Senolytic

A senolytic (from the words "senescence" and "lytic" - destroying) is among the class of senotherapeutics,[1] and refers to small molecules that can selectively induce death of senescent cells.

Senescence is a potent tumor suppressive mechanism.[2] It however drives both degenerative and hyperplastic pathologies, most likely by promoting chronic inflammation.[2] Senescent cells accumulate in aging bodies and accelerate the aging process.[3] Eliminating senescent cells increases the amount of time that mice are free of disease.[4]

Relation to cancer

The senescence response, initially a tumor suppressor mechanism, turns into a tumor promoter apparently as a consequence of aging.[5] As such, chronic accumulation of senescent cells can lead to cancer in addition to aging.[6]

Senescent cells are similar to cancer cells in that they have increased expression of so called pro-survival networks that help them resist apoptosis (programmed cell death).[4]

Certain anti-cancer agents may in low doses decelerate aging and age-related diseases.[7] Moreover, deceleration of aging can in turn postpone cancer.[7] Targeting cancer prevention pathways may confer longevity effects by offering protection from metabolic pathologies during aging, independently of effects on cancer.[8]

Validation

An engineered suicide gene can be used in transgenic mice to delete senescent cells.[9] This approach demonstrates that cellular senescence is causally implicated in generating age-related phenotypes and that removal of senescent cells can prevent or delay tissue dysfunction and extend healthspan.[10] It provided the first direct evidence that senescent cells can, at least in a premature aging mouse model, drive degenerative age-related pathology, and that clearance of such cells can delay or arrest senescence.[2]

AP20187 was used to activate an engineered suicide gene under the promoter for p16 in transgenic mice. Cells expressing p16 are predominantly senescent, and administration of the agent AP20187 lead to selective apoptosis of these cells. AP20187 was used to restore fat tissue and stem cell function in older naturally-aged mice.[11] AP20187 was used similarly in a later study to extend the median lifespan of mice.[12] In these mice, the clearance of p16Ink4a-positive cells delayed tumorigenesis and attenuated age-related deterioration of several organs without apparent side effects.[12] Furthermore, late-life clearance of these cells attenuated progression of cancers and of established age-related disorders.[10]

Agents

The goal of those working to develop senolytic agents is to delay, prevent, alleviate, or reverse age-related diseases.[13] Targeting premalignant senescent cells could also be a preventive and therapeutic strategy against late-life cancer given the deteriorated efficacy of the senescence response in stopping cancer.[5]

Quercetin is a natural compound that acts as an antihistamine, anti-inflammatory and anti-cancer drug. Quercetin eliminates senescent human endothelial cells and mouse bone marrow mesenchymal stem cells.[4]

Dasatinib is a cancer drug. Dasatinib eliminated senescent human fat cell progenitors.[4]

Navitoclax, also known as ABT-263, was originally studied as an anti-cancer drug.[14] It is an inhibitor of the anti-apoptotic proteins BCL-2, BCL-w, and BCL-xL. Navitoclax is senolytic against some senescent cell types (e.g., senescent human umbilical vein epithelial cells (HUVECs), IMR90 human lung fibroblasts and murine embryonic fibroblasts (MEFs), but not all (e.g., senescent human primary preadipocytes).[15] Oral administration of ABT263 to either sublethally irradiated or normally aged mice reduced senescent cells, including senescent bone marrow hematopoietic stem cells and senescent muscle stem cells.[16] This depletion mitigated total-body irradiation-induced premature aging of the hematopoietic system and rejuvenated the aged hematopoietic stem cells and muscle stem cells in normally aged mice.[16] It has toxic side effects including but not limited to thrombocytopenia and lymphopenia.[17][18]

The combination of dasatinib and quercetin, the first senolytic drugs discovered, reduced senescent cell burden in multiple tissues of old mice and in the legs of young mice after senescence had been induced by radiation. The senolytic drugs improved cardiovascular function in old mice as well as mice with atherosclerosis,[19] restored leg function in the younger mice that had received leg irradiation sufficient to impair walking, and enhanced healthspan in mice with an "accelerated aging" condition. In these mice, the combination of dasatinib and quercetin delayed neurological dysfunction, bone loss, and dysfunction of intervertebral discs of the backbone.[4]

Risks

The elimination of p16-expressing senescent cells can impair wound healing.[6][20] This is due to a positive role of senescent cells during tissue repair.[20] The presence of senescent cells also restrains fibrosis.[20] Their absence significantly retards the kinetics of wound closure.[20]

Senolytics induce apoptosis preferentially in senescent cells.[15] Although apoptosis is a mechanism of anti-cancer defense, it can also drive tumor formation.[21] It can promote proliferation critically needed to compensate for cell loss and to restore tissue homeostasis.[21] Apoptosis might drive genomic instability by facilitating the emergence of pathologic clones during phases of proliferation and subsequent replication stress-associated DNA damage.[21] Tumorigenesis is initiated by repeated cell attrition and repopulation, as demonstrated in therapy-induced secondary malignancies and myelodysplastic syndromes.[21]

See also

References

  1. ↑ Childs BG, Durik M, Baker DJ, van Deursen JM (2015). "Cellular senescence in aging and age-related disease: from mechanisms to therapy". Nature Medicine. 21 (12): 1424–35. doi:10.1038/nm.4000. PMC 4748967Freely accessible. PMID 26646499. Retrieved 2015-12-27.
  2. 1 2 3 Campisi J (2013). "Aging, cellular senescence, and cancer". Annual Review of Physiology. 75: 685–705. doi:10.1146/annurev-physiol-030212-183653. PMC 4166529Freely accessible. PMID 23140366. Retrieved 2016-02-07. The senescence response is widely recognized as a potent tumor suppressive mechanism. However, recent evidence strengthens the idea that it also drives both degenerative and hyper-plastic pathologies, most likely by promoting chronic inflammation.
  3. ↑ van Deursen JM (2014). "The role of senescent cells in ageing". Nature. 509 (7501): 439–46. doi:10.1038/nature13193. PMC 4214092Freely accessible. PMID 24848057. Retrieved 2015-12-27.
  4. 1 2 3 4 5 Zhu, Yi; Tchkonia, Tamara; Pirtskhalava, Tamar; Gower, Adam; Ding, Husheng; Giorgadze, Nino; Palmer, Allyson K.; Ikeno, Yuji; Borden, Gene; Lenburg, Marc; O'Hara, Steven P.; LaRusso, Nicholas F.; Miller, Jordan D.; Roos, Carolyn M.; Verzosa, Grace C.; LeBrasseur, Nathan K.; Wren, Jonathan D.; Farr, Joshua N.; Khosla, Sundeep; Stout, Michael B.; McGowan, Sara J.; Fuhrmann-Stroissnigg, Heike; Gurkar, Aditi U.; Zhao, Jing; Colangelo, Debora; Dorronsoro, Akaitz; Ling, Yuan Yuan; Barghouthy, Amira S.; Navarro, Diana C.; Sano, Tokio; Robbins, Paul D.; Niedernhofer, Laura J.; Kirkland, James L. (2015). "The Achilles' Heel of Senescent Cells: From Transcriptome to Senolytic Drugs.". Aging Cell. 14: 644–58. doi:10.1111/acel.12344. PMID 25754370. Retrieved March 2015. Check date values in: |access-date= (help)
  5. 1 2 Loaiza N, Demaria M (2016). "Cellular senescence and tumor promotion: Is aging the key?". Biochimica et Biophysica Acta. 1865: 155–67. doi:10.1016/j.bbcan.2016.01.007. PMID 26845683. Retrieved 2016-02-07. We also discuss how the senescence response, initially a tumor suppressor mechanism, turns into a tumor promoter apparently as a consequence of aging. We argue that three age-related phenomena-senescence-associated secretory phenotype (SASP) dysregulation, decline in the immune system function and genomic instability-could contribute, independently or synergistically, to deteriorate the efficacy of the senescence response in stopping cancer. As a consequence, senescent cells could be considered premalignant cells, and targeting senescent cells could be a preventive and therapeutic strategy against cancer.
  6. 1 2 Lujambio, A (2016). "To clear, or not to clear (senescent cells)? That is the question". Inside the Cell. 1: 87–95. doi:10.1002/icl3.1046. Retrieved 2016-02-28. • chronic accumulation of senescent cells leads to more detrimental consequences, namely, cancer and aging.
    • the genetic elimination of p16-expressing senescent cells was recently shown to impair wound healing
  7. 1 2 Blagosklonny MV (2013). "Selective anti-cancer agents as anti-aging drugs". Cancer Biology & Therapy. 14 (12): 1092–7. doi:10.4161/cbt.27350. PMC 3912031Freely accessible. PMID 24345884. Retrieved 2015-12-27. At low doses, certain agents may decelerate aging and age-related diseases. Importantly, deceleration of aging can in turn postpone cancer, which is an age-related disease.
  8. ↑ Slack C, Alic N, Partridge L (2015). "Could cancer drugs provide ammunition against ageing?". Cell Cycle (Georgetown, Tex.). doi:10.1080/15384101.2015.1118905. PMID 26587873. Retrieved 2015-12-27. Thus, targeting the activity of these cancer prevention pathways may confer longevity effects by offering protection from metabolic pathologies during ageing, independently of effects on cancer.
  9. ↑ US Patent Application No. 20150296755 James L. Kirkland, Tamar Tchkonia, Jan M.A. van Deursen, Darren J. Baker (2015) Transgenic animals capable of being induced to delete senescent cells
  10. 1 2 Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG, van de Sluis B, Kirkland JL, van Deursen JM (2011). "Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders". Nature. 479 (7372): 232–6. doi:10.1038/nature10600. PMC 3468323Freely accessible. PMID 22048312. Retrieved 2016-02-06. Here we show that in the BubR1 progeroid mouse background, INK-ATTAC removes p16Ink4a-positive senescent cells upon drug treatment. In tissues—such as adipose tissue, skeletal muscle and eye—in which p16Ink4a contributes to the acquisition of age-related pathologies, life-long removal of p16Ink4a-expressing cells delayed onset of these phenotypes. Furthermore, late-life clearance attenuated progression of already established age-related disorders. These data indicate that cellular senescence is causally implicated in generating age-related phenotypes and that removal of senescent cells can prevent or delay tissue dysfunction and extend healthspan.
  11. ↑ Xu M, Palmer AK, Ding H, Weivoda MM, Pirtskhalava T, White TA, Sepe A, Johnson KO, Stout MB, Giorgadze N, Jensen MD, LeBrasseur NK, Tchkonia T, Kirkland JL (2015). "Targeting senescent cells enhances adipogenesis and metabolic function in old age". eLife. 4: e12997. doi:10.7554/eLife.12997. PMC 4758946Freely accessible. PMID 26687007. Retrieved 2016-02-10.
  12. 1 2 Baker DJ, Childs BG, Durik M, Wijers ME, Sieben CJ, Zhong J, A Saltness R, Jeganathan KB, Verzosa GC, Pezeshki A, Khazaie K, Miller JD, van Deursen JM (2016). "Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan". Nature. 530: 184–9. doi:10.1038/nature16932. PMID 26840489. To explore the physiological relevance and consequences of naturally occurring senescent cells, here we use a previously established transgene, INK-ATTAC, to induce apoptosis in p16Ink4a-expressing cells of wild-type mice by injection of AP20187 twice a week starting at one year of age. We show that compared to vehicle alone, AP20187 treatment extended median lifespan in both male and female mice of two distinct genetic backgrounds. The clearance of p16Ink4a-positive cells delayed tumorigenesis and attenuated age-related deterioration of several organs without apparent side effects, including kidney, heart and fat, where clearance preserved the functionality of glomeruli, cardio-protective KATP channels and adipocytes, respectively.
  13. ↑ Kirkland JL, Tchkonia T (2015). "Clinical strategies and animal models for developing senolytic agents". Experimental Gerontology. 68: 19–25. doi:10.1016/j.exger.2014.10.012. PMID 25446976. Retrieved 2015-12-28. Development of the optimal animal models and clinical trial paradigms for senolytic agents warrants an intensive effort, since senolytic agents, if successful in delaying, preventing, alleviating, or reversing age-related diseases as a group would be transformative.
  14. ↑ Shoemaker AR, Mitten MJ, Adickes J, Ackler S, Refici M, Ferguson D, Oleksijew A, O'Connor JM, Wang B, Frost DJ, Bauch J, Marsh K, Tahir SK, Yang X, Tse C, Fesik SW, Rosenberg SH, Elmore SW (2008). "Activity of the Bcl-2 family inhibitor ABT-263 in a panel of small cell lung cancer xenograft models". Clinical Cancer Research. 14 (11): 3268–77. doi:10.1158/1078-0432.CCR-07-4622. PMID 18519752. Retrieved 2015-12-30. The purpose of this study was to characterize the activity of the Bcl-2 protein family inhibitor ABT-263 in a panel of small cell lung cancer (SCLC) xenograft models.
  15. 1 2 Zhu, Yi; Tchkonia, T; Fuhrmann-Stroissnigg, H; Dai, HM; Ling, YY; Stout, MB; Pirtskhalava, T; Giorgadze, N; Johnson, KO; Giles, CB; Wren, JD; Niedernhofer, LJ; Robbins, PD; Kirkland, JL (2015). "Identification of a Novel Senolytic Agent, Navitoclax, Targeting the Bcl-2 Family of Anti-Apoptotic Factors". Aging Cell. doi:10.1111/acel.12445. PMID 26711051. This led to identification of dasatinib (D) and quercetin (Q) as senolytics, agents that target some of these pathways and induce apoptosis preferentially in senescent cells. Among other pro-survival regulators identified was Bcl-xl. Here, we tested if the Bcl-2 family inhibitors, navitoclax (N) and TW-37 (T), are senolytic. Like D and Q, N is senolytic in some, but not all types of senescent cells: N reduced viability of senescent human umbilical vein epithelial cells (HUVECs), IMR90 human lung fibroblasts, and murine embryonic fibroblasts (MEFs), but not human primary preadipocytes, consistent with our previous finding that Bcl-xl siRNA is senolytic in HUVECs, but not preadipocytes.
  16. 1 2 Chang J, Wang Y, Shao L, Laberge RM, Demaria M, Campisi J, Janakiraman K, Sharpless NE, Ding S, Feng W, Luo Y, Wang X, Aykin-Burns N, Krager K, Ponnappan U, Hauer-Jensen M, Meng A, Zhou D (2015). "Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice". Nature Medicine. 22: 78–83. doi:10.1038/nm.4010. PMID 26657143. Retrieved 2015-12-23. Oral administration of ABT263 to either sublethally irradiated or normally aged mice effectively depleted SCs, including senescent bone marrow hematopoietic stem cells (HSCs) and senescent muscle stem cells (MuSCs). Notably, this depletion mitigated TBI-induced premature aging of the hematopoietic system and rejuvenated the aged HSCs and MuSCs in normally aged mice. Our results demonstrate that selective clearance of SCs by a pharmacological agent is beneficial in part through its rejuvenation of aged tissue stem cells.
  17. ↑ Wilson WH, O'Connor OA, Czuczman MS, LaCasce AS, Gerecitano JF, Leonard JP, Tulpule A, Dunleavy K, Xiong H, Chiu YL, Cui Y, Busman T, Elmore SW, Rosenberg SH, Krivoshik AP, Enschede SH, Humerickhouse RA (2010). "Navitoclax, a targeted high-affinity inhibitor of BCL-2, in lymphoid malignancies: a phase 1 dose-escalation study of safety, pharmacokinetics, pharmacodynamics, and antitumour activity". The Lancet. Oncology. 11 (12): 1149–59. doi:10.1016/S1470-2045(10)70261-8. PMC 3025495Freely accessible. PMID 21094089. Retrieved 2015-12-30. Navitoclax has a novel mechanism of peripheral thrombocytopenia and T-cell lymphopenia, attributable to high-affinity inhibition of BCL-XL and BCL-2, respectively.
  18. ↑ Kaefer A, Yang J, Noertersheuser P, Mensing S, Humerickhouse R, Awni W, Xiong H (2014). "Mechanism-based pharmacokinetic/pharmacodynamic meta-analysis of navitoclax (ABT-263) induced thrombocytopenia". Cancer Chemotherapy and Pharmacology. 74 (3): 593–602. doi:10.1007/s00280-014-2530-9. PMID 25053389. Retrieved 2015-12-30. Thrombocytopenia is a primary dose-limiting toxicity of navitoclax which exhibited a distinct time profile in circulating platelets from that caused by traditional chemotherapies.
  19. ↑ Roos CM, Zhang B, Palmer AK, Ogrodnik MB, Pirtskhalava T, Thalji NM, Hagler M, Jurk D, Smith LA, Casaclang-Verzosa G, Zhu Y, Schafer MJ, Tchkonia T, Kirkland JL, Miller JD (2016). "Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice". Aging Cell. doi:10.1111/acel.12458. PMID 26864908. Retrieved 2016-02-15. This is the first study to demonstrate that chronic clearance of senescent cells improves established vascular phenotypes associated with aging and chronic hypercholesterolemia, and may be a viable therapeutic intervention to reduce morbidity and mortality from cardiovascular diseases.
  20. 1 2 3 4 Demaria M, Ohtani N, Youssef SA, Rodier F, Toussaint W, Mitchell JR, Laberge RM, Vijg J, Van Steeg H, Dollé ME, Hoeijmakers JH, de Bruin A, Hara E, Campisi J (2014). "An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA". Developmental Cell. 31 (6): 722–33. doi:10.1016/j.devcel.2014.11.012. PMC 4349629Freely accessible. PMID 25499914. Retrieved 2016-03-19.
    • Thus, elimination of senescent cells by GCV depleted wound sites of myofibroblasts, consistent with the slower wound healing shown by GCV-treated p16-3MR mice.
    • These data support a positive role for senescent cells during tissue repair and help to explain why the SASP evolved.
    • In agreement with previous findings (Jun and Lau, 2010; Krizhanovsky et al., 2008), we also found that the presence of senescent cells restrains fibrosis.
    • These data indicate that senescent cells facilitate cutaneous wound repair and that their absence significantly retards the kinetics of wound closure.
  21. 1 2 3 4 Labi V, Erlacher M (2015). "How cell death shapes cancer". Cell Death & Disease. 6: e1675. doi:10.1038/cddis.2015.20. PMC 4385913Freely accessible. PMID 25741600. Retrieved 2015-12-27.

Further reading

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