Could the immune system itself be the best way to purge senescent cells, which accumulate as we age, from the body? A new review takes a look at the role of the immune system in removing these problematic cells.
What are senescent cells?
As you age, increasing numbers of your cells enter into a state known as senescence. Senescent cells do not divide or support the tissues of which they are part; instead, they emit a range of potentially harmful chemical signals that encourage nearby healthy cells to enter the same senescent state. Their presence causes many problems: they reduce tissue repair, increase chronic inflammation, and can even eventually raise the risk of cancer and other age-related diseases.
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.
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. Senescent cells only make up 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.
Reviewing the immune system’s role in senescent cell accumulation
Based on past conversations with Dr. Andrei Gudkov and Dr. Alexandra Stolzing, we wondered if there were potentially better long-term solutions to senescent cells than senolytics?
Both of these leading aging researchers suggested that a potential long-term solution to senescent cells was, instead of periodically destroying them with apoptosis-inducing drugs known as senolytics, to use the immune system to clear them out.
This makes sense given that the immune system can be considered a “living drug” and, when working properly, is a highly efficient and adaptable defense system against invading pathogens, cancer, and other conditions. Unfortunately, like all our biological systems, aging takes its toll, and our immune systems begin to falter and fail in later life.
Immunosenescence, the steady deterioration of the immune system brought on by advancing age, is likely to be a major culprit in allowing senescent cells to accumulate; however, of course, it may not be the sole reason.
Rising levels of chronic inflammation, known as inflammaging, play a key role in causing cells to become dysfunctional and impairing tissue repair and regeneration. Inflammaging has multiple sources, including senescent cell accumulation, cell debris, immunosenescence, inappropriate activation of the immune system, increased microbial burden, and changes to the microbiome.
It is not beyond the realm of plausibility to consider that with the rise of inflammaging comes the decline of the immune system and the efficient clearance of unwanted senescent cells, nor is it unreasonable to think that finding ways to restore the immune system to more youthful function would be a good strategy to deal with senescent cells.
Dr. Stolzing, renowned senescent cell researcher Dr. Judith Campisi, and a number of other scientists have recently joined forces and published an open access review of what is currently known about the role of the immune system in the clearance of senescent cells [1].
Cellular senescence is an essentially irreversible arrest of cell proliferation coupled to a complex senescence-associated secretory phenotype (SASP). The senescence arrest prevents the development of cancer, and the SASP can promote tissue repair. Recent data suggest that the prolonged presence of senescent cells, and especially the SASP, could be deleterious, and their beneficial effects early in life can become maladaptive such that they drive aging phenotypes and pathologies late in life. It is therefore important to develop strategies to eliminate senescent cells. There are currently under development or approved several immune cell-based therapies for cancer, which could be redesigned to target senescent cells. This review focuses on this possible use of immune cells and discusses how current cell-based therapies could be used for senescent cell removal.
Conclusion
Restoring and even boosting the performance of the immune system in the context of senescent cell removal seems like a solid long-term approach to dealing with senescent cells and one that is rather more elegant than the somewhat crude and periodic purging of these cells using senolytics. That said, either senolytics or immunotherapies targeting senescent cells have the potential to work, so the arrival of either would be welcome.
We are already starting to see immunotherapies for cancer being repurposed for senescent cell removal, with CAR-T being the latest in a number of similar approaches. Ultimately, a rejuvenated immune system would be the ideal outcome and the likely long-term solution to senescent cells, and we are looking forward to seeing more progress in this area of research.
Literature
[1] Kale, A., Sharma, A., Stolzing, A., Desprez, P. Y., & Campisi, J. (2020). Role of immune cells in the removal of deleterious senescent cells. Immunity & Ageing, 17(1), 1-9.
