Aging is accompanied by a persistent state of low-grade inflammation, widely referred to as “inflammaging”. Unlike acute inflammation, which is transient and protective, inflammaging represents a chronic, sterile, systemic process that accelerates tissue dysfunction and predisposes individuals to age-related diseases. Its origins are multifactorial, involving cellular senescence, impaired autophagy, mitochondrial dysfunction, dysregulated innate immune signaling, epigenetic alterations, and shifts in gut microbiota composition. These mechanisms converge to form a self-perpetuating cycle of inflammatory activation that compromises tissue homeostasis. The clinical consequences of inflammaging extend across diverse organ systems. It contributes to neurodegeneration through sustained neuroinflammation, promotes cardiovascular pathology by driving endothelial dysfunction and atherosclerosis, and accelerates pulmonary and musculoskeletal decline. Such broad involvement underscores its role as a unifying mechanism linking aging to chronic disease onset and progression. Therapeutic strategies have begun to target inflammaging directly. Senolytics eliminate senescent cells, while senomorphics suppress the senescence-associated secretory phenotype (SASP). Modulation of gut microbiota through dietary interventions, probiotics, or fecal microbiota transplantation restores microbial balance and reduces systemic inflammation. Lifestyle modifications, including caloric restriction, exercise, and improved sleep quality, further mitigate inflammatory burden and enhance resilience. This review synthesizes the current research progress on the molecular and cellular drivers of inflammaging and highlights emerging therapeutic approaches to alleviate chronic inflammation and extend healthy lifespan. It aims to provide a comprehensive framework for understanding inflammaging and deepen our understanding of inflammatory mechanisms, which will facilitate early detection, personalized treatment, and efficacy monitoring.

1. Teissier T, Boulanger E, Cox LS. Interconnections between inflammaging and immunosenescence during ageing. Cells. 2022;11(3):359.

2. Serrano-Lopez J, Martin-Antonio B. Inflammaging, an imbalanced immune response that needs to be restored for cancer prevention and treatment in the elderly. Cells. 2021;10(10):2562.

3. de Lille ÉDBS. Effects of Early-Life and Chronic Exposure to Dietary Advanced Glycation End-Products on Chronic Low-Grade Inflammation and Age-Associated Disorders: Université de Lille; 2023.

4. Jurcau MC, Jurcau A, Cristian A, Hogea VO, Diaconu RG, Nunkoo VS. Inflammaging and brain aging. International Journal of Molecular Sciences. 2024;25(19):10535.

5. Tudorache E, Fira-Mladinescu O, Traila D, Marc M, Rajnoveanu RM, Tofolean DE, et al. Endothelial dysfunction: The possible link between cardiovascular comorbidities and phenomenon of inflammaging from COPD. Medicine. 2022;101(33):e30078.

6. Easter M, Bollenbecker S, Barnes JW, Krick S. Targeting aging pathways in chronic obstructive pulmonary disease. International journal of molecular sciences. 2020;21(18):6924.

7. Künzi L, Easter M, Hirsch MJ, Krick S. Cystic fibrosis lung disease in the aging population. Frontiers in Pharmacology. 2021;12:601438.

8. Ballesteros J, Rivas D, Duque G. The role of the kynurenine pathway in the pathophysiology of frailty, sarcopenia, and osteoporosis. Nutrients. 2023;15(14):3132.

9. Zhang L, Pitcher LE, Prahalad V, Niedernhofer LJ, Robbins PD. Targeting cellular senescence with senotherapeutics: senolytics and senomorphics. The FEBS journal. 2023;290(5):1362-83.

10. Bilal M, Ashraf S, Zhao X. Dietary component-induced inflammation and its amelioration by prebiotics, probiotics, and synbiotics. Frontiers in nutrition. 2022;9:931458.

11. Moreno-Frías C, Figueroa-Vega N, Malacara JM. Sleep extension increases the effect of caloric restriction over body weight and improves the chronic low-grade inflammation in adolescents with obesity. Journal of Adolescent Health. 2020;66(5):575-81.

12. Li X, Li C, Zhang W, Wang Y, Qian P, Huang H. Inflammation and aging: signaling pathways and intervention therapies. Signal transduction and targeted therapy. 2023;8(1):239.

13. Lopes-Paciencia S, Saint-Germain E, Rowell M-C, Ruiz AF, Kalegari P, Ferbeyre G. The senescence-associated secretory phenotype and its regulation. Cytokine. 2019;117:15-22.

14. Zheng W, Liu A, Xia N, Chen N, Meurens F, Zhu J. How the innate immune DNA sensing cGAS-STING pathway is involved in apoptosis. International journal of molecular sciences. 2023;24(3):3029.

15. Zhang Y, Yang W, Li W, Zhao Y. NLRP3 inflammasome: checkpoint connecting innate and adaptive immunity in autoimmune diseases. Frontiers in immunology. 2021;12:732933.

16. Su L, Zhang J, Gomez H, Kellum JA, Peng Z. Mitochondria ROS and mitophagy in acute kidney injury. Autophagy. 2023;19(2):401-14.

17. Dragoumani K, Kletsas D, Chrousos GP, Vlachakis D, Balatsos NA. Molecular and Environmental Modulators of Aging: Interplay Between Inflammation, Epigenetics, and RNA Stability. Genes. 2025;16(7):796.

18. Giroud J, Bouriez I, Paulus H, Pourtier A, Debacq-Chainiaux F, Pluquet O. Exploring the communication of the SASP: dynamic, interactive, and adaptive effects on the microenvironment. International Journal of Molecular Sciences. 2023;24(13):10788.

19. Muraglia A, Utyro O, Nardini M, Santolini M, Ceresa D, Agostini V, et al. A simple cell proliferation assay and the inflammatory protein content show significant differences in human plasmas from young and old subjects. Frontiers in Bioengineering and Biotechnology. 2024;12:1408499.

20. Sun Y, Wang X, Liu T, Zhu X, Pan X. The multifaceted role of the SASP in atherosclerosis: from mechanisms to therapeutic opportunities. Cell & Bioscience. 2022;12(1):74.

21. Liu Z, Wu KK, Jiang X, Xu A, Cheng KK. The role of adipose tissue senescence in obesity-and ageing-related metabolic disorders. Clinical science. 2020;134(2):315-30.

22. Tripathi U, Nchioua R, Prata LGL, Zhu Y, Gerdes EOW, Giorgadze N, et al. SARS-CoV-2 causes senescence in human cells and exacerbates the senescence-associated secretory phenotype through TLR-3. Aging (albany NY). 2021;13(18):21838.

23. Song P, An J, Zou M-H. Immune clearance of senescent cells to combat ageing and chronic diseases. Cells. 2020;9(3):671.

24. Salmonowicz HM. Mitochondrial dysfunction as a driver of cellular senescence: Newcastle University; 2021.

25. Niu Y, Wang L, Zhang Y, Zou Y, Zhou C. Pyroptosis in cardiovascular diseases: roles, mechanisms, and clinical implications. Frontiers in Cardiovascular Medicine. 2025;12:1629016.

26. Jurcău MC, Andronie-Cioara FL, Jurcău A, Marcu F, Ţiț DM, Pașcalău N, et al. The link between oxidative stress, mitochondrial dysfunction and neuroinflammation in the pathophysiology of Alzheimer’s disease: therapeutic implications and future perspectives. Antioxidants. 2022;11(11):2167.

27. Li P, Li S, Wang L, Li H, Wang Y, Liu H, et al. Mitochondrial dysfunction in hearing loss: Oxidative stress, autophagy and NLRP3 inflammasome. Frontiers in Cell and Developmental Biology. 2023;11:1119773.

28. Qu K, Yan F, Qin X, Zhang K, He W, Dong M, et al. Mitochondrial dysfunction in vascular endothelial cells and its role in atherosclerosis. Frontiers in physiology. 2022;13:1084604.

29. Quan Y, Xin Y, Tian G, Zhou J, Liu X. Mitochondrial ROS‐Modulated mtDNA: a potential target for cardiac aging. Oxidative medicine and cellular longevity. 2020;2020(1):9423593.

30. Rudzińska M, Parodi A, Balakireva AV, Chepikova OE, Venanzi FM, Zamyatnin Jr AA. Cellular aging characteristics and their association with age-related disorders. Antioxidants. 2020;9(2):94.

31. Koszła O, Sołek P. Misfolding and aggregation in neurodegenerative diseases: Protein quality control machinery as potential therapeutic clearance pathways. Cell Communication and Signaling. 2024;22(1):421.

32. Cheng J, Liao Y, Dong Y, Hu H, Yang N, Kong X, et al. Microglial autophagy defect causes parkinson disease-like symptoms by accelerating inflammasome activation in mice. Autophagy. 2020;16(12):2193-205.

33. Wang L, Huang Y, Chen J, Gao J, Chen S, Zhao M, et al. Dynamic crosstalk between HSCs and liver microenvironment: multicellular interactions in the regulation of liver fibrosis. Frontiers in Cell and Developmental Biology. 2025;13:1635763.

34. Gabandé-Rodríguez E, M. Gómez de las Heras M, Mittelbrunn M. Control of inflammation by calorie restriction mimetics: on the crossroad of autophagy and mitochondria. Cells. 2019;9(1):82.

35. Makris AP, Karianaki M, Tsamis KI, Paschou SA. The role of the gut-brain axis in depression: endocrine, neural, and immune pathways. Hormones. 2021;20(1):1-12.

36. Silva DF, Empadinhas N, Cardoso SM, Esteves AR. Neurodegenerative microbially-shaped diseases: oxidative stress meets neuroinflammation. Antioxidants. 2022;11(11):2141.

37. Xu Y, Wang J, Yuan R, Qin Z, Long K, Gao P. Targeting the immuno-inflammatory-microbial network: a key strategy for sepsis treatment. Frontiers in Immunology. 2025;16:1575516.

38. Park J, Kim CH. Regulation of common neurological disorders by gut microbial metabolites. Experimental & molecular medicine. 2021;53(12):1821-33.

39. Zheng Z, Wang S, Wu C, Cao Y, Gu Q, Zhu Y, et al. Gut microbiota dysbiosis after traumatic brain injury contributes to persistent microglial activation associated with upregulated Lyz2 and shifted tryptophan metabolic phenotype. Nutrients. 2022;14(17):3467.

40. Chidambaram SB, Rathipriya AG, Mahalakshmi AM, Sharma S, Hediyal TA, Ray B, et al. The influence of gut dysbiosis in the pathogenesis and management of ischemic stroke. Cells. 2022;11(7):1239.

41. Wang K, Liu H, Hu Q, Wang L, Liu J, Zheng Z, et al. Epigenetic regulation of aging: implications for interventions of aging and diseases. Signal transduction and targeted therapy. 2022;7(1):374.

42. López-Gil L, Pascual-Ahuir A, Proft M. Genomic instability and epigenetic changes during aging. International journal of molecular sciences. 2023;24(18):14279.

43. Alimohammadi M, Makaremi S, Rahimi A, Asghariazar V, Taghadosi M, Safarzadeh E. DNA methylation changes and inflammaging in aging-associated diseases. Epigenomics. 2022;14(16):965-86.

44. Chen Q, Li H, Liu Y, Zhao M. Epigenetic regulation of immune and inflammatory responses in rheumatoid arthritis. Frontiers in Immunology. 2022;13:881191.

45. Zhang S, Meng Y, Zhou L, Qiu L, Wang H, Su D, et al. Targeting epigenetic regulators for inflammation: Mechanisms and intervention therapy. MedComm. 2022;3(4):e173.

46. Caldwell BA, Li L. Epigenetic regulation of innate immune dynamics during inflammation. Journal of leukocyte biology. 2024;115(4):589-606.

47. Pereira M, Cruz MT, Fortuna A, Bicker J. Restoring the epigenome in Alzheimer's disease: advancing HDAC inhibitors as therapeutic agents. Drug Discovery Today. 2024;29(7):104052.

48. Zimbru R-I, Zimbru E-L, Bojin F-M, Haidar L, Andor M, Harich OO, et al. Connecting the Dots: How MicroRNAs Link Asthma and Atherosclerosis. International Journal of Molecular Sciences. 2025;26(8):3570.

49. Li X, Yang Y, Wang Z, Jiang S, Meng Y, Song X, et al. Targeting non-coding RNAs in unstable atherosclerotic plaques: Mechanism, regulation, possibilities, and limitations. International Journal of Biological Sciences. 2021;17(13):3413.

50. Li L, Wu Y-Q, Yang J-E. Stress-Related LncRNAs and Their Roles in Diabetes and Diabetic Complications. International Journal of Molecular Sciences. 2025;26(5):2194.

51. Ya J, Bayraktutan U. Senolytics and senomorphics targeting p38MAPK/NF-κB Pathway protect endothelial cells from oxidative stress-mediated premature senescence. Cells. 2024;13(15):1292.

52. Zeng W, Shen J, Bo T, Peng L, Xu H, Nasser MI, et al. Cutting edge: probiotics and fecal microbiota transplantation in immunomodulation. Journal of immunology research. 2019;2019(1):1603758.

53. Li Q, Zhang H, Xiao N, Liang G, Lin Y, Yang X, et al. Aging and Lifestyle Modifications for Preventing Aging‐Related Diseases. The FASEB Journal. 2025;39(9):e70575.

54. Silva E, Tome I, Vasques-Novoa F, Silva A, Conceicao G, Miranda-Silva D, et al. Pharmacological Targeting of Senescence with ABT-263 in Experimental Heart Failure with Preserved Ejection Fraction. Cardiovascular Research. 2022;118(Supplement_1):cvac066. 107.

55. Dabravolski SA, Sukhorukov VN, Kalmykov VA, Orekhov NA, Grechko AV, Orekhov AN. Heat shock protein 90 as therapeutic target for CVDs and heart ageing. International Journal of Molecular Sciences. 2022;23(2):649.

56. Bugide S, Reddy DS, Malvi P, Gupta R, Wajapeyee N. ALK inhibitors suppress HCC and synergize with anti-PD-1 therapy and ABT-263 in preclinical models. Iscience. 2024;27(5).

57. Csekes E, Račková L. Skin aging, cellular senescence and natural polyphenols. International journal of molecular sciences. 2021;22(23):12641.

58. Bahour N, Bleichmar L, Abarca C, Wilmann E, Sanjines S, Aguayo-Mazzucato C. Clearance of p16Ink4a-positive cells in a mouse transgenic model does not change β-cell mass and has limited effects on their proliferative capacity. Aging (Albany NY). 2023;15(2):441.

59. Cuollo L, Antonangeli F, Santoni A, Soriani A. The senescence-associated secretory phenotype (SASP) in the challenging future of cancer therapy and age-related diseases. Biology. 2020;9(12):485.

60. Li Y, Kračun D, Dustin CM, El Massry M, Yuan S, Goossen CJ, et al. Forestalling age-impaired angiogenesis and blood flow by targeting NOX: Interplay of NOX1, IL-6, and SASP in propagating cell senescence. Proceedings of the National Academy of Sciences. 2021;118(42):e2015666118.

61. Groarke EM, Feng X, Aggarwal N, Manley AL, Wu Z, Gao S, et al. Efficacy of JAK1/2 inhibition in murine immune bone marrow failure. Blood. 2023;141(1):72-89.

62. Maiese K. Cognitive impairment with diabetes mellitus and metabolic disease: innovative insights with the mechanistic target of rapamycin and circadian clock gene pathways. Expert review of clinical pharmacology. 2020;13(1):23-34.

63. Dong Z, Luo Y, Yuan Z, Tian Y, Jin T, Xu F. Cellular senescence and SASP in tumor progression and therapeutic opportunities. Molecular Cancer. 2024;23(1):181.

64. Alam MS, Gangiredla J, Hasan NA, Barnaba T, Tartera C. Aging-induced dysbiosis of gut microbiota as a risk factor for increased Listeria monocytogenes infection. Frontiers in Immunology. 2021;12:672353.

65. Ma X, Shin Y-J, Jang H-M, Joo M-K, Yoo J-W, Kim D-H. Lactobacillus rhamnosus and Bifidobacterium longum alleviate colitis and cognitive impairment in mice by regulating IFN-γ to IL-10 and TNF-α to IL-10 expression ratios. Scientific reports. 2021;11(1):20659.

66. Cheng CK, Gao J, Kang L, Huang Y. Fecal microbiota transfer from young mice reverts vascular aging hallmarks and metabolic impairments in aged mice. Aging and disease. 2024;16(3):1576.

67. Li D, Cui L, Gao Y, Li Y, Tan X, Xu H. Fecal microbiota transplantation improves intestinal inflammation in mice with ulcerative colitis by modulating intestinal flora composition and down-regulating NF-kB signaling pathway. Microbial Pathogenesis. 2022;173:105803.

68. Shen H, Guan Q, Zhang X, Yuan C, Tan Z, Zhai L, et al. New mechanism of neuroinflammation in Alzheimer's disease: the activation of NLRP3 inflammasome mediated by gut microbiota. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2020;100:109884.

69. Abad-Jiménez Z, López-Domènech S, Pelechá M, Perea-Galera L, Rovira-Llopis S, Bañuls C, et al. Calorie restriction modulates mitochondrial dynamics and autophagy in leukocytes of patients with obesity. Free Radical Biology and Medicine. 2024;225:677-86.

70. Biolato M, Manca F, Marrone G, Cefalo C, Racco S, Miggiano GA, et al. Intestinal permeability after Mediterranean diet and low-fat diet in non-alcoholic fatty liver disease. World journal of gastroenterology. 2019;25(4):509.

71. Purnomo SP, Rejeki PS, Argarini R, Halim S, Rachmayanti DA, Permataputri CaDA, et al. Regulation of Metabolic Aging Through Adenosine Mono Phosphate-Activated Protein Kinase and Mammalian Target of Rapamycin: A Comparative Study of Intermittent Fasting Variations in Obese Young Women. Nutrients. 2025;17(10):1695.

72. Calcaterra V, Vandoni M, Rossi V, Berardo C, Grazi R, Cordaro E, et al. Use of physical activity and exercise to reduce inflammation in children and adolescents with obesity. International journal of environmental research and public health. 2022;19(11):6908.

73. Colombini B, Dinu M, Murgo E, Lotti S, Tarquini R, Sofi F, et al. Ageing and low-level chronic inflammation: the role of the biological clock. Antioxidants. 2022;11(11):2228.

74. Milligan Armstrong A, Porter T, Quek H, White A, Haynes J, Jackaman C, et al. Chronic stress and A lzheimer's disease: the interplay between the hypothalamic–pituitary–adrenal axis, genetics and microglia. Biological Reviews. 2021;96(5):2209-28.

75. Rådmark L. Mind and body exercises: associations with mental health, antidepressant medication, autonomic functioning and inflammatory biomarkers: Karolinska Institutet (Sweden); 2021.