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Do primary and secondary senescent cells have different consequences?

Image credit: Hoare 2017 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5345188/

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Shubhankar Kulkarni
Shubhankar Kulkarni Aug 20, 2020
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Necessity

Is the problem still unsolved?

Conciseness

Is it concisely described?

Whether primary and secondary senescent cells have different consequences is not currently known. What kind of experiments can be performed to gain a better understanding?

The composition of the senescence-associated secretory phenotype (SASP) depends on the cell type and the inducer of senescence. The factors of SASP induce senescence in a paracrine manner in the neighboring cells. However, two distinct effects of SASP were observed on the target cell populations - a primary endpoint marked by Ras and a secondary endpoint marked by Notch activation. The primary endpoint is characterized by upregulation of pro-inflammatory cytokines, promoting lymphocyte recruitment and senescence surveillance. The secondary oncogene-induced senescence is characterized by the requirement of Notch signaling along with SASP factors, a blunted (immunosuppressive) SASP response, and other transcriptional differences.

The primary senescence uses SASP factors to induce senescence while the secondary Notch-driven senescence promotes ‘lateral induction of senescence’ using a juxtacrine pathway. Also, Notch inhibition during senescence promotes the primary endpoint in vivo. It is, therefore, suggested that Notch activity during senescence controls the SASP composition.

However, whether the two SASP mechanisms have different biological consequences is not known. This information is important for the development of therapeutics that can stop the paracrine spread of senescence. Upregulation of Notch signaling can be used to promote the secondary senescent phenotype. Since the secondary phenotype induces senescence only in cells that are in direct contact, mechanical removal of the senescent cells may prove beneficial.

[1]Moreno-Blas D, Gorostieta-Salas E, Pommer-Alba A, Muciño-Hernández G, Ger�nimo-Olvera C, Maciel-Bar�n LA, et al. Cortical neurons develop a senescence-like phenotype promoted by dysfunctional autophagy. Aging (Albany NY) [Internet]. 2019 Aug 30;11(16). Available from: http://www.aging-us.com/article/102181/text?_escaped_fragment_=

[2]Anderson R, Lagnado A, Maggiorani D, Walaszczyk A, Dookun E, Chapman J, et al. Length‐independent telomere damage drives post‐mitotic cardiomyocyte senescence. EMBO J [Internet]. 2019 Mar 8;38(5). Available from: https://onlinelibrary.wiley.com/doi/abs/10.15252/embj.2018100492

[3]Schmeer C, Kretz A, Wengerodt D, Stojiljkovic M, Witte OW. Dissecting Aging and Senescence—Current Concepts and Open Lessons. Cells [Internet]. 2019 Nov 15;8(11):1446. Available from: https://www.mdpi.com/2073-4409/8/11/1446

[4]Hoare M, Narita M. NOTCH and the 2 SASPs of senescence. Cell Cycle [Internet]. 2017 Feb 1;16(3):239–40. Available from: https://www.tandfonline.com/doi/full/10.1080/15384101.2016.1248730

[5]Teo YV, Rattanavirotkul N, Olova N, Salzano A, Quintanilla A, Tarrats N, et al. Notch Signaling Mediates Secondary Senescence. Cell Rep [Internet]. 2019 Apr;27(4):997-1007.e5. Available from: https://linkinghub.elsevier.com/retrieve/pii/S2211124719304516

[6]Hoare M, Ito Y, Kang T-W, Weekes MP, Matheson NJ, Patten DA, et al. NOTCH1 mediates a switch between two distinct secretomes during senescence. Nat Cell Biol [Internet]. 2016 Sep 15;18(9):979–92. Available from: http://www.nature.com/articles/ncb3397

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