The role of cellular senescence in ageing and endocrine disease.
Journal
Nature reviews. Endocrinology
ISSN: 1759-5037
Titre abrégé: Nat Rev Endocrinol
Pays: England
ID NLM: 101500078
Informations de publication
Date de publication:
05 2020
05 2020
Historique:
accepted:
14
02
2020
pubmed:
13
3
2020
medline:
4
7
2020
entrez:
13
3
2020
Statut:
ppublish
Résumé
With the ageing of the global population, interest is growing in the 'geroscience hypothesis', which posits that manipulation of fundamental ageing mechanisms will delay (in parallel) the appearance or severity of multiple chronic, non-communicable diseases, as these diseases share the same underlying risk factor - namely, ageing. In this context, cellular senescence has received considerable attention as a potential target in preventing or treating multiple age-related diseases and increasing healthspan. Here we review mechanisms of cellular senescence and approaches to target this pathway therapeutically using 'senolytic' drugs that kill senescent cells or inhibitors of the senescence-associated secretory phenotype (SASP). Furthermore, we highlight the evidence that cellular senescence has a causative role in multiple diseases associated with ageing. Finally, we focus on the role of cellular senescence in a number of endocrine diseases, including osteoporosis, metabolic syndrome and type 2 diabetes mellitus, as well as other endocrine conditions. Although much remains to be done, considerable preclinical evidence is now leading to the initiation of proof-of-concept clinical trials using senolytics for several endocrine and non-endocrine diseases.
Identifiants
pubmed: 32161396
doi: 10.1038/s41574-020-0335-y
pii: 10.1038/s41574-020-0335-y
pmc: PMC7227781
mid: NIHMS1586023
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
263-275Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK128552
Pays : United States
Organisme : NIA NIH HHS
ID : R37 AG013925
Pays : United States
Organisme : NIA NIH HHS
ID : P01 AG004875
Pays : United States
Organisme : NIAMS NIH HHS
ID : K01 AR070241
Pays : United States
Organisme : NIA NIH HHS
ID : R33 AG061456
Pays : United States
Organisme : NIAMS NIH HHS
ID : R01 AR027065
Pays : United States
Organisme : NIA NIH HHS
ID : P01 AG062413
Pays : United States
Références
Kirkland, J. L. & Tchkonia, T. Clinical strategies and animal models for developing senolytic agents. Exp. Gerontol. 68, 19–25 (2015).
pubmed: 25446976
Rocca, W. A. et al. Prevalence of multimorbidity in a geographically defined American population: patterns by age, sex, and race/ethnicity. Mayo Clin. Proc. 89, 1336–1349 (2014).
pubmed: 25220409
pmcid: 4186914
Levy, H. B. Polypharmacy reduction strategies: tips on incorporating American Geriatrics Society Beers and Screening Tool of Older People’s Prescriptions criteria. Clin. Geriatr. Med. 33, 177–187 (2017).
pubmed: 28364990
Khosla, S. & Hofbauer, L. C. Osteoporosis treatment: recent developments and ongoing challenges. Lancet Diabetes Endocrinol. 5, 898–907 (2017).
pubmed: 28689769
pmcid: 5798872
Kim, S. C. et al. Impact of the U.S. Food and Drug Administration’s safety-related announcements on the use of bisphosphonates after hip fracture. J. Bone Miner. Res. 31, 1536–1540 (2016).
pubmed: 26969902
pmcid: 5040596
Khosla, S. et al. Addressing the crisis in the treatment of osteoporosis: a path forward. J. Bone Min. Res. 32, 424–430 (2017).
Kennedy, B. K. et al. Geroscience: linking aging to chronic disease. Cell 159, 709–713 (2014). This is a key review outlining the geroscience hypothesis, which posits that manipulation of fundamental mechanisms of ageing will delay (in parallel) the appearance or severity of multiple chronic diseases because these diseases share the same underlying risk factor — namely, ageing.
pubmed: 25417146
pmcid: 25417146
Goldman, D. P. et al. Substantial health and economic returns from delayed aging may warrant a new focus for medical research. Health Aff. 32, 1698–1705 (2013).
Lopez-Otin, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013). This is a landmark perspective summarizing nine fundamental hallmarks of ageing.
pubmed: 23746838
pmcid: 3836174
Hayflick, L. The limited in vitro lifetime of human diploid cell strains. Exp. Cell Res. 37, 614–636 (1965).
pubmed: 14315085
Tchkonia, T., Zhu, Y., van Deursen, J., Campisi, J. & Kirkland, J. L. Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. J. Clin. Invest. 123, 966–972 (2013).
pubmed: 23454759
pmcid: 3582125
Stout, M. B., Tchkonia, T. & Kirkland, J. L. Growth hormone in adipose dysfunction and senescence. Oncotarget 6, 10667–10668 (2015).
pubmed: 25951493
pmcid: 4484409
Tchkonia, T. et al. Cellular senescence and inflammation in obesity. Obesity 17, S57 (2009).
Kandhaya-Pillai, R. et al. TNFalpha-senescence initiates a STAT-dependent positive feedback loop, leading to a sustained interferon signature, DNA damage, and cytokine secretion. Aging 9, 2411–2435 (2017).
pubmed: 29176033
pmcid: 5723694
Kirkland, J. L. & Tchkonia, T. Cellular senescence: a translational perspective. EBioMedicine 21, 21–28 (2017).
pubmed: 28416161
pmcid: 5514381
LeBrasseur, N. K., Tchkonia, T. & Kirkland, J. L. Cellular senescence and the biology of aging, disease, and frailty. Nestle Nutr. Inst. Workshop Ser. 83, 11–18 (2015).
pubmed: 26485647
pmcid: 4780350
Nath, K. A. et al. The murine dialysis fistula model exhibits a senescence phenotype: pathobiologic mechanisms and therapeutic potential. Am. J. Physiol. Ren. Physiol. 315, F1493–F1499 (2018).
Palmer, A. K. et al. Cellular senescence in type 2 diabetes: a therapeutic opportunity. Diabetes 64, 2289–2298 (2015).
pubmed: 26106186
pmcid: 4477358
Parikh, P. et al. Hyperoxia-induced cellular senescence in fetal airway smooth muscle cells. Am. J. Respir. Cell Mol. Biol. 61, 51–60 (2018).
Tchkonia, T. et al. Fat tissue, aging, and cellular senescence. Aging Cell 9, 667–684 (2010).
pubmed: 20701600
pmcid: 2941545
Tran, D. et al. Insulin-like growth factor-1 regulates the SIRT1-p53 pathway in cellular senescence. Aging Cell 13, 669–678 (2014).
pubmed: 25070626
pmcid: 4118446
Zhu, Y., Armstrong, J. L., Tchkonia, T. & Kirkland, J. L. Cellular senescence and the senescent secretory phenotype in age-related chronic diseases. Curr. Opin. Clin. Nutr. Metab. Care 17, 324–328 (2014).
pubmed: 24848532
Palmer, A. K., Gustafson, B., Kirkland, J. L. & Smith, U. Cellular senescence: at the nexus between ageing and diabetes. Diabetologia 62, 1835–1841 (2019).
pubmed: 31451866
pmcid: 6731336
Anderson, R. et al. Length-independent telomere damage drives post-mitotic cardiomyocyte senescence. EMBO J. 38, e100492 (2019).
pubmed: 30737259
pmcid: 6396144
Escande, C. et al. Deleted in Breast Cancer 1 regulates cellular senescence during obesity. Aging Cell 13, 951–953 (2014).
pubmed: 24992635
pmcid: 4172532
Xu, M. et al. Targeting senescent cells enhances adipogenesis and metabolic function in old age. eLife 4, e12997 (2015).
pubmed: 26687007
pmcid: 4758946
Andriani, G. A. et al. Whole chromosome instability induces senescence and promotes SASP. Sci. Rep. 6, 35218 (2016).
pubmed: 27731420
pmcid: 5059742
Baylis, D. et al. Inflammation, telomere length, and grip strength: a 10-year longitudinal study. Calcif. Tissue Int. 95, 54–63 (2014).
pubmed: 24858709
pmcid: 4098723
d’Adda di Fagagna, F. et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature 426, 194–198 (2003).
pubmed: 14608368
von Zglinicki, T., Petrie, J. & Kirkwood, T. B. Telomere-driven replicative senescence is a stress response. Nat. Biotechnol. 21, 229–230 (2003).
Freund, A., Laberge, R. M., Demaria, M. & Campisi, J. Lamin B1 loss is a senescence-associated biomarker. Mol. Biol. Cell 23, 2066–2075 (2012).
pubmed: 22496421
pmcid: 3364172
Tchkonia, T. & Kirkland, J. L. Aging, cell senescence, and chronic disease: Emerging therapeutic strategies. JAMA 320, 1319–1320 (2018).
pubmed: 30242336
Coppé, J. P., Kauser, K., Campisi, J. & Beauséjour, C. M. Secretion of vascular endothelial growth factor by primary human fibroblasts at senescence. J. Biol. Chem. 281, 29568–29574 (2006).
pubmed: 16880208
Xu, M. et al. Senolytics improve physical function and increase lifespan in old age. Nat. Med. 24, 1246–1256 (2018). This study shows that treatment with senolytic agents has the potential to increase both healthspan and lifespan in aged mice.
pubmed: 29988130
pmcid: 6082705
Kim, Y. M., Seo, Y. H., Park, C. B., Yoon, S. H. & Yoon, G. Roles of GSK3 in metabolic shift toward abnormal anabolism in cell senescence. Ann. NY Acad. Sci. 1201, 65–71 (2010).
pubmed: 20649541
De Cecco, M. et al. L1 drives IFN in senescent cells and promotes age-associated inflammation. Nature 566, 73–78 (2019).
pubmed: 30728521
pmcid: 6519963
Hernandez-Segura, A. et al. Unmasking transcriptional heterogeneity in senescent cells. Curr. Biol. 27, 2652–2660 (2017).
pubmed: 28844647
pmcid: 5788810
Wiley, C. D. et al. Mitochondrial dysfunction induces senescence with a distinct secretory phenotype. Cell Metab. 23, 303–314 (2016).
pubmed: 26686024
Laberge, R. M. et al. Glucocorticoids suppress selected components of the senescence-associated secretory phenotype. Aging Cell 11, 569–578 (2012).
pubmed: 22404905
pmcid: 3387333
Moiseeva, O. et al. Metformin inhibits the senescence-associated secretory phenotype by interfering with IKK/NF-kappaB activation. Aging Cell 12, 489–498 (2013).
pubmed: 23521863
Laberge, R. M. et al. MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation. Nat. Cell Biol. 17, 1049–1061 (2015).
pubmed: 26147250
pmcid: 4691706
Huffman, D. M. et al. Evaluating health span in preclinical models of aging and disease: guidelines, challenges, and opportunities for geroscience. J. Gerontol. A Biol. Sci. Med. Sci. 71, 1395–1406 (2016).
pubmed: 27535967
pmcid: 5055649
Hall, B. M. et al. Aging of mice is associated with p16
pubmed: 27391570
pmcid: 4993332
Debacq-Chainiaux, F., Erusalimsky, J. D., Campisi, J. & Toussaint, O. Protocols to detect senescence-associated beta-galactosidase (SA-betagal) activity, a biomarker of senescent cells in culture and in vivo. Nat. Protoc. 4, 1798–1806 (2009).
pubmed: 20010931
Itahana, K., Campisi, J. & Dimri, G. P. Methods to detect biomarkers of cellular senescence: the senescence-associated beta-galactosidase assay. Methods Mol. Biol. 371, 21–31 (2007).
pubmed: 17634571
Hewitt, G. et al. Telomeres are favoured targets of a persistent DNA damage response in ageing and stress-induced senescence. Nat. Commun. 3, 708 (2012).
pubmed: 22426229
pmcid: 3292717
Swanson, E. C., Manning, B., Zhang, H. & Lawrence, J. B. Higher-order unfolding of satellite heterochromatin is a consistent and early event in cell senescence. J. Cell Biol. 203, 929–942 (2013).
pubmed: 24344186
pmcid: 3871423
Davalos, A. R. et al. p53-dependent release of alarmin HMGB1 is a central mediator of senescent phenotypes. J. Cell Biol. 201, 613–629 (2013).
pubmed: 23649808
pmcid: 3653366
Hall, B. M. et al. p16
pubmed: 28768895
pmcid: 5611982
Campisi, J. & d’Adda di Fagagna, F. Cellular senescence: when bad things happen to good cells. Nat. Rev. Mol. Cell Biol. 8, 729–740 (2007).
pubmed: 17667954
Schafer, M. J. et al. Cellular senescence mediates fibrotic pulmonary disease. Nat. Commun. 8, 14532 (2017).
pubmed: 28230051
pmcid: 5331226
Xu, M. et al. Transplanted senescent cells induce an osteoarthritis-like condition in mice. J. Gerontol. A Biol. Sci. Med. Sci 72, 780–785 (2016).
pmcid: 5861939
Meuter, A. et al. Markers of cellular senescence are elevated in murine blastocysts cultured in vitro: molecular consequences of culture in atmospheric oxygen. J. Assist. Reprod. Genet. 31, 1259–1267 (2014).
pubmed: 25106938
pmcid: 4171413
Krishnamurthy, J. et al. Ink4a/Arf expression is a biomarker of aging. J. Clin. Invest. 114, 1299–1307 (2004).
pubmed: 15520862
pmcid: 524230
Jeyapalan, J. C., Ferreira, M., Sedivy, J. M. & Herbig, U. Accumulation of senescent cells in mitotic tissue of aging primates. Mech. Ageing Dev. 128, 36–44 (2007).
pubmed: 17116315
Waaijer, M. E. et al. The number of p16INK4a positive cells in human skin reflects biological age. Aging Cell 11, 722–725 (2012).
pubmed: 22612594
pmcid: 3539756
Hickson, L. J. 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 47, 446–456 (2019). This is the first direct demonstration that administration of senolytic drugs reduces the number of senescent cells in humans.
pubmed: 31542391
pmcid: 6796530
Waldera Lupa, D. M. et al. Characterization of skin aging-associated secreted proteins (SAASP) produced by dermal fibroblasts isolated from intrinsically aged human skin. J. Invest. Dermatol. 135, 1954–1968 (2015).
pubmed: 25815425
Xu, M. et al. JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age. Proc. Natl Acad. Sci. USA 112, 301–310 (2015). Treatment with a JAK inhibitor reduces the SASP in vivo in mice and reduces indices of frailty.
Smith, J. R. et al. Relationship between in vivo age and in vitro aging: assessment of 669 cell cultures derived from members of the Baltimore Longitudinal Study of Aging. J. Gerontol. A Biol. Sci. Med. Sci. 57, B239–B246 (2002).
pubmed: 12023260
Stout, M. B. et al. Growth hormone action predicts age-related white adipose tissue dysfunction and senescent cell burden in mice. Aging 6, 575–586 (2014).
pubmed: 25063774
pmcid: 4153624
Menon, R. Initiation of human parturition: signaling from senescent fetal tissues via extracellular vesicle mediated paracrine mechanism. Obstet. Gynecol. Sci. 62, 199–211 (2019).
pubmed: 31338337
pmcid: 6629986
Faget, D. V., Ren, Q. & Stewart, S. A. Unmasking senescence: context-dependent effects of SASP in cancer. Nat. Rev. Cancer 19, 439–453 (2019).
pubmed: 31235879
Demaria, M. et al. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev. Cell 31, 722–733 (2014). This study demonstrates an important role for acute cellular senescence in the context of skin wound healing.
pubmed: 25499914
pmcid: 4349629
Singh, M. et al. Effect of low-dose rapamycin on senescence markers and physical functioning in older adults with coronary artery disease: results of a pilot study. J. Frailty Aging 5, 204–207 (2016).
pubmed: 27883166
Herranz, N. et al. mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype. Nat. Cell Biol. 17, 1205–1217 (2015).
pubmed: 26280535
pmcid: 4589897
Harrison, D. E. et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460, 392–395 (2009).
pubmed: 19587680
pmcid: 2786175
Li, J., Kim, S. G. & Blenis, J. Rapamycin: one drug, many effects. Cell Metab. 19, 373–379 (2014).
pubmed: 24508508
pmcid: 3972801
Majumder, S. et al. Lifelong rapamycin administration ameliorates age-dependent cognitive deficits by reducing IL-1beta and enhancing NMDA signaling. Aging Cell 11, 326–335 (2012).
pubmed: 22212527
pmcid: 3306461
Wilkinson, J. E. et al. Rapamycin slows aging in mice. Aging Cell 11, 675–682 (2012).
pubmed: 22587563
pmcid: 3434687
Zhang, Y. et al. Rapamycin extends life and health in C57BL/6 mice. J. Gerontol. A Biol. Sci. Med. Sci. 69, 119–130 (2014).
pubmed: 23682161
Mannick, J. B. et al. mTOR inhibition improves immune function in the elderly. Sci. Transl. Med. 6, 268ra179 (2014).
pubmed: 25540326
Mau, T., O’Brien, M., Ghosh, A. K., Miller, R. A. & Yung, R. Lifespan extension drug interventions affect adipose tissue inflammation in aging. J. Gerontol. A Biol. Sci. Med. Sci. 75, 89–98 (2020).
pubmed: 31353414
Arriola Apelo, S. I. & Lamming, D. W. Rapamycin: an inhibitor of aging emerges from the soil of Easter Island. J. Gerontol. A Biol. Sci. Med. Sci. 71, 841–849 (2016).
pubmed: 27208895
pmcid: 4906330
Farr, J. N. et al. Targeting cellular senescence prevents age-related bone loss in mice. Nat. Med. 23, 1072–1079 (2017). This study demonstrates that eliminating senescent cells or inhibiting their SASP prevents age-related bone loss in mice.
pubmed: 28825716
pmcid: 5657592
Verstovsek, S. et al. Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N. Engl. J. Med. 363, 1117–1127 (2010).
pubmed: 20843246
pmcid: 5187954
Bannister, C. A. et al. Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls. Diabetes Obes. Metab. 16, 1165–1173 (2014).
pubmed: 25041462
Lamming, D. W. et al. Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science 335, 1638–1643 (2012).
pubmed: 22461615
pmcid: 3324089
Mannick, J. B. et al. TORC1 inhibition enhances immune function and reduces infections in the elderly. Sci. Transl. Med. 10, eaaq1564 (2018).
pubmed: 29997249
Larsson, L. et al. Sarcopenia: aging-related loss of muscle mass and function. Physiol. Rev. 99, 427–511 (2019).
pubmed: 30427277
Kirkland, J. L., Tchkonia, T., Zhu, Y., Niedernhofer, L. J. & Robbins, P. D. The clinical potential of senolytic drugs. J. Am. Geriatr. Soc. 65, 2297–2301 (2017).
pubmed: 28869295
pmcid: 5641223
Zhu, Y. et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell 14, 644–658 (2015). This study provides the first identification of senolytic drugs, specifically the combination of dasatinib and quercetin.
pubmed: 25754370
pmcid: 4531078
Wang, E. Senescent human fibroblasts resist programmed cell death, and failure to suppress bcl2 is involved. Cancer Res. 55, 2284–2292 (1995).
pubmed: 7757977
Fuhrmann-Stroissnigg, H. et al. Identification of HSP90 inhibitors as a novel class of senolytics. Nat. Commun. 8, 422 (2017).
pubmed: 28871086
pmcid: 5583353
Yi, J.-S. et al. Low-dose dasatinib rescues cardiac function in Noonan syndrome. JCI Insight 1, e90220 (2016).
pubmed: 27942593
pmcid: 5135272
D’Andrea, G. Quercetin: a flavonol with multifaceted therapeutic applications? Fitoterapia 106, 256–271 (2015).
pubmed: 26393898
Zhu, Y. et al. Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors. Aging Cell 15, 428–435 (2016).
pubmed: 26711051
pmcid: 4854923
Chang, J. et al. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat. Med. 22, 78–83 (2016).
pubmed: 26657143
Baar, M. P. et al. Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell 169, 132–147 (2017).
pubmed: 28340339
pmcid: 5556182
Zhu, Y. et al. New agents that target senescent cells: the flavone, fisetin, and the BCL-X
pubmed: 28273655
pmcid: 5391241
Tchkonia, T. & Kirkland, J. L. Therapeutic approaches to aging-reply. JAMA 321, 901–902 (2019).
pubmed: 30835305
Kirkland, J. L. Translating the science of aging into therapeutic interventions. Cold Spring Harb. Perspect. Med. 6, a025908 (2016).
pubmed: 26931808
pmcid: 4772076
Kirkland, J. L., Stout, M. B. & Sierra, F. Resilience in aging mice. J. Gerontol. A Biol. Sci. Med. Sci. 71, 1407–1414 (2016).
pubmed: 27535963
pmcid: 5865545
St Sauver, J. L. et al. Risk of developing multimorbidity across all ages in an historical cohort study: differences by sex and ethnicity. BMJ Open. 5, e006413 (2015).
Musi, N. et al. Tau protein aggregation is associated with cellular senescence in the brain. Aging Cell 17, e12840 (2018). This study provides evidence that a mouse model of dementia is associated with cellular senescence in the brain.
pubmed: 30126037
pmcid: 6260915
Zhang, P. et al. Senolytic therapy alleviates A-beta-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model. Nat. Neurosci. 22, 719–728 (2019).
pubmed: 30936558
pmcid: 6605052
Lewis-McDougall, F. C. et al. Aged-senescent cells contribute to impaired heart regeneration. Aging Cell 18, e12931 (2019).
pubmed: 30854802
pmcid: 6516154
Roos, C. M. et al. Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice. Aging Cell 15, 973–977 (2016).
pubmed: 26864908
pmcid: 5013022
Jeon, O. H. et al. Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat. Med. 23, 775–781 (2017).
pubmed: 28436958
pmcid: 5785239
Moncsek, A. et al. Targeting senescent cholangiocytes and activated fibroblasts with Bcl-xL inhibitors ameliorates fibrosis in Mdr2
pubmed: 28802066
pmcid: 5739965
Yousefzadeh, M. J. et al. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine 36, 18–28 (2018).
pubmed: 30279143
pmcid: 6197652
Justice, J. N. et al. Senolytics in idiopathic pulmonary fibrosis: results from a first-in-human, open-label, pilot study. EBioMedicine 40, 554–563 (2019).
pubmed: 30616998
pmcid: 6412088
Martyanov, V., Whitfield, M. L. & Varga, J. Senescence signature in skin biopsies from systemic sclerosis patients treated with senolytic therapy: potential predictor of clinical response? Arthritis Rheumatol. 71, 1766–1767 (2019).
pubmed: 31112009
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03675724 (2020).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02652052 (2016).
Farr, J. N. et al. Identification of senescent cells in the bone microenvironment. J. Bone Min. Res. 31, 1920–1929 (2016).
Wiley, C. D. et al. Analysis of individual cells identifies cell-to-cell variability following induction of cellular senescence. Aging Cell 16, 1043–1050 (2017).
pubmed: 28699239
pmcid: 5595671
Coppe, J. P. et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 6, 2853–2868 (2008).
pubmed: 19053174
Coppe, J. P., Desprez, P. Y., Krtolica, A. & Campisi, J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu. Rev. Pathol. 5, 99–118 (2010).
pubmed: 20078217
pmcid: 4166495
Piemontese, M. et al. Old age causes de novo intracortical bone remodeling and porosity in mice. JCI Insight 2, 93771 (2017).
pubmed: 28878136
Minamino, T. et al. A crucial role for adipose tissue p53 in the regulation of insulin resistance. Nat. Med. 15, 1082–1087 (2009).
pubmed: 19718037
Jurk, D. et al. Postmitotic neurons develop a p21-dependent senescence-like phenotype driven by a DNA damage response. Aging Cell 11, 996–1004 (2012). This study provides in vivo evidence that postmitotic cells can develop a senescent-like phenotype.
pubmed: 22882466
pmcid: 22882466
Ogrodnik, M. et al. Obesity-induced cellular senescence drives anxiety and impairs neurogenesis. Cell Metab. 29, 1061–1077 (2019).
pubmed: 30612898
pmcid: 6509403
Ogrodnik, M. et al. Cellular senescence drives age-dependent hepatic steatosis. Nat. Commun. 8, 15691 (2017).
pubmed: 28608850
pmcid: 5474745
Baker, D. J. et al. Clearance of p16Ink4a-positive senescent cells delay aging-associated disorders. Nature 479, 232–236 (2011). This is a key article showing that clearance of senescent cells using a genetic approach delays ageing in a mouse model of premature ageing.
pubmed: 22048312
pmcid: 3468323
Khosla, S., Farr, J. N. & Kirkland, J. L. Inhibiting cellular senescence: a new therapeutic paradigm for age-related osteoporosis. J. Clin. Endocrinol. Metab. 103, 1282–1290 (2018).
pubmed: 29425296
pmcid: 6276719
Farr, J. N. & Almeida, M. The spectrum of fundamental basic science discoveries contributing to organismal aging. J. Bone Min. Res. 33, 1568–1584 (2018).
Farr, J. N. & Khosla, S. Cellular senescence in bone. Bone 121, 121–133 (2019).
pubmed: 30659978
pmcid: 6485943
Khosla, S. Odanacatib: location and timing are everything. J. Bone Min. Res. 27, 506–508 (2012).
Schafer, M. J., Miller, J. D. & LeBrasseur, N. K. Cellular senescence: implications for metabolic disease. Mol. Cell Endocrinol. 455, 93–102 (2017).
pubmed: 27591120
Palmer, A. K. et al. Targeting senescent cells alleviates obesity-induced metabolic dysfunction. Aging Cell 18, e12950 (2019). Clearance of senescent cells improves metabolic function in obese mice.
pubmed: 30907060
pmcid: 6516193
Palmer, A. K. & Kirkland, J. L. Aging and adipose tissue: potential interventions for diabetes and regenerative medicine. Exp. Gerontol. 86, 97–105 (2016).
pubmed: 26924669
pmcid: 5001933
Kirkland, J. L., Hollenberg, C. H. & Gillon, W. S. Age, anatomic site, and the replication and differentiation of adipocyte precursors. Am. J. Physiol. 258, C206–C210 (1990).
pubmed: 2305864
Gustafson, B., Nerstedt, A. & Smith, U. Reduced subcutaneous adipogenesis in human hypertrophic obesity is linked to senescent precursor cells. Nat. Commun. 10, 2757 (2019).
pubmed: 31227697
pmcid: 6588633
Hannou, S. A., Wouters, K., Paumelle, R. & Staels, B. Functional genomics of the CDKN2A/B locus in cardiovascular and metabolic disease: what have we learned from GWASs? Trends Endocrinol. Metab. 26, 176–184 (2015).
pubmed: 25744911
Krstic, J., Reinisch, I., Schupp, M., Schulz, T. J. & Prokesch, A. p53 Functions in adipose tissue metabolism and homeostasis. Int. J. Mol. Sci. 19, E2622 (2018).
pubmed: 30181511
Vergoni, B. et al. DNA damage and the activation of the p53 pathway mediate alterations in metabolic and secretory functions of adipocytes. Diabetes 65, 3062–3074 (2016).
pubmed: 27388216
Zaragosi, L. E. et al. Activin a plays a critical role in proliferation and differentiation of human adipose progenitors. Diabetes 59, 2513–2521 (2010).
pubmed: 20530742
pmcid: 3279533
Kuki, S. et al. Hyperglycemia accelerated endothelial progenitor cell senescence via the activation of p38 mitogen-activated protein kinase. Circ. J. 70, 1076–1081 (2006).
pubmed: 16864945
Helman, A. et al. p16
pubmed: 26950362
pmcid: 5546206
Aguayo-Mazzucato, C. et al. Acceleration of beta cell aging determines diabetes and senolysis improves disease outcomes. Cell Metab. 30, 129–142 (2019).
pubmed: 31155496
Walaszczyk, A. et al. Pharmacological clearance of senescent cells improves survival and recovery in aged mice following acute myocardial infarction. Aging Cell 18, e12945 (2019).
pubmed: 30920115
pmcid: 6516151
Kim, S. R. et al. Increased renal cellular senescence in murine high-fat diet: effect of the senolytic drug quercetin. Transl. Res. 213, 112–123 (2019).
pubmed: 31356770
Velarde, M. C. & Menon, R. Positive and negative effects of cellular senescence during female reproductive aging and pregnancy. J. Endocrinol. 230, R59–R76 (2016).
pubmed: 27325241
Munoz-Espin, D. et al. Programmed cell senescence during mammalian embryonic development. Cell 155, 1104–1118 (2013).
pubmed: 24238962
Storer, M. et al. Senescence is a developmental mechanism that contributes to embryonic growth and patterning. Cell 155, 1119–1130 (2013). This study identifies cellular senescence as a physiological mechanism during embryonic growth.
pubmed: 24238961
Suvakov, S. et al. Targeting senescence improves angiogenic potential of adipose-derived mesenchymal stem cells in patients with preeclampsia. Biol. Sex. Differ. 10, 49 (2019).
pubmed: 31521202
pmcid: 6744626
Fernandez, A., Karavitaki, N. & Wass, J. A. Prevalence of pituitary adenomas: a community-based, cross-sectional study in Banbury (Oxfordshire, UK). Clin. Endocrinol. 72, 377–382 (2010).
Scheithauer, B. W. et al. Pathobiology of pituitary adenomas and carcinomas. Neurosurgery 59, 341–353 (2006).
pubmed: 16883174
Melmed, S. Pathogenesis of pituitary tumors. Nat. Rev. Endocrinol. 7, 257–266 (2011).
pubmed: 21423242
Manojlovic-Gacic, E. et al. Oncogene-induced senescence in pituitary adenomas–an immunohistochemical study. Endocr. Pathol. 27, 1–11 (2016).
pubmed: 26573928
Alexandraki, K. I. et al. Oncogene-induced senescence in pituitary adenomas and carcinomas. Hormones 11, 297–307 (2012).
pubmed: 22908062
Justice, J. N. et al. Cellular senescence biomarker p16
pmcid: 6001887
Ashapkin, V. V., Kutueva, L. I., Kurchashova, S. Y. & Kireev, I. I. Are there common mechanisms between the Hutchinson-Gilford progeria syndrome and natural aging? Front. Genet. 10, 455 (2019).
pubmed: 31156709
pmcid: 6529819
Sun, S. et al. HMGB1 and caveolin-1 related to RPE cell senescence in age-related macular degeneration. Aging 11, 4323–4337 (2019).
pubmed: 31284269
pmcid: 6660032
Wang, A. S. & Dreesen, O. Biomarkers of cellular senescence and skin aging. Front. Genet. 9, 247 (2018).
pubmed: 30190724
pmcid: 6115505
Birch, J., Barnes, P. J. & Passos, J. F. Mitochondria, telomeres and cell senescence: implications for lung ageing and disease. Pharmacol. Ther. 183, 34–49 (2018).
pubmed: 28987319
McShea, A., Harris, P. L., Webster, K. R., Wahl, A. F. & Smith, M. A. Abnormal expression of the cell cycle regulators P16 and CDK4 in Alzheimer’s disease. Am. J. Pathol. 150, 1933–1939 (1997).
pubmed: 9176387
pmcid: 1858317
Chinta, S. J. et al. Cellular senescence is induced by the environmental neurotoxin paraquat and contributes to neuropathology linked to Parkinson’s disease. Cell Rep. 22, 930–940 (2018).
pubmed: 29386135
pmcid: 5806534
He, Y. et al. Cellular senescence and radiation-induced pulmonary fibrosis. Transl. Res. 209, 14–21 (2019).
pubmed: 30981698
Alam, P. et al. Inhibition of senescence-associated genes Rb1 and Meis2 in adult cardiomyocytes results in cell cycle reentry and cardiac repair post-myocardial infarction. J. Am. Heart Assoc. 8, e012089 (2019).
pubmed: 31315484
pmcid: 6761626
Minamino, T. et al. Endothelial cell senescence in human atherosclerosis: role of telomere in endothelial dysfunction. Circulation 105, 1541–1544 (2002).
pubmed: 11927518
Papatheodoridi, A. M., Chrysavgis, L., Koutsilieris, M. & Chatzigeorgiou, A. The role of senescence in the development of non-alcoholic fatty liver disease and progression to non-alcoholic steatohepatitis. Hepatology 71, 363–374 (2019).
pubmed: 31230380
Lee, S. & Schmitt, C. A. The dynamic nature of senescence in cancer. Nat. Cell Biol. 21, 94–101 (2019).
pubmed: 30602768
Hou, A. et al. Cellular senescence in osteoarthritis and anti-aging strategies. Mech. Ageing Dev. 175, 83–87 (2018).
pubmed: 30107185
Patil, P. et al. Systemic clearance of p16
pubmed: 30900385
pmcid: 6516165
Miao, D. et al. Severe growth retardation and early lethality in mice lacking the nuclear localization sequence and C-terminus of PTH-related protein. Proc. Natl Acad. Sci. USA 105, 20309–20314 (2008).
pubmed: 19091948
Zhu, M. et al. The p27 pathway modulates the regulation of skeletal growth and osteoblastic bone formation by parathyroid hormone-related peptide. J. Bone Min. Res. 30, 1969–1979 (2015).
Zhang, Y. et al. DNA damage checkpoint pathway modulates the regulation of skeletal growth and osteoblastic bone formation by parathyroid hormone-related peptide. Int. J. Biol. Sci. 14, 508–517 (2018).
pubmed: 29805302
pmcid: 5968843
Li, C. et al. Programmed cell senescence in skeleton during late puberty. Nat. Commun. 8, 1312 (2017).
pubmed: 29101351
pmcid: 5670205
Karimian, E., Chagin, A. S. & Savendahl, L. Genetic regulation of the growth plate. Front. Endocrinol. 2, 113 (2011).