Senescence-associated secretory phenotype explained

Senescence-associated secretory phenotype (SASP) is a phenotype associated with senescent cells wherein those cells secrete high levels of inflammatory cytokines, immune modulators, growth factors, and proteases.[1] [2] SASP may also consist of exosomes and ectosomes containing enzymes, microRNA, DNA fragments, chemokines, and other bioactive factors.[3] [4] Soluble urokinase plasminogen activator surface receptor is part of SASP, and has been used to identify senescent cells for senolytic therapy.[5] Initially, SASP is immunosuppressive (characterized by TGF-β1 and TGF-β3) and profibrotic, but progresses to become proinflammatory (characterized by IL-1β, IL-6 and IL-8) and fibrolytic.[6] [7] SASP is the primary cause of the detrimental effects of senescent cells.[4]

SASP is heterogenous, with the exact composition dependent upon the senescent-cell inducer and the cell type.[8] Interleukin 12 (IL-12) and Interleukin 10 (IL-10) are increased more than 200-fold in replicative senescence in contrast to stress-induced senescence or proteosome-inhibited senescence where the increases are about 30-fold or less.[9] Tumor necrosis factor (TNF) is increased 32-fold in stress-induced senescence, 8-fold in replicative senescence, and only slightly in proteosome-inhibited senescence. Interleukin 6 (IL-6) and interleukin 8 (IL-8) are the most conserved and robust features of SASP.[10] But some SASP components are anti-inflammatory.[11]

Senescence and SASP can also occur in post-mitotic cells, notably neurons.[12] The SASP in senescent neurons can vary according to cell type, the initiator of senescence, and the stage of senescence.

An online SASP Atlas serves as a guide to the various types of SASP.

SASP is one of the three main features of senescent cells, the other two features being arrested cell growth, and resistance to apoptosis.[13] SASP factors can include the anti-apoptotic protein Bcl-xL,[14] but growth arrest and SASP production are independently regulated.[15] Although SASP from senescent cells can kill neighboring normal cells, the apoptosis-resistance of senescent cells protects those cells from SASP.[16]

History

The concept and abbreviation of SASP was first established by Judith Campisi and her group, who first published on the subject in 2008.

Causes

SASP expression is induced by a number of transcription factors, including MLL1 (KMT2A),[17] C/EBPβ, and NF-κB.[18] [19] NF-κB and the enzyme CD38 are mutually activating.[20] NF-κB is expressed as a result of inhibition of autophagy-mediated degradation of the transcription factor GATA4.[21] [22] GATA4 is activated by the DNA damage response factors, which induce cellular senescence. SASP is both a promoter of DNA damage response and a consequence of DNA damage response, in an autocrine and paracrine manner.[23] Aberrant oncogenes, DNA damage, and oxidative stress induce mitogen-activated protein kinases, which are the upstream regulators of NF-κB.[24] Demethylation of DNA packaging protein Histone H3 (H3K27me3) can lead to up-regulation of genes controlling SASP.

mTOR (mammalian target of rapamycin) is also a key initiator of SASP. Interleukin 1 alpha (IL1A) is found on the surface of senescent cells, where it contributes to the production of SASP factors due to a positive feedback loop with NF-κB.[25] [26] [27] Translation of mRNA for IL1A is highly dependent upon mTOR activity.[28] mTOR activity increases levels of IL1A, mediated by MAPKAPK2. mTOR inhibition of ZFP36L1 prevents this protein from degrading transcripts of numerous components of SASP factors.[29] [30] Inhibition of mTOR supports autophagy, which can generate SASP components.[31]

Ribosomal DNA (rDNA) is more vulnerable to DNA damage than DNA elsewhere in the genome such than rDNA instability can lead to cellular senescence, and thus to SASP[32] The high-mobility group proteins (HMGA) can induce senescence and SASP in a p53-dependent manner.

Activation of the retrotransposon LINE1 can result in cytosolic DNA that activates the cGAS–STING cytosolic DNA sensing pathway upregulating SASP by induction of interferon type I.[33] cGAS is essential for induction of cellular senescence by DNA damage.[34]

SASP secretion can also be initiated by the microRNAs miR-146 a/b.[35]

Pathology

Senescent cells are highly metabolically active, producing large amounts of SASP, which is why senescent cells consisting of only 2% or 3% of tissue cells can be a major cause of aging-associated diseases. SASP factors cause non-senescent cells to become senescent.[36] SASP factors induce insulin resistance.[37] SASP disrupts normal tissue function by producing chronic inflammation, induction of fibrosis and inhibition of stem cells.[38] Transforming growth factor beta family members secreted by senescent cells impede differentiation of adipocytes, leading to insulin resistance.[39]

SASP factors IL-6 and TNFα enhance T-cell apoptosis, thereby impairing the capacity of the adaptive immune system.[40]

SASP factors from senescent cells reduce nicotinamide adenine dinucleotide (NAD+) in non-senescent cells,[41] thereby reducing the capacity for DNA repair and sirtuin activity in non-senescent cells.[42] SASP induction of the NAD+ degrading enzyme CD38 on non-senescent cells (macrophages) may be responsible for most of this effect.[43] [44] By contrast, NAD+ contributes to the secondary (pro-inflammatory) manifestation of SASP. SASP induces an unfolded protein response in the endoplasmic reticulum because of an accumulation of unfolded proteins, resulting in proteotoxic impairment of cell function.[45]

SASP cytokines can result in an inflamed stem cell niche, leading to stem cell exhaustion and impaired stem cell function.

SASP can either promote or inhibit cancer, depending on the SASP composition,[46] notably including p53 status. Despite the fact that cellular senescence likely evolved as a means of protecting against cancer early in life, SASP promotes the development of late-life cancers. Cancer invasiveness is promoted primarily though the actions of the SASP factors metalloproteinase, chemokine, interleukin 6 (IL-6), and interleukin 8 (IL-8).[47] In fact, SASP from senescent cells is associated with many aging-associated diseases, including not only cancer, but atherosclerosis and osteoarthritis. For this reason, senolytic therapy has been proposed as a generalized treatment for these and many other diseases. The flavonoid apigenin has been shown to strongly inhibit SASP production.[48]

Benefits

SASP can aid in signaling to immune cells for senescent cell clearance,[49] [50] [51] [52] with specific SASP factors secreted by senescent cells attracting and activating different components of both the innate and adaptive immune system. The SASP cytokine CCL2 (MCP1) recruits macrophages to remove cancer cells.[53] Although transient expression of SASP can recruit immune system cells to eliminate cancer cells as well as senescent cells, chronic SASP promotes cancer.[54] Senescent hematopoietic stem cells produces a SASP that induces an M1 polarization of macrophages which kills the senescent cells in a p53-dependent process.[55]

Autophagy is upregulated to promote survival.

SASP factors can maintain senescent cells in their senescent state of growth arrest, thereby preventing cancerous transformation.[56] Additionally, SASP secreted by cells that have become senescent because of stresses can induce senescence in adjoining cells subject to the same stresses. thereby reducing cancer risk.[57]

SASP can play a beneficial role by promoting wound healing.[58] [59] SASP may play a role in tissue regeneration by signaling for senescent cell clearance by immune cells, allowing progenitor cells to repopulate tissue.[60] In development, SASP also may be used to signal for senescent cell clearance to aid tissue remodeling.[61] The ability of SASP to clear senescent cells and regenerate damaged tissue declines with age.[62] In contrast to the persistent character of SASP in the chronic inflammation of multiple age-related diseases, beneficial SASP in wound healing is transitory. Temporary SASP in the liver or kidney can reduce fibrosis, but chronic SASP could lead to organ dysfunction.[63] [64]

Modification

Senescent cells have permanently active mTORC1 irrespective of nutrients or growth factors, resulting in the continuous secretion of SASP.[65] By inhibiting mTORC1, rapamycin reduces SASP production by senescent cells.

SASP has been reduced through inhibition of p38 mitogen-activated protein kinases and janus kinase.[66]

The protein hnRNP A1 (heterogeneous nuclear ribonucleoprotein A1) antagonizes cellular senescence and induction of the SASP by stabilizing Oct-4 and sirtuin 1 mRNAs.[67] [68]

SASP Index

A SASP index composed of 22 SASP factors has been used to evaluate treatment outcomes of late life depression.[69] Higher SASP index scores corresponded to increased incidence of treatment failure, whereas no individual SASP factors were associated with treatment failure.

Inflammaging

See main article: Inflammaging. Chronic inflammation associated with aging has been termed inflammaging, although SASP may be only one of the possible causes of this condition.[70] Chronic systemic inflammation is associated with aging-associated diseases.[71] Senolytic agents have been recommended to counteract some of these effects. Chronic inflammation due to SASP can suppress immune system function, which is one reason elderly persons are more vulnerable to COVID-19.[72]

See also

For further reading

Notes and References

  1. Coppé JP, Patil CK, Rodier F, Sun Y, Muñoz DP, Goldstein J, Nelson PS, Desprez PY, Campisi J . Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor . . 6 . 12 . 2853–2868 . 2008 . 10.1371/journal.pbio.0060301 . 2592359 . 19053174 . free .
  2. Childs BG, Gluscevic M, Baker DJ, Laberge RM, Marquess D, Dananberg J, van Deursen JM . Senescent cells: an emerging target for diseases of ageing . . 16 . 10 . 718–735 . 2017 . 10.1038/nrd.2017.116 . 5942225 . 28729727 .
  3. Prata LG, Ovsyannikova IG, Tchkonia T, Kirkland JL . Senescent cell clearance by the immune system: Emerging therapeutic opportunities. . 40 . 101275 . 2018 . 10.1016/j.smim.2019.04.003 . 7061456 . 31088710.
  4. Birch J, Gil J . Senescence and the SASP: many therapeutic avenues . . 34 . 1565–1576 . 2020 . 23–24 . 10.1101/gad.343129.120 . 7706700 . 33262144.
  5. Amor C, Feucht J, Lowe SW . Senolytic CAR T cells reverse senescence-associated pathologies . . 583 . 7814 . 127–132 . 2020 . 10.1038/s41586-020-2403-9 . 7583560 . 32555459. 2020Natur.583..127A .
  6. Ito Y, Hoare M, Narita M . Spatial and Temporal Control of Senescence . . 27 . 11 . 820–832 . 2017 . 10.1016/j.tcb.2017.07.004 . 28822679.
  7. Nacarelli T, Lau L, Fukumoto T, David G, Zhang R . NAD + metabolism governs the proinflammatory senescence-associated secretome . . 21 . 3 . 397–407 . 2019 . 10.1038/s41556-019-0287-4 . 6448588 . 30778219 .
  8. Basisty N, Kale A, Jeon O, Kuehnemann C, Payne T, Rao C, Holtz A, Shah S, Vagisha Sharma V, Ferrucci L, Campisi J, Schilling B . A Proteomic Atlas of Senescence-Associated Secretomes for Aging Biomarker Development . . 18 . 1 . e3000599 . 2020 . 10.1371/journal.pbio.3000599 . 6964821 . 31945054 . free .
  9. Maciel-Barón LA, Morales-Rosales SL, Aquino-Cruz AA, Königsberg M . Senescence associated secretory phenotype profile from primary lung mice fibroblasts depends on the senescence induction stimuli . . 38 . 1 . 26 . 2016 . 10.1007/s11357-016-9886-1 . 5005892 . 26867806.
  10. Partridge L, Fuentealba M, Kennedy BK . The quest to slow ageing through drug discovery . . 19 . 8 . 513–532 . 2020 . 10.1038/s41573-020-0067-7 . 32467649. 218912510 .
  11. Chambers ES, Akbar AN . Can blocking inflammation enhance immunity during aging? . . 145 . 5 . 1323–1331 . 2020 . 10.1016/j.jaci.2020.03.016 . 32386656.
  12. Herdy JR, Mertens J, Gage FH . Neuronal senescence may drive brain aging . . 384 . 6703 . 1404-1406 . 2024 . 10.1126/science.adi3450 . 38935713 .
  13. Campisi J, Kapahi P, Lithgow GJ, Melov S, Newman JC, Verdin E . From discoveries in ageing research to therapeutics for healthy ageing . . 571 . 7764 . 183–192 . 2019 . 10.1038/s41586-019-1365-2 . 31292558 . 7205183 . 2019Natur.571..183C . free .
  14. Sundeep Khosla S, Farr JN, Tchkonia T, Kirkland JL . The role of cellular senescence in ageing and endocrine diseasee . . 16 . 5 . 263–275 . 2020 . 10.1038/s41574-020-0335-y . 7227781 . 32161396.
  15. Paez-Ribes M, González-Gualda E, Doherty GJ, Muñoz-Espín D . Targeting senescent cells in translational medicine . . 11 . 12 . e10234 . 2019 . 10.15252/emmm.201810234 . 6895604 . 31746100.
  16. Kirkland JL, Tchkonia T. Senolytic Drugs: From Discovery to Translation . . 2020 . 288 . 5 . 518–536 . 10.1111/joim.13141 . 32686219. 7405395 .
  17. Booth LN, Brunet A . The Aging Epigenome . . 62 . 5 . 728–744 . 2016 . 10.1016/j.molcel.2016.05.013 . 4917370 . 27259204.
  18. Ghosh K, Capell BC . The Senescence-Associated Secretory Phenotype: Critical Effector in Skin Cancer and Aging . . 136 . 11 . 2133–2139 . 2016 . 10.1016/j.jid.2016.06.621 . 5526201 . 27543988 .
  19. Acosta JC, O'Loghlen A, Banito A, Guijarro MV, Augert A, Raguz S, Fumagalli M, Da Costa M, Brown C, Popov N, Takatsu Y, Melamed J, d'Adda di Fagagna F, Bernard D, Hernando E, Gil J . Chemokine signaling via the CXCR2 receptor reinforces senescence . . 133 . 6 . 1006–18 . June 2008 . 18555777 . 10.1016/j.cell.2008.03.038 . 6708172 . free .
  20. Yarbro JR, Emmons RS, Pence BD . Macrophage Immunometabolism and Inflammaging: Roles of Mitochondrial Dysfunction, Cellular Senescence, CD38, and NAD . Immunometabolism . 2 . 3 . e200026 . June 2020 . 10.20900/immunometab20200026 . 7409778 . 32774895.
  21. Kang C, Xu O, Martin TD, Li MZ, Demaria M, Aron L, Lu T, Yankner BA, Campisi J, Elledge SJ . The DNA Damage Response Induces Inflammation and Senescence by Inhibiting Autophagy of GATA4 . . 349 . 6255 . aaa5612 . 2015 . 10.1126/science.aaa5612 . 4942138 . 26404840 .
  22. Yessenkyzy A, Saliev T, Zhanaliyeva M, Nurgozhin T . Polyphenols as Caloric-Restriction Mimetics and Autophagy Inducers in Aging Research . . 12 . 5 . 1344 . 2020 . 10.3390/nu12051344 . 7285205 . 32397145. free .
  23. Rossiello F, Jurk D, Passos JF, di Fagagna F . Telomere dysfunction in ageing and age-related diseases . . 24 . 2 . 135–147 . 2022 . 10.1038/s41556-022-00842-x . 8985209 . 35165420.
  24. Anerillas C, Abdelmohsen K, Gorospe M . Regulation of senescence traits by MAPKs . . 42 . 2 . 397–408 . 2020 . 10.1007/s11357-020-00183-3 . 7205942 . 32300964.
  25. Laberge R, Sun Y, Orjalo AV, Patil CK, Campisi J . MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation . . 17 . 8 . 1049–1061 . 2015 . 10.1038/ncb3195 . 4691706 . 26147250.
  26. Wang R, Yu Z, Sunchu B, Perez VI . Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism . . 16 . 3 . 564–574 . 2017 . 10.1111/acel.12587 . 5418203 . 28371119.
  27. Sharma R, Padwad Y . In search of nutritional anti-aging targets: TOR inhibitors, SASP modulators, and BCL-2 family suppressors. . 65 . 33–38 . 2019 . 10.1016/j.nut.2019.01.020 . 31029919. 86541289.
  28. Wang R, Sunchu B, Perez VI . Rapamycin and the inhibition of the secretory phenotype . . 94 . 89–92 . 2017 . 10.1016/j.exger.2017.01.026 . 28167236. 4960885 .
  29. Weichhart T . mTOR as Regulator of Lifespan, Aging, and Cellular Senescence: A Mini-Review . . 84 . 2 . 127–134 . 2018 . 10.1159/000484629 . 6089343 . 29190625.
  30. Papadopoli D, Boulay K, Kazak L, Hulea L . mTOR as a central regulator of lifespan and aging . . 8 . 2019 . 998 . 10.12688/f1000research.17196.1 . 6611156 . 31316753 . free .
  31. Carosi JM, Fourrier C, Bensalem J, Sargeant TJ . The mTOR-lysosome axis at the centre of ageing . . 12 . 4 . 739–757 . 2022 . 10.1002/2211-5463.13347 . 8972043 . 34878722 .
  32. Paredes S, Angulo-Ibanez M, Tasselli L, Chua KF . The epigenetic regulator SIRT7 guards against mammalian cellular senescence induced by ribosomal DNA instability . . 293 . 28 . 11242–11250 . 2018 . 10.1074/jbc.AC118.003325 . 6052228 . 29728458. free .
  33. Huda N, Liu G, Hong H, Yin X . Hepatic senescence, the good and the bad . . 25 . 34 . 5069–5081 . 2019 . 10.3748/wjg.v25.i34.5069 . 6747293 . 31558857 . free .
  34. Yang H, Wang H, Ren J, Chen ZJ . cGAS is essential for cellular senescence . . 114 . 23 . E4612–E4620 . 2017 . 10.1073/pnas.1705499114 . 5468617 . 28533362. 2017PNAS..114E4612Y . free .
  35. Baechle JJ, Chen N, Winer DA . 2023 . Chronic inflammation and the hallmarks of aging . . 74 . 101755 . 10.1016/j.molmet.2023.101755 . 10359950 . 37329949.
  36. Houssaini A, Breau M, Kebe K, Adnot S . mTOR pathway activation drives lung cell senescence and emphysema . . 3 . 3 . e93203 . 2018 . 10.1172/jci.insight.93203 . 5821218 . 29415880 .
  37. Palmer AK, Gustafson B, Kirkland JL, Smith U . Cellular senescence: at the nexus between ageing and diabetes . . 62 . 10 . 1835–1841 . 2019 . 10.1007/s00125-019-4934-x . 6731336 . 31451866 .
  38. van Deursen JM . Senolytic therapies for healthy longevity . . 364 . 6441 . 636–637 . 2019 . 10.1126/science.aaw1299 . 31097655 . 6816502 . 2019Sci...364..636V .
  39. Palmer AK, Kirkland JL. Aging and adipose tissue: potential interventions for diabetes and regenerative medicine . . 86. 97–105 . 2016 . 10.1016/j.exger.2016.02.013 . 5001933 . 26924669 .
  40. Bartleson JM, Radenkovic D, Verdin E . SARS-CoV-2, COVID-19 and the Ageing Immune System . . 1 . 9 . 769–782 . 2021 . 10.1038/s43587-021-00114-7 . 8570568 . 34746804 .
  41. Chini C, Hogan KA, Warner GM, Tarragó MG, Peclat TR, Tchkonia T, Kirkland JL, Chini E . The NADase CD38 is induced by factors secreted from senescent cells providing a potential link between senescence and age-related cellular NAD+ decline . . 513 . 2 . 486–493 . 2019 . 10.1016/j.bbrc.2019.03.199 . 6486859 . 30975470 .
  42. Eric M. Verdin . 27313960 . NAD⁺ in aging, metabolism, and neurodegeneration . . 350 . 6265 . 1208–1213 . 2015 . 10.1126/science.aac4854 . 26785480 . 2015Sci...350.1208V . Eric M. Verdin .
  43. Sabbatinelli J, Prattichizzo F, Olivieri F, Giuliani A . Where Metabolism Meets Senescence: Focus on Endothelial Cells . . 10 . 1523 . 2019 . 10.3389/fphys.2019.01523 . 6930181 . 31920721. free .
  44. Covarrubias AJ, Perrone R, Grozio A, Verdin E . NAD + metabolism and its roles in cellular processes during ageing . . 22 . 2 . 119–141 . 2021 . 10.1038/s41580-020-00313-x . 7963035 . 33353981.
  45. Soto-Gamez A, Quax WJ, Demaria M . Regulation of Survival Networks in Senescent Cells: From Mechanisms to Interventions . . 431 . 15 . 2629–2643 . 2019 . 10.1016/j.jmb.2019.05.036 . 31153901. free .
  46. Liu X, Ding J, Meng L . Oncogene-induced senescence: a double edged sword in cancer. . 39 . 10 . 1553–1558 . 2018 . 10.1038/aps.2017.198 . 6289471 . 29620049.
  47. Kim YH, Park TJ . Cellular senescence in cancer . BMB Reports . 52 . 1 . 42–46 . 2019 . 10.5483/BMBRep.2019.52.1.295 . 6386235 . 30526772.
  48. Lim H, Heo MY, Kim HP. Flavonoids: Broad Spectrum Agents on Chronic Inflammation . Biomolecules & Therapeutics . 27 . 3 . 241–253 . 2019 . 10.4062/biomolther.2019.034 . 6513185 . 31006180.
  49. Katlinskaya YV, Carbone CJ, Yu Q, Fuchs SY . Type 1 interferons contribute to the clearance of senescent cell . Cancer Biology & Therapy . 16 . 8 . 1214–1219 . 2015 . 10.1080/15384047.2015.1056419 . 4622626 . 26046815.
  50. Sagiv A, Krizhanovsky V . 2775067 . Immunosurveillance of senescent cells: the bright side of the senescence program . Biogerontology . 14 . 6 . 617–628 . 2013 . 10.1007/s10522-013-9473-0 . 24114507.
  51. Thiers. B.H.. January 2008. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Yearbook of Dermatology and Dermatologic Surgery. 2008. 312–313. 10.1016/s0093-3619(08)70921-3. 0093-3619.
  52. Rao. Sonia G.. Jackson. James G.. November 2016. SASP: Tumor Suppressor or Promoter? Yes!. Trends in Cancer. 2. 11. 676–687. 10.1016/j.trecan.2016.10.001. 28741506. 2405-8033. free.
  53. Alexander E, Hildebrand DG, Schulze-Osthoff K, Essmann F . IκBζ is a regulator of the senescence-associated secretory phenotype in DNA damage- and oncogene-induced senescence . . 126 . Pt 16 . 3738–3745 . 2013 . 10.1242/jcs.128835 . 23781024. free .
  54. Yang J, Liu M, Zhang X . The Paradoxical Role of Cellular Senescence in Cancer . . 9 . 722205 . 2021 . 10.3389/fcell.2021.722205 . 8388842 . 34458273. free .
  55. Lujambio A . To clear, or not to clear (senescent cells)? That is the question . . 38 . Suppl 1 . s56–s64 . 2016 . 10.1002/bies.201670910 . 27417123 . 3785916 . free .
  56. Freund A, Orjalo AV, Desprez P, Campisi J . Inflammatory networks during cellular senescence: causes and consequences . . 16 . 5 . 238–246 . 2010 . 10.1016/j.molmed.2010.03.003 . 2879478 . 20444648 .
  57. Herranz N, Gil J . Mechanisms and functions of cellular senescence . . 128 . 4 . 1238–1246 . 2018 . 10.1172/JCI95148 . 5873888 . 29608137 .
  58. Demaria M, Ohtani N, Youssef SA, Rodier F, Toussaint W, Mitchell JR, Laberge RM, Vijg J, Van Steeg H, Dollé ME, Hoeijmakers JH, de Bruin A, Hara E, Campisi J . An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA . . 31 . 6 . 722–733 . 2014 . 10.1016/j.devcel.2014.11.012 . 4349629 . 25499914 .
  59. Basisty N, Kale A, Campisi J, Schilling B . The power of proteomics to monitor senescence-associated secretory phenotypes and beyond: toward clinical applications . Expert Review of Proteomics . 17 . 4 . 297–308 . 2020 . 10.1080/14789450.2020.1766976 . 7416420 . 32425074 .
  60. Muñoz-Espín. Daniel. Serrano. Manuel. 20062510. July 2014. Cellular senescence: from physiology to pathology. Nature Reviews Molecular Cell Biology. en. 15. 7. 482–496. 10.1038/nrm3823. 24954210. 1471-0080.
  61. Muñoz-Espín. Daniel. Cañamero. Marta. Maraver. Antonio. Gómez-López. Gonzalo. Contreras. Julio. Murillo-Cuesta. Silvia. Rodríguez-Baeza. Alfonso. Varela-Nieto. Isabel. Ruberte. Jesús. Collado. Manuel. Serrano. Manuel. 2013-11-21. Programmed Cell Senescence during Mammalian Embryonic Development. Cell. en. 155. 5. 1104–1118. 10.1016/j.cell.2013.10.019. 24238962. 0092-8674. free. 20.500.11940/3668. free.
  62. Zhu Y, Liu X, Geng X . Telomere and its role in the aging pathways: telomere shortening, cell senescence and mitochondria dysfunction . . 20 . 1 . 1–16 . 2019 . 10.1007/s10522-018-9769-1 . 30229407 .
  63. Zhang M, Serna-Salas S, Moshage H . Hepatic stellate cell senescence in liver fibrosis: Characteristics, mechanisms and perspectives. . 199 . 111572 . 2021 . 10.1016/j.mad.2021.111572 . 0047-6374 . 34536446. 237524296. free .
  64. Valentijn FA, Falke LL, Nguyen TQ, Goldschmeding R . Cellular senescence in the aging and diseased kidney . . 12 . 1 . 69–82 . 2018 . 10.1007/s12079-017-0434-2 . 5842195 . 29260442.
  65. Liu GY, Sabatini DM . mTOR at the nexus of nutrition, growth, ageing and disease . . 21 . 4 . 183-203 . 2020 . 10.1038/s41580-019-0199-y . 7102936 . 31937935.
  66. Ji S, Xiong M, Sun X . Cellular rejuvenation: molecular mechanisms and potential therapeutic interventions for diseases . . 8 . 1 . 116 . 2023 . 10.1038/s41392-023-01343-5 . 10015098 . 36918530 .
  67. Han Y, Ramprasath T, Zou M . β-hydroxybutyrate and its metabolic effects on age-associated pathology . . 52 . 548–555 . 2020 . 4 . 10.1038/s12276-020-0415-z . 7210293 . 32269287 .
  68. Stubbs BJ, Koutnik AP, Volek JS, Newman JC . From bedside to battlefield: intersection of ketone body mechanisms in geroscience with military resilience . . 43 . 3 . 1071–1081 . 2021 . 10.1007/s11357-020-00277-y . 8190215 . 33006708 .
  69. Diniz BS, Mulsant BM, Lenze EJ . Association of Molecular Senescence Markers in Late-Life Depression With Clinical Characteristics and Treatment Outcome . . 5 . 6 . e2219678 . 2022 . 10.1001/jamanetworkopen.2022.19678 . 9247739 . 35771573 .
  70. Franceschi C, Campisi J . Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases . . 69 . Supp 1 . s4–s9 . 2014 . 10.1093/gerona/glu057 . 24833586 . free .
  71. Prašnikar E, Borišek J, Perdih A . Senescent cells as promising targets to tackle age-related diseases . . 66 . 101251 . 2021 . 10.1016/j.arr.2020.10125 . 33385543.
  72. Akbar AN, Gilroy DW . Aging immunity may exacerbate COVID-19 . . 369 . 6501 . 256–257 . 2020 . 10.1126/science.abb0762 . 32675364. 2020Sci...369..256A . free .

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