Reversing T cell immunosenescence: why, who, and how

Abstract

Immunosenescence is the term commonly used to describe the multifaceted phenomenon encompassing all changes occurring in the immune system during aging. It contributes to render older adults more prone to develop infectious disease and main age-related diseases. While age clearly imposes drastic changes in immune physiology, older adults have heterogeneous health and immune phenotypes. This confronts scientists and researcher to develop more age-specific interventions rather than simply adopting intervention regimes used in younger people and this in order to maintain immune protection in older adults. Thus, this review provides evidences of the central role played by cell-mediated immunity in the immunosenescence process and explores the means by which senescent state of the cell-mediated immune function could be identified and predicted using biomarkers. Furthermore considerations are given to recent advances made in the field of age-specific immune interventions that could contribute to maintain immune protection, to improve quality of life, and/or to promote healthy aging of the growing part of the population.

Fig. 1

Schematic representation of the main features observed within the T cell-mediated immune system with advancing age. Thymic atrophy is characterized by a progressive, age-related reduction in the size of the thymus due to profound changes in its anatomy (i.e., progressive loss of thymic mass and replacement of thymocytes with adipocytes). This is a key contributory factor in the reduced ability of the immune system to respond to new antigen. While the quantification of T cell numbers shows that they are maintained throughout the life span, with the age-associated reduction in thymic output (i.e., naïve T cells), the constituent of the T cell pool progress towards their replicative limit (i.e., senescent cells). Potential beneficial impacts of the 3Rs of Rejuvenation are also represented

Fig. 2

Schematic representation of the somatic rearrangement process undergoing in every immature T cell TCR loci during the development from hematopoietic stem cell to mature naïve T cells. During the rearrangement process, the intervening DNA sequences, both for α- and β-chain, are deleted and circularized into episomal DNA molecules, called TCR excision circles (TRECs) (Adapted from Lang et al. (2011b))

Fig. 3

Schematic representation of the age-related changes in TREC values across the life span based on Zubakov et al. (2010) and Mitchell et al. (2010) study results. The red line depicts the decline in TREC value in healthy individuals, and the two dashed lines on either side are the upper and lower TREC values for a given age observed within this population. The whole figure shows the age-related decrease in TREC values but also demonstrates the convergence of the overall spread of the TREC values with advancing age

Fig. 4

Graphic representation of the age-related changes in TREC/10⁵ T cells ratio. a Demonstrates (1) the slow decline in the ratio values between the sixth and ninth decades of life with a more pronounced decline seen in individuals more than 90 years of age and (2) a convergence of the sample heterogeneity observed in the TREC levels with increasing age. b Shows an annotated diagram of the age-related changes observed in TREC measurement. The dashed horizontal line indicates the median TREC/10⁵ T cell ratio in the sample population and the dashed vertical line is the average life expectancy across the study population (79.0 years). Upper left (UL), lower left (LL), upper right (UR), and lower left (LR) quadrants refer to different quadrants formed by the bisection of the data horizontal and vertical lines (Adapted from Mitchell WA 2010)