INSIGHTS | PERSPECTIVES

AGING Senolytic therapies for healthy longevity Clearing senescent cells with targeted drugs could combat age-associated disease

By Jan M. van Deursen Paradoxically, although cellular proteins (5, 6). BCL-2 inhibitors are senolytic has evolved as a tumor protective program, across species, in multiple cell types, and in he estimated “natural” life span of the SASP can include factors that stimulate SNCs resulting from multiple senescence- humans is ~30 years, but improve- neoplastic cell growth, tumor angiogen- inducing stressors. In mice, pharmacological ments in working conditions, hous- esis, and metastasis, thereby promoting the inhibition of BCL-2 family members elimi- ing, sanitation, and medicine have development of late-life . Indeed, nates various kinds of senescent stem cells, extended this to ~80 years in most elimination of SNCs with aging attenuates including hair follicle, skeletal muscle, and developed countries. However, much tumor formation in mice, raising the pos- hematopoietic stem cells. This results in Tof the population now experiences aging- sibility that senolysis might be an effective rejuvenation of the stem cell populations, associated tissue deterioration. Healthy strategy to treat (2). presumably by restoring the stem cell mi- aging is limited by a lack of natural selec- Given that our knowledge of SNCs in vivo croenvironment (niche) (5, 6). In mouse tion, which favors genetic programs that is limited, how should researchers identify models for two major age-associated human confer fitness early in life to maximize re- senolytic drug targets? One strategy is to diseases, atherosclerosis and neurodegenera- Downloaded from productive output. There is no selection for identify vulnerabilities shared by cancer tion, ABT-263 cleared SNCs from atheroscle- whether these alterations have detrimental cells and SNCs and then use tailored vari- rotic plaques and brain tissue, respectively, effects later in life. One such program is cel- ants of anticancer agents to target such vul- substantially attenuating the progression of lular senescence, whereby cells become un- nerabilities to selectively eliminate SNCs. key disease phenotypes (7, 8). able to divide. enhances Cytotoxic anticancer agents have consider- Another example of learning from oncol- reproductive success by blocking cancer cell able limitations, including the emergence of ogy pertains to the apoptotic pathway. http://science.sciencemag.org/ proliferation, but it decreases the health of therapy-induced resistance due to the high Molecules that interfere with the interac- the old by littering tissues with dysfunc- mutation rate of cancer cells and the need tion between the E3 ubiquitin ligase MDM2 tional senescent cells (SNCs). In mice, the for the complete eradication of cancer cells (which negatively regulates p53) and p53 selective elimination of SNCs (senolysis) ex- to achieve disease remission. These same increase p53 activity and thereby induce tends median life span and prevents or at- challenges are unlikely to occur with seno- in cancer cells that express wild- tenuates age-associated diseases (1, 2). This lytic drugs for several reasons. Although ev- type p53. Treatment of a murine osteoar- has inspired the development of targeted idence is emerging that SNCs are subject to thritis model with the drug UBX0101, which senolytic drugs to eliminate the SNCs that genomic instability, they do not proliferate, interferes with this regulatory mechanism, drive age-associated disease in humans. thereby precluding the propagation of ther- triggers apoptosis of SNCs that accumulate

Much of our current knowledge about the apy-resistant clones. Additionally, although in articular cartilage and synovium—cells on May 21, 2019 properties of SNCs is based on experiments rates of senescence increase with aging, the that are causally implicated in the develop- in cultured cells, largely because SNCs in absolute numbers of SNCs that accumulate ment of osteoarthritis (9). tissues and organs are difficult to identify in tissues remain generally low. Moreover, In addition to the challenge of drug re- and collect. One key characteristic of SNCs cancer cells need to be entirely eradicated sistance, most cancer therapies are lim- is that they are in a state of permanent cell- for successful treatment. In mice, partial ited by toxic side effects. This is also the cycle arrest, typically initiated and main- (60 to 80%) elimination of SNCs can pre- case for BCL-2 inhibitors, which reduce tained by the p53-p21-retinoblastoma (RB) vent or attenuate age-associated disease the number of neutrophils (neutropenia) and p16-RB tumor suppressor pathways (3). phenotypes (1, 2). Although cancer thera- and thrombocytes (thrombocytopenia). Various stresses induce this state, includ- peutics that interfere with cell division are However, because SNCs accumulate slowly ing oxidative and genotoxic stress, shorten- unsuitable as senolytic drugs, agents that and are nonproliferative, their abundance ing of telomeres (repetitive sequences that block the pathways that cancer cells rely might be controlled by intermittent dos- protect the ends of chromosomes), exces- on for survival might be worth pursuing as ing, which could prevent side effects from sive mitogenic signaling, DNA replication senolytics. For example, resistance to apop- developing. Similarly, drugs that target p53- errors, mitotic defects, and mitochondrial tosis (a form of programmed cell death) is MDM2 binding are selective but not specific dysfunction. Furthermore, SNCs produce a feature shared by cancer cells and SNCs. for cancer cells and SNCs. Therefore, some a bioactive “secretome,” referred to as the Proof-of-principle evidence for the effec- normal cell populations are likely to be af- senescence-associated secretory phenotype tiveness of this strategy comes from target- fected, which may cause side effects. (SASP) (4). This can disrupt normal tissue ing the B cell lymphoma 2 (BCL-2) protein Various other approaches have been used architecture and function through diverse family members: BCL-2, BCL-XL, and BCL-W. to trigger the elimination of SNCs, including mechanisms, including recruitment of in- These antiapoptotic proteins are frequently the treatment of SNCs with a peptide drug flammatory immune cells, remodeling of overexpressed in both cancer cells and SNCs designed to interfere with the interaction of the extracellular matrix, induction of fibro- (see the figure). Two targeted cancer thera- p53 and forkhead box protein O4 (FOXO4), sis, and inhibition of stem cell function (3). peutic agents, ABT-263 and ABT-737, have thereby directing p53 to mitochondria for been shown to selectively eliminate SNCs in induction of apoptosis (10). The creation of mice by blocking the interaction of BCL-2, galacto-oligosaccharide–coated nanoparti- Departments of Biochemistry and Molecular Biology, and Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, BCL-XL, and BCL-W with BCL-2 homology cles can selectively deliver cytotoxic agents MN 55905, USA. Email: [email protected] 3 (BH3) domain–containing proapoptotic to SNCs that are positive for the senescence

636 17 MAY 2019 • VOL 364 ISSUE 6441 sciencemag.org SCIENCE

Published by AAAS marker b-galactosidase (11). Senolytic therapies for optimized aging which diversity in SASP compo- Moreover, natural products with sition translates into phenotypic anticancer properties, such as Senescent cells (SNCs) resist apoptosis by activating prosurvival pathways heterogeneity in disease and ag- and inhibiting proapoptotic pathways. and , and quer- ing remains to be established. cetin in combination with the SNC Proapoptotic signaling Senolysis Moreover, the SASP is complex pan- inhibitor and consists of hundreds of se- , have been reported BAD creted proteins, raising the ques- p53 to eliminate SNCs in vitro and BAX tion of whether the phenotypes in mice (12, 13). Although quer- result from the effects of many cetin, fisetin, and dasatinib are factors or a subset. BCL-2 often referred to as senolytics, it BAD As knowledge of the fun- MDM2 p53 BCL-XL should be noted that they each BAX Ongoing biological damental biology and vulner- BCL-W and translational act on a myriad of pathways and research abilities of SNCs expands, the mechanisms implicated in di- ABT263 rational design of targeted seno- verse biological processes. This SASP UBX0101 ABT737 lytics is expected to yield thera- makes it difficult to decipher UBX1967 pies to eliminate SNCs that drive how these drugs eliminate or degeneration and disease. This otherwise impact SNCs and to Diseases of aging First-generation Second-generation positive outlook is based on suc- attribute any therapeutic or det- targeted targeted and cesses in oncology and because rimental effects they may have senolytics plus selective senolytics the main limitation of cancer in clinical trials to senolysis. local delivery therapies—the clonal expansion Downloaded from Senolytic drugs that inhibit of drug-resistant cells—does targets originally discovered in Systemic senolysis not apply to SNCs. Additional oncology could yield promising Neurodegeneration confidence comes from the re- first-generation drugs to treat Local senolysis IPF cent progress in bringing seno- Osteoarthritis COPD humans. However, this strat- lytic agents into clinical trials. Eye diseases Atherosclerosis egy may not accomplish the The first clinical trial is testing http://science.sciencemag.org/ long-term goal of developing First-generation senolytics Second-generation senolytics UBX0101 for the treatment of os- ideal senolytics that selectively, Drugs developed to target key Development of selective senolytics teoarthritis of the knee. Another components of prosurvival pathways that safely and eLectively eliminate safely, and effectively eliminate eliminate SNCs and thereby SNCs upon systemic administration drug, UBX1967, a BCL-2 family SNCs upon systemic administra- the SASP that drives diseases awaits further understanding inhibitor specifically tailored for tion (see the figure). Efforts to of aging. of SNCs. diseases of the aging eye, is also identify such “next-generation” BAD, BCL-2–associated agonist of cell death; BAX, BCL2-associated X; BCL-2, B cell lymphoma 2; COPD, advancing to human testing. chronic obstructive pulmonary disease; IPF, idiopathic pulmonary fbrosis; SASP, senescence-associated senolytics could nonetheless secretory phenotype. Multiple clinical trials treating benefit from general principles diverse diseases of aging with that have been used in anticancer drug dis- properties of SNCs in vitro are preserved senolytic drugs are expected to follow soon.

covery. For instance, it will be important to in vivo and to identify which cells become This includes two-step cancer treatment ap- on May 21, 2019 focus drug development on age-associated senescent in a particular disease of aging. proaches whereby malignant cells are first degenerative diseases in which SNCs are Additionally, it is increasingly likely that, forced into a senescent state by one drug and clear drivers of pathophysiology and in rather than being a static endpoint, cel- then eliminated with a senolytic agent. Suc- which senolysis could be disease modify- lular senescence is a series of progressive cess in these first clinical studies is the next ing (e.g., osteoarthritis and atherosclerosis). and phenotypically diverse cellular states critical milestone on the road to the develop- SNCs implicated in conditions that meet that are acquired after initial growth arrest ment of treatments that can extend healthy these requirements should be characterized (3). This SNC evolution is at least partially longevity in people. j to identify any distinct mechanisms that un- driven by processes that introduce genomic derlie their survival. Agents that selectively diversity, such as the formation of micronu- REFERENCES AND NOTES 1. D. J. Baker et al., Nature 479, 232 (2011). target such mechanisms are likely to have clei and activation of retrotransposons (15). 2. D. J. Baker et al., Nature 530, 184 (2016). the lowest risk of side effects. These findings predict that SNCs are het- 3. J. M. van Deursen, Nature 509, 439 (2014). The development of next-generation tar- erogeneous collections of cells with fewer 4. J. P. Coppé et al., PLOS Biol. 6, 2853 (2008). 5. R. Yosef et al., Nat. Commun. 7, 11190 (2016). geted senolytics will require a richer mo- shared core properties than anticipated. 6. J. Chang et al., Nat. Med. 22, 78 (2016). lecular description of the in vivo properties The SASP is considered the driver of tis- 7. T. J. Bussian et al., Nature 562, 578 (2018). of SNCs. This includes potentially beneficial sue deterioration and disease, but several 8. B. G. Childs et al., Science 354, 472 (2016). SNCs that arise during tissue repair and fundamental questions regarding the bio- 9. O. H. Jeon et al., Nat. Med. 23, 775 (2017). 10. M. P. Baar et al., Cell 169, 132 (2017). regeneration to facilitate tissue remodel- active secretome of SNCs in vivo remain 11. D. Muñoz-Espín et al., EMBO Mol. Med. 10, e9355 (2018). ing and limit fibrosis through the SASP unanswered. For instance, it is unclear to 12. M. Xu et al., Nat. Med. 24, 1246 (2018). factors that they produce (14). One prob- what extent SASP factors systemically drive 13. M. J. Yousefzadeh et al., EBioMedicine 36, 18 (2018). 14. D. Muñoz-Espín et al., Cell 155, 1104 (2013). lem in acquiring such information is that age-associated pathologies by entering the 15. Z. Dou et al., Nature 550, 402 (2017). SNC-specific markers in vivo are only now circulation. If this is substantial, local clear- SCIENCE being developed. Until such markers are ance of SNCs at specific disease sites may not ACKNOWLEDGMENTS validated, accurate visualization, collection, provide therapeutic benefit, and systemic J.M.v.D. is a cofounder of Unity Biotechnology and an inventor on patents licensed to or filed by Unity Biotechnology. J.M.v.D. and tracking of SNCs in tissues and organs senolysis may be required. Additionally, cell is supported by the Glenn Foundation for Medical Research and and at sites of age-associated disease is diffi- culture experiments indicate that the com- NIH grants R01CA096985 and R01AG057493. J.M.v.D. thanks B. cult. The same challenge also applies for ex- position of the SASP varies by cell type and Childs, N. David, and D. Baker for helpful discussions.

GRAPHIC: A. KITTERMAN/ A. GRAPHIC: periments designed to determine whether senescence-inducing stressor. The extent to 10.1126/science aaw1299

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Published by AAAS Senolytic therapies for healthy longevity Jan M. van Deursen

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