A Cellular Senescence-Centric Integrated Approach to Understanding
Organismal Aging

Rohit      Sharma; Bhawna      Diwan
Abstract

Aging remains the fundamental cause of the increased rate of morbidity and mortality in the elderly. Despite continuing research, an integrative and holistic understanding of the molecular mechanisms and effects of aging is still elusive. This presents a major challenge in biogerontology, and therefore novel strategies aimed at integrating the multifaceted nature of aging for the identification and development of successful therapeutic targets are highly desirable. At present, cellular senescence, immunosenescence, and gut microbiota dysbiosis are key known modulators of aging. However, a cellular senescence-centric integrative view that relates to the seemingly distinct processes of immunosenescence and gut microbiota dysbiosis can be envisaged, which implies a more inclusive and targetable understanding of aging. The present manuscript discusses the emerging evidence and significance of cellular senescence vis-à-vis immunosenescence and gut microbiota dysbiosis in the development of potential anti-aging therapies. Underlying interconnections and mechanisms amongst these individual modulators have been deliberated to present a more coherent and tangible understanding of biological aging. It is emphasized that aging be studied within the integrative purview of these processes that may ultimately help devise a new inclusive and consolidated theory of aging with well-defined therapeutic targets.
Keywords: Aging, Cellular senescence, Gut microbiota dysbiosis, Immunosenescence, Nutrition, Longevity, Immunity, Microbiome
Graphical Abstract

[1]
Jin K. Modern biological theories of aging. Aging Dis  2010; 1(2): 72-4.
 [PMID: 21132086]

[2]
Bhatia-Dey N, Kanherkar RR, Stair SE, Makarev EO, Csoka AB. Cellular senescence as the causal nexus of aging. Front Genet  2016; 7: 13.
 [http://dx.doi.org/10.3389/fgene.2016.00013] [PMID: 26904101]

[3]
Santra M, Dill KA, de Graff AMR. Proteostasis collapse is a driver of cell aging and death. Proc Natl Acad Sci  2019; 116(44): 22173-8.
 [http://dx.doi.org/10.1073/pnas.1906592116] [PMID: 31619571]

[4]
Rattan SIS. Increased molecular damage and heterogeneity as the basis of aging. Biol Chem  2008; 389(3): 267-72.
 [http://dx.doi.org/10.1515/BC.2008.030] [PMID: 18208348]

[5]
Yin D, Chen K. The essential mechanisms of aging: Irreparable damage accumulation of biochemical side-reactions. Exp Gerontol  2005; 40(6): 455-65.
 [http://dx.doi.org/10.1016/j.exger.2005.03.012] [PMID: 15935593]

[6]
López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell  2013; 153(6): 1194-217.
 [http://dx.doi.org/10.1016/j.cell.2013.05.039] [PMID: 23746838]

[7]
Rattan S. Aging is not a disease: Implications for intervention. Aging Dis  2014; 5(3): 196-202.
 [http://dx.doi.org/10.14336/ad.2014.0500196] [PMID: 24900942]

[8]
Bulterijs S, Hull RS, Björk VCE, Roy AG. It is time to classify biological aging as a disease. Front Genet  2015; 6: 205.
 [http://dx.doi.org/10.3389/fgene.2015.00205] [PMID: 26150825]

[9]
Gladyshev TV, Gladyshev VN. A disease or not a disease? Aging as a pathology. Trends Mol Med  2016; 22(12): 995-6.
 [http://dx.doi.org/10.1016/j.molmed.2016.09.009] [PMID: 27793599]

[10]
Fulop T, Larbi A, Khalil A, Cohen AA, Witkowski JM. Are we ill because we age? Front Physiol  2019; 10: 1508.
 [http://dx.doi.org/10.3389/fphys.2019.01508] [PMID: 31956310]

[11]
Scott AJ, Ellison M, Sinclair DA. The economic value of targeting aging. Nature Aging  2021; 1(7): 616-23.
 [http://dx.doi.org/10.1038/s43587-021-00080-0]

[12]
Blagosklonny MV. Prospective treatment of age-related diseases by slowing down aging. Am J Pathol  2012; 181(4): 1142-6.
 [http://dx.doi.org/10.1016/j.ajpath.2012.06.024] [PMID: 22841821]

[13]
Hayflick L. The greatest risk factor for the leading cause of death is ignored. Biogerontology  2021; 22(1): 133-41.
 [http://dx.doi.org/10.1007/s10522-020-09901-y] [PMID: 33058001]

[14]
Burch JB, Augustine AD, Frieden LA, Hadley E, Howcroft TK, Johnson R. et al. Advances in geroscience: Impact on healthspan and chronic disease. J Gerontol  2014; 69(S1): S1-3.

[15]
Omidifar N. moghadami M, Mousavi SM, et al. Trends in natural nutrients for oxidative stress and cell senescence. Oxid Med Cell Longev  2021; 2021: 1-7.
 [http://dx.doi.org/10.1155/2021/7501424] [PMID: 34306314]

[16]
Englund DA, Sakamoto AE, Fritsche CM. et al. Exercise reduces circulating biomarkers of cellular senescence in humans. Aging Cell  2021; 20(7): e13415.
 [http://dx.doi.org/10.1111/acel.13415] [PMID: 34101960]

[17]
Verburgh K. Nutrigerontology: Why we need a new scientific discipline to develop diets and guidelines to reduce the risk of aging related diseases. Aging Cell  2015; 14(1): 17-24.
 [http://dx.doi.org/10.1111/acel.12284] [PMID: 25470422]

[18]
Chen K, Shen W, Zhang Z, Xiong F, Ouyang Q, Luo C. Age-dependent decline in stress response capacity revealed by proteins dynamics analysis. Sci Rep  2020; 10(1): 15211.
 [http://dx.doi.org/10.1038/s41598-020-72167-4] [PMID: 32939000]

[19]
Kozakiewicz M, Kornatowski M, Krzywińska O, Kędziora-Kornatowska K. Changes in the blood antioxidant defense of advanced age people. Clin Interv Aging  2019; 14: 763-71.
 [http://dx.doi.org/10.2147/CIA.S201250] [PMID: 31118597]

[20]
Gemma C, Mesches MH, Sepesi B, Choo K, Holmes DB, Bickford PC. Diets enriched in foods with high antioxidant activity reverse age-induced decreases in cerebellar beta-adrenergic function and increases in proinflammatory cytokines. J Neurosci  2002; 22(14): 6114-20.
 [http://dx.doi.org/10.1523/JNEUROSCI.22-14-06114.2002] [PMID: 12122072]

[21]
Kobayashi S, Asakura K, Suga H, Sasaki S. Inverse association between dietary habits with high total antioxidant capacity and prevalence of frailty among elderly Japanese women: A multicenter cross-sectional study. J Nutr Health Aging  2014; 18(9): 827-36.
 [http://dx.doi.org/10.1007/s12603-014-0556-7] [PMID: 25389961]

[22]
Fadnes LT, Økland JM, Haaland ØA, Johansson KA. Estimating impact of food choices on life expectancy: A modeling study. PLoS Med  2022; 19(2): e1003889.
 [http://dx.doi.org/10.1371/journal.pmed.1003889] [PMID: 35134067]

[23]
Diwan B, Sharma R. Nutritional components as mitigators of cellular senescence in organismal aging: A comprehensive review. Food Sci Biotechnol  2022; 31(9): 1089-109.
 [http://dx.doi.org/10.1007/s10068-022-01114-y] [PMID: 35756719]

[24]
Baker DJ, Childs BG, Durik M. et al. Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature  2016; 530(7589): 184-9.
 [http://dx.doi.org/10.1038/nature16932] [PMID: 26840489]

[25]
Baker DJ, Wijshake T, Tchkonia T. et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature  2011; 479(7372): 232-6.
 [http://dx.doi.org/10.1038/nature10600] [PMID: 22048312]

[26]
Karin O, Agrawal A, Porat Z, Krizhanovsky V, Alon U. Senescent cell turnover slows with age providing an explanation for the Gompertz law. Nat Commun  2019; 10(1): 5495.
 [http://dx.doi.org/10.1038/s41467-019-13192-4] [PMID: 31792199]

[27]
Gil J. Cellular senescence causes ageing. Nat Rev Mol Cell Biol  2019; 20(7): 388.
 [http://dx.doi.org/10.1038/s41580-019-0128-0] [PMID: 30962572]

[28]
Khosla S, Farr JN, Tchkonia T, Kirkland JL. The role of cellular senescence in ageing and endocrine disease. Nat Rev Endocrinol  2020; 16(5): 263-75.
 [http://dx.doi.org/10.1038/s41574-020-0335-y] [PMID: 32161396]

[29]
Aguayo-Mazzucato C, Andle J, Lee TB Jr. et al. Acceleration of β cell aging determines diabetes and senolysis improves disease out-comes. Cell Metab  2019; 30(1): 129-142.e4.
 [http://dx.doi.org/10.1016/j.cmet.2019.05.006] [PMID: 31155496]

[30]
Amaya-Montoya M, Pérez-Londoño A, Guatibonza-García V, Vargas-Villanueva A, Mendivil CO. Cellular senescence as a therapeutic target for age-related diseases: A review. Adv Ther  2020; 37(4): 1407-24.
 [http://dx.doi.org/10.1007/s12325-020-01287-0] [PMID: 32185730]

[31]
Ogrodnik M, Miwa S, Tchkonia T. et al. Cellular senescence drives age-dependent hepatic steatosis. Nat Commun  2017; 8(1): 15691.
 [http://dx.doi.org/10.1038/ncomms15691] [PMID: 28608850]

[32]
Bartleson JM, Radenkovic D, Covarrubias AJ, Furman D, Winer DA, Verdin E. SARS-CoV-2, COVID-19 and the aging immune system. Nature Aging  2021; 1(9): 769-82.
 [http://dx.doi.org/10.1038/s43587-021-00114-7] [PMID: 34746804]

[33]
Del Giudice G, Goronzy JJ, Grubeck-Loebenstein B. et al. Fighting against a protean enemy: Immunosenescence, vaccines, and healthy aging. npj Aging Mech Dis 2017; 4(1): 1.

[34]
Kale A, Sharma A, Stolzing A, Desprez PY, Campisi J. Role of immune cells in the removal of deleterious senescent cells. Immun Ageing  2020; 17(1): 16.
 [http://dx.doi.org/10.1186/s12979-020-00187-9] [PMID: 32518575]

[35]
Prata LGPL, Ovsyannikova IG, Tchkonia T, Kirkland JL. Senescent cell clearance by the immune system: Emerging therapeutic opportu-nities. Semin Immunol  2018; 40: 101275.
 [http://dx.doi.org/10.1016/j.smim.2019.04.003] [PMID: 31088710]

[36]
Badal VD, Vaccariello ED, Murray ER. et al. The gut microbiome, aging, and longevity: A systematic review. Nutrients  2020; 12(12): 3759.
 [http://dx.doi.org/10.3390/nu12123759] [PMID: 33297486]

[37]
Iebba V, Totino V, Gagliardi A. et al. Eubiosis and dysbiosis: The two sides of the microbiota. New Microbiol  2016; 39(1): 1-12.
 [PMID: 26922981]

[38]
Vijay A, Valdes AM. Role of the gut microbiome in chronic diseases: A narrative review. Eur J Clin Nutr  2022; 76(4): 489-501.
 [http://dx.doi.org/10.1038/s41430-021-00991-6] [PMID: 34584224]

[39]
Kim S, Jazwinski SM. The gut microbiota and healthy aging: A mini-review. Gerontology  2018; 64(6): 513-20.
 [http://dx.doi.org/10.1159/000490615] [PMID: 30025401]

[40]
Miller LE, Lehtoranta L, Lehtinen MJ. Short-term probiotic supplementation enhances cellular immune function in healthy elderly: Sys-tematic review and meta-analysis of controlled studies. Nutr Res  2019; 64: 1-8.
 [http://dx.doi.org/10.1016/j.nutres.2018.12.011] [PMID: 30802719]

[41]
Hong MHY, Christopher MCH, Yan MJW, Ko OH, Tao Z, Leung CFK. IDDF2020-ABS-0202 Meta-analysis on the effect of probiotics on neurodegenerative disorders in humans clinical trials. Gut  2020; 69(S2): A63-4.

[42]
Kumar R, Sharma A, Gupta M, Padwad Y, Sharma R. Cell-free culture supernatant of probiotic Lactobacillus fermentum protects against H2O2-induced premature senescence by suppressing ROS-Akt-mTOR axis in murine preadipocytes. Probiotics Antimicrob Proteins  2020; 12(2): 563-76.
 [http://dx.doi.org/10.1007/s12602-019-09576-z] [PMID: 31332650]

[43]
Donato V, Ayala FR, Cogliati S. et al. Bacillus subtilis biofilm extends Caenorhabditis elegans longevity through downregulation of the insulin-like signalling pathway. Nat Commun  2017; 8(1): 14332.
 [http://dx.doi.org/10.1038/ncomms14332] [PMID: 28134244]

[44]
Khan SS, Singer BD, Vaughan DE. Molecular and physiological manifestations and measurement of aging in humans. Aging Cell  2017; 16(4): 624-33.
 [http://dx.doi.org/10.1111/acel.12601] [PMID: 28544158]

[45]
Ahmed ASI, Sheng MHC, Wasnik S, Baylink DJ, Lau KHW. Effect of aging on stem cells. World J Exp Med  2017; 7(1): 1-10.
 [http://dx.doi.org/10.5493/wjem.v7.i1.1] [PMID: 28261550]

[46]
Hayflick L, Moorhead PS. The serial cultivation of human diploid cell strains. Exp Cell Res  1961; 25(3): 585-621.
 [http://dx.doi.org/10.1016/0014-4827(61)90192-6] [PMID: 13905658]

[47]
Herranz N, Gil J. Mechanisms and functions of cellular senescence. J Clin Invest  2018; 128(4): 1238-46.
 [http://dx.doi.org/10.1172/JCI95148] [PMID: 29608137]

[48]
Kumar R, Sharma A, Kumari A, Gulati A, Padwad Y, Sharma R. Epigallocatechin gallate suppresses premature senescence of preadipo-cytes by inhibition of PI3K/Akt/mTOR pathway and induces senescent cell death by regulation of Bax/Bcl-2 pathway. Biogerontology  2019; 20(2): 171-89.
 [http://dx.doi.org/10.1007/s10522-018-9785-1] [PMID: 30456590]

[49]
Singh BK, Tripathi M, Sandireddy R, Tikno K, Zhou J, Yen PM. Decreased autophagy and fuel switching occur in a senescent hepatic cell model system. Aging  2020; 12(14): 13958-78.
 [http://dx.doi.org/10.18632/aging.103740] [PMID: 32712601]

[50]
Campisi J. Aging, cellular senescence, and cancer. Annu Rev Physiol  2013; 75(1): 685-705.
 [http://dx.doi.org/10.1146/annurev-physiol-030212-183653] [PMID: 23140366]

[51]
Jurk D, Wang C, Miwa S. et al. Postmitotic neurons develop a p21 dependent senescence like phenotype driven by a DNA damage re-sponse. Aging Cell  2012; 11(6): 996-1004.
 [http://dx.doi.org/10.1111/j.1474-9726.2012.00870.x] [PMID: 22882466]

[52]
Chou JP, Effros RB. T cell replicative senescence in human aging. Curr Pharm Des  2013; 19(9): 1680-98.
 [PMID: 23061726]

[53]
Demaria M, Ohtani N, Youssef SA. et al. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev Cell  2014; 31(6): 722-33.
 [http://dx.doi.org/10.1016/j.devcel.2014.11.012] [PMID: 25499914]

[54]
Idda ML, McClusky WG, Lodde V. et al. Survey of senescent cell markers with age in human tissues. Aging  2020; 12(5): 4052-66.
 [http://dx.doi.org/10.18632/aging.102903] [PMID: 32160592]

[55]
Yousefzadeh MJ, Zhao J, Bukata C. et al. Tissue specificity of senescent cell accumulation during physiologic and accelerated aging of mice. Aging Cell  2020; 19(3): e13094.
 [http://dx.doi.org/10.1111/acel.13094] [PMID: 31981461]

[56]
Song S, Lam EWF, Tchkonia T, Kirkland JL, Sun Y. Senescent cells: Emerging targets for human aging and age-related diseases. Trends Biochem Sci  2020; 45(7): 578-92.
 [http://dx.doi.org/10.1016/j.tibs.2020.03.008] [PMID: 32531228]

[57]
Sharma R, Kumar R, Sharma A, Goel A, Padwad Y. Long-term consumption of green tea EGCG enhances murine health span by mitigat-ing multiple aspects of cellular senescence in mitotic and post-mitotic tissues, gut dysbiosis, and immunosenescence. J Nutr Biochem  2022; 107: 109068.
 [http://dx.doi.org/10.1016/j.jnutbio.2022.109068] [PMID: 35618244]

[58]
Kim SR, Jiang K, Ferguson CM. et al. Transplanted senescent renal scattered tubular-like cells induce injury in the mouse kidney. Am J Physiol Renal Physiol  2020; 318(5): F1167-76.
 [http://dx.doi.org/10.1152/ajprenal.00535.2019] [PMID: 32223312]

[59]
Xu M, Bradley EW, Weivoda MM. et al. Transplanted senescent cells induce an osteoarthritis-like condition in mice. J Gerontol A Biol Sci Med Sci  2017; 72(6): 780-5.
 [PMID: 27516624]

[60]
Iske J, Maenosono R, Seyda M. et al. Transplantation of older organs transfers senescence. Transplantation  2020; 104(S3): S29.
 [http://dx.doi.org/10.1097/01.tp.0000698396.81371.d8]

[61]
Katzir I, Adler M, Karin O, Mendelsohn-Cohen N, Mayo A, Alon U. Senescent cells and the incidence of age related diseases. Aging Cell  2021; 20(3): e13314.
 [http://dx.doi.org/10.1111/acel.13314] [PMID: 33559235]

[62]
Davalos AR, Coppe JP, Campisi J, Desprez PY. Senescent cells as a source of inflammatory factors for tumor progression. Cancer Metastasis Rev  2010; 29(2): 273-83.
 [http://dx.doi.org/10.1007/s10555-010-9220-9] [PMID: 20390322]

[63]
Nelson G, Kucheryavenko O, Wordsworth J, von Zglinicki T. The senescent bystander effect is caused by ROS-activated NF-κB signal-ling. Mech Ageing Dev  2018; 170: 30-6.
 [http://dx.doi.org/10.1016/j.mad.2017.08.005] [PMID: 28837845]

[64]
Sturmlechner I, Zhang C, Sine CC. et al. p21 produces a bioactive secretome that places stressed cells under immunosurveillance. Science  2021; 374(6567): eabb3420.
 [http://dx.doi.org/10.1126/science.abb3420] [PMID: 34709885]

[65]
Lagoumtzi SM, Chondrogianni N. Senolytics and senomorphics: Natural and synthetic therapeutics in the treatment of aging and chronic diseases. Free Radic Biol Med  2021; 171: 169-90.
 [http://dx.doi.org/10.1016/j.freeradbiomed.2021.05.003] [PMID: 33989756]

[66]
Liang Y, Liu C, Lu M. et al. Calorie restriction is the most reasonable anti-ageing intervention: A meta-analysis of survival curves. Sci Rep  2018; 8(1): 5779.
 [http://dx.doi.org/10.1038/s41598-018-24146-z] [PMID: 29636552]

[67]
Fontana L, Mitchell SE, Wang B. et al. The effects of graded caloric restriction: XII. Comparison of mouse to human impact on cellular senescence in the colon. Aging Cell  2018; 17(3): e12746.
 [http://dx.doi.org/10.1111/acel.12746] [PMID: 29575469]

[68]
Fontana L, Nehme J, Demaria M. Caloric restriction and cellular senescence. Mech Ageing Dev  2018; 176: 19-23.
 [http://dx.doi.org/10.1016/j.mad.2018.10.005] [PMID: 30395873]

[69]
Kim DH, Bang E, Jung HJ. et al. Anti-aging effects of Calorie Restriction (CR) and CR mimetics based on the senoinflammation concept. Nutrients  2020; 12(2): 422.
 [http://dx.doi.org/10.3390/nu12020422] [PMID: 32041168]

[70]
de Magalhães JP, Passos JF. Stress, cell senescence and organismal ageing. Mech Ageing Dev  2018; 170: 2-9.
 [http://dx.doi.org/10.1016/j.mad.2017.07.001] [PMID: 28688962]

[71]
Marcotte R, Wang E. Replicative senescence revisited. J Gerontol  2002; 57(7): B257-69.
 [http://dx.doi.org/10.1093/gerona/57.7.B257]

[72]
Fan DNY, Schmitt CA. Genotoxic stress-induced senescence. Methods Mol Biol  2019; 1896: 93-105.
 [http://dx.doi.org/10.1007/978-1-4939-8931-7_10] [PMID: 30474843]

[73]
Robinson AR, Yousefzadeh MJ, Rozgaja TA. et al. Spontaneous DNA damage to the nuclear genome promotes senescence, redox imbal-ance and aging. Redox Biol  2018; 17: 259-73.
 [http://dx.doi.org/10.1016/j.redox.2018.04.007] [PMID: 29747066]

[74]
Epel E. Psychological and metabolic stress: A recipe for accelerated cellular aging? Hormones  2009; 8(1): 7-22.
 [http://dx.doi.org/10.14310/horm.2002.1217] [PMID: 19269917]

[75]
Epel ES, Blackburn EH, Lin J. et al. Accelerated telomere shortening in response to life stress. Proc Natl Acad Sci  2004; 101(49): 17312-5.
 [http://dx.doi.org/10.1073/pnas.0407162101] [PMID: 15574496]

[76]
Dues DJ, Andrews EK, Schaar CE, Bergsma AL, Senchuk MM, Van Raamsdonk JM. Aging causes decreased resistance to multiple stress-es and a failure to activate specific stress response pathways. Aging  2016; 8(4): 777-95.
 [http://dx.doi.org/10.18632/aging.100939] [PMID: 27053445]

[77]
Zhang Y, Unnikrishnan A, Deepa SS. et al. A new role for oxidative stress in aging: The accelerated aging phenotype in Sod1− mice is correlated to increased cellular senescence. Redox Biol  2017; 11: 30-7.
 [http://dx.doi.org/10.1016/j.redox.2016.10.014] [PMID: 27846439]

[78]
Herbig U, Ferreira M, Condel L, Carey D, Sedivy JM. Cellular senescence in aging primates. Science  2006; 311(5765): 1257.
 [http://dx.doi.org/10.1126/science.1122446] [PMID: 16456035]

[79]
He S, Sharpless NE. Senescence in health and disease. Cell  2017; 169(6): 1000-11.
 [http://dx.doi.org/10.1016/j.cell.2017.05.015] [PMID: 28575665]

[80]
Matzinger P. The danger model: A renewed sense of self. Science  2002; 296(5566): 301-5.
 [http://dx.doi.org/10.1126/science.1071059] [PMID: 11951032]

[81]
McElhaney JE. The unmet need in the elderly: Designing new influenza vaccines for older adults. Vaccine  2005; 23(S1): S10-25.
 [http://dx.doi.org/10.1016/j.vaccine.2005.04.019] [PMID: 15908062]

[82]
Pietrobon AJ, Teixeira FME, Sato MN. Immunosenescence and inflammaging: Risk factors of severe COVID-19 in older people. Front Immunol  2020; 11: 579220.
 [http://dx.doi.org/10.3389/fimmu.2020.579220] [PMID: 33193377]

[83]
Aiello A, Farzaneh F, Candore G. et al. Immunosenescence and its hallmarks: How to oppose aging strategically? A review of potential options for therapeutic intervention. Front Immunol  2019; 10(2247): 2247.
 [http://dx.doi.org/10.3389/fimmu.2019.02247] [PMID: 31608061]

[84]
Fulop T, Larbi A, Dupuis G. et al. Immunosenescence and inflamm-aging as two sides of the same coin: Friends or foes? Front Immunol  2018; 8: 1960.
 [http://dx.doi.org/10.3389/fimmu.2017.01960] [PMID: 29375577]

[85]
Franceschi C, Campisi J. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci  2014; 69 (Suppl. 1): S4-9.
 [http://dx.doi.org/10.1093/gerona/glu057] [PMID: 24833586]

[86]
Sharma R, Kapila R, Haq MRU, Salingati V, Kapasiya M, Kapila S. Age-associated aberrations in mouse cellular and humoral immune responses. Aging Clin Exp Res  2014; 26(4): 353-62.
 [http://dx.doi.org/10.1007/s40520-013-0190-y] [PMID: 24343854]

[87]
Pawelec G, Bronikowski A, Cunnane SC. et al. The conundrum of human immune system “senescence”. Mech Ageing Dev  2020; 192: 111357.
 [http://dx.doi.org/10.1016/j.mad.2020.111357] [PMID: 32949594]

[88]
Goronzy JJ, Weyand CM. Understanding immunosenescence to improve responses to vaccines. Nat Immunol  2013; 14(5): 428-36.
 [http://dx.doi.org/10.1038/ni.2588] [PMID: 23598398]

[89]
Sayed N, Huang Y, Nguyen K. et al. An inflammatory aging clock (iAge) based on deep learning tracks multimorbidity, immunosenes-cence, frailty and cardiovascular aging. Nature Aging  2021; 1(7): 598-615.
 [http://dx.doi.org/10.1038/s43587-021-00082-y] [PMID: 34888528]

[90]
Messaoudi I, Warner J, Fischer M. et al. Delay of T cell senescence by caloric restriction in aged long-lived nonhuman primates. Proc Natl Acad Sci  2006; 103(51): 19448-53.
 [http://dx.doi.org/10.1073/pnas.0606661103] [PMID: 17159149]

[91]
Yan X, Imano N, Tamaki K, Sano M, Shinmura K. The effect of caloric restriction on the increase in senescence-associated T cells and metabolic disorders in aged mice. PLoS One  2021; 16(6): e0252547.
 [http://dx.doi.org/10.1371/journal.pone.0252547] [PMID: 34143796]

[92]
Antonangeli F, Soriani A, Ricci B. et al. Natural killer cell recognition of in vivo drug-induced senescent multiple myeloma cells. OncoImmunology  2016; 5(10): e1218105.
 [http://dx.doi.org/10.1080/2162402X.2016.1218105] [PMID: 27853638]

[93]
Sagiv A, Krizhanovsky V. Immunosurveillance of senescent cells: The bright side of the senescence program. Biogerontology  2013; 14(6): 617-28.
 [http://dx.doi.org/10.1007/s10522-013-9473-0] [PMID: 24114507]

[94]
Ponnappan S, Ponnappan U. Aging and immune function: Molecular mechanisms to interventions. Antioxid Redox Signal  2011; 14(8): 1551-85.
 [http://dx.doi.org/10.1089/ars.2010.3228] [PMID: 20812785]

[95]
Quinn KM, Fox A, Harland KL. et al. Age-related decline in primary CD8+ T cell responses is associated with the development of senes-cence in virtual memory CD8+ T cells. Cell Rep  2018; 23(12): 3512-24.
 [http://dx.doi.org/10.1016/j.celrep.2018.05.057] [PMID: 29924995]

[96]
Ovadya Y, Landsberger T, Leins H. et al. Impaired immune surveillance accelerates accumulation of senescent cells and aging. Nat Commun  2018; 9(1): 5435.
 [http://dx.doi.org/10.1038/s41467-018-07825-3] [PMID: 30575733]

[97]
Pereira BI, Devine OP, Vukmanovic-Stejic M. et al. Senescent cells evade immune clearance via HLA-E-mediated NK and CD8+ T cell inhibition. Nat Commun  2019; 10(1): 2387.
 [http://dx.doi.org/10.1038/s41467-019-10335-5] [PMID: 31160572]

[98]
Valdes AM, Walter J, Segal E, Spector TD. Role of the gut microbiota in nutrition and health. BMJ  2018; 361: k2179.
 [http://dx.doi.org/10.1136/bmj.k2179] [PMID: 29899036]

[99]
Ding RX, Goh WR, Wu RN. et al. Revisit gut microbiota and its impact on human health and disease. Yao Wu Shi Pin Fen Xi  2019; 27(3): 623-31.
 [PMID: 31324279]

[100]
Wilmanski T, Diener C, Rappaport N. et al. Gut microbiome pattern reflects healthy ageing and predicts survival in humans. Nat Metab  2021; 3(2): 274-86.
 [http://dx.doi.org/10.1038/s42255-021-00348-0] [PMID: 33619379]

[101]
Lynn MA, Eden G, Ryan FJ. et al. The composition of the gut microbiota following early-life antibiotic exposure affects host health and longevity in later life. Cell Rep  2021; 36(8): 109564.
 [http://dx.doi.org/10.1016/j.celrep.2021.109564] [PMID: 34433065]

[102]
Smith BJ, Miller RA, Ericsson AC, Harrison DC, Strong R, Schmidt TM. Changes in the gut microbiome and fermentation products con-current with enhanced longevity in acarbose-treated mice. BMC Microbiol  2019; 19(1): 130.
 [http://dx.doi.org/10.1186/s12866-019-1494-7] [PMID: 31195972]

[103]
Boehme M, Guzzetta KE, Bastiaanssen TFS. et al. Microbiota from young mice counteracts selective age-associated behavioral deficits. Nature Aging  2021; 1(8): 666-76.
 [http://dx.doi.org/10.1038/s43587-021-00093-9]

[104]
Chen Y, Zhang S, Zeng B. et al. Transplant of microbiota from long-living people to mice reduces aging-related indices and transfers bene-ficial bacteria. Aging  2020; 12(6): 4778-93.
 [http://dx.doi.org/10.18632/aging.102872] [PMID: 32176868]

[105]
Ke S, Mitchell S, MacArthur M. et al. Gut microbiota predicts healthy late-life aging in male mice. Nutrients  2021; 13(9): 3290.
 [http://dx.doi.org/10.3390/nu13093290] [PMID: 34579167]

[106]
Galkin F, Mamoshina P, Aliper A. et al. Human gut microbiome aging clock based on taxonomic profiling and deep learning. iScience  2020; 23(6): 101199.
 [http://dx.doi.org/10.1016/j.isci.2020.101199] [PMID: 32534441]

[107]
Sato Y, Atarashi K, Plichta DR. et al. Novel bile acid biosynthetic pathways are enriched in the microbiome of centenarians. Nature  2021; 599(7885): 458-64.
 [http://dx.doi.org/10.1038/s41586-021-03832-5] [PMID: 34325466]

[108]
Cӑtoi AF, Corina A, Katsiki N. et al. Gut microbiota and aging-A focus on centenarians. Biochim Biophys Acta Mol Basis Dis  2020; 1866(7): 165765.
 [http://dx.doi.org/10.1016/j.bbadis.2020.165765] [PMID: 32169505]

[109]
Fransen F, van Beek AA, Borghuis T. et al. Aged gut microbiota contributes to systemical inflammaging after transfer to germ-free mice. Front Immunol  2017; 8(1385): 1385.
 [http://dx.doi.org/10.3389/fimmu.2017.01385] [PMID: 29163474]

[110]
Bosco N, Noti M. The aging gut microbiome and its impact on host immunity. Genes Immun  2021; 22(5-6): 289-303.
 [http://dx.doi.org/10.1038/s41435-021-00126-8] [PMID: 33875817]

[111]
Conway JA, Duggal N. Ageing of the gut microbiome: Potential influences on immune senescence and inflammageing. Ageing Res Rev  2021; 68: 101323.
 [http://dx.doi.org/10.1016/j.arr.2021.101323] [PMID: 33771720]

[112]
Li WZ, Stirling K, Yang JJ, Zhang L. Gut microbiota and diabetes: From correlation to causality and mechanism. World J Diabetes  2020; 11(7): 293-308.
 [http://dx.doi.org/10.4239/wjd.v11.i7.293] [PMID: 32843932]

[113]
Liu F, Li J, Guan Y. et al. Dysbiosis of the gut microbiome is associated with tumor biomarkers in lung cancer. Int J Biol Sci  2019; 15(11): 2381-92.
 [http://dx.doi.org/10.7150/ijbs.35980] [PMID: 31595156]

[114]
Kurup K, Matyi S, Giles CB. et al. Calorie restriction prevents age-related changes in the intestinal microbiota. Aging  2021; 13(5): 6298-329.
 [http://dx.doi.org/10.18632/aging.202753] [PMID: 33744869]

[115]
Cox LM, Schafer MJ, Sohn J. et al. Calorie restriction slows age-related microbiota changes in an Alzheimer’s disease model in female mice. Sci Rep  2019; 9(1): 17904.
 [http://dx.doi.org/10.1038/s41598-019-54187-x] [PMID: 31784610]

[116]
Lavelle A, Sokol H. Gut microbiota-derived metabolites as key actors in inflammatory bowel disease. Nat Rev Gastroenterol Hepatol  2020; 17(4): 223-37.
 [http://dx.doi.org/10.1038/s41575-019-0258-z] [PMID: 32076145]

[117]
Agus A, Clément K, Sokol H. Gut microbiota-derived metabolites as central regulators in metabolic disorders. Gut  2021; 70(6): 1174-82.
 [http://dx.doi.org/10.1136/gutjnl-2020-323071] [PMID: 33272977]

[118]
Vernocchi P, Del Chierico F, Putignani L. Gut microbiota metabolism and interaction with food components. Int J Mol Sci  2020; 21(10): 3688.
 [http://dx.doi.org/10.3390/ijms21103688] [PMID: 32456257]

[119]
Han S, Van Treuren W, Fischer CR. et al. A metabolomics pipeline for the mechanistic interrogation of the gut microbiome. Nature  2021; 595(7867): 415-20.
 [http://dx.doi.org/10.1038/s41586-021-03707-9] [PMID: 34262212]

[120]
Tran SMS, Mohajeri MH. The role of gut bacterial metabolites in brain development, aging and disease. Nutrients  2021; 13(3): 732.
 [http://dx.doi.org/10.3390/nu13030732] [PMID: 33669008]

[121]
D’Amico D, Andreux PA, Valdés P, Singh A, Rinsch C, Auwerx J. Impact of the natural compound urolithin a on health, disease, and aging. Trends Mol Med  2021; 27(7): 687-99.
 [http://dx.doi.org/10.1016/j.molmed.2021.04.009] [PMID: 34030963]

[122]
Yoshimoto S, Mitsuyama E, Yoshida K, Odamaki T, Xiao J. Enriched metabolites that potentially promote age-associated diseases in subjects with an elderly-type gut microbiota. Gut Microbes  2021; 13(1): 1865705.
 [http://dx.doi.org/10.1080/19490976.2020.1865705] [PMID: 33430687]

[123]
Luo D, Chen K, Li J. et al. Gut microbiota combined with metabolomics reveals the metabolic profile of the normal aging process and the anti-aging effect of FuFang Zhenshu TiaoZhi(FTZ) in mice. Biomed Pharmacother  2020; 121: 109550.
 [http://dx.doi.org/10.1016/j.biopha.2019.109550] [PMID: 31704617]

[124]
Martínez TI, Ceprián N, Díaz-Del CE, Fuente M. The role of immune cells in oxi-inflamm-aging. Cells  2021; 10(11): 2974.
 [http://dx.doi.org/10.3390/cells10112974] [PMID: 34831197]

[125]
Narasimhan H, Ren CC, Deshpande S, Sylvia KE. Young at gut-turning back the clock with the gut microbiome. Microorganisms  2021; 9(3): 555.
 [http://dx.doi.org/10.3390/microorganisms9030555] [PMID: 33800340]

[126]
Budamagunta V, Foster TC, Zhou D. Cellular senescence in lymphoid organs and immunosenescence. Aging  2021; 13(15): 19920-41.
 [http://dx.doi.org/10.18632/aging.203405] [PMID: 34382946]

[127]
Yoshimoto S, Mun Loo T, Hara E. Cellular senescence and liver cancer: A gut microbial connection. Inflamm Regen  2015; 35(3): 106-13.
 [http://dx.doi.org/10.2492/inflammregen.35.106]

[128]
Elder SS, Emmerson E. Senescent cells and macrophages: Key players for regeneration? Open Biol  2020; 10(12): 200309.
 [http://dx.doi.org/10.1098/rsob.200309] [PMID: 33352064]

[129]
Song P, An J, Zou MH. Immune clearance of senescent cells to combat ageing and chronic diseases. Cells  2020; 9(3): 671.
 [http://dx.doi.org/10.3390/cells9030671] [PMID: 32164335]

[130]
Sikora E, Bielak-Zmijewska A, Mosieniak G. Targeting normal and cancer senescent cells as a strategy of senotherapy. Ageing Res Rev  2019; 55: 100941.
 [http://dx.doi.org/10.1016/j.arr.2019.100941] [PMID: 31408714]

[131]
Sharma R. Perspectives on the dynamic implications of cellular senescence and immunosenescence on macrophage aging biology. Biogerontology  2021; 22(6): 571-87.
 [http://dx.doi.org/10.1007/s10522-021-09936-9] [PMID: 34490541]

[132]
Burton DGA, Stolzing A. Cellular senescence: Immunosurveillance and future immunotherapy. Ageing Res Rev  2018; 43: 17-25.
 [http://dx.doi.org/10.1016/j.arr.2018.02.001] [PMID: 29427795]

[133]
Martínez-Zamudio RI, Dewald HK, Vasilopoulos T, Gittens-Williams L, Fitzgerald-Bocarsly P, Herbig U. Senescence associated β galactosidase reveals the abundance of senescent CD8+ T cells in aging humans. Aging Cell  2021; 20(5): e13344.
 [http://dx.doi.org/10.1111/acel.13344] [PMID: 33939265]

[134]
Liu Y, Sanoff HK, Cho H. et al. Expression of p16INK4a in peripheral blood T-cells is a biomarker of human aging. Aging Cell  2009; 8(4): 439-48.
 [http://dx.doi.org/10.1111/j.1474-9726.2009.00489.x] [PMID: 19485966]

[135]
Shen J, Song R, Fuemmeler BF, McGuire KP, Chow WH, Zhao H. Biological aging marker p16INK4a in T cells and breast cancer risk. Cancers  2020; 12(11): 3122.
 [http://dx.doi.org/10.3390/cancers12113122] [PMID: 33114473]

[136]
Janelle V, Neault M, Lebel MÈ. et al. p16INK4a regulates cellular senescence in pd-1-expressing human t cells. Front Immunol  2021; 12: 698565.
 [http://dx.doi.org/10.3389/fimmu.2021.698565] [PMID: 34434190]

[137]
Hall BM, Balan V, Gleiberman AS. et al. Aging of mice is associated with p16(Ink4a)- and β-galactosidase-positive macrophage accumula-tion that can be induced in young mice by senescent cells. Aging  2016; 8(7): 1294-315.
 [http://dx.doi.org/10.18632/aging.100991] [PMID: 27391570]

[138]
Liu JY, Souroullas GP, Diekman BO. et al. Cells exhibiting strong p16INK4a promoter activation in vivo display features of senescence. Proc Natl Acad Sci  2019; 116(7): 2603-11.
 [http://dx.doi.org/10.1073/pnas.1818313116] [PMID: 30683717]

[139]
Wang Q, Nie L, Zhao P. et al. Diabetes fuels periodontal lesions via GLUT1-driven macrophage inflammaging. Int J Oral Sci  2021; 13(1): 11.
 [http://dx.doi.org/10.1038/s41368-021-00116-6] [PMID: 33762572]

[140]
Prattichizzo F, De Nigris V, Mancuso E. et al. Short-term sustained hyperglycaemia fosters an archetypal senescence-associated secretory phenotype in endothelial cells and macrophages. Redox Biol  2018; 15: 170-81.
 [http://dx.doi.org/10.1016/j.redox.2017.12.001] [PMID: 29253812]

[141]
Kumar R, Sharma A, Padwad Y, Sharma R. Preadipocyte secretory factors differentially modulate murine macrophage functions during aging which are reversed by the application of phytochemical EGCG. Biogerontology  2020; 21(3): 325-43.
 [http://dx.doi.org/10.1007/s10522-020-09861-3] [PMID: 32043170]

[142]
Hall BM, Balan V, Gleiberman AS. et al. p16(Ink4a) and senescence-associated β-galactosidase can be induced in macrophages as part of a reversible response to physiological stimuli. Aging  2017; 9(8): 1867-84.
 [http://dx.doi.org/10.18632/aging.101268] [PMID: 28768895]

[143]
Yousefzadeh MJ, Flores RR, Zhu Y. et al. An aged immune system drives senescence and ageing of solid organs. Nature  2021; 594(7861): 100-5.
 [http://dx.doi.org/10.1038/s41586-021-03547-7] [PMID: 33981041]

[144]
Desdín-Micó G, Soto-Heredero G, Aranda JF. et al. T cells with dysfunctional mitochondria induce multimorbidity and premature senes-cence. Science  2020; 368(6497): 1371-6.
 [http://dx.doi.org/10.1126/science.aax0860] [PMID: 32439659]

[145]
Ogata Y, Yamada T, Hasegawa S. et al. SASP induced macrophage dysfunction may contribute to accelerated senescent fibroblast accumulation in the dermis. Exp Dermatol  2021; 30(1): 84-91.
 [http://dx.doi.org/10.1111/exd.14205] [PMID: 33010063]

[146]
Lagnado A, Leslie J, Ruchaud-Sparagano MH. et al. Neutrophils induce paracrine telomere dysfunction and senescence in ROS dependent manner. EMBO J  2021; 40(9): e106048.
 [http://dx.doi.org/10.15252/embj.2020106048] [PMID: 33764576]

[147]
Lee YS, Kim TY, Kim Y. et al. Microbiota-derived lactate accelerates intestinal stem-cell-mediated epithelial development. Cell Host Microbe  2018; 24(6): 833-846.e6.
 [http://dx.doi.org/10.1016/j.chom.2018.11.002] [PMID: 30543778]

[148]
Ma Q, Xing C, Long W, Wang HY, Liu Q, Wang RF. Impact of microbiota on central nervous system and neurological diseases: The gut-brain axis. J Neuroinflammation  2019; 16(1): 53.
 [http://dx.doi.org/10.1186/s12974-019-1434-3] [PMID: 30823925]

[149]
Willms RJ, Jones LO, Hocking JC, Foley E. A cell atlas of microbe-responsive processes in the zebrafish intestine. Cell Rep  2022; 38(5): 110311.
 [http://dx.doi.org/10.1016/j.celrep.2022.110311] [PMID: 35108531]

[150]
Jeong JJ, Kim KA, Jang SE, Woo JY, Han MJ, Kim DH. Orally administrated Lactobacillus pentosus var. plantarum C29 ameliorates age-dependent colitis by inhibiting the nuclear factor-kappa B signaling pathway via the regulation of lipopolysaccharide production by gut mi-crobiota. PLoS One  2015; 10(2): e0116533.
 [http://dx.doi.org/10.1371/journal.pone.0116533] [PMID: 25689583]

[151]
Jeong JJ, Kim KA, Hwang YJ, Han MJ, Kim DH. Anti-inflammaging effects of Lactobacillus brevis OW38 in aged mice. Benef Microbes  2016; 7(5): 707-18.
 [http://dx.doi.org/10.3920/BM2016.0016] [PMID: 27824273]

[152]
Matsumoto M, Kurihara S, Kibe R, Ashida H, Benno Y. Longevity in mice is promoted by probiotic-induced suppression of colonic se-nescence dependent on upregulation of gut bacterial polyamine production. PLoS One  2011; 6(8): e23652.
 [http://dx.doi.org/10.1371/journal.pone.0023652] [PMID: 21858192]

[153]
Siddiqui R, Maciver S, Elmoselhi A, Soares NC, Khan NA. Longevity, cellular senescence and the gut microbiome: Lessons to be learned from crocodiles. Heliyon  2021; 7(12): e08594.
 [http://dx.doi.org/10.1016/j.heliyon.2021.e08594] [PMID: 34977412]

[154]
Saccon TD, Nagpal R, Yadav H. et al. Senolytic combination of dasatinib and quercetin alleviates intestinal senescence and inflammation and modulates the gut microbiome in aged mice. J Gerontol A Biol Sci Med Sci  2021; 76(11): 1895-905.
 [http://dx.doi.org/10.1093/gerona/glab002] [PMID: 33406219]

[155]
Cho SY, Kim J, Lee JH. et al. Modulation of gut microbiota and delayed immunosenescence as a result of syringaresinol consumption in middle-aged mice. Sci Rep  2016; 6(1): 39026.
 [http://dx.doi.org/10.1038/srep39026] [PMID: 27976725]

[156]
Shen H, Tong X, Yang J. et al. Biotransformation of natural hydroxycinnamic acids by gut microbiota from normal and cerebral ischemia-reperfusion injured rats: A comparative study. Food Funct  2020; 11(6): 5389-95.
 [http://dx.doi.org/10.1039/D0FO00775G] [PMID: 32469016]

[157]
An CY, Sun ZZ, Shen L, Ji HF. Biotransformation of food spice curcumin by gut bacterium Bacillus megaterium DCMB-002 and its pharmacological implications. Food Nutr Res  2017; 61(1): 1412814.
 [http://dx.doi.org/10.1080/16546628.2017.1412814]

[158]
Sharma R, Kumari M, Kumari A. et al. Diet supplemented with phytochemical epigallocatechin gallate and probiotic Lactobacillus fermen-tum confers second generation synbiotic effects by modulating cellular immune responses and antioxidant capacity in aging mice. Eur J Nutr  2019; 58(7): 2943-57.
 [http://dx.doi.org/10.1007/s00394-018-01890-6] [PMID: 30607562]

[159]
Wang LC, Pan TM, Tsai TY. Lactic acid bacteria-fermented product of green tea and Houttuynia cordata leaves exerts anti-adipogenic and anti-obesity effects. Yao Wu Shi Pin Fen Xi  2018; 26(3): 973-84.
 [PMID: 29976415]

[160]
Farag MA, Abdelwareth A, Sallam IE. et al. Metabolomics reveals impact of seven functional foods on metabolic pathways in a gut mi-crobiota model. J Adv Res  2020; 23: 47-59.
 [http://dx.doi.org/10.1016/j.jare.2020.01.001] [PMID: 32071791]

[161]
Nagpal R, Neth BJ, Wang S, Craft S, Yadav H. Modified Mediterranean-ketogenic diet modulates gut microbiome and short-chain fatty acids in association with Alzheimer’s disease markers in subjects with mild cognitive impairment. E Biol Med  2019; 47: 529-42.
 [http://dx.doi.org/10.1016/j.ebiom.2019.08.032] [PMID: 31477562]

[162]
Ghosh TS, Rampelli S, Jeffery IB. et al. Mediterranean diet intervention alters the gut microbiome in older people reducing frailty and improving health status: The NU-AGE 1-year dietary intervention across five European countries. Gut  2020; 69(7): 1218-28.
 [http://dx.doi.org/10.1136/gutjnl-2019-319654] [PMID: 32066625]

[163]
Nagpal R, Mainali R, Ahmadi S. et al. Gut microbiome and aging: Physiological and mechanistic insights. Nutr Healthy Aging  2018; 4(4): 267-85.
 [http://dx.doi.org/10.3233/NHA-170030] [PMID: 29951588]

[164]
Maï ME, Guigonis JM, Pourchet T, Kang D, Yue J-X, Ferreira MG. Telomere elongation in the gut extends zebrafish lifespan. bioRxiv  2022.01.10.475664..2022; 

[165]
Pyrkov TV, Avchaciov K, Tarkhov AE, Menshikov LI, Gudkov AV, Fedichev PO. Longitudinal analysis of blood markers reveals pro-gressive loss of resilience and predicts human lifespan limit. Nat Commun  2021; 12(1): 2765.
 [http://dx.doi.org/10.1038/s41467-021-23014-1] [PMID: 34035236]

[166]
Hickson LJ, Langhi Prata LGP, Bobart SA. et al. Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease. E Biol Med  2019; 47: 446-56.
 [http://dx.doi.org/10.1016/j.ebiom.2019.08.069] [PMID: 31542391]

[167]
McBurney MI, Davis C, Fraser CM. et al. Establishing what constitutes a healthy human gut microbiome: State of the science, regulatory considerations, and future directions. J Nutr  2019; 149(11): 1882-95.
 [http://dx.doi.org/10.1093/jn/nxz154] [PMID: 31373365]

[168]
Kang C, Wang B, Kaliannan K. et al. Gut microbiota mediates the protective effects of dietary capsaicin against chronic low-grade inflam-mation and associated obesity induced by high-fat diet. MBio  2017; 8(3): e00470-17.
 [http://dx.doi.org/10.1128/mBio.00470-17] [PMID: 28536285]

[169]
Wu CS, Muthyala SDV, Klemashevich C. et al. Age-dependent remodeling of gut microbiome and host serum metabolome in mice. Aging  2021; 13(5): 6330-45.
 [http://dx.doi.org/10.18632/aging.202525] [PMID: 33612480]

[170]
Zhang X, Yang Y, Su J. et al. Age-related compositional changes and correlations of gut microbiome, serum metabolome, and immune factor in rats. Geroscience  2021; 43(2): 709-25.
 [http://dx.doi.org/10.1007/s11357-020-00188-y] [PMID: 32418021]

[171]
Zhu X, Chen Z, Shen W. et al. Inflammation, epigenetics, and metabolism converge to cell senescence and ageing: The regulation and intervention. Signal Transduct Target Ther  2021; 6(1): 245.
 [http://dx.doi.org/10.1038/s41392-021-00646-9] [PMID: 34176928]
Cite As
Current Aging Science

A Cellular Senescence-Centric Integrated Approach to Understanding Organismal Aging

Abstract

Graphical Abstract
