REFERENCES
1. Barnett K, Mercer SW, Norbury M, Watt G, Wyke S, Guthrie B. Epidemiology of multimorbidity and implications for health care, research, and medical education: a cross-sectional study. Lancet. 2012;380:37-43.
2. Nguyen H, Manolova G, Daskalopoulou C, Vitoratou S, Prince M, Prina AM. Prevalence of multimorbidity in community settings: a systematic review and meta-analysis of observational studies. J Comorb. 2019;9:2235042X19870934.
3. Chowdhury SR, Chandra Das D, Sunna TC, Beyene J, Hossain A. Global and regional prevalence of multimorbidity in the adult population in community settings: a systematic review and meta-analysis. EClinicalMedicine. 2023;57:101860.
4. Zhang X, Padhi A, Wei T, et al. Community prevalence and dyad disease pattern of multimorbidity in China and India: a systematic review. BMJ Glob Health. 2022;7:e008880.
5. Hajat C, Stein E. The global burden of multiple chronic conditions: a narrative review. Prev Med Rep. 2018;12:284-93.
6. Marengoni A, Angleman S, Melis R, et al. Aging with multimorbidity: a systematic review of the literature. Ageing Res Rev. 2011;10:430-9.
7. Nunes BP, Flores TR, Mielke GI, Thumé E, Facchini LA. Multimorbidity and mortality in older adults: a systematic review and meta-analysis. Arch Gerontol Geriatr. 2016;67:130-8.
8. Upshur REG, Tracy S. Chronicity and complexity: is what’s good for the diseases always good for the patients? Can Fam Physician. 2008;54:1655-8.
10. Fortin M, Dionne J, Pinho G, Gignac J, Almirall J, Lapointe L. Randomized controlled trials: do they have external validity for patients with multiple comorbidities? Ann Fam Med. 2006;4:104-8.
11. Muth C, van den Akker M, Blom JW, et al. The Ariadne principles: how to handle multimorbidity in primary care consultations. BMC Med. 2014;12:223.
12. Franceschi C, Bonafè M, Valensin S, et al. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci. 2000;908:244-54.
13. Franceschi C, Campisi J. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci. 2014;69 Suppl 1:S4-9.
14. Ferrucci L, Fabbri E. Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nat Rev Cardiol. 2018;15:505-22.
15. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: an expanding universe. Cell. 2023;186:243-78.
17. Wang B, Han J, Elisseeff JH, Demaria M. The senescence-associated secretory phenotype and its physiological and pathological implications. Nat Rev Mol Cell Biol. 2024;25:958-78.
18. 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 Biol. 2021;22:75-95.
19. Ajoolabady A, Pratico D, Tang D, Zhou S, Franceschi C, Ren J. Immunosenescence and inflammaging: mechanisms and role in diseases. Ageing Res Rev. 2024;101:102540.
20. Liu Z, Liang Q, Ren Y, et al. Immunosenescence: molecular mechanisms and diseases. Signal Transduct Target Ther. 2023;8:200.
21. Rodríguez-Morales P, Franklin RA. Macrophage phenotypes and functions: resolving inflammation and restoring homeostasis. Trends Immunol. 2023;44:986-98.
22. Timmerman R, Burm SM, Bajramovic JJ. Tissue-specific features of microglial innate immune responses. Neurochem Int. 2021;142:104924.
23. Tilstra JS, Robinson AR, Wang J, et al. NF-κB inhibition delays DNA damage-induced senescence and aging in mice. J Clin Invest. 2012;122:2601-12.
24. Bosco N, Noti M. The aging gut microbiome and its impact on host immunity. Genes Immun. 2021;22:289-303.
25. Thevaranjan N, Puchta A, Schulz C, et al. Age-associated microbial dysbiosis promotes intestinal permeability, systemic inflammation, and macrophage dysfunction. Cell Host Microbe. 2017;21:455-66.e4.
26. Luo R, Yao Y, Chen Z, Sun X. An examination of the LPS-TLR4 immune response through the analysis of molecular structures and protein-protein interactions. Cell Commun Signal. 2025;23:142.
27. Ghosh TS, Shanahan F, O’Toole PW. The gut microbiome as a modulator of healthy ageing. Nat Rev Gastroenterol Hepatol. 2022;19:565-84.
29. Li X, Li C, Zhang W, Wang Y, Qian P, Huang H. Inflammation and aging: signaling pathways and intervention therapies. Signal Transduct Target Ther. 2023;8:239.
30. Desdín-Micó G, Soto-Heredero G, Aranda JF, et al. T cells with dysfunctional mitochondria induce multimorbidity and premature senescence. Science. 2020;368:1371-6.
31. Banzato E, Roverato A, Buja A, Boccuzzo G. Understanding multimorbidity: insights with graphical models. BMC Med Res Methodol. 2025;25:84.
32. Henein MY, Vancheri S, Longo G, Vancheri F. The role of inflammation in cardiovascular disease. Int J Mol Sci. 2022;23:12906.
33. Ridker PM, Rane M. Interleukin-6 signaling and anti-interleukin-6 therapeutics in cardiovascular disease. Circ Res. 2021;128:1728-46.
34. Dobre MZ, Virgolici B, Dunca-Stefan DCA, Doicin IC, Stanescu-Spinu II. Inflammation-insulin resistance crosstalk and the central role of myokines. Int J Mol Sci. 2025;27:60.
35. Ndumele CE, Neeland IJ, Tuttle KR, et al.; American Heart Association. A synopsis of the evidence for the science and clinical management of cardiovascular-kidney-metabolic (CKM) syndrome: a scientific statement from the American Heart Association. Circulation. 2023;148:1636-64.
36. Caiazzo E, Sharma M, Rezig AOM, et al. Circulating cytokines and risk of developing hypertension: a systematic review and meta-analysis. Pharmacol Res. 2024;200:107050.
37. Livingston G, Huntley J, Liu KY, et al. Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission. Lancet. 2024;404:572-628.
38. Aboukhater D, Morad B, Nasrallah N, et al. Inflammation and hypertension: underlying mechanisms and emerging understandings. J Cell Physiol. 2023;238:1148-59.
39. Guzik TJ, Nosalski R, Maffia P, Drummond GR. Immune and inflammatory mechanisms in hypertension. Nat Rev Cardiol. 2024;21:396-416.
40. Huang X, Hussain B, Chang J. Peripheral inflammation and blood-brain barrier disruption: effects and mechanisms. CNS Neurosci Ther. 2021;27:36-47.
41. Leng F, Edison P. Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here? Nat Rev Neurol. 2021;17:157-72.
42. Du Q, Yao M, Wang W, et al. Association between multimorbidity and depression in older adults: evidence from six large longitudinal cohorts. Am J Geriatr Psychiatry. 2025;33:702-15.
43. Ng A, Tam WW, Zhang MW, et al. IL-1β, IL-6, TNF-α and CRP in elderly patients with depression or Alzheimer’s disease: systematic review and meta-analysis. Sci Rep. 2018;8:12050.
44. Berk M, Williams LJ, Jacka FN, et al. So depression is an inflammatory disease, but where does the inflammation come from? BMC Med. 2013;11:200.
45. Herrera PA, Campos-Romero S, Szabo W, Martínez P, Guajardo V, Rojas G. Understanding the relationship between depression and chronic diseases such as diabetes and hypertension: a grounded theory study. Int J Environ Res Public Health. 2021;18:12130.
47. Sciorati C, Gamberale R, Monno A, et al. Pharmacological blockade of TNFα prevents sarcopenia and prolongs survival in aging mice. Aging. 2020;12:23497-508.
48. Andonian BJ, Hippensteel JA, Abuabara K, et al. Inflammation and aging-related disease: a transdisciplinary inflammaging framework. Geroscience. 2025;47:515-42.
49. Li J, Ortí-Casañ N, Bayraktaroglu I, et al. Psychosocial stressors and cognitive function: an analysis using data from the English longitudinal study of ageing. J Prev Alzheimers Dis. 2025;12:100232.
50. Senaratne DNS, Thakkar B, Smith BH, Hales TG, Marryat L, Colvin LA. The impact of adverse childhood experiences on multimorbidity: a systematic review and meta-analysis. BMC Med. 2024;22:315.
51. Lin L, Wang HH, Lu C, Chen W, Guo VY. Adverse childhood experiences and subsequent chronic diseases among middle-aged or older adults in China and associations with demographic and socioeconomic characteristics. JAMA Netw Open. 2021;4:e2130143.
52. Arzate-Mejia RG, Carullo NVN, Mansuy IM. The epigenome under pressure: on regulatory adaptation to chronic stress in the brain. Curr Opin Neurobiol. 2024;84:102832.
53. Miller GE, Chen E, Parker KJ. Psychological stress in childhood and susceptibility to the chronic diseases of aging: moving toward a model of behavioral and biological mechanisms. Psychol Bull. 2011;137:959-97.
54. Zhou Y, Kivimäki M, Holt-Lunstad J, et al. Stressful life events in childhood and adulthood and risk of physical, psychological and cognitive multimorbidities: a multicohort study. EClinicalMedicine. 2025;83:103225.
55. Haapanen MJ, Vetrano DL, Mikkola TM, et al. Early growth, stress, and socioeconomic factors as predictors of the rate of multimorbidity accumulation across the life course: a longitudinal birth cohort study. Lancet Healthy Longev. 2024;5:e56-65.
56. Dannefer D. Cumulative advantage/disadvantage and the life course: cross-fertilizing age and social science theory. J Gerontol B Psychol Sci Soc Sci. 2003;58:S327-37.
57. Liu H, Zhang M, Zhang X, Zhao X. Exposure to early-life adversity and long-term trajectories of multimorbidity among older adults in China: analysis of longitudinal data from the China Health and Retirement Longitudinal Study. BMJ Open. 2024;14:e075834.
58. Bonaccio M, Di Castelnuovo A, de Gaetano G, Iacoviello L. Socioeconomic gradient in health: mind the gap in 'invisible' disparities. Ann Transl Med. 2020;8:1200.
59. Chen J, Zhang Y, Liu S, et al. Neural-genetic-environmental evidence for a disease factor in mental and physical health multimorbidity. Nat Commun. 2025;16:10088.
60. Zhu Y, Tchkonia T, Pirtskhalava T, et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell. 2015;14:644-58.
61. Koning M, Kovynev A, Fondevila MF, et al. Senolytics dasatinib and quercetin in metabolic dysfunction-associated steatohepatitis: a proof-of-principle randomized, controlled trial. Nat Metab. 2026.
62. Farr JN, Atkinson EJ, Achenbach SJ, et al. Effects of intermittent senolytic therapy on bone metabolism in postmenopausal women: a phase 2 randomized controlled trial. Nat Med. 2024;30:2605-12.
63. Nambiar A, Kellogg D 3rd, Justice J, et al. Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability. EBioMedicine. 2023;90:104481.
64. Garbarino VR, Palavicini JP, Melendez J, et al. Evaluation of exploratory fluid biomarkers from a phase 1 senolytic trial in mild Alzheimer’s disease. Neurotherapeutics. 2025;22:e00591.
65. Silva M, Wacker DA, Driver BE, et al.; STOP-Sepsis Investigators. Senolytics To slOw Progression of Sepsis (STOP-Sepsis) in elderly patients: study protocol for a multicenter, randomized, adaptive allocation clinical trial. Trials. 2024;25:698.
66. Greenberg EF, Voorbach MJ, Smith A, et al. Navitoclax safety, tolerability, and effect on biomarkers of senescence and neurodegeneration in aged nonhuman primates. Heliyon. 2024;10:e36483.
67. Langenberg C, Hingorani AD, Whitty CJM. Biological and functional multimorbidity-from mechanisms to management. Nat Med. 2023;29:1649-57.
68. Amor C, Feucht J, Leibold J, et al. Senolytic CAR T cells reverse senescence-associated pathologies. Nature. 2020;583:127-32.
69. Ridker PM, Everett BM, Thuren T, et al.; CANTOS Trial Group. Antiinflammatory therapy with Canakinumab for atherosclerotic disease. N Engl J Med. 2017;377:1119-31.
70. Fischer R, Kontermann RE, Pfizenmaier K. Selective targeting of TNF receptors as a novel therapeutic approach. Front Cell Dev Biol. 2020;8:401.
71. Dong Y, Fischer R, Naudé PJ, et al. Essential protective role of tumor necrosis factor receptor 2 in neurodegeneration. Proc Natl Acad Sci U S A. 2016;113:12304-9.
72. Woods JA, Wilund KR, Martin SA, Kistler BM. Exercise, inflammation and aging. Aging Dis. 2012;3:130-40.
73. Pikula A, Gulati M, Bonnet JP, et al. Promise of lifestyle medicine for heart disease, diabetes mellitus, and cerebrovascular diseases. Mayo Clin Proc Innov Qual Outcomes. 2024;8:151-65.
74. Gleeson M, Bishop NC, Stensel DJ, Lindley MR, Mastana SS, Nimmo MA. The anti-inflammatory effects of exercise: mechanisms and implications for the prevention and treatment of disease. Nat Rev Immunol. 2011;11:607-15.
75. Bonaccio M, Pounis G, Cerletti C, Donati MB, Iacoviello L, de Gaetano G; MOLI-SANI Study Investigators. Mediterranean diet, dietary polyphenols and low grade inflammation: results from the MOLI-SANI study. Br J Clin Pharmacol. 2017;83:107-13.
76. Garbarino S, Lanteri P, Bragazzi NL, Magnavita N, Scoditti E. Role of sleep deprivation in immune-related disease risk and outcomes. Commun Biol. 2021;4:1304.
77. Sheffler JL, Meng Z, Sachs-Ericsson N, Caimary VG, Patel J, Pickett S. Sleep quality as a critical pathway between adverse childhood experiences and multimorbidity and the impact of lifestyle. J Aging Health. 2025;37:167-81.
78. Paudel D, Nair DVT, Joseph G, Castro R, Tiwari AK, Singh V. Gastrointestinal microbiota-directed nutritional and therapeutic interventions for inflammatory bowel disease: opportunities and challenges. Gastroenterol Rep. 2024;12:goae033.
79. Ghosh TS, Das M, Jeffery IB, O’Toole PW. Adjusting for age improves identification of gut microbiome alterations in multiple diseases. Elife. 2020;9:e50240.
80. Wang XM, Fan L, Meng CC, et al. Gut microbiota influence frailty syndrome in older adults: mechanisms and therapeutic strategies. Biogerontology. 2024;25:107-29.
81. Awad K, Zaki MM, Mohammed M, Lewek J, Lavie CJ, Banach M; Lipid and Blood Pressure Meta-analysis Collaboration Group. Effect of the renin-angiotensin system inhibitors on inflammatory markers: a systematic review and meta-analysis of randomized controlled trials. Mayo Clin Proc. 2022;97:1808-23.
82. Gomaz SB, Charan J, Mohandas A, et al. Anti-inflammatory potential of telmisartan compared to other antihypertensives: secondary outcomes from a randomized trial. Inflammopharmacology. 2025;33:6983-91.
83. Rijken M, Struckmann V, van der Heide I, et al; on behalf of ICARE4EU consortium. How to improve care for people with multimorbidity in Europe? Copenhagen (Denmark): European Observatory on Health Systems and Policies © NIVEL and TU Berlin; 2017. Available from: https://www.ncbi.nlm.nih.gov/books/NBK464548/. [Last accessed on 29 Oct 2026].
84. van der Feltz-Cornelis C, Attree E, Heightman M, Gabbay M, Allsopp G. Integrated care pathways: a new approach for integrated care systems. Br J Gen Pract. 2023;73:422.
85. Tian Y, Wang S, Zhang Y, Meng L, Li X. Effectiveness of information and communication technology-based integrated care for older adults: a systematic review and meta-analysis. Front Public Health. 2023;11:1276574.
86. Hayes C, Manning M, Fitzgerald C, et al. Effectiveness of community‐based multidisciplinary integrated care for older adults with general practitioner involvement: a systematic review and meta‐analysis. Health Soc Care Community. 2024.
87. Zhang Y, Stokes J, Anselmi L, Bower P, Xu J. Can integrated care interventions strengthen primary care and improve outcomes for patients with chronic diseases? A systematic review and meta-analysis. Health Res Policy Syst. 2025;23:5.
88. Endalamaw A, Zewdie A, Wolka E, Assefa Y. A scoping review of digital health technologies in multimorbidity management: mechanisms, outcomes, challenges, and strategies. BMC Health Serv Res. 2025;25:382.
89. Guo R, Zhang J, Yang F, Wu Y. Efficacy of an intelligent and integrated older adult care model on quality of life among home-dwelling older adults: randomized controlled trial. J Med Internet Res. 2025;27:e67950.
90. Oei SP, Bakkes THGF, Mischi M, Bouwman RA, van Sloun RJG, Turco S. Artificial intelligence in clinical decision support and the prediction of adverse events. Front Digit Health. 2025;7:1403047.
91. Sheffler JL, Piazza JR, Quinn JM, Sachs-Ericsson NJ, Stanley IH. Adverse childhood experiences and coping strategies: identifying pathways to resiliency in adulthood. Anxiety Stress Coping. 2019;32:594-609.
92. Brown AF, Ma GX, Miranda J, et al. Structural interventions to reduce and eliminate health disparities. Am J Public Health. 2019;109:S72-8.
93. Sun Y. An updated landscape of cellular senescence heterogeneity: mechanisms, technologies and senotherapies. Transl Med Aging. 2023;7:46-51.
94. Karras A, Lioulios G, Kantartzi K, Fylaktou A, Panagoutsos S, Stangou M. Measuring the senescence-associated secretory phenotype. Biomedicines. 2025;13:2062.
95. Chew-Harris J, Appleby S, Richards AM, Troughton RW, Pemberton CJ. Analytical, biochemical and clearance considerations of soluble urokinase plasminogen activator receptor (suPAR) in healthy individuals. Clin Biochem. 2019;69:36-44.
96. Vetrano DL, Calderón-Larrañaga A, Marengoni A, et al. An international perspective on chronic multimorbidity: approaching the elephant in the room. J Gerontol A Biol Sci Med Sci. 2018;73:1350-6.
97. Berner K, Nizeyimana E, Bedada DT, Louw QA. Multimorbidity patterns and function among adults in low- and middle-income countries: a scoping review. BMJ Open. 2025;15:e096522.
