The interconnections between gerontogen, aging, and senotherapy

Rahma Rahma; Agian Jeffilano Barinda

doi:10.7324/JAPS.2024.184140

Abstract References Article Metrics Similar Articles Request Permission Related Search Citation Alert By Google Scholar Comment On This Article

Abstract

Aging causes various degenerative diseases in the older adult population. Senescence, a state of permanent cell-cycle arrest accompanied by the production of various pro-inflammatory factors known as senescence-associated secretory phenotype (SASP), is considered a significant contributor to the aging process and its chronic diseases. Ample evidence showed that various stressors could induce senescence, including DNA damage, telomere shortening and damage, activation of oncogenes, and mitochondrial dysfunction. Numerous credible findings indicate that environmental agents can induce senescence, including UV radiation, a high-fat diet, heavy metal exposure, cigarette smoke, and adverse social environment. These findings posed the possibility that many more environmental agents may induce senescence and accelerate aging but remain unidentified. Senescence also becomes more intriguing due to its promising future as a pharmacological target to blunt the detrimental effects of aging and prevent aging-related diseases, either by eliminating the senescent cells or by controlling the SASP. On the other hand, investigating senescence has become more intricate due to the need for a multimarker approach and translation in vivo analysis. This review will discuss senescence and its biomarkers, how to identify gerontogens in vivo, recent research about gerontogen, and also the development of senotherapy.

Keyword: Aging senescence toxicology gerontogen senotherapy

Citation:

Rahma R, Barinda, AJ. The interconnections between gerontogen, aging, and senotherapy. J Appl Pharm Sci. 2024. Online First. http://doi.org/10.7324/JAPS.2024.184140

Copyright: © The Author(s). This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

HTML Full Text

Reference

1. Litke R, Garcharna LC, Jiwani S, Neugroschl J. Modifiable risk factors in Alzheimer disease and related dementias: a review. ClinTher. 2021;43(6):953-65. https://doi.org/10.1016/j.clinthera.2021.05.006
2. Wu J, Li T, Song X, Sun W, Zhang Y, Liu Y, et al. Prevalence anddistribution of hypertension and related risk factors in Jilin Province,China 2015: a cross-sectional study. BMJ Open. 2018;8(3):e020126. https://doi.org/10.1136/bmjopen-2017-020126
3. Nguyen CT, Pham NM, Lee AH, Binns CW. Prevalence ofand risk factors for type 2 diabetes mellitus in Vietnam: asystematic review. Asia Pac J Public Health. 2015;27(6):588-600. https://doi.org/10.1177/1010539515595860
4. Arafat HM, Omar J, Muhamad R, Al-Astani TAD, Shafii N, Al LahamNA, et al. Breast cancer risk from modifiable and non-modifiablerisk factors among palestinian women: a systematic review andmeta-analysis. Asian Pac J Cancer Prev. 2021;22(7):1987-95. https://doi.org/10.31557/APJCP.2021.22.7.1987
5. Nguyen H, Manolova G, Daskalopoulou C, Vitoratou S,Prince M, Prina AM. Prevalence of multimorbidity incommunity settings: a systematic review and meta-analysis of observational studies. J Comorb. 2019;9:2235042X1987093. https://doi.org/10.1177/2235042X19870934
6. Kennedy BK, Berger SL, Brunet A, Campisi J, Cuervo AM, Epel ES, et al. Geroscience: linking aging to chronic disease. Cell. 2014;159(4):709-13. https://doi.org/10.1016/j.cell.2014.10.039
7. Sorrentino JA, Sanoff HK, Sharpless NE. Defining the toxicology of aging. Trends Mol Med. 2014;20(7):375-84. https://doi.org/10.1016/j.molmed.2014.04.004
8. Salam R, Saliou A, Bielle F, Bertrand M, Antoniewski C, Carpentier C, et al. Cellular senescence in malignant cells promotes tumor progression in mouse and patient Glioblastoma. Nat Commun. 2023;14(1):441. https://doi.org/10.1038/s41467-023-36124-9
9. Matsudaira T, Nakano S, Konishi Y, Kawamoto S, Uemura K, Kondo T, et al. Cellular senescence in white matter microglia is induced during ageing in mice and exacerbates the neuroinflammatory phenotype. Commun Biol. 2023;6(1):665. https://doi.org/10.1038/s42003-023-05027-2
10. Gorgoulis V, Adams PD, Alimonti A, Bennett DC, Bischof O, Bishop C, et al. Cellular senescence: defining a path forward. Cell. 2019;179(4):813-27. https://doi.org/10.1016/j.cell.2019.10.005
11. Gasek NS, Kuchel GA, Kirkland JL, Xu M. Strategies for targeting senescent cells in human disease. Nat Aging. 2021;1(10):870-9. https://doi.org/10.1038/s43587-021-00121-8
12. Mario Gonzalez-Meljem J, Haston S, Carreno G, Apps JR, Pozzi S, Stache C, et al. Stem cell senescence drives age-attenuated induction of pituitary tumours in mouse models of paediatric craniopharyngioma. Nat Commun. 2017;8(1):1819. https://doi.org/10.1038/s41467-017-01992-5
13. Dou X, Fu Q, Long Q, Liu S, Zou Y, Fu D, et al. PDK4-dependent hypercatabolism and lactate production of senescent cells promotes cancer malignancy. Nat Metab. Published online November 1, 2023;5(11):1887-910. https://doi.org/10.1038/s42255-023-00912-w
14. Yoshimoto S, Loo TM, Atarashi K, Kanda H, Sato S, Oyadomari S, et al. Obesity-induced gut microbial metabolite promotes live cancer through senescence secretome. Nature. 2013;499(7456):97-101. https://doi.org/10.1038/nature12347
15. Barinda AJ, Ikeda K, Nugroho DB, Wardhana DA, Sasaki N, Honda S, et al. Endothelial progeria induces adipose tissue senescence and impairs insulin sensitivity through senescence associated secretory phenotype. Nat Commun. 2020;11(1):1-13. https://doi.org/10.1038/s41467-020-14387-w
16. Palmer AK, Tchkonia T, LeBrasseur NK, Chini EN, Xu M, Kirkland JL. Cellular senescence in type 2 diabetes: a therapeutic opportunity. Diabetes. 2015;64(7):2289-98. https://doi.org/10.2337/db14-1820
17. Frescas D, Hall BM, Strom E, Virtuoso LP, Gupta M, Gleiberman AS, et al. Murine mesenchymal cells that express elevated levels of the CDK inhibitor p16(Ink4a) in vivo are not necessarily senescent. Cell Cycle. 2017;16(16):1526-33. https://doi.org/10.1080/15384101.2017.1339850
18. Zonari A, Brace LE, Al-Katib K, Porto WF, Foyt D, Guiang M, et al. Senotherapeutic peptide treatment reduces biological age and senescence burden in human skin models. npj Aging. 2023;9(1):10. https://doi.org/10.1038/s41514-023-00109-1
19. Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG, van de Sluis B, et al. Clearance of p16 Ink4a-positive senescent cells delays ageing-associated disorders. Nature. 2011;479(7372):232-6. https://doi.org/10.1038/nature10600
20. Roos CM, Zhang B, Palmer AK, Ogrodnik MB, Pirtskhalava T, Thalji NM, et al. Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice. Aging Cell. 2016;15(5):973-7. https://doi.org/10.1111/acel.12458
21. 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(2):75-95. https://doi.org/10.1038/s41580-020-00314-w
22. Rossiello F, Jurk D, Passos JF, d'Adda di Fagagna F. Telomere dysfunction in ageing and age-related diseases. Nat Cell Biol. 2022;24(2):135-47. https://doi.org/10.1038/s41556-022-00842-x
23. van Steensel B, Smogorzewska A, de Lange T. TRF2 Protects human telomeres from end-to-end fusions. Cell. 1998;92(3):401-13. https://doi.org/10.1016/S0092-8674(00)80932-0
24. Karlseder J, Smogorzewska A, de Lange T. Senescence induced by altered telomere state, not telomere loss. Science (1979). 2002;295(5564):2446-9. https://doi.org/10.1126/science.1069523
25. Domen A, Deben C, Verswyvel J, Flieswasser T, Prenen H, Peeters M, et al. Cellular senescence in cancer : clinical detection and prognostic implications. J Exp Clin Cancer Res. Published online 2022:41(1):360. https://doi.org/10.1186/s13046-022-02555-3
26. Bartkova J, Rezaei N, Liontos M, Karakaidos P, Kletsas D, Issaeva N, et al. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature. 2006;444(7119):633-7. https://doi.org/10.1038/nature05268
27. Wiley CD, Velarde MC, Lecot P, Liu S, Sarnoski EA, Freund A, et al. Mitochondrial dysfunction induces senescence with a distinc secretory phenotype. Cell Metab. 2016;23(2):303-14. https://doi.org/10.1016/j.cmet.2015.11.011
28. González-Gualda E, Baker AG, Fruk L, Muñoz-Espín D. A guide to assessing cellular senescence in vitro and in vivo. FEBS J. 2021;288(1):56-80. https://doi.org/10.1111/febs.15570
29. Tuttle CSL, Luesken SWM, Waaijer MEC, Maier AB. Senescence n tissue samples of humans with age-related diseases: a systematic review. Ageing Res Rev. 2021;68(March):101334. https://doi.org/10.1016/j.arr.2021.101334
30. Kohli J, Wang B, Brandenburg SM, Basisty N, Evangelou K, Varela- Eirin M, et al. Algorithmic assessment of cellular senescence in experimental and clinical specimens. Nat Protoc. 2021;16:2471-98; https://doi.org/10.1038/s41596-021-00505-5
31. Uxa S, Castillo-Binder P, Kohler R, Stangner K, Müller GA, Engeland K. Ki-67 gene expression. Cell Death Differ. 2021;28(12):3357-70. https://doi.org/10.1038/s41418-021-00823-x
32. Kurz DJ, Decary S, Hong Y, Erusalimsky JD. Senescenceassociated β-galactosidase reflects an increase in lysosomal mass during replicative ageing of human endothelial cells. J Cell Sci. 2000;113(20):3613-22. https://doi.org/10.1242/jcs.113.20.3613
33. Willcox BJ, Willcox DC, Suzuki M. Demographic, phenotypic, and genetic characteristics of centenarians in Okinawa and Japan: Part 1-centenarians in Okinawa. Mech Ageing Dev. 2017;165:75-9. https://doi.org/10.1016/j.mad.2016.11.001
34. Willcox DC, Willcox BJ, Shimajiri S, Kurechi S, Suzuki M. Aging gracefully: a retrospective analysis of functional status in okinawan centenarians. Am J Geriatr Psychiatry. 2007;15(3):252-6. https://doi.org/10.1097/JGP.0b013e31803190cc
35. Torigoe TH, Willcox DC, Shimabukuro M, Higa M, Gerschenson M, Andrukhiv A, et al. Novel protective effect of the FOXO3 longevity genotype on mechanisms of cellular aging in Okinawans. npj Aging. 2024;10(1):18. https://doi.org/10.1038/s41514-024-00142-8
36. Graham Ruby J, Wright KM, Rand KA, Kermany A, Noto K, Curtis D, et al. Estimates of the heritability of human longevity are substantially inflated due to assortative mating. Genetics. 2018;210(3):1109-24. https://doi.org/10.1534/genetics.118.301613
37. Fitsiou E, Pulido T, Campisi J, Alimirah F, Demaria M. Cellular senescence and the senescence-associated secretory phenotype as drivers of skin photoaging. J Investig Dermatol. 2021;141(4):1119- 26. https://doi.org/10.1016/j.jid.2020.09.031
38. Ma HM, Liu W, Zhang P, Yuan XY. Human skin fibroblast telomeres are shortened after ultraviolet irradiation. J Int Med Res. 2012;40(5):1871-7. https://doi.org/10.1177/030006051204000526
39. Kim SR, Jiang K, Ogrodnik M, Chen X, Zhu XY, Lohmeier H, et al. Increased renal cellular senescence in murine high-fat diet: effect of the senolytic drug quercetin. Transl Res. 2019;213:112-23. https://doi.org/10.1016/j.trsl.2019.07.005
40. Jurk D, Wilson C, Passos JF, Oakley F, Correia-Melo C, Greaves L, et al. Chronic inflammation induces telomere dysfunction and accelerates ageing in mice. Nat Commun. 2014;2:4172. https://doi.org/10.1038/ncomms5172
41. Moreno-Navarrete JM, Ortega F, Sabater M, Ricart W, Fernández- Real JM. Telomere length of subcutaneous adipose tissue cells is shorter in obese and formerly obese subjects. Int J Obes. 2010;34(8):1345-8. https://doi.org/10.1038/ijo.2010.49
42. Clemente DBP, Maitre L, Bustamante M, Chatzi L, Roumeliotaki T, Fossati S, et al. Obesity is associated with shorter telomeres in 8 year-old children. Sci Rep. 2019;9(1):18739. https://doi.org/10.1038/s41598-019-55283-8
43. Batsis JA, Mackenzie TA, Vasquez E, Germain CM, Emeny RT, ippberger P, et al. Association of adiposity, telomere length and mortality: data from the NHANES 1999-2002. Int J Obes. 2018;42(2):198-204. https://doi.org/10.1038/ijo.2017.202
44. Grun LK, Teixeira N da R, Mengden L von, de Bastiani MA, Parisi MM, Bortolin R, et al. TRF1 as a major contributor for telomeres'shortening in the context of obesity. Free Radic Biol Med. 2018;129(September):286-95. https://doi.org/10.1016/j.freeradbiomed.2018.09.039
45. Sorrentino JA, Krishnamurthy J, Tilley S, Alb JG, Burd CE, Sharpless NE. P16INK4a reporter mice reveal age-promoting effects of environmental toxicants. J Clin Investig. 2014;124(1):169-73. https://doi.org/10.1172/JCI70960
46. Vielee ST, Wise JP. Among gerontogens, heavy metals are a class of their own: a review of the evidence for cellular senescence. Brain Sci. 2023;13(3):500. https://doi.org/10.3390/brainsci13030500
47. Okamura K, Sato M, Suzuki T, Nohara K. Inorganic arsenic exposure-induced premature senescence and senescence-associated secretory phenotype (SASP) in human hepatic stellate cells1. Toxicol Appl Pharmacol. 2022;454(September):116231. https://doi.org/10.1016/j.taap.2022.116231
48. Maher BA, González-Maciel A, Reynoso-Robles R, Torres-Jardón R, Calderón-Garcidueñas L. Iron-rich air pollution nanoparticles: an unrecognised environmental risk factor for myocardial mitochondrial dysfunction and cardiac oxidative stress. Environ Res. 2020;188:109816. https://doi.org/10.1016/j.envres.2020.109816
49. Nakamura T, Naguro I, Ichijo H. Iron homeostasis and iron-regulated ROS in cell death, senescence and human diseases. Biochim Biophys Acta Gen Subj. 2019;1863(9):1398-409. https://doi.org/10.1016/j.bbagen.2019.06.010
50. Noh B, Blasco-Conesa MP, Rahman SM, Monga S, Ritzel R, Guzman G, et al. Iron overload induces cerebral endothelial senescence in aged mice and in primary culture in a sex- dependent manner. Aging Cell. 2023 Nov;22(11):e13977. https://doi.org/10.1111/acel.13977
51. Schafer MJ, White TA, Iijima K, Haak AJ, Ligresti G, Atkinson EJ, et al. Cellular senescence mediates fibrotic pulmonary disease. Nat Commun. 2017;8:14532. https://doi.org/10.1038/ncomms14532
52. Zeng M, Zhang X, Xing W, Wang Q, Liang G, He Z. Cigarette smoke extract mediates cell premature senescence in chronic obstructive pulmonary disease patients by up-regulating USP7 to activate p300-p53/p21 pathway. Toxicol Lett. 2022;359:31-45. https://doi.org/10.1016/j.toxlet.2022.01.017
53. Ahmad T, Sundar IK, Lerner CA, Gerloff J, Tormos AM, Yao H, et al. Impaired mitophagy leads to cigarette smoke stressinduced cellular senescence: implications for chronic obstructive pulmonary disease. FASEB J. 2015;29(7):2912-29. https://doi.org/10.1096/fj.14-268276
54. Bodas M, Van Westphal C, Carpenter-Thompson R, Mohanty DK, Vij N. Nicotine exposure induces bronchial epithelial cell apoptosis and senescence via ROS mediated autophagy-impairment. Free Radic Biol Med. 2016;97:441-53. https://doi.org/10.1016/j.freeradbiomed.2016.06.017
55. Rentscher KE, Carroll JE, Repetti RL, Cole SW, Reynolds BM, Robles TF. Chronic stress exposure and daily stress appraisals relate to biological aging marker p16 INK4a. Psychoneuroendocrinology. 2019;102:139-48. https://doi.org/10.1016/j.psyneuen.2018.12.006
56. Carroll JE, Diez Roux A V, Fitzpatrick AL, Seeman T. Low social support is associated with shorter leukocyte telomere length in late life: multi-ethnic study of atherosclerosis. Psychosom Med. 2013;75(2):171-7. https://journals.lww.com/psychosomaticmedicine/fulltext/2013/02000/low_social_support_ is_associated_with_shorter.10.aspx https://doi.org/10.1097/PSY.0b013e31828233bf
57. Lin YF, Wang LY, Chen CS, Li CC, Hsiao YH. Cellular senescence as a driver of cognitive decline triggered by chronic unpredictable stress. Neurobiol Stress. 2021;15:100341. https://doi.org/10.1016/j.ynstr.2021.100341
58. Siracusa ER, Higham JP, Snyder-Mackler N, Brent LJN. Social ageing: exploring the drivers of late-life changes in social behaviour in mammals. Biol Lett. 2022;18(3):20210643. https://doi.org/10.1098/rsbl.2021.0643
59. Dong X, Milholland B, Vijg J. Evidence for a limit to human lifespan. Nature. 2016;538(7624):257-9. https://doi.org/10.1038/nature19793
60. Lenart A, Vaupel JW. Questionable evidence for a limit to human lifespan. Nature. 2017;546(7660):E13-4. https://doi.org/10.1038/nature22790
61. Rozing MP, Kirkwood TBL, Westendorp RGJ. Is there evidence for a limit to human lifespan? Nature. 2017;546(7660):E11-2. https://doi.org/10.1038/nature22788
62. de Beer J, Bardoutsos A, Janssen F. Maximum human lifespan may increase to 125 years. Nature. 2017;546(7660):E16-7. https://doi.org/10.1038/nature22792
63. Brown NJL, Albers CJ, Ritchie SJ. Contesting the evidence for limited human lifespan. Nature. 2017;546(7660):E6-E7. https://doi.org/10.1038/nature22784
64. Suda M, Shimizu I, Katsuumi G, Yoshida Y, Hayashi Y, Ikegami R, et al. Senolytic vaccination improves normal and pathological agerelated phenotypes and increases lifespan in progeroid mice. Nat Aging. 2021;1(12):1117-26. https://doi.org/10.1038/s43587-021-00151-2
65. Novais EJ, Tran VA, Johnston SN, Darris KR, Roupas AJ, Sessions GA, et al. Long-term treatment with senolytic drugs Dasatinib and Quercetin ameliorates age-dependent intervertebral disc degeneraation in mice. Nat Commun. 2021;12(1):5213. https://doi.org/10.1038/s41467-021-25453-2
66. Van houcke J, Mariën V, Zandecki C, Ayana R, Pepermans E, Boonen K, et al. A short dasatinib and quercetin treatment is sufficient to reinstate potent adult neuroregenesis in the aged killifish. NPJ Regen Med. 2023;8(1):31. https://doi.org/10.1038/s41536-023-00304-4
67. Hickson LTJ, Langhi Prata LGP, Bobart SA, Evans TK, Giorgadze N, Hashmi SK, et al. Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease. EBioMedicine. 2019;47:446-56. https://doi.org/10.1016/j.ebiom.2019.08.069
68. Justice JN, Nambiar AM, Tchkonia T, LeBrasseur NK, Pascual R, Hashmi SK, et al. Senolytics in idiopathic pulmonary fibrosis: results from a first-in-human, open-label, pilot study. EBioMedicine. 2019;40:554-63. https://doi.org/10.1016/j.ebiom.2018.12.052
69. Barinda AJ, Arozal W, Yuasa S. A review of pathobiological mechanisms and potential application of medicinal plants for vascular aging: focus on endothelial cell senescence. Med J Indones. 2022;31(2):132-40. https://doi.org/10.13181/mji.rev.226064
70. Chaib S, Tchkonia T, Kirkland JL. Cellular senescence and senolytics: the path to the clinic. Nat Med. 2022;28(8):1556-68. https://doi.org/10.1038/s41591-022-01923-y
71. Kang C. Senolytics and senostatics: a two-pronged approach to target cellular senescence for delaying aging and age-related diseases. Mol Cells. 2019;42(12):821-7.
72. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: an expanding universe. Cell. 2023;186(2):243- 78. https://doi.org/10.1016/j.cell.2022.11.001
73. López-Otín C, Pietrocola F, Roiz-Valle D, Galluzzi L, Kroemer G. Meta-hallmarks of aging and cancer. Cell Metab. 2023;35(1):12-35. https://doi.org/10.1016/j.cmet.2022.11.001
74. Wilson DM, Cookson MR, Van Den Bosch L, Zetterberg H, Holtzman DM, Dewachter I. Hallmarks of neurodegenerative diseases. Cell. 2023;186(4):693-714. https://doi.org/10.1016/j.cell.2022.12.032
75. Evangelou K, Vasileiou PVS, Papaspyropoulos A, Hazapis O, Petty R, Demaria M, et al. Cellular senescence and cardiovascular diseases: moving to the "heart" of the problem. Physiol Rev. 2023;103(1):609-47. https://doi.org/10.1152/physrev.00007.2022

Article Metrics

75 Views 14 Downloads 89 Total

Year

Month

Related Search

By author names

Rahma R [PubMed] [Google Scholar ]

Barinda A J [PubMed] [Google Scholar ]

By article title

1. Litke R, Garcharna LC, Jiwani S, Neugroschl J. Modifiable risk factors in Alzheimer disease and related dementias: a review. ClinTher. 2021;43(6):953-65. https://doi.org/10.1016/j.clinthera.2021.05.006

2. Wu J, Li T, Song X, Sun W, Zhang Y, Liu Y, et al. Prevalence anddistribution of hypertension and related risk factors in Jilin Province,China 2015: a cross-sectional study. BMJ Open. 2018;8(3):e020126. https://doi.org/10.1136/bmjopen-2017-020126

3. Nguyen CT, Pham NM, Lee AH, Binns CW. Prevalence ofand risk factors for type 2 diabetes mellitus in Vietnam: asystematic review. Asia Pac J Public Health. 2015;27(6):588-600. https://doi.org/10.1177/1010539515595860

4. Arafat HM, Omar J, Muhamad R, Al-Astani TAD, Shafii N, Al LahamNA, et al. Breast cancer risk from modifiable and non-modifiablerisk factors among palestinian women: a systematic review andmeta-analysis. Asian Pac J Cancer Prev. 2021;22(7):1987-95. https://doi.org/10.31557/APJCP.2021.22.7.1987

5. Nguyen H, Manolova G, Daskalopoulou C, Vitoratou S,Prince M, Prina AM. Prevalence of multimorbidity incommunity settings: a systematic review and meta-analysis of observational studies. J Comorb. 2019;9:2235042X1987093. https://doi.org/10.1177/2235042X19870934

6. Kennedy BK, Berger SL, Brunet A, Campisi J, Cuervo AM, Epel ES, et al. Geroscience: linking aging to chronic disease. Cell. 2014;159(4):709-13. https://doi.org/10.1016/j.cell.2014.10.039

7. Sorrentino JA, Sanoff HK, Sharpless NE. Defining the toxicology of aging. Trends Mol Med. 2014;20(7):375-84. https://doi.org/10.1016/j.molmed.2014.04.004

8. Salam R, Saliou A, Bielle F, Bertrand M, Antoniewski C, Carpentier C, et al. Cellular senescence in malignant cells promotes tumor progression in mouse and patient Glioblastoma. Nat Commun. 2023;14(1):441. https://doi.org/10.1038/s41467-023-36124-9

9. Matsudaira T, Nakano S, Konishi Y, Kawamoto S, Uemura K, Kondo T, et al. Cellular senescence in white matter microglia is induced during ageing in mice and exacerbates the neuroinflammatory phenotype. Commun Biol. 2023;6(1):665. https://doi.org/10.1038/s42003-023-05027-2

10. Gorgoulis V, Adams PD, Alimonti A, Bennett DC, Bischof O, Bishop C, et al. Cellular senescence: defining a path forward. Cell. 2019;179(4):813-27. https://doi.org/10.1016/j.cell.2019.10.005

11. Gasek NS, Kuchel GA, Kirkland JL, Xu M. Strategies for targeting senescent cells in human disease. Nat Aging. 2021;1(10):870-9. https://doi.org/10.1038/s43587-021-00121-8

12. Mario Gonzalez-Meljem J, Haston S, Carreno G, Apps JR, Pozzi S, Stache C, et al. Stem cell senescence drives age-attenuated induction of pituitary tumours in mouse models of paediatric craniopharyngioma. Nat Commun. 2017;8(1):1819. https://doi.org/10.1038/s41467-017-01992-5

13. Dou X, Fu Q, Long Q, Liu S, Zou Y, Fu D, et al. PDK4-dependent hypercatabolism and lactate production of senescent cells promotes cancer malignancy. Nat Metab. Published online November 1, 2023;5(11):1887-910. https://doi.org/10.1038/s42255-023-00912-w

14. Yoshimoto S, Loo TM, Atarashi K, Kanda H, Sato S, Oyadomari S, et al. Obesity-induced gut microbial metabolite promotes live cancer through senescence secretome. Nature. 2013;499(7456):97-101. https://doi.org/10.1038/nature12347

15. Barinda AJ, Ikeda K, Nugroho DB, Wardhana DA, Sasaki N, Honda S, et al. Endothelial progeria induces adipose tissue senescence and impairs insulin sensitivity through senescence associated secretory phenotype. Nat Commun. 2020;11(1):1-13. https://doi.org/10.1038/s41467-020-14387-w

16. Palmer AK, Tchkonia T, LeBrasseur NK, Chini EN, Xu M, Kirkland JL. Cellular senescence in type 2 diabetes: a therapeutic opportunity. Diabetes. 2015;64(7):2289-98. https://doi.org/10.2337/db14-1820

17. Frescas D, Hall BM, Strom E, Virtuoso LP, Gupta M, Gleiberman AS, et al. Murine mesenchymal cells that express elevated levels of the CDK inhibitor p16(Ink4a) in vivo are not necessarily senescent. Cell Cycle. 2017;16(16):1526-33. https://doi.org/10.1080/15384101.2017.1339850

18. Zonari A, Brace LE, Al-Katib K, Porto WF, Foyt D, Guiang M, et al. Senotherapeutic peptide treatment reduces biological age and senescence burden in human skin models. npj Aging. 2023;9(1):10. https://doi.org/10.1038/s41514-023-00109-1

19. Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG, van de Sluis B, et al. Clearance of p16 Ink4a-positive senescent cells delays ageing-associated disorders. Nature. 2011;479(7372):232-6. https://doi.org/10.1038/nature10600

20. Roos CM, Zhang B, Palmer AK, Ogrodnik MB, Pirtskhalava T, Thalji NM, et al. Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice. Aging Cell. 2016;15(5):973-7. https://doi.org/10.1111/acel.12458

21. 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(2):75-95. https://doi.org/10.1038/s41580-020-00314-w

22. Rossiello F, Jurk D, Passos JF, d'Adda di Fagagna F. Telomere dysfunction in ageing and age-related diseases. Nat Cell Biol. 2022;24(2):135-47. https://doi.org/10.1038/s41556-022-00842-x

23. van Steensel B, Smogorzewska A, de Lange T. TRF2 Protects human telomeres from end-to-end fusions. Cell. 1998;92(3):401-13. https://doi.org/10.1016/S0092-8674(00)80932-0

24. Karlseder J, Smogorzewska A, de Lange T. Senescence induced by altered telomere state, not telomere loss. Science (1979). 2002;295(5564):2446-9. https://doi.org/10.1126/science.1069523

25. Domen A, Deben C, Verswyvel J, Flieswasser T, Prenen H, Peeters M, et al. Cellular senescence in cancer : clinical detection and prognostic implications. J Exp Clin Cancer Res. Published online 2022:41(1):360. https://doi.org/10.1186/s13046-022-02555-3

26. Bartkova J, Rezaei N, Liontos M, Karakaidos P, Kletsas D, Issaeva N, et al. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature. 2006;444(7119):633-7. https://doi.org/10.1038/nature05268

27. Wiley CD, Velarde MC, Lecot P, Liu S, Sarnoski EA, Freund A, et al. Mitochondrial dysfunction induces senescence with a distinc secretory phenotype. Cell Metab. 2016;23(2):303-14. https://doi.org/10.1016/j.cmet.2015.11.011

28. González-Gualda E, Baker AG, Fruk L, Muñoz-Espín D. A guide to assessing cellular senescence in vitro and in vivo. FEBS J. 2021;288(1):56-80. https://doi.org/10.1111/febs.15570

29. Tuttle CSL, Luesken SWM, Waaijer MEC, Maier AB. Senescence n tissue samples of humans with age-related diseases: a systematic review. Ageing Res Rev. 2021;68(March):101334. https://doi.org/10.1016/j.arr.2021.101334

30. Kohli J, Wang B, Brandenburg SM, Basisty N, Evangelou K, Varela- Eirin M, et al. Algorithmic assessment of cellular senescence in experimental and clinical specimens. Nat Protoc. 2021;16:2471-98; https://doi.org/10.1038/s41596-021-00505-5

31. Uxa S, Castillo-Binder P, Kohler R, Stangner K, Müller GA, Engeland K. Ki-67 gene expression. Cell Death Differ. 2021;28(12):3357-70. https://doi.org/10.1038/s41418-021-00823-x

32. Kurz DJ, Decary S, Hong Y, Erusalimsky JD. Senescenceassociated β-galactosidase reflects an increase in lysosomal mass during replicative ageing of human endothelial cells. J Cell Sci. 2000;113(20):3613-22. https://doi.org/10.1242/jcs.113.20.3613

33. Willcox BJ, Willcox DC, Suzuki M. Demographic, phenotypic, and genetic characteristics of centenarians in Okinawa and Japan: Part 1-centenarians in Okinawa. Mech Ageing Dev. 2017;165:75-9. https://doi.org/10.1016/j.mad.2016.11.001

34. Willcox DC, Willcox BJ, Shimajiri S, Kurechi S, Suzuki M. Aging gracefully: a retrospective analysis of functional status in okinawan centenarians. Am J Geriatr Psychiatry. 2007;15(3):252-6. https://doi.org/10.1097/JGP.0b013e31803190cc

35. Torigoe TH, Willcox DC, Shimabukuro M, Higa M, Gerschenson M, Andrukhiv A, et al. Novel protective effect of the FOXO3 longevity genotype on mechanisms of cellular aging in Okinawans. npj Aging. 2024;10(1):18. https://doi.org/10.1038/s41514-024-00142-8

36. Graham Ruby J, Wright KM, Rand KA, Kermany A, Noto K, Curtis D, et al. Estimates of the heritability of human longevity are substantially inflated due to assortative mating. Genetics. 2018;210(3):1109-24. https://doi.org/10.1534/genetics.118.301613

37. Fitsiou E, Pulido T, Campisi J, Alimirah F, Demaria M. Cellular senescence and the senescence-associated secretory phenotype as drivers of skin photoaging. J Investig Dermatol. 2021;141(4):1119- 26. https://doi.org/10.1016/j.jid.2020.09.031

38. Ma HM, Liu W, Zhang P, Yuan XY. Human skin fibroblast telomeres are shortened after ultraviolet irradiation. J Int Med Res. 2012;40(5):1871-7. https://doi.org/10.1177/030006051204000526

39. Kim SR, Jiang K, Ogrodnik M, Chen X, Zhu XY, Lohmeier H, et al. Increased renal cellular senescence in murine high-fat diet: effect of the senolytic drug quercetin. Transl Res. 2019;213:112-23. https://doi.org/10.1016/j.trsl.2019.07.005

40. Jurk D, Wilson C, Passos JF, Oakley F, Correia-Melo C, Greaves L, et al. Chronic inflammation induces telomere dysfunction and accelerates ageing in mice. Nat Commun. 2014;2:4172. https://doi.org/10.1038/ncomms5172

41. Moreno-Navarrete JM, Ortega F, Sabater M, Ricart W, Fernández- Real JM. Telomere length of subcutaneous adipose tissue cells is shorter in obese and formerly obese subjects. Int J Obes. 2010;34(8):1345-8. https://doi.org/10.1038/ijo.2010.49

42. Clemente DBP, Maitre L, Bustamante M, Chatzi L, Roumeliotaki T, Fossati S, et al. Obesity is associated with shorter telomeres in 8 year-old children. Sci Rep. 2019;9(1):18739. https://doi.org/10.1038/s41598-019-55283-8

43. Batsis JA, Mackenzie TA, Vasquez E, Germain CM, Emeny RT, ippberger P, et al. Association of adiposity, telomere length and mortality: data from the NHANES 1999-2002. Int J Obes. 2018;42(2):198-204. https://doi.org/10.1038/ijo.2017.202

44. Grun LK, Teixeira N da R, Mengden L von, de Bastiani MA, Parisi MM, Bortolin R, et al. TRF1 as a major contributor for telomeres'shortening in the context of obesity. Free Radic Biol Med. 2018;129(September):286-95. https://doi.org/10.1016/j.freeradbiomed.2018.09.039

45. Sorrentino JA, Krishnamurthy J, Tilley S, Alb JG, Burd CE, Sharpless NE. P16INK4a reporter mice reveal age-promoting effects of environmental toxicants. J Clin Investig. 2014;124(1):169-73. https://doi.org/10.1172/JCI70960

46. Vielee ST, Wise JP. Among gerontogens, heavy metals are a class of their own: a review of the evidence for cellular senescence. Brain Sci. 2023;13(3):500. https://doi.org/10.3390/brainsci13030500

47. Okamura K, Sato M, Suzuki T, Nohara K. Inorganic arsenic exposure-induced premature senescence and senescence-associated secretory phenotype (SASP) in human hepatic stellate cells1. Toxicol Appl Pharmacol. 2022;454(September):116231. https://doi.org/10.1016/j.taap.2022.116231

48. Maher BA, González-Maciel A, Reynoso-Robles R, Torres-Jardón R, Calderón-Garcidueñas L. Iron-rich air pollution nanoparticles: an unrecognised environmental risk factor for myocardial mitochondrial dysfunction and cardiac oxidative stress. Environ Res. 2020;188:109816. https://doi.org/10.1016/j.envres.2020.109816

49. Nakamura T, Naguro I, Ichijo H. Iron homeostasis and iron-regulated ROS in cell death, senescence and human diseases. Biochim Biophys Acta Gen Subj. 2019;1863(9):1398-409. https://doi.org/10.1016/j.bbagen.2019.06.010

50. Noh B, Blasco-Conesa MP, Rahman SM, Monga S, Ritzel R, Guzman G, et al. Iron overload induces cerebral endothelial senescence in aged mice and in primary culture in a sex- dependent manner. Aging Cell. 2023 Nov;22(11):e13977. https://doi.org/10.1111/acel.13977

51. Schafer MJ, White TA, Iijima K, Haak AJ, Ligresti G, Atkinson EJ, et al. Cellular senescence mediates fibrotic pulmonary disease. Nat Commun. 2017;8:14532. https://doi.org/10.1038/ncomms14532

52. Zeng M, Zhang X, Xing W, Wang Q, Liang G, He Z. Cigarette smoke extract mediates cell premature senescence in chronic obstructive pulmonary disease patients by up-regulating USP7 to activate p300-p53/p21 pathway. Toxicol Lett. 2022;359:31-45. https://doi.org/10.1016/j.toxlet.2022.01.017

53. Ahmad T, Sundar IK, Lerner CA, Gerloff J, Tormos AM, Yao H, et al. Impaired mitophagy leads to cigarette smoke stressinduced cellular senescence: implications for chronic obstructive pulmonary disease. FASEB J. 2015;29(7):2912-29. https://doi.org/10.1096/fj.14-268276

54. Bodas M, Van Westphal C, Carpenter-Thompson R, Mohanty DK, Vij N. Nicotine exposure induces bronchial epithelial cell apoptosis and senescence via ROS mediated autophagy-impairment. Free Radic Biol Med. 2016;97:441-53. https://doi.org/10.1016/j.freeradbiomed.2016.06.017

55. Rentscher KE, Carroll JE, Repetti RL, Cole SW, Reynolds BM, Robles TF. Chronic stress exposure and daily stress appraisals relate to biological aging marker p16 INK4a. Psychoneuroendocrinology. 2019;102:139-48. https://doi.org/10.1016/j.psyneuen.2018.12.006

56. Carroll JE, Diez Roux A V, Fitzpatrick AL, Seeman T. Low social support is associated with shorter leukocyte telomere length in late life: multi-ethnic study of atherosclerosis. Psychosom Med. 2013;75(2):171-7. https://journals.lww.com/psychosomaticmedicine/fulltext/2013/02000/low_social_support_ is_associated_with_shorter.10.aspx https://doi.org/10.1097/PSY.0b013e31828233bf

57. Lin YF, Wang LY, Chen CS, Li CC, Hsiao YH. Cellular senescence as a driver of cognitive decline triggered by chronic unpredictable stress. Neurobiol Stress. 2021;15:100341. https://doi.org/10.1016/j.ynstr.2021.100341

58. Siracusa ER, Higham JP, Snyder-Mackler N, Brent LJN. Social ageing: exploring the drivers of late-life changes in social behaviour in mammals. Biol Lett. 2022;18(3):20210643. https://doi.org/10.1098/rsbl.2021.0643

59. Dong X, Milholland B, Vijg J. Evidence for a limit to human lifespan. Nature. 2016;538(7624):257-9. https://doi.org/10.1038/nature19793

60. Lenart A, Vaupel JW. Questionable evidence for a limit to human lifespan. Nature. 2017;546(7660):E13-4. https://doi.org/10.1038/nature22790

61. Rozing MP, Kirkwood TBL, Westendorp RGJ. Is there evidence for a limit to human lifespan? Nature. 2017;546(7660):E11-2. https://doi.org/10.1038/nature22788

62. de Beer J, Bardoutsos A, Janssen F. Maximum human lifespan may increase to 125 years. Nature. 2017;546(7660):E16-7. https://doi.org/10.1038/nature22792

63. Brown NJL, Albers CJ, Ritchie SJ. Contesting the evidence for limited human lifespan. Nature. 2017;546(7660):E6-E7. https://doi.org/10.1038/nature22784

64. Suda M, Shimizu I, Katsuumi G, Yoshida Y, Hayashi Y, Ikegami R, et al. Senolytic vaccination improves normal and pathological agerelated phenotypes and increases lifespan in progeroid mice. Nat Aging. 2021;1(12):1117-26. https://doi.org/10.1038/s43587-021-00151-2

65. Novais EJ, Tran VA, Johnston SN, Darris KR, Roupas AJ, Sessions GA, et al. Long-term treatment with senolytic drugs Dasatinib and Quercetin ameliorates age-dependent intervertebral disc degeneraation in mice. Nat Commun. 2021;12(1):5213. https://doi.org/10.1038/s41467-021-25453-2

66. Van houcke J, Mariën V, Zandecki C, Ayana R, Pepermans E, Boonen K, et al. A short dasatinib and quercetin treatment is sufficient to reinstate potent adult neuroregenesis in the aged killifish. NPJ Regen Med. 2023;8(1):31. https://doi.org/10.1038/s41536-023-00304-4

67. Hickson LTJ, Langhi Prata LGP, Bobart SA, Evans TK, Giorgadze N, Hashmi SK, et al. Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease. EBioMedicine. 2019;47:446-56. https://doi.org/10.1016/j.ebiom.2019.08.069

68. Justice JN, Nambiar AM, Tchkonia T, LeBrasseur NK, Pascual R, Hashmi SK, et al. Senolytics in idiopathic pulmonary fibrosis: results from a first-in-human, open-label, pilot study. EBioMedicine. 2019;40:554-63. https://doi.org/10.1016/j.ebiom.2018.12.052

69. Barinda AJ, Arozal W, Yuasa S. A review of pathobiological mechanisms and potential application of medicinal plants for vascular aging: focus on endothelial cell senescence. Med J Indones. 2022;31(2):132-40. https://doi.org/10.13181/mji.rev.226064

70. Chaib S, Tchkonia T, Kirkland JL. Cellular senescence and senolytics: the path to the clinic. Nat Med. 2022;28(8):1556-68. https://doi.org/10.1038/s41591-022-01923-y

71. Kang C. Senolytics and senostatics: a two-pronged approach to target cellular senescence for delaying aging and age-related diseases. Mol Cells. 2019;42(12):821-7.

72. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: an expanding universe. Cell. 2023;186(2):243- 78. https://doi.org/10.1016/j.cell.2022.11.001

73. López-Otín C, Pietrocola F, Roiz-Valle D, Galluzzi L, Kroemer G. Meta-hallmarks of aging and cancer. Cell Metab. 2023;35(1):12-35. https://doi.org/10.1016/j.cmet.2022.11.001

74. Wilson DM, Cookson MR, Van Den Bosch L, Zetterberg H, Holtzman DM, Dewachter I. Hallmarks of neurodegenerative diseases. Cell. 2023;186(4):693-714. https://doi.org/10.1016/j.cell.2022.12.032

75. Evangelou K, Vasileiou PVS, Papaspyropoulos A, Hazapis O, Petty R, Demaria M, et al. Cellular senescence and cardiovascular diseases: moving to the "heart" of the problem. Physiol Rev. 2023;103(1):609-47. https://doi.org/10.1152/physrev.00007.2022