Cells in the body become senescent constantly, in response to reaching the Hayflick limit on replication, to DNA damage, to a toxic local environment, to injury. A senescent cell grows large, ceases replication, and secretes a potent mix of signals, the senescence-associated secretory phenotype (SASP). The SASP rouses the immune system into an inflammatory state, disrupts tissue maintenance and structure, and encourages other cells to also become senescent. In the short term this is a necessary part of wound healing and cancer suppression. If maintained for the long term, the SASP becomes very harmful, however.
Near all senescent cells cells are rapidly destroyed, either by programmed cell death or by the immune system. This is a requirement to maintain functional tissues, given the harms produced by a sustained SASP. Unfortunately senescent cells accumulate with age. It remains unclear as to the degree to which this is an imbalance between creation and destruction versus a small fraction of senescent cells being resistant to clearance. It is certainly the case that clearance mechanisms appear to slow down in older individuals, while on the other hand some senescent cells find ways to evade the immune system.
In today’s open access paper, researchers outline what is known of the role of the immune system in the clearance of senescent cells. It is likely that the characteristic age-related decline in immune function that takes place with advancing age is the most important determinant of the significant growth in the senescent cell burden in tissues in later life. This is one the many ways in which immune aging sabotages health and reduces life span.
Role of immune cells in the removal of deleterious senescent cells
Cellular senescence is an essentially irreversible arrest of cell proliferation coupled to a complex senescence-associated secretory phenotype (SASP). The SASP is conserved between mice and humans, and even to some extent between mammals and insects. Its components include growth factors, chemokines and cytokines, proteases, bioactive lipids and extracellular vesicles, many of which are pro-inflammatory. The number of senescent cells increases with age in most tissues, although they rarely exceed a few percent. Nonetheless, mounting evidence suggests that senescent cells can drive a surprisingly diverse array of aging phenotypes and diseases, mainly through the SASP. The presence of senescent cells also exacerbates several diseases including, but not limited to, osteoarthritis, osteoporosis, atherosclerosis, Parkinson’s disease, and Alzheimer’s disease.
Importantly, eliminating senescent cells in transgenic mouse models often delays age-related tissue dysfunction and increases health span. Furthermore, several laboratories are developing new classes of drugs termed senolytics, which kill senescent cells, or senomorphics, which alleviate SASP effects. These drugs can help maintain homeostasis in aged or damaged tissues, and postpone or ameliorate many age-related pathologies.
Current thinking is that the short-term presence of senescent cells is beneficial, largely by adjusting the plasticity of neighboring cells, but that their prolonged presence can be deleterious. The timely clearance of senescent cells is required to maintain tissue and organismal homeostasis. Although cellular senescence has been studied in detail in the context of disease, the interaction of senescent cells with immune cells have been less thoroughly investigated. Due in large measure to the SASP, senescent cells likely interact extensively with the immune system. The production and secretion of SASP factors (resulting in local inflammation) can be a potent means to recruit immune cells. The SASP recruits macrophages, natural killer (NK) cells, neutrophils, and T lymphocytes, which eliminate them, but senescent cells can also interact with immune cells to avoid elimination.
There are currently several immune cell therapies for cancer under development or approved, which could potentially be redesigned to target senescent cells. Chimeric antigen receptor (CAR) T cell therapy has been successful in recent years for treating diseases such as cancer. CAR-T cell therapy uses autologous cells that are genetically modified ex vivo to encode a synthetic receptor that binds a known antigen. The modified cells are then infused back into the patient to kill the target cells. Evidence that there are senescent-specific surface markers is spotty, and specificity needs further validation. Nonetheless, once a good target has been identified, it can be used to create a CAR-T cell.
As senescent cells are naturally targeted for elimination by NK cells, it could be beneficial to use NK cells to eliminate persistent pro-inflammatory senescent cells, particularly as they accumulate during aging. Even though technical, logistical, and financial challenges are still limiting factors for applications of circulating NK cells as promising cancer therapies, over the past decade, several studies demonstrated the safety and efficacy of allogeneic NK cells against various hematological malignancies. The same technology could be used to target senescent cells by NK cells.
Macrophages can eliminate senescent cells. Transplanted macrophages can migrate into tissues and become tissue-resident with much longer half-lives and self-renewal abilities. Because macrophages are phenotypically plastic, and cancer cells often express a “don’t eat me” signal, macrophage cell therapies have not been very successful in treating cancer. Whether this limitation poses a difficulty in using macrophages against senescent cells is not clear. NFκB-dependent pro-inflammatory signaling appears to upregulate the “don’t eat me” marker CD47, at least in some cancers, facilitating their escape from immune surveillance. Senescent cells generally upregulate NFκB activity, which can activate CD47 transcription.
A better understanding of the interplay between immune cells and senescent cells would illuminate changes that happen during aging, and also speed the development of novel therapeutic interventions for eliminating deleterious senescent cells. Different approaches could be formulated to remove senescent cells using the natural ability of immune cells. What is needed now is a more thorough understanding of the heterogeneity of senescent cells and of the specific targets for immune cells.