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Can we differentiate between beneficial and detrimental senescent cells?

Image credit: https://www.nature.com/articles/s41570-019-0108-0?platform=oscar&draft=collection

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Shubhankar Kulkarni
Shubhankar Kulkarni Aug 04, 2020
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Senescence is not always detrimental to human health. During embryonic development, programmed senescence eliminates senescent cells and reshapes tissues, and loss of senescence at this stage leads to developmental abnormalities. Senescence also improves glucose homeostasis and tissue repair and regeneration and elimination of senescent cells hampers these processes. Even optimum exposure to senescence-associated secretory phenotype was shown to initiate pro-regenerative stemness (cellular plasticity) in mouse keratinocytes.

Therefore, is there a difference between beneficial and detrimental senescent cells or is it completely context-dependent?

[1]Muñoz-Espín D, Cañamero M, Maraver A, Gómez-López G, Contreras J, Murillo-Cuesta S, et al. Programmed Cell Senescence during Mammalian Embryonic Development. Cell [Internet]. 2013 Nov;155(5):1104–18. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0092867413012956

[2]Storer M, Mas A, Robert-Moreno A, Pecoraro M, Ortells MC, Di Giacomo V, et al. Senescence Is a Developmental Mechanism that Contributes to Embryonic Growth and Patterning. Cell [Internet]. 2013 Nov;155(5):1119–30. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0092867413013597

[3]Helman A, Klochendler A, Azazmeh N, Gabai Y, Horwitz E, Anzi S, et al. p16Ink4a-induced senescence of pancreatic beta cells enhances insulin secretion. Nat Med [Internet]. 2016 Apr 7;22(4):412–20. Available from: http://www.nature.com/articles/nm.4054

[4]Demaria M, Ohtani N, Youssef SA, Rodier F, Toussaint W, Mitchell JR, et al. An Essential Role for Senescent Cells in Optimal Wound Healing through Secretion of PDGF-AA. Dev Cell [Internet]. 2014 Dec;31(6):722–33. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1534580714007291

[5]Ritschka B, Storer M, Mas A, Heinzmann F, Ortells MC, Morton JP, et al. The senescence-associated secretory phenotype induces cellular plasticity and tissue regeneration. Genes Dev [Internet]. 2017 Jan 15;31(2):172–83. Available from: http://genesdev.cshlp.org/lookup/doi/10.1101/gad.290635.116

senescencelongevity
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Jamila
Jamila Aug 10, 2020
When senescent cells have targeted specific cells and completed their job (tissue remodelling, embryonic development, etc) the immune cells easily remove them; this is termed as acute senescence. However, prolonged cellular stress can induce chronic senescence, and that’s where the issues begin. In chronic senescence, specific cell types are not targeted and the senescent cells are not cleared away efficiently. It is already known that the immune system function deteriorates with age; therefore, the immune cells may not be able to cope with the accumulation of senescent cells. Furthermore, the ability of immune cells to clear the senescent cells may depend on SASP.(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4214092/) It does seem that there are differences between early-stage and late-stage senescent cells. Acute senescence is a tightly controlled process, whereas, chronic senescence is highly dysregulated. The differences between early and late-stage senescent cells should be further explored. It seems that a combination of these chronic senescent cells (late-stage) and the conditions may promote the negative effects of cellular senescence and thus accelerate aging.
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In vitro experiment idea - senescent cells with and without key ageing markers

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jnikola
jnikola Aug 05, 2022
Why?
  • if senescence can be good (as Shubhankar Kulkarni mentioned), but can also be bad (causing or due to ageing), maybe we can differ senescent cells by checking their "ageing clocks"
How would it work?
DNA damage
One way to do it would be to check the amount of DNA damage in the cells. There are many mutations, misfolded proteins or corresponding epigenetic changes that can serve as markers of DNA damage. For example, DNA damage repair biomarkers could be checked within a custom-made palette. Cells that have both senescence and DNA damage repair proteins in high abundance could be considered non-beneficial senescent cells. It could be done by simple cell extraction and sequencing, or by in vivo probing with probes bound to fluorescent proteins.
Telomere length
The other way to do it could be to check the telomere length of the senescent cells. Since telomeres are shortening with age, their lenghts could be good markers differing if senescence was beneficial or detrimental. This could be done in vitro by flow cytometry FISH protocols , but for a rapid in vivo testing, a new method should be developed. Cells that are positive for senescence biomarkers and have shorter telomeres could be considered non-beneficially senescent and those with long could be considered to be senescent for reasons beneficial to the organism.

[1]https://www.ptglab.com/products/featured-products/dna-damage-repair-markers/

[2]https://www.nature.com/articles/leu20106

[3]https://www.nature.com/articles/nprot.2006.263

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Shubhankar Kulkarni
Shubhankar Kulkarni2 years ago
Thank you for reviving the challenge! I like the idea. When you said "Cells that have both senescence and DNA damage repair proteins in high abundance could be considered non-beneficial senescent cells," you meant "beneficial cells", right? Since they have the DNA damage repair proteins that can still repair the revitalize the cell.
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jnikola
jnikola2 years ago
Shubhankar Kulkarni It's an interesting problem, so I would also like to see it solved :) Well, I agree with you that it's poorly written. What I want to say is that I would develop a palette of antibodies that detect proteins related to senescence and increased DNA damage. In that sense, these proteins, if found in high abundance, would signal that this senescence could be detrimental. If only senescence-related proteins were recorded, but DNA damage is still low, they could be considered beneficially senescent.
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Is there a fairly simple answer that opens a new question?

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jnikola
jnikola Dec 02, 2022
I was thinking a lot about this topic and want to comment on it.
Redefining what's beneficial and what's detrimental
I was a bit confused when Shubhankar Kulkarni talked about senescent cells because he defined them in a question as beneficial and detrimental. However, if the process of senescence is beneficial, the senescent cells will be cleared away. If they, on the other hand, persisted in the tissue and caused negative effects, that could be called detrimental. That's the reason why they are considered hallmarks of ageing . Since senescence is a process that pushes cells into restricted proliferation and cell cycle exit due to oncogene activation or irreparable DNA damage, I would rather try to explain senescence in terms of clearance efficiency and its relations to ageing. Therefore, I want to redefine these terms into:
  • Beneficial senescent cells --> successfully cleared senescent cells; not directly related to ageing
  • Detrimental senescent cells --> uncleared senescent cells that remain in the tissue; related to ageing = amitosenescent cells?
Now when the terms are defined, I think that could help us distinguish between wanted and unwanted senescence, or, in other words, senescence followed by clearance or senescence without the clearance. It is now obvious that the answer to Shubhankar Kulkarni's question could be:
  1. Beneficial senescent cells are beneficial if they do not exist. That's why clearing them helps slowing down ageing.
  2. Detrimental senescent cells are senescent cells that are not cleared away.
Would you agree and, if not, why?
However, this opens a new question and a possible topic:
  1. What determines if the senescent cell will be cleared or not?
Any ideas?

[1]https://pubmed.ncbi.nlm.nih.gov/23746838/

[2]https://pubmed.ncbi.nlm.nih.gov/24848057/

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Shubhankar Kulkarni
Shubhankar Kulkarni2 years ago
I agree that beneficial senescent cells could be the ones that are cleared. This is because the acute effects of the presence of senescent cells may be beneficial. If they are not cleared for some time, they show chronic effects, which are disadvantageous. Therefore, the time the senescent cells spend in the body may matter.
Beneficial senescent cells do directly affect aging because they initiate regenerative behavior. Again, this may be the acute effect and if they are not cleared, their negative effect may supersede their positive ones (regeneration).
Yes, "senescence followed by clearance and that not followed by clearance" makes much more sense. However, that does not mean that "beneficial senescent cells are beneficial if they do not exist". Beneficial senescent cells are beneficial because they DO EXIST but for a shorter duration. If they continue to exist beyond that period, they may cause negative effects and become detrimental senescent cells.
Their existence initiates the further cascade of positive effects like regeneration. I hope this is clearer.
However, your open question is valid and remains to be answered. The same question could be rephrased as "Why are some cells cleared easily (beneficial senescent cells) and the others not (detrimental senescent cells)?" Answering this will give us the difference between beneficial and detrimental senescent cells.
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jnikola
jnikola2 years ago
Shubhankar Kulkarni Thank you! Your comment makes my question more concrete and clear. I'll try to find an answer to it.
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