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Review
. 2020 Dec;19(12):e13270.
doi: 10.1111/acel.13270. Epub 2020 Nov 9.

On the evolution of cellular senescence

Axel Kowald  1   2 , João F Passos  3 , Thomas B L Kirkwood  1   4
Affiliations
Review

On the evolution of cellular senescence

Axel Kowald et al. Aging Cell. 2020 Dec.

Abstract

The idea that senescent cells are causally involved in aging has gained strong support from findings that the removal of such cells alleviates many age-related diseases and extends the life span of mice. While efforts proceed to make therapeutic use of such discoveries, it is important to ask what evolutionary forces might have been behind the emergence of cellular senescence, in order better to understand the biology that we might seek to alter. Cellular senescence is often regarded as an anti-cancer mechanism, since it limits the division potential of cells. However, many studies have shown that senescent cells often also have carcinogenic properties. This is difficult to reconcile with the simple idea of an anti-cancer mechanism. Furthermore, other studies have shown that cellular senescence is involved in wound healing and tissue repair. Here, we bring these findings and ideas together and discuss the possibility that these functions might be the main reason for the evolution of cellular senescence. Furthermore, we discuss the idea that senescent cells might accumulate with age because the immune system had to strike a balance between false negatives (overlooking some senescent cells) and false positives (destroying healthy body cells).

Keywords: aging; anti-aging; cellular senescence; evolution; senolytics.

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Conflict of interest statement

The authors declare that there are no conflicts of interest.

Figures

Figure 1
Figure 1
Cellular senescence has been suggested to be an anti‐cancer strategy. However, the senescence‐associated secretory phenotype (SASP) has many negative consequences (shown in red), which are difficult to reconcile with this idea
Figure 2
Figure 2
The curves show a typical relationship between time (i.e., organismal age) and the level of senescent cells, SC, under scenario 1. The plot on the left side shows the results on a linear scale, while the right plot displays SC on a logarithmic scale. Parameters used were k = 0.01 and d = 100 with the shown values for c. For this simple model SC is given in arbitrary units
Figure 3
Figure 3
The curves show a typical relationship between time and the level of senescent cells, SC under scenario 2. The plot is drawn on a logarithmic scale and shows the accumulation of SC for various values of the parameter p. Other parameters used were IM=1, k = 0.01 and d = 100
Figure 4
Figure 4
Left: Typical relationship between time and the level of removable and non‐removable senescent cells under scenario 3. Parameters used are IM=1, k = 0.01, p = 20, d = 100 and a = 0.99. Right: Sum of SCr and SCn with parameters fitted to longitudinal measurements of senescent cells taken from Burd et al. (2013) and normalized to give a mean abundance of 1 at 24 weeks of age. Best fit parameters: k = 0.148, p = 0.128, d = 0.637 and a = 0.883 (with IM = 1)
Figure 5
Figure 5
Cellular senescence might have evolved as a tissue repair strategy. In this case, senescent cells were only present temporarily and their SASP would serve a meaningful purpose. According to this proposal, senescent cells would accumulate and cause negative effects (shown in red) because the immune system is not capable of performing a complete immune clearance (see main text for details)
See this image and copyright information in PMC

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