Facebook PixelDoes the "bystander effect" affect the rate of aging?
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Does the "bystander effect" affect the rate of aging?

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Shubhankar Kulkarni
Shubhankar Kulkarni Jul 28, 2020
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Can we come up with an experiment to test whether the "bystander effect" affects the rate of aging?

Continuous exposure to senescent cells induces cell senescence in intact bystander fibroblasts, spreading senescence towards their neighbors in vitro and, possibly, in vivo. The underlying mechanism of this bystander effect is probably the pro-oxidant and pro-inflammatory signals (especially, reactive oxygen species) from primary senescent founder cells triggering DNA damage and premature senescence in surrounding primary cells. This may contribute to the increasing frequency of senescent cells with age and to the impact senescent cells may have upon their environment.

However, whether the bystander effect affects the rate of aging is not known.

Application: Elimination of senescent cells attenuates tissue inflammation, probably due to reduced secretion of the senescent cells, leading to suppression of the bystander effect and slowdown of damage accumulation. If the inhibition of the bystander effect reduces the rate of aging, that can be a therapeutic opportunity.

[1]Nelson G, Wordsworth J, Wang C, Jurk D, Lawless C, Martin-Ruiz C, et al. A senescent cell bystander effect: senescence-induced senescence. Aging Cell [Internet]. 2012 Apr;11(2):345–9. Available from: http://doi.wiley.com/10.1111/j.1474-9726.2012.00795.x

[2]Xu M, Palmer AK, Ding H, Weivoda MM, Pirtskhalava T, White TA, et al. Targeting senescent cells enhances adipogenesis and metabolic function in old age. Elife [Internet]. 2015 Dec 19;4. Available from: https://elifesciences.org/articles/12997

[3]Baker DJ, Childs BG, Durik M, Wijers ME, Sieben CJ, Zhong J, et al. Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Nature [Internet]. 2016 Feb 3;530(7589):184–9. Available from: http://www.nature.com/articles/nature16932

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Possibly, through a chronic inflammation mediated by IL17

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J. Nikola
J. Nikola Feb 01, 2022
In 2020 paper , scientists wanted to understand how can implants made of synthetic materials induce an immune-mediated process and potentiate the formation of a fibrous capsule around an implant.
They analyzed fibrotic capsules from 12 patients and found increased numbers of interleukin 17 (IL17)-producing γδ+ T cells and CD4+ T helper 17 (TH17) cells as well as senescent stromal cells in the fibrotic capsules. They did additional research on mice and found that there was an early innate IL-17 response to the implant material mediated by innate lymphoid cells and γδ+ T cells, which was followed by chronic adaptive CD4+ TH17 cell response that was antigen-dependent, that finally led to chronic IL-17 production in response to synthetic material and - fibrosis. When IL17A−/− and IL17RA−/− knockout mice were used, no fibrotic response and p16INK4a senescent cells occurred. IL6 produced by senescent cells was sufficient for the induction of IL17 expression in T cells. Treatment with a senolytic agent (navitoclax) that killed senescent cells reduced IL17 expression and fibrosis in the mouse implant model.
That meant that:
  • SASP secreted by senescent cells includes cytokines associated with a TH17 immune response including IL6 and IL1β
  • these findings support the connection between IL17 production and senescent cell formation
This could mean that bystander effect you are talking about
  • is happening due to chronic inflammation mediated by IL-17 signaling
  • further supported by the SASP and IL-6 from senescent cells
  • which act in a chronic positive-feedback-loop manner with Th17
  • whic ll raesults in faster and faster aging with increasing number of senescent cells
It could also prove how senolytic cell clearance manages to reduce inflammatory processes and reduce the rate of aging. The important thing to find out why the senescent cells appeared at the site of inflammation.
What do you think?

[1]https://pubmed.ncbi.nlm.nih.gov/32295900/#:~:text=Mice%20deficient%20in%20IL17%20signaling,IL17%20expression%20in%20T%20cells.

[2]https://www.biorxiv.org/content/10.1101/2022.01.31.478459v1

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Shubhankar Kulkarni
Shubhankar Kulkarni4 months ago
Great find J. Nikola! I think as the number of senescent cells increases, the chances that healthy cells turn senescent also increase. This, in turn, increases the rate of aging. Senolytics postpone aging by reducing the senescent cells and, thereby, decreasing the bystander effect. Is there any other way the bystander effect increases "the rate" of aging?
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J. Nikola
J. Nikola4 months ago
Shubhankar Kulkarni What exactly do you mean by the rate of aging? I would say yes, due to the chronic inflammation, that drives more cells into senescence, that drives more inflammation, that drives more cells into senescence, that drives.... :)
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J. Nikola
J. Nikola4 months ago
Another paper showed the same principle of IL-17 and senescent cells feedback loop that could increase aging.

[1]https://www.jci.org/articles/view/134091

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