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Review
. 2023 Nov:70:101838.
doi: 10.1016/j.smim.2023.101838. Epub 2023 Sep 12.

Proteostasis in T cell aging

A Elisabeth Gressler  1 , Houfu Leng  2 , Heidi Zinecker  3 , Anna Katharina Simon  4
Affiliations
Review

Proteostasis in T cell aging

A Elisabeth Gressler et al. Semin Immunol. 2023 Nov.

Abstract

Aging leads to a decline in immune cell function, which leaves the organism vulnerable to infections and age-related multimorbidities. One major player of the adaptive immune response are T cells, and recent studies argue for a major role of disturbed proteostasis contributing to reduced function of these cells upon aging. Proteostasis refers to the state of a healthy, balanced proteome in the cell and is influenced by synthesis (translation), maintenance and quality control of proteins, as well as degradation of damaged or unwanted proteins by the proteasome, autophagy, lysosome and cytoplasmic enzymes. This review focuses on molecular processes impacting on proteostasis in T cells, and specifically functional or quantitative changes of each of these upon aging. Importantly, we describe the biological consequences of compromised proteostasis in T cells, which range from impaired T cell activation and function to enhancement of inflamm-aging by aged T cells. Finally, approaches to improve proteostasis and thus rejuvenate aged T cells through pharmacological or physical interventions are discussed.

Keywords: Aging; Degradation; Inflamm-aging; Proteostasis; T cell; Translation.

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Conflict of interest statement

Declaration of Competing Interest The authors declare no competing financial interests.

Figures

Fig. 1
Fig. 1
Factors contributing to cellular proteostasis. Maintaining a healthy proteome involves protein synthesis, maintenance and quality control, as well as degradation. Transcription and translation control the synthesis of proteins, while correct folding of proteins and maintenance are executed by the unfolded protein response (UPR) and chaperones. To recycle or degrade damaged or unwanted proteins, various cellular systems like the ubiquitin-proteasome-system (UPS), the calpain-calpastatin system (CCS), autophagy and lysosomes are employed.
Fig. 2
Fig. 2
Cellular changes in CD4+T cell and CD8+T cell affect their functionality upon aging. Aging CD4+ and CD8+ T cells adapt to various age-related factors, like oxidative stress, protein aging and a changing cellular environment. These adaptations comprise both quantitative and functional changes, e.g. reduced abundance and impaired activity of proteins and mechanisms maintaining cellular proteostasis. This leads to a general reduction of activation and proliferation potential, as well as decreased memory T cell formation and maintenance of T memory cells for both, CD4+ and CD8+ T cell subsets, but also disturbances in CD4+ T cell differentiation and impaired cytotoxic activity of CD8+ T cells. UPR: Unfolded protein response, CCS: Calpain-calpastatin system.
Fig. 3
Fig. 3
Different approaches to rejuvenate aged T cells. Several interventions have been proposed to either prevent T cell aging or rejuvenate aged T cells. Those include administration of pharmacological compounds like spermidine, resveratrol, metformin, and rapamycin, but also physiological interventions like exercise and caloric restriction. Those act on different factors of the proteostasis network, leading to improved or altered T cell function and rejuvenation of T cells.
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