Removing Some Senescent Cells May Have Consequences



Senescent cell accumulation is a likely reason we age, but removing some populations of specialized cells that have turned senescent may have negative consequences, according to a new study.

What are senescent cells?

As you get older, more and more of your cells enter into a state known as cellular senescence. Senescent cells no longer divide or support the tissues of which they are part; instead, they secrete a variety of proinflammatory cytokines, chemokines, and extracellular matrix proteases, which, together, form the senescence-associated secretory phenotype, or SASP.

The SASP increases the level of chronic inflammation, leads to impaired tissue repair, and is linked to the progression of various age-related diseases. If that is not bad enough, their presence can cause nearby healthy cells to become senescent after exposure to the SASP.

Senescent cells normally destroy themselves via a programmed process called apoptosis, and they are also removed by the immune system; however, the immune system weakens with age, and increasing numbers of senescent cells escape this process and begin to accumulate in all the tissues of the body.


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By the time people reach old age, significant numbers of these senescent cells have built up, causing chronic inflammation and damage to surrounding cells and tissue. The accumulation of senescent cells is thought to be one of the proposed reasons we age.

Removing senescent cells may not be without some risks

One proposed solution to the problem of senescent cell accumulation and the resulting pro-inflammatory SASP is their therapeutic removal through a new class of drugs known as senolytics. Various past animal studies have shown that the removal of senescent cells appears to be beneficial to health and, in some studies, increases healthy lifespan.

These results have been replicated enough times in the past few years that senolytics should be considered a viable approach to treating aging and its resulting age-related diseases.

However, despite these promising results and the current efforts underway to translate them to people in clinical trials, there are some researchers who caution against senolytic, as senescence is partially an adaptive response to aging, and disturbing it could be harmful.


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Another concern is that some specialized cell populations do not replace themselves, such as heart cells and, later in life when the thymus shrinks and barely works, T cells. The concern is that removing these specialized cells, even though they are senescent and clearly causing harm via their secretions, could lead to worse consequences. Stem cell exhaustion is another proposed reason we age, and it is plausible that removing highly specialized populations of cells without providing for their replacements could accelerate that aging process.

Today, we want to highlight a new study that suggests a specialized population of liver endothelial cells could be one such cell population at risk from senolytics [1].

The accumulation of senescent cells can drive many age-associated phenotypes and pathologies. Consequently, it has been proposed that removing senescent cells might extend lifespan. Here, we generated two knockin mouse models targeting the best-characterized marker of senescence, p16Ink4a. Using a genetic lineage tracing approach, we found that age-induced p16High senescence is a slow process that manifests around 10–12 months of age. The majority of p16High cells were vascular endothelial cells mostly in liver sinusoids (LSECs), and to lesser extent macrophages and adipocytes. In turn, continuous or acute elimination of p16High senescent cells disrupted blood-tissue barriers with subsequent liver and perivascular tissue fibrosis and health deterioration. Our data show that senescent LSECs are not replaced after removal and have important structural and functional roles in the aging organism. In turn, delaying senescence or replacement of senescent LSECs could represent a powerful tool in slowing down aging.


Does removing these specialized but senescent populations of cells outweigh the harm that they would otherwise do by their secreted SASP? It seems doubtful, given the broadly positive results that previous studies have shown when senolytic therapies are used systemically. However, removing them may open another can of worms and, in the long term, may accelerate another aging process, such as stem cell exhaustion.

If this is the case, then replacing senescent cells is something that should be done in combination with senolytic therapies that remove them; fortunately, that is something that has been suggested long ago and is part of the proposed toolkit for treating aging, which has solutions for every reason we age.


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[1] Grosse, L., Wagner, N., Emelyanov, A., Molina, C., Lacas-Gervais, S., Wagner, K. D., & Bulavin, D. V. (2020). Defined p16High Senescent Cell Types Are Indispensable for Mouse Healthspan. Cell Metabolism.

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.