Reviewing Recent Work on the Mechanisms of Cellular Senescence

Impressive results have been produced in mice via clearance of senescent cells: rejuvenation, extension of life, and reversal of numerous different age-related conditions. This has provoked an increasing number of research groups to focus on the mechanisms of cellular senescence, in search of novel ways to identify and destroy these cells, or to suppress the senescence-associated secretory phenotype (SASP) that they produce. The secreted signal molecules of the SASP alter surrounding cell behavior and rouse the immune system to chronic inflammation. This is the means by which the comparatively small number of lingering senescent cells present in late life can produce such a sweeping disruption of tissue function and health.

One of the key stumbling blocks in the field of senescence is the lack of a single, universal, robust, biomarker that allows identification of senescent cells with high sensitivity and specificity and is capable of differentiating them from terminally differentiated, quiescent, and other non-dividing cells. Growth arrest is a key feature which can be readily demonstrated in vitro using assays that measure DNA synthesis. However, DNA synthesis measurement is not totally specific since DNA repair may still be active. Measuring the expression levels of p16INK4A and p21WAF1/CIP1 are key to detecting cell cycle arrest but are not expressed persistently particularly p21WAF1/CIP1 by senescent cells. Accumulation of high levels of p16INK4A is required to maintain the senescent state enabling it to be extensively used as a marker for senescence in most normal untransformed cells and tissues. However, p16INK4A is also expressed in non-senescent cells and cells that are transiently arrested, and senescence can also occur independently of p16INK4A. Coupled with the lack of specific antibodies, this limits its use as a biomarker for senescence.

Accumulating evidence has demonstrated that both anti-senescence and pro-senescence therapies could be beneficial depending on the context. Pro-senescence therapies help limit damage by restraining proliferation and fibrosis during carcinogenesis and active tissue repair whereas anti-senescence agents enable elimination of accumulated senescent cells to restore tissue function, and potentially aid organ rejuvenation. It has been found that cells which escape from senescence post-chemotherapy re-enter the cell cycle, are highly aggressive, chemo-resistant, and exhibit stem cell characteristics and can contribute to cancer recurrence. Since several therapeutic modalities trigger senescence in tumors, it is important to decipher the mechanisms involved in the escape from senescence as a more detailed understanding may allow the development of better therapies and also help to reduce the off-target effects contributing to unwanted toxicity.

A thorough understanding of SASP regulation is required to exploit it for therapeutic purposes. There is a growing need for further research to investigate how the different signaling pathways regulating SASP such as p38MAPK, mTOR, GATA4, TAK1, cGAS/cGAMP/STING are interconnected and how SASP manifests the age-related pathologies. Inhibition of SASP without perturbing the stable growth arrest would allow reduction of the deleterious effects while maintaining tissue homeostasis and other physiological roles. However, targeting SASP for therapeutic purposes has to be undertaken with great care since it has both beneficial and deleterious roles due to the plethora of components.

Identification of key SASP factors secreted by senescent cells in aged tissues and residual tumors in the post-treatment period might have potential as biomarkers for real-time medical surveillance. The advent of powerful genetic and pharmacological tools to dissect the relationship between accumulated senescent cells and aging should improve our understanding of how accumulated senescent cells lead to age associated decline.

Link: https://doi.org/10.3389/fcell.2021.645593

Comments

Biomarkers do need to be found. Otherwise we can't determine dose, effectiveness, overdoing it, etc. As the article states, this is very difficult. There may be hope for a skin bio marker however…

https://www.lifespan.io/news/skin-aging/

Posted by: august33 at May 11th, 2021 9:51 PM

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