemic inflammation on human brain barrier function.Brain Behav Immun2017;62:35-40 PMCID:PMC5380128

[182] Dukhinova M,Kopeikina E.Platelets mediate protective neuroinflammation and promote neuronal plasticity at the site of neuronal injury.Brain Behav Immun2018;74:7-27

[183] Sagar RC,Naseem KM.Non-traditional pathways for platelet pathophysiology in diabetes: implications for future therapeutic targets.Int J Mol Sci2022;23:4973 PMCID:PMC9104718

[184] Wu KK,Cheng KK.NLRP3 inflammasome activation in adipose tissues and its implications on metabolic diseases.Int J Mol Sci2020;21:4184 PMCID:PMC7312293

[185] Wree A,McGeough MD.NLRP3 inflammasome activation results in hepatocyte pyroptosis, liver inflammation, and fibrosis in mice.Hepatology2014;59:898-910 PMCID:PMC4008151

[186] Hanslik KL.The role of microglia and the Nlrp3 inflammasome in Alzheimer’s disease.Front Neurol2020;11:570711 PMCID:PMC7530640

[187] Domingo E,Francisco V,Sanz MJ.Targeting systemic inflammation in metabolic disorders. A therapeutic candidate for the prevention of cardiovascular diseases?.Pharmacol Res2024;200:107058

[188] Mohamed W,Alghamdi BS,Toshihide Y.Neurodegeneration and inflammation crosstalk: Therapeutic targets and perspectives.IBRO Neurosci Rep2023;14:95-110 PMCID:PMC10300452

[189] Haran JP.Aging, frailty, and the microbiome-how dysbiosis influences human aging and disease.Gastroenterology2021;160:507-23 PMCID:PMC7856216

[190] Marchesi JR,Fava F.The gut microbiota and host health: a new clinical frontier.Gut2016;65:330-9 PMCID:PMC4752653

[191] Wu YL,Rong XY,Wang HJ.Gut microbiota alterations and health status in aging adults: from correlation to causation.Aging Med2021;4:206-13 PMCID:PMC8444961

[192] Bradley E.The human gut microbiome and aging.Gut Microbes2024;16:2359677 PMCID:PMC11152108

[193] Intili G,Rappa F.From dysbiosis to neurodegenerative diseases through different communication pathways: an overview.Biology2023;12:195 PMCID:PMC9952972

[194] Lista S,Caraci F.Gut microbiota in Alzheimer’s disease: understanding molecular pathways and potential therapeutic perspectives.Ageing Res Rev2025;104:102659

[195] Ahmed H,Koistinen V.Microbiota-derived metabolites as drivers of gut-brain communication.Gut Microbes2022;14:2102878 PMCID:PMC9341364

[196] Romano S,Bedarf JR,Hildebrand F.Meta-analysis of the Parkinson’s disease gut microbiome suggests alterations linked to intestinal inflammation.NPJ Parkinsons Dis2021;7:27 PMCID:PMC7946946

[197] Bandopadhyay P.Gut dysbiosis and metabolic diseases.Prog Mol Biol Transl Sci2022;191:153-74

[198] Chanda D.Meta-analysis reveals obesity associated gut microbial alteration patterns and reproducible contributors of functional shift.Gut Microbes2024;16:2304900 PMCID:PMC10810176

[199] Fan S,Lin L.Research progress of gut microbiota and obesity caused by high-fat diet.Front Cell Infect Microbiol2023;13:1139800 PMCID:PMC10040832

[200] Clemente-Postigo M,Coin-Aragüez L.Metabolic endotoxemia promotes adipose dysfunction and inflammation in human obesity.Am J Physiol Endocrinol Metab2019;316:E319-32

[201] Tang W,Feng Y,Wan D.The impact of gut microbiota disorders on the blood-brain barrier.Infect Drug Resist2020;13:3351-63 PMCID:PMC7532923

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

[203] Zhang M,Li X.Interactions between gut microbiota, host circadian rhythms, and metabolic diseases.Adv Nutr2025;16:100416 PMCID:PMC12148639

[204] Hablitz LM,Giannetto M.Circadian control of brain glymphatic and lymphatic fluid flow.Nat Commun2020;11:4411 PMCID:PMC7468152

[205] Yoo JY.Probiotics and prebiotics: present status and future perspectives on metabolic disorders.Nutrients2016;8:173 PMCID:PMC4808900

[206] Ojha S,Jain M,Kaushik P.Probiotics for neurodegenerative diseases: a systemic review.Microorganisms2023;11:1083 PMCID:PMC10140855

[207] Zheng L,Wen XL.Fecal microbiota transplantation in the metabolic diseases: current status and perspectives.World J Gastroenterol2022;28:2546-60 PMCID:PMC9254144

[208] Matheson JT.The role of fecal microbiota transplantation in the treatment of neurodegenerative diseases: a review.Int J Mol Sci2023;24:1001 PMCID:PMC9864694

[209] Freude KK,Rodriguez-Ortiz CJ.Editorial: metabolic alterations in neurodegenerative disorders.Front Aging Neurosci2022;14:833109 PMCID:PMC8894844

[210] de Araújo Boleti AP, de Oliveira Flores TM, Moreno SE, Anjos LD, Mortari MR, Migliolo L. Neuroinflammation: an overview of neurodegenerative and metabolic diseases and of biotechnological studies.Neurochem Int2020;136:104714

[211] Mullins RJ,Chia CW.Insulin resistance as a link between amyloid-beta and tau pathologies in Alzheimer’s disease.Front Aging Neurosci2017;9:118 PMCID:PMC5413582

[212] Komleva Y,Lopatina O.Inflamm-aging and brain insulin resistance: new insights and role of life-style strategies on cognitive and social determinants in aging and neurodegeneration.Front Neurosci2020;14:618395 PMCID:PMC7841337

[213] Surguchov A.Caveolin: a new link between diabetes and AD.Cell Mol Neurobiol2020;40:1059-66 PMCID:PMC11448860

[214] Jinesh S,Aditi P.Premature aging and metabolic diseases: the impact of telomere attrition.Front Aging2025;6:1541127 PMCID:PMC11995884

[215] Silberman DM.Metabolism, neurodegeneration and epigenetics: emerging role of Sirtuins.Neural Regen Res2018;13:417-8 PMCID:PMC5900499

[216] Bagherniya M,Barreto GE.The effect of fasting or calorie restriction on autophagy induction: a review of the literature.Ageing Res Rev2018;47:183-97

[217] Fontana L,Cross AH.Effects of dietary restriction on neuroinflammation in neurodegenerative diseases.J Exp Med2021;218:e20190086 PMCID:PMC7802371

[218] Kruczkowska W,Buczek P,Kciuk M.Overview of metformin and neurodegeneration: a comprehensive review.Pharmaceuticals2025;18:486 PMCID:PMC12030719

[219] Nah J,Jung YK.Autophagy in neurodegenerative diseases: from mechanism to therapeutic approach.Mol Cells2015;38:381-9 PMCID:PMC4443278

[220] Guerville F,Ader I.Revisiting the hallmarks of aging to identify markers of biological age.J Prev Alzheimers Dis2020;7:56-64

[221] Hampel H, Nisticò R, Seyfried NT, et al; Alzheimer Precision Medicine Initiative (APMI). Omics sciences for systems biology in Alzheimer’s disease: state-of-the-art of the evidence. Ageing Res Rev. 2021;69:101346.

[222] Santoro A,Conte M,Franceschi C.Inflammaging, hormesis and the rationale for anti-aging strategies.Ageing Res Rev2020;64:101142

[223] James DL,Mohr AE.Impact of intermittent fasting and/or caloric restriction on aging-related outcomes in adults: a scoping review of randomized controlled trials.Nutrients2024;16:316 PMCID:PMC10820472

[224] Garatachea N,Sanchis-Gomar F.Exercise attenuates the major hallmarks of aging.Rejuvenation Res2015;18:57-89 PMCID:PMC4340807

[225] Poljšak B,Špalj S.The central role of the NAD+ molecule in the development of aging and the prevention of chronic age-related diseases: strategies for NAD+ modulation.Int J Mol Sci2023;24:2959 PMCID:PMC9917998

[226] Imb M,Maurer M.Exploring senolytic and senomorphic properties of medicinal plants for anti-aging therapies.Int J Mol Sci2024;25:10419 PMCID:PMC11476546

[227] Liu SZ,Rabinovitch PS.Mitochondrial targeted interventions for aging.Cold Spring Harb Perspect Med2024;14:a041199 PMCID:PMC10910403

[228] Trisal A.Clinical insights on caloric restriction mimetics for mitigating brain aging and related neurodegeneration.Cell Mol Neurobiol2024;44:67 PMCID:PMC11485046

[229] Barthet VJA.Killing wisely: precision senolytics in the age of frailty.Genes Dev2025;39:910-3 PMCID:PMC12315863

[230] Mason SA,Keske MA.Effect of mitochondrial-targeted antioxidants on glycaemic control, cardiovascular health, and oxidative stress in humans: a systematic review and meta-analysis of randomized controlled trials.Diabetes Obes Metab2022;24:1047-60 PMCID:PMC9314850