The Clinical Potential of Senolytic Drugs

Journal of the American Geriatrics Society

Volumn 65, Issue 10, 2017, Pages 2297-2301

  Kirkland, James L ^a   Tchkonia, Tamara ^a   Zhu, Yi ^a   Niedernhofer, Laura J ^b   Robbins, Paul D ^b  

^a MAYO CLINIC   (United States)

^b SCRIPPS RESEARCH INSTITUTE   (United States)

Author keywords

cellular senescence; chronic diseases; geroscience hypothesis; SCAPs; senolytics

Indexed keywords

BIOLOGICAL PRODUCT; SENOLYTIC DRUG; UNCLASSIFIED DRUG;

ACHILLES TENDON; AGING; ARTICLE; CELL AGING; CLINICAL TRIAL; GERIATRICS; HUMAN; NONHUMAN; PHENOTYPE; SUICIDE GENE THERAPY; TRANSGENIC MOUSE; AGED; ANIMAL; CHRONIC DISEASE; DRUG EFFECTS; MOUSE; VERY ELDERLY;

AGED; AGED, 80 AND OVER; AGING; ANIMALS; CELL AGING; CHRONIC DISEASE; HUMANS; MICE;

EID: 85028699170     PISSN: 00028614     EISSN: 15325415     Source Type: Journal    
DOI: 10.1111/jgs.14969     Document Type: Article

References (46)

1. Kirkland JL. Translating the science of aging into therapeutic interventions. Cold Spring Harb Perspect Med 2016;6:a025908.
2. Kirkland JL, Stout MB, Sierra F. Resilience in aging mice. J Gerontol A Biol Sci Med Sci 2016;71:1407–1414.
3. St Sauver JL, Boyd CM, Grossardt BR et al. Risk of developing multimorbidity across all ages in an historical cohort study: Differences by sex and ethnicity. BMJ Open 2015;5:e006413.
4. Fang EF, Scheibye-Knudsen M, Brace LE et al. Defective mitophagy in XPA via PARP-1 hyperactivation and NAD(+)/SIRT1 reduction. Cell 2014;157:882–896.
5. Lavasani M, Robinson AR, Lu A et al. Muscle-derived stem/progenitor cell dysfunction limits healthspan and lifespan in a murine progeria model. Nature Commun 2012;3:608.
6. Armstrong GT, Kawashima T, Leisenring W et al. Aging and risk of severe, disabling, life-threatening, and fatal events in the childhood cancer survivor study. J Clin Oncol 2014;32:1218–1227.
7. Tchkonia T, Zhu Y, van Deursen J et al. Cellular senescence and the senescent secretory phenotype: Therapeutic opportunities. J Clin Invest 2013;123:966–972.
8. Xu M, Palmer AK, Ding H et al. Targeting senescent cells enhances adipogenesis and metabolic function in old age. eLife 2015;4:e12997.
9. Zhu Y, Armstrong JL, Tchkonia T et al. Cellular senescence and the senescent secretory phenotype in age-related chronic diseases. Current Opin Clin Nutr Metab Care 2014;17:324–328.
10. Xu M, Bradley EW, Weivoda MM et al. Transplanted senescent cells induce an osteoarthritis-like condition in mice. J Gerontol A Biol Sci Med Sci 2017;72:780–785.
11. Kim YM, Seo YH, Park CB et al. Roles of GSK3 in metabolic shift toward abnormal anabolism in cell senescence. Ann N Y Acad Sci 2010;1201:65–71.
12. Krishnamurthy J, Torrice C, Ramsey MR et al. Ink4a/Arf expression is a biomarker of aging. J Clin Invest 2004;114:1299–1307.
13. Tchkonia T, Morbeck DE, von Zglinicki T et al. Fat tissue, aging, and cellular senescence. Aging Cell 2010;9:667–684.
14. Jeyapalan JC, Ferreira M, Sedivy JM et al. Accumulation of senescent cells in mitotic tissue of aging primates. Mech Ageing Devel 2007;128:36–44.
15. Waaijer ME, Parish WE, Strongitharm BH et al. The number of p16INK4a positive cells in human skin reflects biological age. Aging Cell 2012;11:722–725.
16. Stout MB, Tchkonia T, Pirtskhalava T et al. Growth hormone action predicts age-related white adipose tissue dysfunction and senescent cell burden in mice. Aging (Milano) 2014;6:575–586.
17. Baker DJ, Wijshake T, Tchkonia T et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 2011;479:232–236.
18. Roos CM, Zhang B, Palmer AK et al. Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice. Aging Cell 2016;15:973–977.
19. Schafer MJ, White TA, Iijima K et al. Cellular senescence mediates fibrotic pulmonary disease. Nature Commun 2017;8:14532.
20. Hall BM, Balan V, Gleiberman AS 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 (Milano) 2016;8:1294–1315.
21. Kirkland JL, Tchkonia T. Clinical strategies and animal models for developing senolytic agents. Exp Gerontol 2015;68:19–25.
22. Zhu Y, Tchkonia T, Pirtskhalava T et al. The Achilles’ heel of senescent cells: From transcriptome to senolytic drugs. Aging Cell 2015;14:644–658.
23. Wang E. Senescent human fibroblasts resist programmed cell death, and failure to suppress bcl2 is involved. Cancer Res 1995;55:2284–2292.
24. Fuhrmann-Stroissnigg H, Ling YY, Zhao J et al. Identification of HSP90 inhibitors as senolytics for extending healthspan. Nature Commun 2017 in press.
25. Chang J, Wang Y, Shao L et al. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nature Med 2016;22:78–83.
26. Baar MP, Brandt RM, Putavet DA et al. Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell 2017;169:132.e116–147.e116.
27. Zhu Y, Tchkonia T, Fuhrmann-Stroissnigg H et al. Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors. Aging Cell 2016;15:428–435.
28. Childs BG, Baker DJ, Wijshake T et al. Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science 2016;354:472–477.
29. Demaria M, Ohtani N, Youssef SA et al. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev Cell 2014;31:722–733.
30. Newman JC, Milman S, Hashmi SK et al. Strategies and challenges in clinical trials targeting human aging. J Gerontol A Biol Sci Med Sci 2016;71:1424–1434.
31. Justice J, Miller JD, Newman JC et al. Frameworks for proof-of-concept clinical trials of interventions that target fundamental aging processes. J Gerontol A Biol Sci Med Sci 2016;71:1415–1423.
32. Huffman DM, Justice JN, Stout MB 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 2016;71:1395–1406.
33. Burd CE, Gill MS, Niedernhofer LJ et al. Barriers to the preclinical development of therapeutics that target aging mechanisms. J Gerontol A Biol Sci Med Sci 2016;71:1388–1394.
34. Tabibian JH, O'Hara SP, Splinter PL et al. Cholangiocyte senescence by way of N-ras activation is a characteristic of primary sclerosing cholangitis. Hepatology 2014;59:2263–2275.
35. Oubaha M, Miloudi K, Dejda A et al. Senescence-associated secretory phenotype contributes to pathological angiogenesis in retinopathy. Sci Trans Med 2016;8:362ra144.
36. Mannick JB, Del Giudice G, Lattanzi M et al. mTOR inhibition improves immune function in the elderly. Sci Trans Med 2014;6:268ra179.
37. Xu M, Tchkonia T, Ding H et al. JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age. Proc Natl Acad Sci U S A 2015;112:E6301–E6310.
38. Yosef R, Pilpel N, Tokarsky-Amiel R et al. Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL. Nature Commun 2016;7:11190.
39. Pal HC, Sharma S, Elmets CA et al. Fisetin inhibits growth, induces G(2) /M arrest and apoptosis of human epidermoid carcinoma A431 cells: Role of mitochondrial membrane potential disruption and consequent caspases activation. Exp Dermatol 2013;22:470–475.
40. Zhu Y, Doornebal EJ, Pirtskhalava T et al. New agents that target senescent cells: The flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463. Aging (Albany NY) 2017;9:955–963.
41. Zhang XJ, Jia SS. Fisetin inhibits laryngeal carcinoma through regulation of AKT/NF-kappaB/mTOR and ERK1/2 signaling pathways. Biomed Pharmacother 2016;83:1164–1174.
42. Makhov P, Golovine K, Teper E et al. Piperlongumine promotes autophagy via inhibition of Akt/mTOR signalling and mediates cancer cell death. Br J Cancer 2014;110:899–907.
43. Wang F, Mao Y, You Q et al. Piperlongumine induces apoptosis and autophagy in human lung cancer cells through inhibition of PI3K/Akt/mTOR pathway. Int J Immunopathol Pharmacol 2015;28:362–373.
44. Li J, Cheng Y, Qu W et al. Fisetin, a dietary flavonoid, induces cell cycle arrest and apoptosis through activation of p53 and inhibition of NF-kappa B pathways in bladder cancer cells. Basic Clin Pharmacol Toxicol 2011;108:84–93.
45. Golovine KV, Makhov PB, Teper E et al. Piperlongumine induces rapid depletion of the androgen receptor in human prostate cancer cells. Prostate 2013;73:23–30.
46. Triantafyllou A, Mylonis I, Simos G et al. Flavonoids induce HIF-1alpha but impair its nuclear accumulation and activity. Free Radic Biol Med 2008;44:657–670.