The Harm Done by Senescent T Cells

Senescent cells accumulate with age in all tissues, and their presence is one of the root causes of aging. Cells become senescent in large numbers at all ages, and under a variety of circumstances: toxins, wound healing, ordinary somatic cells reaching the Hayflick limit, random mutational damage to important genes, and so forth. Senescence irreversibly shuts down cellular replication, making it a useful defense against cancer. Near all newly senescent cells are destroyed quickly. They either self-destruct or they are destroyed by the immune system, but both paths to a reliable natural clearance of senescent cells falter with the damage and dysfunction of aging.

Lingering senescent cells that have evaded destruction never rise to more than a few percent of all cells by number, even in very late life, but that is more than enough to produce major disruption to tissue function. Senescent cells secrete a potent mix of signals that remodel the extracellular matrix, encourage nearby cells to become senescent, produce chronic inflammation and immune system overactivation, and generally make a mess of things in many other ways. This is particularly disruptive for regenerative capacity, even though senescent cells are necessary for wound healing: their activity is generally useful in the short term for specific circumstances like this, it is when the signaling continues for the long term that the problems arise.

Immune cells, such as the T cells of the adaptive immune system, can also become senescent. Since these cells roam the body, the detrimental consequences can be broad and varied, unlike the case for senescent cells that reside in a given organ. Some of those consequences are examined in the open access review paper noted below. Roaming or not, it is the case that selective destruction of these cells via some form of senolytic therapy will provide benefits. We might think of the signals produced by senescent cells as a mechanism that actively maintains a more aged, damaged state of the body and brain. Destroying these cells is a narrow form of rejuvenation, turning back one of the causes of aging wherever it can be achieved.

The impact of senescence-associated T cells on immunosenescence and age-related disorders

Immunosenescence is age-associated changes in the immunological functions, including diminished acquired immunity against infection, pro-inflammatory traits, and increased risk of autoimmunity. The proportions of memory-phenotype T cells in the peripheral T cell population steadily increase with age, but the relationship between this change and immunosenescent phenotypes remains elusive. Recently, we identified a minor memory-phenotype CD4+ T cell subpopulation that constitutively expressed PD-1 and CD153 as a bona fide age-dependent T cell population; we termed these cells senescence-associated T (SA-T) cells. SA-T cells exhibit characteristic features of cellular senescence, with defective T cell receptor-mediated proliferation and T cell cytokine production.

The T cell receptor (TCR) responsiveness of the overall CD4+ T-cell population, in terms of proliferation and regular cytokine production, diminished gradually with age. Our careful studies, however, revealed that these effects were attributed primarily to the increase in the proportions of SA-T cells with age, given that the residual naïve and PD-1- (CD153-) MP CD4+ T cells in aged mice exhibited TCR responsiveness comparable to those from young mice. Senescent cells tend to resist apoptosis; consistent with this, SA-T cells were quite stable over long-term culture, probably accounting for the progressive accumulation of SA-T cells with age despite their defective proliferation capacity.

The age-dependent increase in SA-T cells could be due to CD4+ T cell-intrinsic effects or to the tissue environment of aged individuals. We found that the naïve CD4+ T cells transferred from young mice robustly proliferated in an aged host environment and underwent significant conversion to SA-T cells, whereas in young hosts, the same T cells barely proliferated and generated few SA-T cells. Thus, the aged, but not young, host environment plays a crucial role in the development of SA-T cells from naïve CD4+ T cells.

Accumulating evidence indicates that the SA-T cells are markedly increased in the tissues under persisted inflammation, often in association with the tertiary lymphoid tissues, of chronic inflammatory disorders. Recent evidence indicates that the selective elimination of tissue senescent cells leads to a significant improvement of age-associated tissue dysfunctions with prolonged lifespan. Consequently, tissue senescent cells are emerging as a crucial target for preventive and therapeutic intervention of age-related chronic disorders. Targeted elimination of SA-T cells represents a promising strategy for controlling chronic inflammatory disorders and possibly cancer.


>We found that the naïve CD4+ T cells transferred from young mice robustly proliferated in an aged host environment and underwent significant conversion to SA-T cells, whereas in young hosts, the same T cells barely proliferated and generated few SA-T cells

it seems the T cells are senescence-associated not really senescent cells on their own. They seem to be a bit downstream from the root cause...

Posted by: cuberat at January 8th, 2019 8:19 PM

Very similar to the senescence-associated macrophages (SAMs) that Gudkov talks about and how their polarization is moved from M2 to M1 type driving further inflammation. The immune system is messed up by chronic inflammation and the cytokines it creates. That inflammation comes from various sources including SASP, cell debris, and gut microbiome to name a few culprits. Seems managing the sources of inflammation may correct the immune system.

Posted by: Steve Hill at January 9th, 2019 9:47 AM

In a TedX talk*, Gudkov relayed some intriguing ideas re: endogenous viruses but did not present any supporting evidence. A search of PubMed turned up nothing. Perhaps empirical support is forthcoming, but until then, nullius in verba ...


Posted by: CD at January 9th, 2019 12:00 PM
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