Cellular senescence, first described in vitro in 1961, has become a focus for biotech companies that target it to ameliorate a variety of human conditions. Eminently characterized by a permanent proliferation arrest, cellular senescence occurs in response to endogenous and exogenous stresses, including telomere dysfunction, oncogene activation and persistent DNA damage. Cellular senescence can also be a controlled programme occurring in diverse biological processes, including embryonic development. Senescent cell extrinsic activities, broadly related to the activation of a senescence-associated secretory phenotype, amplify the impact of cell-intrinsic proliferative arrest and contribute to impaired tissue regeneration, chronic age-associated diseases and organismal ageing. This Review discusses the mechanisms and modulators of cellular senescence establishment and induction of a senescence-associated secretory phenotype, and provides an overview of cellular senescence as an emerging opportunity to intervene through senolytic and senomorphic therapies in ageing and ageing-associated diseases.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Hayflick, L. & Moorhead, P. S. The serial cultivation of human diploid cell strains. Exp. Cell. Res. 25, 585–621 (1961).
Hayflick, L. The limited in vitro lifetime of human diploid cell strains. Exp. Cell. Res. 37, 614–636 (1965).
Serrano, M., Hannon, G. J. & Beach, D. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature 366, 704–707 (1993).
Alcorta, D. A. et al. Involvement of the cyclin-dependent kinase inhibitor p16 (INK4a) in replicative senescence of normal human fibroblasts. Proc. Natl Acad. Sci. USA 93, 13742–13747 (1996).
Serrano, M. et al. Role of the INK4a locus in tumor suppression and cell mortality. Cell 85, 27–37 (1996).
Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D. & Lowe, S. W. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88, 593–602 (1997).
Di Micco, R. et al. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature 444, 638–642 (2006).
Bartkova, J. et al. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature 444, 633–637 (2006).
Campisi, J. Cellular senescence and apoptosis: how cellular responses might influence aging phenotypes. Exp. Gerontol. 38, 5–11 (2003).
Giaimo, S. & d’Adda di Fagagna, F. Is cellular senescence an example of antagonistic pleiotropy? Aging Cell 11, 378–383 (2012).
Baker, D. J. et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479, 232–236 (2011). This study demonstrates that selective elimination of p16-expressing senescent cells is safe and capable of modulating age-related dysfunction in a premature aged mouse model.
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).
Childs, B. G. et al. Senescent cells: an emerging target for diseases of ageing. Nat. Rev. Drug Discov. 16, 718–735 (2017).
Yosef, R. et al. Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL. Nat. Commun. 7, 11190 (2016).
Chang, J. et al. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat. Med. 22, 78–83 (2016).
Childs, B. G., Baker, D. J., Kirkland, J. L., Campisi, J. & van Deursen, J. M. Senescence and apoptosis: dueling or complementary cell fates? EMBO Rep. 15, 1139–1153 (2014).
Kirschner, K. et al. Phenotype specific analyses reveal distinct regulatory mechanism for chronically activated p53. PLoS Genet. 11, e1005053 (2015).
Milanovic, M. et al. Senescence-associated reprogramming promotes cancer stemness. Nature 553, 96–100 (2018).
Herranz, N. & Gil, J. Mechanisms and functions of cellular senescence. J. Clin. Invest. 128, 1238–1246 (2018).
Ovadya, Y. et al. Impaired immune surveillance accelerates accumulation of senescent cells and aging. Nat. Commun. 9, 5435 (2018).
Jackson, S. P. & Bartek, J. The DNA-damage response in human biology and disease. Nature 461, 1071–1078 (2009).
Fumagalli, M., Rossiello, F., Mondello, C. & d’Adda di Fagagna, F. Stable cellular senescence is associated with persistent DDR activation. PLoS ONE 9, e110969 (2014).
Galbiati, A., Beausejour, C. & d’Adda di Fagagna, F. A novel single-cell method provides direct evidence of persistent DNA damage in senescent cells and aged mammalian tissues. Aging Cell 16, 422–427 (2017).
d’Adda di Fagagna, F. et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature 426, 194–198 (2003). This study demonstrates that the activation of the DDR pathways by critically short telomeres is key in the enforcement of cellular senescence.
Mallette, F. A. & Ferbeyre, G. The DNA damage signaling pathway connects oncogenic stress to cellular senescence. Cell Cycle 6, 1831–1836 (2007).
Beausejour, C. M. et al. Reversal of human cellular senescence: roles of the p53 and p16 pathways. EMBO J. 22, 4212–4222 (2003).
Dulic, V., Beney, G. E., Frebourg, G., Drullinger, L. F. & Stein, G. H. Uncoupling between phenotypic senescence and cell cycle arrest in aging p21-deficient fibroblasts. Mol. Cell. Biol. 20, 6741–6754 (2000).
Kamijo, T. et al. Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19ARF. Cell 91, 649–659 (1997).
Sherr, C. J. Divorcing ARF and p53: an unsettled case. Nat. Rev. Cancer 6, 663–673 (2006).
Kamijo, T. et al. Loss of the ARF tumor suppressor reverses premature replicative arrest but not radiation hypersensitivity arising from disabled atm function. Cancer Res. 59, 2464–2469 (1999).
Velimezi, G. et al. Functional interplay between the DNA-damage-response kinase ATM and ARF tumour suppressor protein in human cancer. Nat. Cell Biol. 15, 967–977 (2013).
Herbig, U., Jobling, W. A., Chen, B. P., Chen, D. J. & Sedivy, J. M. Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21(CIP1), but not p16(INK4a). Mol. Cell 14, 501–513 (2004).
Hemann, M. T., Strong, M. A., Hao, L. Y. & Greider, C. W. The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability. Cell 107, 67–77 (2001).
Bodnar, A. G. et al. Extension of life-span by introduction of telomerase into normal human cells. Science 279, 349–352 (1998).
Fumagalli, M. et al. Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation. Nat. Cell Biol. 14, 355–365 (2012).
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).
Bae, N. S. & Baumann, P. A RAP1/TRF2 complex inhibits nonhomologous end-joining at human telomeric DNA ends. Mol. Cell 26, 323–334 (2007).
Rossiello, F. et al. DNA damage response inhibition at dysfunctional telomeres by modulation of telomeric DNA damage response RNAs. Nat. Commun. 8, 13980 (2017).
Halazonetis, T. D., Gorgoulis, V. G. & Bartek, J. An oncogene-induced DNA damage model for cancer development. Science 319, 1352–1355 (2008).
Alimonti, A. et al. A novel type of cellular senescence that can be enhanced in mouse models and human tumor xenografts to suppress prostate tumorigenesis. J. Clin. Invest. 120, 681–693 (2010).
Parisotto, M. et al. PTEN deletion in luminal cells of mature prostate induces replication stress and senescence in vivo. J. Exp. Med. 215, 1749–1763 (2018).
Astle, M. V. et al. AKT induces senescence in human cells via mTORC1 and p53 in the absence of DNA damage: implications for targeting mTOR during malignancy. Oncogene 31, 1949–1962 (2012).
Chan, K. T. et al. A functional genetic screen defines the AKT-induced senescence signaling network. Cell Death Differ. 27, 725–741 (2020).
Suram, A. et al. Oncogene-induced telomere dysfunction enforces cellular senescence in human cancer precursor lesions. EMBO J. 31, 2839–2851 (2012).
Ogrunc, M. et al. Oncogene-induced reactive oxygen species fuel hyperproliferation and DNA damage response activation. Cell Death Differ. 21, 998–1012 (2014).
Chapman, J., Fielder, E. & Passos, J. F. Mitochondrial dysfunction and cell senescence: deciphering a complex relationship. FEBS Lett. 593, 1566–1579 (2019).
Wiley, C. D. et al. Mitochondrial dysfunction induces senescence with a distinct secretory phenotype. Cell Metab. 23, 303–314 (2016).
Correia-Melo, C. et al. Mitochondria are required for pro-ageing features of the senescent phenotype. EMBO J. 35, 724–742 (2016).
Narita, M. et al. Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell 113, 703–716 (2003).
Zhang, R. et al. Formation of MacroH2A-containing senescence-associated heterochromatin foci and senescence driven by ASF1a and HIRA. Dev. Cell 8, 19–30 (2005).
Chandra, T. et al. Independence of repressive histone marks and chromatin compaction during senescent heterochromatic layer formation. Mol. Cell 47, 203–214 (2012).
Di Micco, R. et al. Interplay between oncogene-induced DNA damage response and heterochromatin in senescence and cancer. Nat. Cell Biol. 13, 292–302 (2011).
Zhang, R., Chen, W. & Adams, P. D. Molecular dissection of formation of senescence-associated heterochromatin foci. Mol. Cell. Biol. 27, 2343–2358 (2007).
Sadaie, M. et al. Redistribution of the lamin B1 genomic binding profile affects rearrangement of heterochromatic domains and SAHF formation during senescence. Genes Dev. 27, 1800–1808 (2013).
Samaraweera, L., Adomako, A., Rodriguez-Gabin, A. & McDaid, H. M. A novel indication for panobinostat as a senolytic drug in NSCLC and HNSCC. Sci. Rep. 7, 1900 (2017).
Munro, J., Barr, N. I., Ireland, H., Morrison, V. & Parkinson, E. K. Histone deacetylase inhibitors induce a senescence-like state in human cells by a p16-dependent mechanism that is independent of a mitotic clock. Exp. Cell. Res. 295, 525–538 (2004).
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).
Ivanov, A. et al. Lysosome-mediated processing of chromatin in senescence. J. Cell Biol. 202, 129–143 (2013).
Dou, Z. et al. Autophagy mediates degradation of nuclear lamina. Nature 527, 105–109 (2015).
Dou, Z. et al. Cytoplasmic chromatin triggers inflammation in senescence and cancer. Nature 550, 402–406 (2017). This study demonstrates that cytoplasmic chromatin in senescent and cancer cells activates the innate immunity through the cGAS–STING pathway.
Tsantoulis, P. K. et al. Oncogene-induced replication stress preferentially targets common fragile sites in preneoplastic lesions. A genome-wide study. Oncogene 27, 3256–3264 (2008).
De Cecco, M. et al. L1 drives IFN in senescent cells and promotes age-associated inflammation. Nature 566, 73–78 (2019).
Vizioli, M. G. et al. Mitochondria-to-nucleus retrograde signaling drives formation of cytoplasmic chromatin and inflammation in senescence. Genes Dev. 34, 428–445 (2020).
Cruickshanks, H. A. et al. Senescent cells harbour features of the cancer epigenome. Nat. Cell Biol. 15, 1495–1506 (2013).
Xie, W. et al. DNA methylation patterns separate senescence from transformation potential and indicate cancer risk. Cancer Cell 33, 309–321 e305 (2018).
Parry, A. J. et al. NOTCH-mediated non-cell autonomous regulation of chromatin structure during senescence. Nat. Commun. 9, 1840 (2018).
De Cecco, M. et al. Genomes of replicatively senescent cells undergo global epigenetic changes leading to gene silencing and activation of transposable elements. Aging Cell 12, 247–256 (2013).
Shah, P. P. et al. Lamin B1 depletion in senescent cells triggers large-scale changes in gene expression and the chromatin landscape. Genes Dev. 27, 1787–1799 (2013).
Freund, A., Laberge, R. M., Demaria, M. & Campisi, J. Lamin B1 loss is a senescence-associated biomarker. Mol. Biol. Cell 23, 2066–2075 (2012).
Shimi, T. et al. The role of nuclear lamin B1 in cell proliferation and senescence. Genes Dev. 25, 2579–2593 (2011).
Tasdemir, N. et al. BRD4 connects enhancer remodeling to senescence immune surveillance. Cancer Discov. 6, 612–629 (2016).
Sen, P. et al. Histone acetyltransferase p300 induces de novo super-enhancers to drive cellular senescence. Mol. Cell 73, 684–698 e688 (2019).
Acosta, J. C. et al. A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat. Cell Biol. 15, 978–990 (2013).
Kuilman, T. et al. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 133, 1019–1031 (2008).
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).
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).
Coppe, J. P. et al. A human-like senescence-associated secretory phenotype is conserved in mouse cells dependent on physiological oxygen. PLoS ONE 5, e9188 (2010).
Eren, M. et al. PAI-1-regulated extracellular proteolysis governs senescence and survival in Klotho mice. Proc. Natl Acad. Sci. USA 111, 7090–7095 (2014).
Ozcan, S. et al. Unbiased analysis of senescence associated secretory phenotype (SASP) to identify common components following different genotoxic stresses. Aging 8, 1316–1329 (2016).
Basisty, N. et al. A proteomic atlas of senescence-associated secretomes for aging biomarker development. PLoS Biol. 18, e3000599 (2020).
Faget, D. V., Ren, Q. & Stewart, S. A. Unmasking senescence: context-dependent effects of SASP in cancer. Nat. Rev. Cancer 19, 439–453 (2019).
Tanaka, T. et al. Plasma proteomic signature of age in healthy humans. Aging Cell 17, e12799 (2018).
Borghesan, M. et al. Small extracellular vesicles are key regulators of non-cell autonomous intercellular communication in senescence via the interferon protein IFITM3. Cell Rep. 27, 3956–3971 e3956 (2019).
Jakhar, R. & Crasta, K. Exosomes as emerging pro-tumorigenic mediators of the senescence-associated secretory phenotype. Int. J. Mol. Sci. https://doi.org/10.3390/ijms20102547 (2019).
Coppe, J. P. et al. Tumor suppressor and aging biomarker p16(INK4a) induces cellular senescence without the associated inflammatory secretory phenotype. J. Biol. Chem. 286, 36396–36403 (2011).
Rodier, F. et al. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat. Cell Biol. 11, 973–979 (2009). This study demonstrates that persistent DDR activation controls SASP induction in senescent cells.
Chen, H. et al. MacroH2A1 and ATM play opposing roles in paracrine senescence and the senescence-associated secretory phenotype. Mol. Cell 59, 719–731 (2015).
Freund, A., Patil, C. K. & Campisi, J. p38MAPK is a novel DNA damage response-independent regulator of the senescence-associated secretory phenotype. EMBO J. 30, 1536–1548 (2011).
White, R. R., Vijg, J. & Do, D. N. A. Double-strand breaks drive aging? Mol. Cell 63, 729–738 (2016).
Ou, H. L. & Schumacher, B. DNA damage responses and p53 in the aging process. Blood 131, 488–495 (2018).
Gorbunova, V. & Seluanov, A. DNA double strand break repair, aging and the chromatin connection. Mutat. Res. 788, 2–6 (2016).
Shmulevich, R. & Krizhanovsky, V. Cell senescence, DNA damage, and metabolism. Antioxid. Redox Signal. https://doi.org/10.1089/ars.2020.8043 (2020).
Acosta, J. C. et al. Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell 133, 1006–1018 (2008).
Hoare, M. et al. NOTCH1 mediates a switch between two distinct secretomes during senescence. Nat. Cell Biol. 18, 979–992 (2016).
Kang, C. et al. The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4. Science 349, aaa5612 (2015).
Mazzucco, A. E. et al. Genetic interrogation of replicative senescence uncovers a dual role for USP28 in coordinating the p53 and GATA4 branches of the senescence program. Genes Dev. 31, 1933–1938 (2017).
Orjalo, A. V., Bhaumik, D., Gengler, B. K., Scott, G. K. & Campisi, J. Cell surface-bound IL-1alpha is an upstream regulator of the senescence-associated IL-6/IL-8 cytokine network. Proc. Natl Acad. Sci. USA 106, 17031–17036 (2009).
Toso, A. et al. Enhancing chemotherapy efficacy in Pten-deficient prostate tumors by activating the senescence-associated antitumor immunity. Cell Rep. 9, 75–89 (2014).
Xu, M. et al. JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age. Proc. Natl Acad. Sci. USA 112, E6301–E6310 (2015).
Hernandez-Segura, A. et al. Unmasking transcriptional heterogeneity in senescent cells. Curr. Biol. 27, 2652–2660 e2654 (2017).
Vermezovic, J. et al. Notch is a direct negative regulator of the DNA-damage response. Nat. Struct. Mol. Biol. 22, 417–424 (2015).
Adamowicz, M., Vermezovic, J. & d’Adda di Fagagna, F. NOTCH1 inhibits activation of ATM by impairing the formation of an ATM-FOXO3a-KAT5/Tip60 complex. Cell Rep. 16, 2068–2076 (2016).
Stathis, A. & Bertoni, F. BET proteins as targets for anticancer treatment. Cancer Discov. 8, 24–36 (2018).
Wakita, M. et al. A BET family protein degrader provokes senolysis by targeting NHEJ and autophagy in senescent cells. Nat. Commun. 11, 1935 (2020).
Wang, S. et al. BRD4 inhibitors block telomere elongation. Nucleic Acids Res. 45, 8403–8410 (2017).
Ito, T., Teo, Y. V., Evans, S. A., Neretti, N. & Sedivy, J. M. Regulation of cellular senescence by polycomb chromatin modifiers through distinct DNA damage- and histone methylation-dependent pathways. Cell Rep. 22, 3480–3492 (2018).
Capell, B. C. et al. MLL1 is essential for the senescence-associated secretory phenotype. Genes Dev. 30, 321–336 (2016).
Aird, K. M. et al. HMGB2 orchestrates the chromatin landscape of senescence-associated secretory phenotype gene loci. J. Cell Biol. 215, 325–334 (2016).
Huang, J. et al. DAMPs, ageing, and cancer: the ‘DAMP hypothesis’. Ageing Res. Rev. 24, 3–16 (2015).
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).
Boumendil, C., Hari, P., Olsen, K. C. F., Acosta, J. C. & Bickmore, W. A. Nuclear pore density controls heterochromatin reorganization during senescence. Genes Dev. 33, 144–149 (2019).
Gluck, S. et al. Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence. Nat. Cell Biol. 19, 1061–1070 (2017).
Yang, H., Wang, H., Ren, J., Chen, Q. & Chen, Z. J. cGAS is essential for cellular senescence. Proc. Natl Acad. Sci. USA 114, E4612–E4620 (2017).
Hopfner, K. P. & Hornung, V. Molecular mechanisms and cellular functions of cGAS-STING signalling. Nat. Rev. Mol. Cell Biol. 21, 501–521 (2020).
Takahashi, A. et al. Downregulation of cytoplasmic DNases is implicated in cytoplasmic DNA accumulation and SASP in senescent cells. Nat. Commun. 9, 1249 (2018).
Haag, S. M. et al. Targeting STING with covalent small-molecule inhibitors. Nature 559, 269–273 (2018).
Broz, P. & Dixit, V. M. Inflammasomes: mechanism of assembly, regulation and signalling. Nat. Rev. Immunol. 16, 407–420 (2016).
Hari, P. et al. The innate immune sensor Toll-like receptor 2 controls the senescence-associated secretory phenotype. Sci. Adv. 5, eaaw0254 (2019).
Simon, M. et al. LINE1 derepression in aged wild-type and SIRT6-deficient mice drives inflammation. Cell Metab. 29, 871–885 e875 (2019).
Warren, L. A. & Rossi, D. J. Stem cells and aging in the hematopoietic system. Mech. Ageing Dev. 130, 46–53 (2009).
Rossi, D. J. et al. Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age. Nature 447, 725–729 (2007).
McNeely, T., Leone, M., Yanai, H. & Beerman, I. DNA damage in aging, the stem cell perspective. Hum. Genet. https://doi.org/10.1007/s00439-019-02047-z (2019).
Sperka, T., Wang, J. & Rudolph, K. L. DNA damage checkpoints in stem cells, ageing and cancer. Nat. Rev. Mol. Cell Biol. 13, 579–590 (2012).
Inomata, K. et al. Genotoxic stress abrogates renewal of melanocyte stem cells by triggering their differentiation. Cell 137, 1088–1099 (2009). This study demonstrates that DNA damage can induce stem cell differentiation.
Wang, J. et al. A differentiation checkpoint limits hematopoietic stem cell self-renewal in response to DNA damage. Cell 158, 1444 (2014).
Schiroli, G. et al. Precise gene editing preserves hematopoietic stem cell function following transient p53-mediated DNA damage response. Cell Stem Cell 24, 551–565 e558 (2019).
Flach, J. et al. Replication stress is a potent driver of functional decline in ageing haematopoietic stem cells. Nature 512, 198–202 (2014).
Schneider, L. et al. DNA damage in mammalian neural stem cells leads to astrocytic differentiation mediated by BMP2 signaling through JAK-STAT. Stem Cell Rep. 1, 123–138 (2013).
Zou, Y. et al. Responses of human embryonic stem cells and their differentiated progeny to ionizing radiation. Biochem. Biophys. Res. Commun. 426, 100–105 (2012).
Li, M. et al. Distinct regulatory mechanisms and functions for p53-activated and p53-repressed DNA damage response genes in embryonic stem cells. Mol. Cell 46, 30–42 (2012).
Storer, M. et al. Senescence is a developmental mechanism that contributes to embryonic growth and patterning. Cell 155, 1119–1130 (2013).
Munoz-Espin, D. et al. Programmed cell senescence during mammalian embryonic development. Cell 155, 1104–1118 (2013).
Sapieha, P. & Mallette, F. A. Cellular senescence in postmitotic cells: beyond growth arrest. Trends Cell Biol. 28, 595–607 (2018).
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).
Ogrodnik, M. et al. Obesity-induced cellular senescence drives anxiety and impairs neurogenesis. Cell Metab. 29, 1061–1077.e1068 (2019).
Musi, N. et al. Tau protein aggregation is associated with cellular senescence in the brain. Aging Cell 17, e12840 (2018).
Oubaha, M. et al. Senescence-associated secretory phenotype contributes to pathological angiogenesis in retinopathy. Sci. Transl Med. 8, 362ra144 (2016).
Minamino, T. et al. A crucial role for adipose tissue p53 in the regulation of insulin resistance. Nat. Med. 15, 1082–1087 (2009).
Farr, J. N. et al. Targeting cellular senescence prevents age-related bone loss in mice. Nat. Med. 23, 1072–1079 (2017).
Anderson, R. et al. Length-independent telomere damage drives post-mitotic cardiomyocyte senescence. EMBO J. https://doi.org/10.15252/embj.2018100492 (2019).
Burton, D. G. & Krizhanovsky, V. Physiological and pathological consequences of cellular senescence. Cell. Mol. Life Sci. 71, 4373–4386 (2014).
Chuprin, A. et al. Cell fusion induced by ERVWE1 or measles virus causes cellular senescence. Genes Dev. 27, 2356–2366 (2013).
Gal, H. et al. Molecular pathways of senescence regulate placental structure and function. EMBO J. 38, e100849 (2019).
Davaapil, H., Brockes, J. P. & Yun, M. H. Conserved and novel functions of programmed cellular senescence during vertebrate development. Development 144, 106–114 (2017).
Krizhanovsky, V. et al. Senescence of activated stellate cells limits liver fibrosis. Cell 134, 657–667 (2008). This study demonstrates that immune cell targeting of senescent cells limits dysfunction in the liver.
Kim, K. H., Chen, C. C., Monzon, R. I. & Lau, L. F. Matricellular protein CCN1 promotes regression of liver fibrosis through induction of cellular senescence in hepatic myofibroblasts. Mol. Cell. Biol. 33, 2078–2090 (2013).
Jun, J. I. & Lau, L. F. The matricellular protein CCN1 induces fibroblast senescence and restricts fibrosis in cutaneous wound healing. Nat. Cell Biol. 12, 676–685 (2010).
Fitzner, B. et al. Senescence determines the fate of activated rat pancreatic stellate cells. J. Cell Mol. Med. 16, 2620–2630 (2012).
Da Silva-Álvarez, S. et al. Cell senescence contributes to tissue regeneration in zebrafish. Aging Cell 19, e13052 (2020).
Yun, M. H., Davaapil, H. & Brockes, J. P. Recurrent turnover of senescent cells during regeneration of a complex structure. eLife https://doi.org/10.7554/eLife.05505 (2015).
Sagiv, A. & Krizhanovsky, V. Immunosurveillance of senescent cells: the bright side of the senescence program. Biogerontology 14, 617–628 (2013).
Freund, A., Orjalo, A. V., Desprez, P. Y. & Campisi, J. Inflammatory networks during cellular senescence: causes and consequences. Trends Mol. Med. 16, 238–246 (2010).
Lujambio, A. et al. Non-cell-autonomous tumor suppression by p53. Cell 153, 449–460 (2013).
Soriani, A. et al. ATM-ATR-dependent up-regulation of DNAM-1 and NKG2D ligands on multiple myeloma cells by therapeutic agents results in enhanced NK-cell susceptibility and is associated with a senescent phenotype. Blood 113, 3503–3511 (2009).
Xue, W. et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445, 656–660 (2007).
Kang, T. W. et al. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479, 547–551 (2011).
Sagiv, A. et al. NKG2D ligands mediate immunosurveillance of senescent cells. Aging 8, 328–344 (2016).
Biran, A. et al. Senescent cells communicate via intercellular protein transfer. Genes Dev. 29, 791–802 (2015).
Ruscetti, M. et al. NK cell-mediated cytotoxicity contributes to tumor control by a cytostatic drug combination. Science 362, 1416–1422 (2018).
Di Mitri, D. et al. Tumour-infiltrating Gr-1+ myeloid cells antagonize senescence in cancer. Nature 515, 134–137 (2014).
Eggert, T. et al. Distinct functions of senescence-associated immune responses in liver tumor surveillance and tumor progression. Cancer Cell 30, 533–547 (2016).
Yoshimoto, S. et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 499, 97–101 (2013).
Gonzalez-Meljem, J. M. et al. Stem cell senescence drives age-attenuated induction of pituitary tumours in mouse models of paediatric craniopharyngioma. Nat. Commun. 8, 1819 (2017).
Lau, L., Porciuncula, A., Yu, A., Iwakura, Y. & David, G. Uncoupling the senescence-associated secretory phenotype from cell cycle exit via interleukin-1 inactivation unveils its protumorigenic role. Mol. Cell. Biol. 39, e00586-18 (2019).
Demaria, M. et al. Cellular senescence promotes adverse effects of chemotherapy and cancer relapse. Cancer Discov. 7, 165–176 (2017).
Franceschi, C. et al. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann. N. Y. Acad. Sci. 908, 244–254 (2000).
Jeck, W. R., Siebold, A. P. & Sharpless, N. E. Review: a meta-analysis of GWAS and age-associated diseases. Aging Cell 11, 727–731 (2012).
Melzer, D. Genetic polymorphisms and human aging: association studies deliver. Rejuvenation Res. 11, 523–526 (2008).
Melzer, D. et al. A common variant of the p16(INK4a) genetic region is associated with physical function in older people. Mech. Ageing Dev. 128, 370–377 (2007).
Johnson, S. C., Dong, X., Vijg, J. & Suh, Y. Genetic evidence for common pathways in human age-related diseases. Aging Cell 14, 809–817 (2015).
D’Mello, M. J. et al. Association between shortened leukocyte telomere length and cardiometabolic outcomes: systematic review and meta-analysis. Circ. Cardiovasc. Genet. 8, 82–90 (2015).
Benetos, A. et al. Tracking and fixed ranking of leukocyte telomere length across the adult life course. Aging Cell 12, 615–621 (2013).
Fabbri, E. et al. Aging and the burden of multimorbidity: associations with inflammatory and anabolic hormonal biomarkers. J. Gerontol. A Biol. Sci. Med. Sci 70, 63–70 (2015).
Xu, M. et al. Senolytics improve physical function and increase lifespan in old age. Nat. Med. 24, 1246–1256 (2018). This study demonstrates that transplanting senescent cells in young mice causes persistent physical dysfunction that can be alleviated by senolytic drugs.
Childs, B. G. et al. Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science 354, 472–477 (2016).
Holdt, L. M. et al. Expression of Chr9p21 genes CDKN2B (p15(INK4b)), CDKN2A (p16(INK4a), p14(ARF)) and MTAP in human atherosclerotic plaque. Atherosclerosis 214, 264–270 (2011).
Cavalli, G., Biavasco, R., Borgiani, B. & Dagna, L. Oncogene-induced senescence as a new mechanism of disease: the paradigm of erdheim-chester disease. Front. Immunol. 5, 281 (2014).
Cangi, M. G. et al. BRAFV600E-mutation is invariably present and associated to oncogene-induced senescence in Erdheim-Chester disease. Ann. Rheum. Dis. 74, 1596–1602 (2015).
Sousa-Victor, P., Garcia-Prat, L., Serrano, A. L., Perdiguero, E. & Munoz-Canoves, P. Muscle stem cell aging: regulation and rejuvenation. Trends Endocrinol. Metab. 26, 287–296 (2015).
Gnani, D. et al. An early-senescence state in aged mesenchymal stromal cells contributes to hematopoietic stem and progenitor cell clonogenic impairment through the activation of a pro-inflammatory program. Aging Cell 18, e12933 (2019).
Krizhanovsky, V. & Lowe, S. W. Stem cells: The promises and perils of p53. Nature 460, 1085–1086 (2009).
Banito, A. et al. Senescence impairs successful reprogramming to pluripotent stem cells. Genes Dev. 23, 2134–2139 (2009).
Li, H. et al. The Ink4/Arf locus is a barrier for iPS cell reprogramming. Nature 460, 1136–1139 (2009).
Mosteiro, L. et al. Tissue damage and senescence provide critical signals for cellular reprogramming in vivo. Science https://doi.org/10.1126/science.aaf4445 (2016).
Wajapeyee, N., Serra, R. W., Zhu, X., Mahalingam, M. & Green, M. R. Oncogenic BRAF induces senescence and apoptosis through pathways mediated by the secreted protein IGFBP7. Cell 132, 363–374 (2008).
Takasugi, M. et al. Small extracellular vesicles secreted from senescent cells promote cancer cell proliferation through EphA2. Nat. Commun. 8, 15729 (2017).
Katlinskaya, Y. V. et al. Suppression of type I interferon signaling overcomes oncogene-induced senescence and mediates melanoma development and progression. Cell Rep. 15, 171–180 (2016).
Bird, T. G. et al. TGFbeta inhibition restores a regenerative response in acute liver injury by suppressing paracrine senescence. Sci. Transl Med. https://doi.org/10.1126/scitranslmed.aan1230 (2018).
Ritschka, B. et al. The senescence-associated secretory phenotype induces cellular plasticity and tissue regeneration. Genes Dev. 31, 172–183 (2017).
Chiche, A. et al. Injury-induced senescence enables in vivo reprogramming in skeletal muscle. Cell Stem Cell 20, 407–414.e404 (2017).
Baker, D. J. et al. BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice. Nat. Genet. 36, 744–749 (2004).
Baker, D. J., Jin, F. & van Deursen, J. M. The yin and yang of the Cdkn2a locus in senescence and aging. Cell Cycle 7, 2795–2802 (2008).
Baker, D. J. et al. Opposing roles for p16Ink4a and p19Arf in senescence and ageing caused by BubR1 insufficiency. Nat. Cell Biol. 10, 825–836 (2008).
Baker, D. J. et al. Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature 530, 184–189 (2016).
Laberge, R. M. et al. Mitochondrial DNA damage induces apoptosis in senescent cells. Cell Death Dis. 4, e727 (2013).
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).
Bussian, T. J. et al. Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline. Nature 562, 578–582 (2018).
Zhang, P. et al. Senolytic therapy alleviates Aβ-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model. Nat. Neurosci. 22, 719–728 (2019).
Schafer, M. J. et al. Cellular senescence mediates fibrotic pulmonary disease. Nat. Commun. 8, 14532 (2017).
Sagiv, A. et al. p53 in bronchial club cells facilitates chronic lung inflammation by promoting senescence. Cell Rep. 22, 3468–3479 (2018).
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).
Zhu, Y. et al. New agents that target senescent cells: the flavone, fisetin, and the BCL-X(L) inhibitors, A1331852 and A1155463. Aging 9, 955–963 (2017).
Guerrero, A. et al. Cardiac glycosides are broad-spectrum senolytics. Nat. Metab. 1, 1074–1088 (2019).
Triana-Martinez, F. et al. Identification and characterization of cardiac glycosides as senolytic compounds. Nat. Commun. 10, 4731 (2019).
Li, W., He, Y., Zhang, R., Zheng, G. & Zhou, D. The curcumin analog EF24 is a novel senolytic agent. Aging 11, 771–782 (2019).
Baar, M. P. et al. Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell 169, 132–147 e116 (2017).
Zhu, Y. et al. Inflammation and the depot-specific secretome of human preadipocytes. Obesity 23, 989–999 (2015).
Roos, C. M. et al. Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice. Aging Cell 15, 973–977 (2016).
Yousefzadeh, M. J. et al. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine 36, 18–28 (2018).
Zhu, Y. et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell 14, 644–658 (2015).
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).
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).
Fuhrmann-Stroissnigg, H., Niedernhofer, L. J. & Robbins, P. D. Hsp90 inhibitors as senolytic drugs to extend healthy aging. Cell Cycle 17, 1048–1055 (2018).
Fuhrmann-Stroissnigg, H. et al. Identification of HSP90 inhibitors as a novel class of senolytics. Nat. Commun. 8, 422 (2017).
Wang, Y. et al. Discovery of piperlongumine as a potential novel lead for the development of senolytic agents. Aging 8, 2915–2926 (2016).
Liu, X. et al. Senolytic activity of piperlongumine analogues: synthesis and biological evaluation. Bioorg. Med. Chem. 26, 3925–3938 (2018).
Ozsvari, B., Nuttall, J. R., Sotgia, F. & Lisanti, M. P. Azithromycin and roxithromycin define a new family of “senolytic” drugs that target senescent human fibroblasts. Aging 10, 3294–3307 (2018).
Munoz-Espin, D. et al. A versatile drug delivery system targeting senescent cells. EMBO Mol. Med. https://doi.org/10.15252/emmm.201809355 (2018).
Guerrero, A. et al. Galactose-modified duocarmycin prodrugs as senolytics. Aging Cell 19, e13133 (2020).
González-Gualda, E. et al. Galacto-conjugation of navitoclax as an efficient strategy to increase senolytic specificity and reduce platelet toxicity. Aging Cell 19, e13142 (2020).
Ovadya, Y. & Krizhanovsky, V. Strategies targeting cellular senescence. J. Clin. Invest. 128, 1247–1254 (2018).
McMichael, E. L. et al. IL-21 enhances natural killer cell response to cetuximab-coated pancreatic tumor cells. Clin. Cancer Res. 23, 489–502 (2017).
Brady, J. et al. The interactions of multiple cytokines control NK cell maturation. J. Immunol. 185, 6679–6688 (2010).
Elpek, K. G., Rubinstein, M. P., Bellemare-Pelletier, A., Goldrath, A. W. & Turley, S. J. Mature natural killer cells with phenotypic and functional alterations accumulate upon sustained stimulation with IL-15/IL-15Ralpha complexes. Proc. Natl Acad. Sci. USA 107, 21647–21652 (2010).
Rautela, J. & Huntington, N. D. IL-15 signaling in NK cell cancer immunotherapy. Curr. Opin. Immunol. 44, 1–6 (2017).
Amor, C. et al. Senolytic CAR T cells reverse senescence-associated pathologies. Nature 583, 127–132 (2020). This study demonstrates the feasibility of targeting senescent cells in a variety of conditions by chimeric antigen receptor T cell-mediated therapy.
Frescas, D. et al. Senescent cells expose and secrete an oxidized form of membrane-bound vimentin as revealed by a natural polyreactive antibody. Proc. Natl Acad. Sci. USA 114, E1668–E1677 (2017).
Kim, K. M. et al. Identification of senescent cell surface targetable protein DPP4. Genes Dev. 31, 1529–1534 (2017).
Althubiti, M. et al. Characterization of novel markers of senescence and their prognostic potential in cancer. Cell Death Dis. 5, e1528 (2014).
Herranz, N. et al. mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype. Nat. Cell Biol. 17, 1205–1217 (2015).
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).
Zhang, B. et al. The senescence-associated secretory phenotype is potentiated by feedforward regulatory mechanisms involving Zscan4 and TAK1. Nat. Commun. 9, 1723 (2018).
Thapa, R. K. et al. Progressive slowdown/prevention of cellular senescence by CD9-targeted delivery of rapamycin using lactose-wrapped calcium carbonate nanoparticles. Sci. Rep. 7, 43299 (2017).
Harrison, D. E. et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460, 392–395 (2009).
Moiseeva, O. et al. Metformin inhibits the senescence-associated secretory phenotype by interfering with IKK/NF-kappaB activation. Aging Cell 12, 489–498 (2013).
Maruthur, N. M. et al. Diabetes medications as monotherapy or metformin-based combination therapy for type 2 diabetes: a systematic review and meta-analysis. Ann. Intern. Med. 164, 740–751 (2016).
Noren Hooten, N. et al. Metformin-mediated increase in DICER1 regulates microRNA expression and cellular senescence. Aging Cell 15, 572–581 (2016).
Lim, H., Park, H. & Kim, H. P. Effects of flavonoids on senescence-associated secretory phenotype formation from bleomycin-induced senescence in BJ fibroblasts. Biochem. Pharmacol. 96, 337–348 (2015).
Nacarelli, T. et al. NAD+ metabolism governs the proinflammatory senescence-associated secretome. Nat. Cell Biol. 21, 397–407 (2019).
Liu, S. et al. Simvastatin suppresses breast cancer cell proliferation induced by senescent cells. Sci. Rep. 5, 17895 (2015).
Laberge, R. M. et al. Glucocorticoids suppress selected components of the senescence-associated secretory phenotype. Aging Cell 11, 569–578 (2012).
Cohen, S. et al. Treatment of rheumatoid arthritis with anakinra, a recombinant human interleukin-1 receptor antagonist, in combination with methotrexate: results of a twenty-four-week, multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 46, 614–624 (2002).
Kuemmerle-Deschner, J. B. et al. Canakinumab (ACZ885, a fully human IgG1 anti-IL-1β mAb) induces sustained remission in pediatric patients with cryopyrin-associated periodic syndrome (CAPS). Arthritis Res. Ther. 13, R34 (2011).
Hoffman, H. M. et al. Efficacy and safety of rilonacept (interleukin-1 trap) in patients with cryopyrin-associated periodic syndromes: results from two sequential placebo-controlled studies. Arthritis Rheum. 58, 2443–2452 (2008).
Klareskog, L. et al. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet 363, 675–681 (2004).
Jobanputra, P., Barton, P., Bryan, S. & Burls, A. The effectiveness of infliximab and etanercept for the treatment of rheumatoid arthritis: a systematic review and economic evaluation. Health Technol. Assess. 6, 1–110 (2002).
Emery, P. et al. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial. Ann. Rheum. Dis. 67, 1516–1523 (2008).
van Rhee, F. et al. Siltuximab for multicentric Castleman’s disease: a randomised, double-blind, placebo-controlled trial. Lancet Oncol. 15, 966–974 (2014).
Harrison, D. E. et al. Acarbose, 17-α-estradiol, and nordihydroguaiaretic acid extend mouse lifespan preferentially in males. Aging Cell 13, 273–282 (2014).
Michelini, F. et al. Damage-induced lncRNAs control the DNA damage response through interaction with DDRNAs at individual double-strand breaks. Nat. Cell Biol. 19, 1400–1411 (2017).
Aguado, J. et al. Inhibition of DNA damage response at telomeres improves the detrimental phenotypes of Hutchinson-Gilford progeria syndrome. Nat. Commun. 10, 4990 (2019).
Hall, B. M. et al. Aging of mice is associated with p16(Ink4a)- and beta-galactosidase-positive macrophage accumulation that can be induced in young mice by senescent cells. Aging 8, 1294–1315 (2016).
Liu, J. Y. et al. Cells exhibiting strong p16 (INK4a) promoter activation in vivo display features of senescence. Proc. Natl Acad. Sci. USA 116, 2603–2611 (2019).
Grosse, L. et al. Defined p16(High) senescent cell types are indispensable for mouse healthspan. Cell Metab. https://doi.org/10.1016/j.cmet.2020.05.002 (2020).
Fontana, L., Partridge, L. & Longo, V. D. Extending healthy life span–from yeast to humans. Science 328, 321–326 (2010).
Krishnamurthy, J. et al. Ink4a/Arf expression is a biomarker of aging. J. Clin. Invest. 114, 1299–1307 (2004).
Fontana, L. et al. The effects of graded caloric restriction: XII. Comparison of mouse to human impact on cellular senescence in the colon. Aging Cell 17, e12746 (2018).
Wang, C. et al. Adult-onset, short-term dietary restriction reduces cell senescence in mice. Aging 2, 555–566 (2010).
Satyanarayana, A. et al. Mitogen stimulation cooperates with telomere shortening to activate DNA damage responses and senescence signaling. Mol. Cell. Biol. 24, 5459–5474 (2004).
Martinez, P. & Blasco, M. A. Telomere-driven diseases and telomere-targeting therapies. J. Cell Biol. 216, 875–887 (2017).
Salvador, L. et al. A natural product telomerase activator lengthens telomeres in humans: a randomized, double blind, and placebo controlled study. Rejuvenation Res. 19, 478–484 (2016).
Bar, C., Huber, N., Beier, F. & Blasco, M. A. Therapeutic effect of androgen therapy in a mouse model of aplastic anemia produced by short telomeres. Haematologica 100, 1267–1274 (2015).
Bernardes de Jesus, B. et al. Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer. EMBO Mol. Med. 4, 691–704 (2012).
Alvarez, D. et al. IPF lung fibroblasts have a senescent phenotype. Am. J. Physiol. Lung Cell Mol. Physiol. 313, L1164–L1173 (2017).
Povedano, J. M. et al. Therapeutic effects of telomerase in mice with pulmonary fibrosis induced by damage to the lungs and short telomeres. eLife https://doi.org/10.7554/eLife.31299 (2018).
Munoz-Lorente, M. A. et al. AAV9-mediated telomerase activation does not accelerate tumorigenesis in the context of oncogenic K-Ras-induced lung cancer. PLoS Genet. 14, e1007562 (2018).
Conboy, M. J., Conboy, I. M. & Rando, T. A. Heterochronic parabiosis: historical perspective and methodological considerations for studies of aging and longevity. Aging Cell 12, 525–530 (2013).
Castellano, J. M. et al. Human umbilical cord plasma proteins revitalize hippocampal function in aged mice. Nature 544, 488–492 (2017).
Conboy, I. M. & Rando, T. A. Heterochronic parabiosis for the study of the effects of aging on stem cells and their niches. Cell Cycle 11, 2260–2267 (2012).
Yousefzadeh, M. J. et al. Heterochronic parabiosis regulates the extent of cellular senescence in multiple tissues. Geroscience https://doi.org/10.1007/s11357-020-00185-1 (2020).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04057872 (2019).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT03702920 (2018).
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. 10, 5495 (2019).
Kang, H. T. et al. Chemical screening identifies ATM as a target for alleviating senescence. Nat. Chem. Biol. 13, 616–623 (2017).
Dimri, G. P. et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc. Natl Acad. Sci. USA 92, 9363–9367 (1995).
Hall, B. M. et al. p16(Ink4a) and senescence-associated beta-galactosidase can be induced in macrophages as part of a reversible response to physiological stimuli. Aging 9, 1867–1884 (2017).
Evangelou, K. et al. Robust, universal biomarker assay to detect senescent cells in biological specimens. Aging Cell 16, 192–197 (2017).
Neurohr, G. E. et al. excessive cell growth causes cytoplasm dilution and contributes to senescence. Cell 176, 1083–1097 e1018 (2019).
Biran, A. et al. Quantitative identification of senescent cells in aging and disease. Aging Cell 16, 661–671 (2017).
Witkiewicz, A. K., Knudsen, K. E., Dicker, A. P. & Knudsen, E. S. The meaning of p16(ink4a) expression in tumors: functional significance, clinical associations and future developments. Cell Cycle 10, 2497–2503 (2011).
Herbig, U., Ferreira, M., Condel, L., Carey, D. & Sedivy, J. M. Cellular senescence in aging primates. Science 311, 1257 (2006).
Lozano-Torres, B. et al. The chemistry of senescence. Nat. Rev. Chem. 3, 426–441 (2019).
Paez-Ribes, M., González-Gualda, E., Doherty, G. J. & Muñoz-Espín, D. Targeting senescent cells in translational medicine. EMBO Mol. Med. 11, e10234 (2019).
Wang, Y. et al. Real-time imaging of senescence in tumors with DNA damage. Sci. Rep. 9, 2102 (2019).
Doherty, J. & Baehrecke, E. H. Life, death and autophagy. Nat. Cell Biol. 20, 1110–1117 (2018).
Narita, M. et al. Spatial coupling of mTOR and autophagy augments secretory phenotypes. Science 332, 966–970 (2011).
Young, A. R. et al. Autophagy mediates the mitotic senescence transition. Genes Dev. 23, 798–803 (2009).
Dorr, J. R. et al. Synthetic lethal metabolic targeting of cellular senescence in cancer therapy. Nature 501, 421–425 (2013).
Garcia-Prat, L. et al. Autophagy maintains stemness by preventing senescence. Nature 529, 37–42 (2016).
Tai, H. et al. Autophagy impairment with lysosomal and mitochondrial dysfunction is an important characteristic of oxidative stress-induced senescence. Autophagy 13, 99–113 (2017).
R.D.M. is supported by Telethon (TIGET grant E5), a Career Development Award from the Human Frontier Science Program, an Advanced Research Grant from the European Haematology Association, “Pilot and Seed Grant 2015” from San Raffaele Hospital, a Hollis Brownstein Research Grant from the Leukemia Research Foundation, the Interstellar Initiative on Healthy Longevity of the New York Academy of Sciences and the Japan Agency for Medical Research and Development, and the Italian AIRC under MFAG 2019, ID. 23321 project PI Di Micco Raffaella. V.K. is supported by grants from the European Research Council under the European Union’s Seventh Framework Proframme (309688) and under Horizon 2020 (856487), from the Israel Science Foundation (634-15; 2633-17), from the Israel Ministry of Health, Minerva Center “Ageing, from Physical Materials to Human Tissues”, and from the Sagol Institute for Longevity Research. V.K. is an incumbent of the Georg F. Duckwitz Professorial Chair. D.B. is supported by the Ellison Medical Foundation, the Glenn Foundation for Medical Research, the US National Institutes of Health (R01AG053229 and R01AG068076), the Mayo Clinic Children’s Research Center, the Alzheimer’s Disease Research Center at Mayo Clinic and the Cure Alzheimer’s Fund. F.d’A.d.F. is supported by AIRC (application 12971), Fondazione Telethon (GGP17111), PRIN 2015, the InterOmics Project, the AMANDA project Accordo Quadro Regione Lombardia-CNR, a European Research Council advanced grant (322726), a European Research Council proof-of-concept grant (875139), AriSLA (project “DDRNA and ALS”), the AIRC Special Program 5 per mille metastases (Project-21091) and the European Joint Programme on Rare Diseases (EJP RD).The authors apologize for not being able to cite all the important contributions of their colleagues owing to space limitations.
D.B. is a co-inventor on patent applications licensed to or filed by Unity Biotechnology, a company developing senolytic medicines, including small molecules that selectively eliminate senescent cells. Research in the Baker laboratory has been reviewed by the Mayo Clinic Conflict of Interest Review Board and is being conducted in compliance with Mayo Clinic conflict of interest policies. V.K. is a co-inventor on patent applications in the field of senolytics, some of which are licensed to Sentaur Bio. F.d’A.d.F. is among the inventors on patent applications for the use of antisense oligonucleotides to target DNA damage-induced transcripts. R.D.M. declares no competing interests.
Peer review information
Nature Reviews Molecular Cell Biology thanks Daniel Muñoz-Espín and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Transgenic mouse model with drug-inducible caspase 8 under the control of a minimal p16 promoter element active in senescent cells to allow selective elimination of p16-expressing senescent cells.
Transgenic mouse model expressing a trimodal reporter of red fluorescent protein, luciferase and herpes simplex virus thymidine kinase under the control of the p16 promoter to allow tracking and elimination of p16-expressing senescent cells.
Nicotinamide dinucleotide (NAD+)-dependent deacylases that regulate diverse cellular processes, including DNA repair, inflammation, metabolism and ageing.
- Mitochondrial dysfunction-associated senescence
(MiDAS). Mitochondrial damage triggers senescence with a distinct secretory phenotype that lacks IL-1-dependent inflammation.
Extracellular vesicles produced by the endosomal compartment involved in intercellular communication.
- HMGB proteins
Non-histone molecules that bind DNA and affect chromatin compaction.
- Myeloid skewing
An age-related proportional increase in myeloid cells at the expense of other lineages as observed in the bone marrow and blood.
A protein found in neurons that is important for maintaining microtubule structure in axons. Mutants and hyperphosphorylated forms are found in a variety of neurodegenerative diseases, including Alzheimer disease.
Pathological accumulation of extracellular matrix in diseases tissue that limits normal tissue function and leads to long-term tissue scaring.
- LDL receptor
Mediates entry of LDL into cells. Mutations in the gene encoding this receptor predispose to the development of atherosclerosis.
Clouding of the lens in the eye leading to inability to have clear vision. Surgical intervention to replace diseased lenses is a common medical procedure in aged humans.
Abnormal rearward curvature of the spine, observed both in laboratory mice and in humans.
Abnormal distribution of adipose tissue in the body, can refer to both excessive or insufficient deposition.
A molecular chaperone that promotes proper protein folding and degradation, which also contributes to heat stress resilience.
Compounds that are metabolized into an active drug to modify drug bioavailability and activity.
A pore forming protein expressed in cytotoxic T cells and natural killer cells. When these cells execute cytotoxicity, they secrete granules containing perforin, which binds to the target cell’s membrane and forms pores on the target cell in order to allow cytotoxicity.
- Chimeric antigen receptor T (CAR T) cells
T cells that have been genetically engineered to express T cell receptor developed to bind a defined target in order to eliminate the cells that have the target on their membrane.
A protein expressed on the cell surface that inhibits the ability of the immune system to target the cells that express the protein. Inhibition of interaction of PD1 with its ligand is a potent immunotherapy approach.
About this article
Cite this article
Di Micco, R., Krizhanovsky, V., Baker, D. et al. Cellular senescence in ageing: from mechanisms to therapeutic opportunities. Nat Rev Mol Cell Biol 22, 75–95 (2021). https://doi.org/10.1038/s41580-020-00314-w
Circulation Research (2021)
Food and Chemical Toxicology (2021)
Trends in Cell Biology (2021)
Hepatology Communications (2021)