The Role of T Cell Senescence in Neurological Diseases and Its Regulation by Cellular Metabolism

Abstract

Immunosenescence is a state of dysregulated leukocyte function characterised by arrested cell cycle, telomere shortening, expression of markers of cellular stress, and secretion of pro-inflammatory mediators. Immunosenescence principally develops during aging, but it may also be induced in other pathological settings, such as chronic viral infections and autoimmune diseases. Appearance of senescent immune cells has been shown to potentially cause chronic inflammation and tissue damage, suggesting an important role for this process in organismal homeostasis. In particular, the presence of senescent T lymphocytes has been reported in neurological diseases, with some works pointing towards a direct connection between T cell senescence, inflammation and neuronal damage. In this minireview, we provide an overview on the role of T cell senescence in neurological disorders, in particular in multiple sclerosis and Alzheimer disease. We also discuss recent literature investigating how metabolic remodelling controls the development of a senescence phenotype in T cells. Targeting metabolic pathways involved in the induction of senescent T cells may indeed represent a novel approach to limit their inflammatory activity and prevent neuroinflammation and neurodegeneration.

The Glial Aging & Senescence Hypothesis of Late-onset Alzheimer’s

“…Other peripheral immune cells, particularly those in the adaptive immune system in lymphocytes versus innate immune microglia, may also become senescent and contribute to LOAD. This could occur via increased systemic inflammation, and/or infiltration and senescence-mediated exacerbation of A/hp-tau seeding 29,67,142 . However, there is currently insufficient evidence that peripheral immune cells infiltrate the brain, become senescent, and directly participate in Braak staging and LOAD compared to microglia.…”

A causal relationship between leukocyte telomere length and multiple sclerosis: A Mendelian randomization study

“…Immunosenescence, which is defined as natural age-associated immunity and closely related to the aging of inflammatory function, may contribute to the higher possibility of developing such pathological alterations. In addition, immunosenescence has been related to chronological age (4). Understanding the role of immunosenescence in MS onset is of paramount significance to uncover the very nature of MS pathogenesis.…”

“…Telomere shortening is related to dysregulated immune function and a hallmark of immunosenescence (4). Recently, a growing number of studies concerning the role of LTL in MS have come into view (7,8).…”

Immunosenescence in Neurological Diseases—Is There Enough Evidence?

“…Thymic involution begins at birth, is likely to be evident from puberty onwards, and leads to a decreased ability of the generation of naïve T cells. The number of naïve T cells as well as clonal diversity decreases with age, and vice versa with the proportion of memory T cells, which increase [ 10 , 11 ]. Cellular changes lead to an altered secretion profile of cytokines and chemokines with increasing age [ 12 ].…”

“…Changes of the immune system are numerous and difficult to capture in their completeness, reflecting the heterogeneity and complexity of the aging immune system and strongly limiting the establishment of clear definitions or biomarkers. Recently, the role of the aging immune system has been discussed in the onset or progression of neurological disorders [ 10 ].…”