TERM DATING BACK TO THE 1960S, IGNORED FOR DECADES, UNTIL 2008
Senescent cells excrete an excess of molecules that affect the functionality of neighboring cells
AGING AT THE CELLULAR LEVEL:
The term cellular senescence dates back to 1961. Two microbiologists Leonard Hayflick and Paul Moorhead had identified aging at the cellular level. For decades, studies were not developed, until 2008. Three research groups identified what they called the “dark side” of senescence: senescent cells excrete an excess of molecules designed to affect the function of neighboring cells and thus stimulate local inflammation. In a young and healthy tissue these secretions are probably part of a process in which damaged cells stimulate the repair of neighboring tissues, inducing the immune system to eliminate them.
Cellular senescence is an essentially irreversible arrest of cell proliferation coupled with a senescence-associated secretory phenotype (SASP). Senescence arrest prevents cancer development and SASP can promote tissue repair. Recent data suggest that the prolonged presence of senescent cells, and in particular SASP, may be deleterious and that their beneficial effects early in life may become maladaptive such that they induce aging phenotypes and diseases later in life. Therefore, it is important to develop strategies to eliminate senescent cells. There are several immune cell-based therapies for cancer currently in development or approved that could be redesigned to target senescent cells.
Cellular senescence involves an essentially irreversible arrest of proliferation in damaged or stressed cells that are at risk for malignant transformation. Two major pathways establish and maintain this growth arrest, which is a powerful anticancer mechanism.
Numerous stimuli can trigger these pathways, leading to senescence in cells in culture and in vivo
Important stimuli for senescence include replicative depletion, which generally causes telomere attrition (also known as replicative senescence) and DNA damage such as that caused by ionizing and, to some extent, non-ionizing radiation. In addition, some chemotherapy drugs such as doxorubicin or bleomycin also cause DNA damage, and other drugs such as abemaciclib or palbociclib directly inhibit CDKs to induce senescence arrest
Senescence arrest is generally coupled to a senescence-associated secretory phenotype (SASP) [11]. SASP is conserved between mice and humans [12], and even to some extent between mammals and insects [13]. Its components include growth factors, chemokines and cytokines, proteases, bioactive lipids, and extracellular vesicles, many of which are pro-inflammatory [14]. The number of senescent cells increases with age in most tissues, although it rarely exceeds a few percent. However, growing evidence suggests that senescent cells may drive a surprisingly diverse range of aging phenotypes and diseases, primarily through SASP. The presence of senescent cells also exacerbates several diseases including, but not limited to, osteoarthritis [20], osteoporosis [21], atherosclerosis [22], Parkinson’s disease (23), and Alzheimer’s disease [24, 25]. Importantly, elimination of senescent cells in transgenic mouse models often delays age-related tissue dysfunction and increases healthspan [26]. In addition, several laboratories are developing new classes of drugs called senolytics, which kill senescent cells, or senomorphs, which alleviate the effects of SASP. These drugs can help maintain homeostasis in aged or damaged tissues and postpone or ameliorate many age-related diseases.
In contrast to their deleterious roles in driving aging and age-associated diseases, senescent cells may have beneficial roles during tissue development and repair, regeneration, and reprogramming. For example, in mice, SASP from senescent cells enhances reprogramming in neighboring cells and short-term expression of reprogramming factors promotes tissue regeneration and reduces tissue aging [31, 32]. Senescent cells can also promote wound healing in the skin and liver and promote or suppress fibrotic responses depending on the tissue and biological context . Senescent cells also optimize mouse embryogenesis and the absence of senescent cells may delay development and promote patterning defects. In adult animals, senescent cells promote regeneration of the heart and their elimination may impair regeneration and repair in this tissue .