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Senescent Cell Clearance Declines With Age

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A new study sheds light on the accumulation of senescent cells and suggests that therapies that remove them could be beneficial both immediately and in the long term for human health and longevity.

Normally, as cells become damaged beyond repair, exhausted, and no longer able to replicate, they are removed from the body via a process known as apoptosis, which is a kind of self-destruct program initiated by the cell, or removed by the immune system. This system acts as a safety net to prevent damaged cells from remaining active and, in the context of cells damaged by mutations, a way to prevent cancer.

Unfortunately, as we age, this disposal system, like many others in our body, begins to falter and ultimately fail. This leads to the accumulation of unwanted, damaged senescent cells in every tissue of our body. This build-up of senescent cells is one of the proposed reasons we age and has been the focus of intense research in the last few years.

While senescent cells are eventually cleared even in older people, the process is painfully slow compared to when we are younger, and these cells might linger for years, resisting apoptosis and preventing the immune system from removing them. This new study suggests that senescent cells accumulate primarily because our natural disposal systems slow down to the point that they can no longer keep pace with the accumulation of these cells.

Senescent cells comprise a small number of total cells in the body, but they secrete proinflammatory cytokines, chemokines, and extracellular matrix proteases, which, together, form the senescence-associated secretory phenotype, or SASP. The SASP contributes to the chronic low-grade background of inflammation that is typically observed in older people, harms tissue repair and regeneration, and is implicated in the development of many age-related diseases.

The SASP is thought to significantly contribute to aging [1] and cancer [2]; thus, some researchers believe that the removal of the SASP is a potential strategy for promoting health and longevity.

Senolytics may be the solution

If it is the case that the accumulation of senescent cells is primarily due to the decline of clearance processes, as this new study suggests, then this has implications for senolytics, which are therapies that are designed to remove these cells [3]. Senolytics are a new class of therapies that encourage stubborn senescent cells to stop resisting apoptosis and destroy themselves.

However, it is not quite as simple as using a drug to induce these cells to enter apoptosis, as there is a great deal of variation between populations of senescent cells, and each cell is somewhat unique. Different senescent cells use different strategies to avoid destruction: some favor one pro-survival pathway, and others use alternative pathways to remain alive.

Therefore, there is no single drug that can target every type of senescent cell, and the race is now on to discern just how many kinds of senescent cells there are and what pathways they are using in order to develop effective therapies against them. It is likely that, ultimately, a “cocktail” of drugs will be necessary to hit all the survival pathways that these varied cells use in order to remove significant numbers of them.

Fortunately, it is likely that these subtypes of senescent cells and their pathways will soon be understood and that effective removal therapies will follow. There are now multiple companies working on senolytic therapies that address the already known pathways that these cells use to evade cell death, so it really is just a matter of time before comprehensive therapies are developed and move to the clinic.

A causal factor in mammalian aging is the accumulation of senescent cells (SnCs). SnCs cause chronic inflammation, and removing SnCs decelerates aging in mice. Despite their importance, turnover rates of SnCs are unknown, and their connection to aging dynamics is unclear. Here we use longitudinal SnC measurements and induction experiments to show that SnCs turn over rapidly in young mice, with a half-life of days, but slow their own removal rate to a half-life of weeks in old mice. This leads to a critical-slowing-down that generates persistent SnC fluctuations. We further demonstrate that a mathematical model, in which death occurs when fluctuating SnCs cross a threshold, quantitatively recapitulates the Gompertz law of mortality in mice and humans. The model can go beyond SnCs to explain the effects of lifespan-modulating interventions in Drosophila and C. elegans, including scaling of survival-curves and rapid effects of dietary shifts on mortality.

Our results suggest that treatments that remove SnCs can therefore have a double benefit: an immediate benefit from a reduced SnC load, and a longer-term benefit from increased SnC removal. Similarly, interventions that increase removal capacity, for example by augmenting the immune surveillance of SnC, are predicted to be an effective approach to reduce SnC levels. More generally, the present combination of experiment and theory can be extended to explore further stochastic processes in aging, in order to bridge between the population-level and molecular-level understanding of aging.


This study has some potentially interesting implications for senolytics because, as its results suggest, the effective removal of these problem cells could not only quickly reduce the pro-inflammatory SASP, potentially improving tissue regeneration and repair, but, in the long term, could also increase the rate of senescent cell removal.

Therapies that remove senescent cells hold a great deal of potential, as do those that can increase our innate removal capacity, including boosting the immune system so that it destroys these cells more rapidly. If the current human trials of senolytics match the results seen in animal studies, and there is plenty of reason to believe they might, they have the possibility of dramatically changing the way we age and how we address age-related diseases.

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[1] Freund, A., Orjalo, A. V., Desprez, P. Y., & Campisi, J. (2010). Inflammatory networks during cellular senescence: causes and consequences. Trends in molecular medicine, 16(5), 238-246.

[2] Coppé, J. P., Desprez, P. Y., Krtolica, A., & Campisi, J. (2010). The senescence-associated secretory phenotype: the dark side of tumor suppression. Annual review of pathology, 5, 99.

[3] Karin, O., Agrawal, A., Porat, Z., Krizhanovsky, V., & Alon, U. (2019). Senescent cell turnover slows with age providing an explanation for the Gompertz law. Nature Communications, 10(1), 1-9.

About the author

Steve Hill

Steve serves on the LEAF Board of Directors and is the Editor in Chief, coordinating the daily news articles and social media content of the organization. He is an active journalist in the aging research and biotechnology field and has to date written over 600 articles on the topic, interviewed over 100 of the leading researchers in the field, hosted livestream events focused on aging, as well as attending various medical industry conferences. His work has been featured in H+ magazine, Psychology Today, Singularity Weblog, Standpoint Magazine, Swiss Monthly, Keep me Prime, and New Economy Magazine. Steve is one of three recipients of the 2020 H+ Innovator Award and shares this honour with Mirko Ranieri – Google AR and Dinorah Delfin – Immortalists Magazine. The H+ Innovator Award looks into our community and acknowledges ideas and projects that encourage social change, achieve scientific accomplishments, technological advances, philosophical and intellectual visions, author unique narratives, build fascinating artistic ventures, and develop products that bridge gaps and help us to achieve transhumanist goals. Steve has a background in project management and administration which has helped him to build a united team for effective fundraising and content creation, while his additional knowledge of biology and statistical data analysis allows him to carefully assess and coordinate the scientific groups involved in the project.
  1. December 17, 2019

    There’s a decent chance some if these senolytics will end up being effective treatments for fibrotic diseases as well — that is, the senolytics that target antiapoptotic mechanisms also used by persistent myofibroblasts. And as I understand it, different myofibroblasts in different tissues utilize different pro-survival pathways as well

    It would be nice if significant treatments for IPF (a nasty disease), Dupuytren’s Contracture, Peyronie’s, scleroderma, etc, came along for the ride.

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