Pathogenic modulators of cellular senescence

Cellular senescence is characterized by irreversible cell-cycle arrest, with cells remaining viable and metabolically active. This state features a proinflammatory senescence-associated secretory phenotype (SASP) that can harm neighboring tissues. Accumulation of senescent cells accelerates age-related physiological decline and associated pathologies. Furthermore, cellular senescence is implicated in various physiological processes, including embryonic development, wound healing, tumor progression, and immune response regulation. The complexity of the aging process arises from its diverse underlying mechanisms, potential reversibility, and intrinsic heterogeneity. Experimental gerontology focuses on identifying pathogenic modulators that regulate the formation and accumulation of senescent cells, as well as investigating their impact on tissue function. Within the field of experimental gerontology, considerable attention is devoted to identifying pathogenic modulators that regulate the formation and accumulation of senescent cells, as well as to investigating their impact on tissue function. Of particular interest is the characterization of novel molecular mechanisms that govern cellular aging. Key pathogenic molecular pathways include the p53-dependent senescence pathway, the p16INK4a/pRb pathway, and non-canonical pathways like IFIH1-MAVS, which contribute to oxidative stress, DNA damage, activation of SASP, and other cellular dysfunction. This study critically examines how viral and bacterial agents induce cellular senescence, particularly in vitro, reviewing the regulatory mechanisms involved. It discusses genetic variants affecting infection susceptibility and categorizes senescence markers. Investigating the molecular mechanisms underlying cellular aging presents promising avenues for the development of targeted and effective therapeutic interventions. Such strategies may include the selective induction of senescence in cancer cells, suppression of senescence to mitigate age-related diseases, or the comprehensive modulation of aging processes to optimize clinical outcomes.

1. Aguado J., Amarilla A.A., Taherian Fard A., Albornoz E.A., Tyshkovskiy A., Schwabenland M., Chaggar H.K., … Gladyshev V.N., Woodruff T.M., Mar J.C., Watterson D., Wolvetang E.J. Senolytic therapy alleviates physiological human brain aging and COVID-19 neuropathology. Nat Aging. 2023;3(12):1561-1575. doi 10.1038/s43587-023-00519-6

2. Aguirre M., Escobar M., Forero Amézquita S., Cubillos D., Rincón C., Vanegas P., Tarazona M.P., Atuesta Escobar S., Blanco J.C., Celis L.G. Application of the Yamanaka transcription factors Oct4, Sox2, Klf4, and c-Myc from the laboratory to the clinic. Genes. 2023; 14(9):1697. doi 10.3390/genes14091697

3. Alam M.S., Gangiredla J., Hasan N.A., Barnaba T., Tartera C. Aginginduced dysbiosis of gut microbiota as a risk factor for increased Listeria monocytogenes infection. Front Immunol. 2021;12:672353. doi 10.3389/fimmu.2021.672353

4. Aman Y., Schmauck-Medina T., Hansen M., Morimoto R.I., Simon A.K., Bjedov I., Palikaras K., … Rubinsztein D.C., Partridge L., Kroemer G., Labbadia J., Fang E.F. Autophagy in healthy aging and disease. Nat Aging. 2021;1(8):634-650. doi 10.1038/s43587-021-00098-4

5. Arakelyan N.A., Kupriyanova D.A., Vasilevska J., Rogaev E.I. Sexual dimorphism in immunity and longevity among the oldest old. Front Immunol. 2025;16:1525948. doi 10.3389/fimmu.2025.1525948

6. Augusto D.G., Murdolo L.D., Chatzileontiadou D.S.M., Sabatino J.J., Yusufali T., Peyser N.D., Butcher X., … Olgin J.E., Pletcher M.J., Maiers M., Gras S., Hollenbach J.A. A common allele of HLA is associated with asymptomatic SARS-CoV-2 infection. Nature. 2023; 620(7972):128-136. doi 10.1038/s41586-023-06331-x

7. Azcarate D., Olasagasti Arsuaga F., Granizo Rodriguez E., AranaArri E., España P.P., Intxausti M., Sancho C., García De Vicuña Meléndez A., Ibarrondo O., De Pancorbo M.M. Human-genetic variants associated with susceptibility to SARS-CoV-2 infection. Gene. 2025;953:149423. doi 10.1016/j.gene.2025.149423

8. Azman K.F., Zakaria R. d-Galactose-induced accelerated aging model: an overview. Biogerontology. 2019;20(6):763-782. doi 10.1007/s10522-019-09837-y

9. Beaupere C., Garcia M., Larghero J., Fève B., Capeau J., Lagathu C. The HIV proteins Tat and Nef promote human bone marrow mesenchymal stem cell senescence and alter osteoblastic differentiation. Aging Cell. 2015;14(4):534-546. doi 10.1111/acel.12308

10. Beckmann N., Becker K.A. Ceramide and related molecules in viral infections. Int J Mol Sci. 2021;22(11):5676. doi 10.3390/ijms22115676

11. Bian T., Gibbs J.D., Örvell C., Imani F. Respiratory syncytial virus matrix protein induces lung epithelial cell cycle arrest through a p53 dependent pathway. PLoS One. 2012;7(5):e38052. doi 10.1371/journal.pone.0038052

12. Bitencourt T.C., Vargas J.E., Silva A.O., Fraga L.R., Filippi‐Chiela E. Subcellular structure, heterogeneity, and plasticity of senescent cells. Aging Cell. 2024;23(4):e14154. doi 10.1111/acel.14154

13. Blackhurst B.M., Funk K.E. Viral pathogens increase risk of neurodegenerative disease. Nat Rev Neurol. 2023;19(5):259-260. doi 10.1038/s41582-023-00790-6

14. Bobak C.A., Abhimanyu, Natarajan H., Gandhi T., Grimm S.L., Nishiguchi T., Koster K., … Cirillo J.D., O’Malley J., Hill J.E., Coarfa C., DiNardo A.R. Increased DNA methylation, cellular senescence and premature epigenetic aging in guinea pigs and humans with tuberculosis. Aging. 2022;14(5):2174-2193. doi 10.18632/aging.203936

15. Cai Q., Shi P., Yuan Y., Peng J., Ou X., Zhou W., Li J., Su T., Lin L., Cai S., He Y., Xu J. Inflammation-associated senescence promotes Helicobacter pylori – induced atrophic gastritis. Cell Mol Gastroenterol Hepatol. 2021;11(3):857-880. doi 10.1016/j.jcmgh.2020.10.015

16. Casto A.M., Seo S., Levine D.M., Storer B.E., Dong X., Hansen J.A., Boeckh M., Martin P.J. Genetic variants associated with cytomegalovirus infection after allogeneic hematopoietic cell transplantation. Blood. 2021;138(17):1628-1636. doi 10.1182/blood.2021012153

17. Chatzopoulou F., Gioula G., Kioumis I., Chatzidimitriou D., Exindari M. Identification of complement-related host genetic risk factors associated with influenza A(H1N1)pdm09 outcome: challenges ahead. Med Microbiol Immunol. 2019;208(5):631-640. doi 10.1007/s00430-018-0567-9

18. Chen C., Wang M., Zhu Z., Qu J., Xi X., Tang X., Lao X., … Bai C., Zhang Z., Lu S., Song Y., Zhou W. Multiple gene mutations identified in patients infected with influenza A (H7N9) virus. Sci Rep. 2016;6(1):25614. doi 10.1038/srep25614

19. Chen N.C., Partridge A.T., Tuzer F., Cohen J., Nacarelli T., Navas-Martín S., Sell C., Torres C., Martín-García J. Induction of a senescencelike phenotype in cultured human fetal microglia during HIV-1 infection. J Gerontol A Biol Sci Med Sci. 2018;73(9):1187-1196. doi 10.1093/gerona/gly022

20. Chumduri C., Gurumurthy R.K., Zietlow R., Meyer T.F. Subversion of host genome integrity by bacterial pathogens. Nat Rev Mol Cell Biol. 2016;17(10):659-673. doi 10.1038/nrm.2016.100

21. De Jong S.J., Créquer A., Matos I., Hum D., Gunasekharan V., Lorenzo L., Jabot-Hanin F., … Franco J.L., Burger B., Orth G., Jouanguy E., Casanova J.-L. The human CIB1–EVER1–EVER2 complex governs keratinocyte-intrinsic immunity to β-papillomaviruses. J Exp Med. 2018;215(9):2289-2310. doi 10.1084/jem.20170308

22. Dean M., Carrington M., Winkler C., Huttley G.A., Smith M.W., Allikmets R., Goedert J.J., … Kaslow R., Saah A., Rinaldo C., Detels R., O’Brien S.J. Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Science. 1996;273(5283):1856-1862. doi 10.1126/science.273.5283.1856

23. DeSantis C.E., Miller K.D., Dale W., Mohile S.G., Cohen H.J., Leach C.R., Goding Sauer A., Jemal A., Siegel R.L. Cancer statistics for adults aged 85 years and older, 2019. CA Cancer J Clin. 2019; 69(6):452-467. doi 10.3322/caac.21577

24. Di Giorgio E., Ranzino L., Tolotto V., Dalla E., Burelli M., Gualandi N., Brancolini C. Transcription of endogenous retroviruses in senescent cells contributes to the accumulation of double-stranded RNAs that trigger an anti-viral response that reinforces senescence. Cell Death Dis. 2024;15(2):157. doi 10.1038/s41419-024-06548-2

25. Donato A.J., Machin D.R., Lesniewski L.A. Mechanisms of dysfunction in the aging vasculature and role in age-related disease. Circ Res. 2018;123(7):825-848. doi 10.1161/CIRCRESAHA.118.312563

26. Esposito S., Molteni C.G., Giliani S., Mazza C., Scala A., Tagliaferri L., Pelucchi C., Fossali E., Plebani A., Principi N. Toll-like receptor 3 gene polymorphisms and severity of pandemic A/H1N1/2009 influenza in otherwise healthy children. Virol J. 2012;9(1):270. doi 10.1186/1743-422X-9-270

27. Fafián-Labora J.A., O’Loghlen A. Classical and nonclassical intercellular communication in senescence and ageing. Trends Cell Biol. 2020;30(8):628-639. doi 10.1016/j.tcb.2020.05.003

28. Grompone G., Martorell P., Llopis S., González N., Genovés S., Mulet A.P., Fernández-Calero T., Tiscornia I., Bollati-Fogolín M., Chambaud I., Foligné B., Montserrat A., Ramón D. Anti-inflammatory Lactobacillus rhamnosus CNCM I-3690 strain protects against oxidative stress and increases lifespan in Caenorhabditis elegans. PLoS One. 2012;7(12):e52493. doi 10.1371/journal.pone.0052493

29. Gu P., Wei R., Liu R., Yang Q., He Y., Guan J., He W., … Zeng Z., Chen Z., Jiang Y., Liu Z., Chen P. Aging‐induced alternation in the gut microbiota impairs host antibacterial defense. Adv Sci. 2025; 12(12):2411008. doi 10.1002/advs.202411008

30. Hale A.E., Collins-McMillen D., Lenarcic E.M., Igarashi S., Kamil J.P., Goodrum F., Moorman N.J. FOXO transcription factors activate alternative major immediate early promoters to induce human cytomegalovirus reactivation. Proc Natl Acad Sci USA. 2020; 117(31):18764-18770. doi 10.1073/pnas.2002651117

31. Han S.-J., Stacy A., Corral D., Link V.M., De Siqueira M.K., Chi L., Teijeiro A., Yong D.S., Perez-Chaparro P.J., Bouladoux N., Lim A.I., Enamorado M., Belkaid Y., Collins N. Microbiota configuration determines nutritional immune optimization. Proc Natl Acad Sci USA. 2023;120(49):e2304905120. doi 10.1073/pnas.2304905120

32. Hasegawa T., Oka T., Son H.G., Oliver-García V.S., Azin M., Eisenhaure T.M., Lieb D.J., Hacohen N., Demehri S. Cytotoxic CD4+ T cells eliminate senescent cells by targeting cytomegalovirus antigen. Cell. 2023;186(7):1417-1431.e20. doi 10.1016/j.cell.2023.02.033

33. Hellani F., Leleu I., Saidi N., Martin N., Lecoeur C., Werkmeister E., Koffi D., Trottein F., Yapo-Etté H., Das B., Abbadie C., Pied S. Role of astrocyte senescence regulated by the non-canonical autophagy in the neuroinflammation associated to cerebral malaria. Brain Behav Immun. 2024;117:20-35. doi 10.1016/j.bbi.2023.12.030

34. Hidaka F., Matsuo S., Muta T., Takeshige K., Mizukami T., Nunoi H. A missense mutation of the Toll-like receptor 3 gene in a patient with influenza-associated encephalopathy. Clin Immunol. 2006;119(2): 188-194. doi 10.1016/j.clim.2006.01.005

35. Hwang H.J., Kang D., Shin J., Jung J., Ko S., Jung K.H., Hong S.- S., Park J.E., Oh M.J., An H.J., Yang W.-H., Ko Y.-G., Cha J.-H., Lee J.- S. Therapy-induced senescent cancer cells contribute to cancer progression by promoting ribophorin 1-dependent PD-L1 upregulation. Nat Commun. 2025;16(1):353. doi 10.1038/s41467-024-54132-1

36. Jallow M., Teo Y.Y., Small K.S., Rockett K.A., Deloukas P., Clark T.G., Kivinen K., … Williams T.N., Wilson M., Kwiatkowski D.P.; Wellcome Trust Case Control Consortium; Malaria Genomic Epidemiology Network. Genome-wide and fine-resolution association analysis of malaria in West Africa. Nat Genet. 2009;41(6):657-665. doi 10.1038/ng.388

37. Jeanpierre M., Cognard J., Tusseau M., Riller Q., Bui L.-C., Berthelet J., Laurent A., … Rodrigues Lima F., Walzer T., Rieux-Laucat F., Belot A., Mathieu A.-L. Haploinsufficiency in PTPN2 leads to earlyonset systemic autoimmunity from Evans syndrome to lupus. J Exp Med. 2024;221(9):e20232337. doi 10.1084/jem.20232337

38. Jiang M., Xu Q., Wu Z. Optimized Yamanaka factors combined with TERT gene therapy for enhanced anti-aging effects. Genes Dis. 2026;13(2):101669. doi 10.1016/j.gendis.2025.101669

39. Kamat P., Macaluso N., Li Y., Agrawal A., Winston A., Pan L., Stewart T., Starich B., Milcik N., Min C., Wu P.-H., Walston J., Fan J., Phillip J.M. Single-cell morphology encodes functional subtypes of senescence in aging human dermal fibroblasts. Sci Adv. 2025;11(17):eads1875. doi 10.1126/sciadv.ads1875

40. Kannampuzha S., Gopalakrishnan A.V., Padinharayil H., Alappat R.R., Anilkumar K.V., George A., Dey A., Vellingiri B., Madhyastha H., Ganesan R., Ramesh T., Jayaraj R., Prabakaran D.S. Onco-pathogen mediated cancer progression and associated signaling pathways in cancer development. Pathogens. 2023;12(6):770. doi 10.3390/pathogens12060770

41. Kawamoto S., Uemura K., Hori N., Takayasu L., Konishi Y., Katoh K., Matsumoto T., … Ohtani N., Standley D.M., Suda W., Fukuda S., Hara E. Bacterial induction of B cell senescence promotes agerelated changes in the gut microbiota. Nat Cell Biol. 2023;25(6): 865-876. doi 10.1038/s41556-023-01145-5

42. Kovtonyuk L.V., Caiado F., Garcia-Martin S., Manz E.-M., Helbling P., Takizawa H., Boettcher S., Al-Shahrour F., Nombela-Arrieta C., Slack E., Manz M.G. IL-1 mediates microbiome-induced inflammaging of hematopoietic stem cells in mice. Blood. 2022;139(1): 44-58. doi 10.1182/blood.2021011570

43. Lee S., Yu Y., Trimpert J., Benthani F., Mairhofer M., Richter-Pechanska P., Wyler E., … Ralser M., Eils R., Reimann M., Fan D.N.Y., Schmitt C.A. Virus-induced senescence is a driver and therapeutic target in COVID-19. Nature. 2021;599(7884):283-289. doi 10.1038/s41586-021-03995-1

44. Li Y., Choi H., Leung K., Jiang F., Graham D.Y., Leung W.K. Global prevalence of Helicobacter pylori infection between 1980 and 2022: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2023;8(6):553-564. doi 10.1016/S2468-1253(23)00070-5

45. Lin P.L., Flynn J.L. Understanding latent tuberculosis: a moving target. J Immunol. 2010;185(1):15-22. doi 10.4049/jimmunol.0903856

46. Lipskaia L., Delval L., Sencio V., Born E., Heumel S., Houssaini A., Valentin C., … Le Grand R., Le Goffic R., Bernard D., Adnot S., Trottein F. Virus‐induced cellular senescence causes pulmonary sequelae post‐influenza infection. Aging Cell. 2025;24(9):e70140. doi 10.1111/acel.70140

47. Liu L., Hao X., Bai Y., Tian Y. The soil Mycobacterium sp. promotes health and longevity through different bacteria‐derived molecules in Caenorhabditis elegans. Aging Cell. 2025;24(3):e14416. doi 10.1111/acel.14416

48. Liu Yu., Gu S., Su Y., Wang S., Cheng Y., Sang X., Jin L., Liu Yi., Li C., Liu W., Chen M., Wang X., Wang Z. Embryonic stem cell extracellular vesicles reverse the senescence of retinal pigment epithelial cells by the p38MAPK pathway. Exp Eye Res. 2023;227:109365. doi 10.1016/j.exer.2022.109365

49. Liu Z., Liang Q., Ren Y., Guo C., Ge X., Wang L., Cheng Q., Luo P., Zhang Y., Han X. Immunosenescence: molecular mechanisms and diseases. Sig Transduct Target Ther. 2023;8(1):200. doi 10.1038/s41392-023-01451-2

50. Ma F., Liu X., Zhang Y., Tao Y., Zhao L., Abusalamah H., Huffman C., Harbison R.A., Puram S.V., Wang Y., Peng G. Tumor extracellular vesicle-derived PD-L1 promotes T cell senescence through lipid metabolism reprogramming. Sci Transl Med. 2025;17(785):eadm7269. doi 10.1126/scitranslmed.adm7269

51. Majeed A.Y., Zulkafli N.E.S., Ad’hiah A.H. The IFIH1 gene variants rs1990760 and rs2111485 are associated with COVID-19 susceptibility and affect IFIH1 protein levels in Iraqis. Egypt J Med Hum Genet. 2024;25(1):132. doi 10.1186/s43042-024-00601-7

52. Majewska J., Agrawal A., Mayo A., Roitman L., Chatterjee R., Sekeresova Kralova J., Landsberger T., … Wagner W., Maimon A., Amit I., Alon U., Krizhanovsky V. p16-dependent increase of PD-L1 stability regulates immunosurveillance of senescent cells. Nat Cell Biol. 2024;26(8):1336-1345. doi 10.1038/s41556-024-01465-0

53. Mao J., Zhang Q., Zhuang Y., Zhang Y., Li L., Pan J., Xu L., Ding Y., Wang M., Cong Y.-S. Reactivation of senescence-associated endogenous retroviruses by ATF3 drives interferon signaling in aging. Nat Aging. 2024;4(12):1794-1812. doi 10.1038/s43587-024-00745-6

54. Martin M.P. Genetic acceleration of AIDS progression by a promoter variant of CCR5. Science. 1998;282(5395):1907-1911. doi 10.1126/science.282.5395.1907

55. Martínez I., García-Carpizo V., Guijarro T., García-Gomez A., Navarro D., Aranda A., Zambrano A. Induction of DNA double-strand breaks and cellular senescence by human respiratory syncytial virus. Virulence. 2016;7(4):427-442. doi 10.1080/21505594.2016.1144001

56. Masters M.C., Landay A.L., Robbins P.D., Tchkonia T., Kirkland J.L., Kuchel G.A., Niedernhofer L.J., Palella F.J. Chronic HIV infection and aging: application of a geroscience-guided approach. J Acquir Immune Defic Syndr. 2022;89(Suppl.1):S34-S46. doi 10.1097/QAI.0000000000002858

57. Mathiasen S.L., Gall-Mas L., Pateras I.S., Theodorou S.D.P., Namini M.R.J., Hansen M.B., Martin O.C.B., … Akbar A.N., Gorgoulis V.G., Frisan T., Ødum N., Krejsgaard T. Bacterial genot oxins induce T cell senescence. Cell Rep. 2021;35(10):109220. doi 10.1016/j.celrep.2021.109220

58. McGovern K.E., Sonar S.A., Watanabe M., Coplen C.P., Bradshaw C.M., Nikolich J.Ž. The aging of the immune system and its implications for transplantation. GeroScience. 2023;45(3):13831400. doi 10.1007/s11357-022-00720-2

59. Mei F., Xie M., Huang X., Long Y., Lu X., Wang X., Chen L. Porphyromonas gingivalis and its systemic impact: current status. Pathogens. 2020;9(11):944. doi 10.3390/pathogens9110944

60. Nong C., Wu Z., Yang C., Xu W., Luo L., Zhou J., Shen L., Chen Y., Yuan Y., Hu G. Cdc42 improve SARS-CoV-2 spike protein-induced cellular senescence through activating of Wnt/β-Catenin signaling pathway. Front Cell Infect Microbiol. 2024;14:1449423. doi 10.3389/fcimb.2024.1449423

61. Ogrodnik M., Carlos Acosta J., Adams P.D., d’Adda Di Fagagna F., Baker D.J., Bishop C.L., Chandra T., … Witwer K., Von Zgli nicki T., Yun M.H., Grillari J., Demaria M. Guidelines for minimal information on cellular senescence experimentation in vivo. Cell. 2024; 187(16):4150-4175. doi 10.1016/j.cell.2024.05.059

62. Okumura S., Konishi Y., Narukawa M., Sugiura Y., Yoshimoto S., Arai Y., Sato S., … Fukunaga Y., Ueno M., Sakai Y., Nagayama S., Hara E. Gut bacteria identified in colorectal cancer patients promote tumourigenesis via butyrate secretion. Nat Commun. 2021;12(1): 5674. doi 10.1038/s41467-021-25965-x

63. Omodeo-Salè F., Motti A., Basilico N., Parapini S., Olliaro P., Taramelli D. Accelerated senescence of human erythrocytes cultured with Plasmodium falciparum. Blood. 2003;102(2):705-711. doi 10.1182/blood-2002-08-2437

64. Powell T.R., Duarte R.R.R., Hotopf M., Hatch S.L., De Mulder Rougvie M., Breen G.D., Lewis C.M., Nixon D.F. The behavioral, cellular and immune mediators of HIV-1 acquisition: new insights from population genetics. Sci Rep. 2020;10(1):3304. doi 10.1038/s41598-020-59256-0

65. Pringsheim T., Jette N., Frolkis A., Steeves T.D.L. The prevalence of Parkinson’s disease: a systematic review and meta‐analysis. Mov Disord. 2014;29(13):1583-1590. doi 10.1002/mds.25945

66. Raviola S., Griffante G., Iannucci A., Chandel S., Lo Cigno I., Lacarbonara D., Caneparo V., … Boldorini R., Cantaluppi V., Landolfo S., Gariglio M., De Andrea M. Human cytomegalovirus infection triggers a paracrine senescence loop in renal epithelial cells. Commun Biol. 2024;7(1):292. doi 10.1038/s42003-024-05957-5

67. Reimann M., Lee S., Schmitt C.A. Cellular senescence: neither irreversible nor reversible. J Exp Med. 2024;221(4):e20232136. doi 10.1084/jem.20232136

68. Ryu S., Shchukina I., Youm Y.-H., Qing H., Hilliard B., Dlugos T., Zhang X., … Horvath T.L., Dietrich M.O., Artyomov M., Wang A., Dixit V.D. Ketogenic diet restrains aging-induced exacerbation of coronavirus infection in mice. eLife. 2021;10:e66522. doi 10.7554/eLife.66522

69. Sadighi Akha A.A. Aging and the immune system: an overview. J Immunol Methods. 2018;463:21-26. doi 10.1016/j.jim.2018.08.005

70. Saeedi Saravi S.S., Pugin B., Constancias F., Shabanian K., Spalinger M., Thomas A., Le Gludic S., … Falchi M., Alimonti A., Ruschitzka F., Paneni F., Beer J.H. Gut microbiota-dependent increase in phenylacetic acid induces endothelial cell senescence during aging. Nat Aging. 2025;5(6):1025-1045. doi 10.1038/s43587-025-00864-8

71. Saito Y., Murata-Kamiya N., Hirayama T., Ohba Y., Hatakeyama M. Conversion of Helicobacter pylori CagA from senescence inducer to oncogenic driver through polarity-dependent regulation of p21. J Exp Med. 2010;207(10):2157-2174. doi 10.1084/jem.20100602

72. Salas A., Pardo-Seco J., Cebey-López M., Gómez-Carballa A., ObandoPacheco P., Rivero-Calle I., Currás-Tuala M.-J., … Martínez-Padilla M.D.C., Baca-Cots M., Moreno-Pérez D., Beatriz-Reyes S., LeónLeón M.C. Whole exome sequencing reveals new candidate genes in host genomic susceptibility to respiratory syncytial virus disease. Sci Rep. 2017;7(1):15888. doi 10.1038/s41598-017-15752-4

73. Scarpa E., Oliveri D., Moschetti G., Griego A., Vianello A., Rondelli D., Antinori B., … Franzè S., Cidonio G., Manganaro L., Lorè N.I., Rizzello L. Chronic mycobacteria infection triggers macrophage senescence. bioRxiv. 2024. doi 10.1101/2024.11.05.622137

74. Schmitt C.A., Tchkonia T., Niedernhofer L.J., Robbins P.D., Kirkland J.L., Lee S. COVID-19 and cellular senescence. Nat Rev Immunol. 2023;23(4):251-263. doi 10.1038/s41577-022-00785-2

75. Seoane R., Vidal S., Bouzaher Y.H., El Motiam A., Rivas C. The interaction of viruses with the cellular senescence response. Biology. 2020;9(12):455. doi 10.3390/biology9120455

76. Shi S., Zhang Q., Sang Y., Ge S., Wang Q., Wang R., He J. Probiotic Bifidobacterium longum BB68S improves cognitive functions in healthy older adults: a randomized, double-blind, placebo-controlled trial. Nutrients. 2022;15(1):51. doi 10.3390/nu15010051

77. Smith M.W., Dean M., Carrington M., Winkler C., Huttley G.A., Lomb D.A., Goedert J.J., … Multicenter AIDS Cohort Study (MACS); Multicenter Hemophilia Cohort Study (MHCS); San Francisco City Cohort (SFCC); ALIVE Study; O’Brien S.J. Contrasting genetic influence of CCR2 and CCR5 variants on HIV-1 infection and disease progression. Science. 1997;277(5328):959-965. doi 10.1126/science.277.5328.959

78. Smolgovsky S., Ibeh U., Tamayo T.P., Alcaide P. Adding insult to injury – inflammation at the heart of cardiac fibrosis. Cell Signal. 2021; 77:109828. doi 10.1016/j.cellsig.2020.109828

79. Thangaraj A., Chivero E.T., Tripathi A., Singh S., Niu F., Guo M.L., Pillai P., Periyasamy P., Buch S. HIV TAT-mediated microglial senescence: role of SIRT3-dependent mitochondrial oxidative stress. Redox Biol. 2021;40:101843. doi 10.1016/j.redox.2020.101843

80. Thye T., Vannberg F.O., Wong S.H., Owusu-Dabo E., Osei I., Gyapong J., Sirugo G., … Wellcome Trust Case Control Consortium; Morris A.P., Meyer C.G., Horstmann R.D., Hill A.V.S. Genome-wide association analyses identifies a susceptibility locus for tuberculosis on chromosome 18q11.2. Nat Genet. 2010;42(9):739-741. doi 10.1038/ng.639

81. Trevisan K., Cristina-Pereira R., Silva-Amaral D., Aversi-Ferreira T.A. Theories of aging and the prevalence of Alzheimer’s disease. BioMed Res Int. 2019;2019:9171424. doi 10.1155/2019/9171424

82. Tulic M.K., Hurrelbrink R.J., Prêle C.M., Laing I.A., Upham J.W., Le Souef P., Sly P.D., Holt P.G. TLR4 polymorphisms mediate impaired Conflict of interest. The authors declare no conflict of interest. Received December 23, 2025. Revised April 28, 2026. Accepted May 4, 2026. responses to respiratory syncytial virus and lipopolysaccharide. J Immunol. 2007;179(1):132-140. doi 10.4049/jimmunol.179.1.132

83. Wang H., Feng L., Pei Z., Zhao J., Lu S., Lu W. Gut microbiota metabolism of branched‐chain amino acids and their metabolites can improve the physiological function of aging mice. Aging Cell. 2025; 24(4):e14434. doi 10.1111/acel.14434

84. Wang Z., Ge S., Liao T., Yuan M., Qian W., Chen Q., Liang W., Cheng X., Zhou Q., Ju Z., Zhu H., Xiong W. Integrative single-cell metabolomics and phenotypic profiling reveals metabolic heterogeneity of cellular oxidation and senescence. Nat Commun. 2025;16(1):2740. doi 10.1038/s41467-025-57992-3

85. Wyles S.P., Yu G.T., Gold M., Behfar A. Topical platelet exosomes reduce senescence signaling in human skin: an exploratory prospective trial. Dermatol Surg. 2024;50(11S):S160-S165. doi 10.1097/DSS.0000000000004426

86. Xu F., Wang G., Zhao F., Huang Y., Fan Z., Mei S., Xie Y., … Cen S., Liang C., Ren L., Guo F., Wang J. IFITM3 inhibits SARS-CoV-2 infection and is associated with COVID-19 susceptibility. Viruses. 2022;14(11):2553. doi 10.3390/v14112553

87. Yan J., Chen S., Yi Z., Zhao R., Zhu J., Ding S., Wu J. The role of p21 in cellular senescence and aging-related diseases. Mol Cells. 2024; 47(11):100113. doi 10.1016/j.mocell.2024.100113

88. Zhang D., Chen G., Manwani D., Mortha A., Xu C., Faith J.J., Burk R.D., Kunisaki Y., Jang J.-E., Scheiermann C., Merad M., Frenette P.S. Neutrophil ageing is regulated by the microbiome. Nature. 2015;525(7570):528-532. doi 10.1038/nature15367

89. Zúñiga J., Buendía-Roldán I., Zhao Y., Jiménez L., Torres D., Romo J., Ramírez G., … Su L., Tager A.M., Pardo A., Selman M., Christiani D.C. Genetic variants associated with severe pneumonia in A/ H1N1 influenza infection. Eur Respir J. 2012;39(3):604-610. doi 10.1183/09031936.00020611