This paper captures a part of the present uncertainty over characterization of senescent cells, particularly in the aged immune system. There is some concern that present markers are not sufficiently selective for senescent immune cells, and that some of these possibly problematic populations are something else entirely. Immune system aging is already known to be complex, and there are certainly harmful populations that are not senescent: exhausted T cells, age-associated B cells, overly active microglia and macrophages, various small subpopulations that appear to be doing something counterproductive in a specific tissue, and so forth. The research community is perhaps more concerned with obtaining an accurate picture than with testing methods of clearance of subsets of the immune cell population in search of benefits.
In young and healthy individuals, damaged cells can enter a state of cellular senescence, which limits the spread of dysfunctional cells. These senescent cells produce a senescence-associated secretory phenotype (SASP) which attracts immune cells that may ultimately clear these senescent cells. Recent studies suggest that when the immune cells themselves become senescent, they fail to clear other senescent cells and drive senescence, and age-related dysfunction of other organs.
As we age, T cells may develop cellular senescence, similar to fibroblasts and other cell types in which the state of cellular senescence has been extensively investigated. But importantly, the cell surface markers frequently used to detect immunosenescent T cells, such as the loss of CD27 and CD28 expression or the upregulated KLRG-1 or Leu7 expression, or the exhaustion marker PD-1, do not accurately demarcate the population that is in a true state of senescence. Rather, they mark a heterogenous population of T cells, mostly but not exclusively consisting of senescent cells. Referring to this population as senescent T cells is, at best, an oversimplification and leads to a significant underestimation and misinterpretation of the actual number of senescent T cells in individual patients. Several hallmarks of cellular senescence, such as p16, p21, absence of proliferation, DNA-SCARS, telomere-associated foci (TAFs), senescence-associated heterochromatin foci (SAHFs), loss of LMNB1 and increased senescence-associated β-gal activity, should be included to accurately measure senescent T cells.
Future studies should investigate the functional properties of T cells that are in a state of cellular senescence in the different T cell differentiation stages. For a long time, research into T cell senescence has focused on late-stage differentiation stages, such as the CD28null population, the CD57+ TEMRA cells (the effector memory cells that re-express CD45RA), or the exhausted T cells. The question now arises whether earlier T cell differentiation stages can also become senescent. Knowledge on the functional consequences of accumulating senescent naïve or central memory T cells is lacking. It is essential to determine whether these subpopulations of senescent T cells increase in age-related diseases and actively contribute to pathology. Additionally, it is important to explore whether they secrete a SASP and how they differ functionally from non-senescent T cells of the same differentiation stage. These are critical open questions that require further investigation.
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