Major features of immunesenescence, including reduced thymic output, are ameliorated by high levels of physical activity in adulthood

Abstract

It is widely accepted that aging is accompanied by remodelling of the immune system including thymic atrophy and increased frequency of senescent T cells, leading to immune compromise. However, physical activity, which influences immunity but declines dramatically with age, is not considered in this literature. We assessed immune profiles in 125 adults (55-79 years) who had maintained a high level of physical activity (cycling) for much of their adult lives, 75 age-matched older adults and 55 young adults not involved in regular exercise. The frequency of naïve T cells and recent thymic emigrants (RTE) were both higher in cyclists compared with inactive elders, and RTE frequency in cyclists was no different to young adults. Compared with their less active counterparts, the cyclists had significantly higher serum levels of the thymoprotective cytokine IL-7 and lower IL-6, which promotes thymic atrophy. Cyclists also showed additional evidence of reduced immunesenescence, namely lower Th17 polarization and higher B regulatory cell frequency than inactive elders. Physical activity did not protect against all aspects of immunesenescence: CD28^-ve CD57^+ve senescent CD8 T-cell frequency did not differ between cyclists and inactive elders. We conclude that many features of immunesenescence may be driven by reduced physical activity with age.

Keywords: immunesenescence; inflammation; interleukin-7; physical activity; thymic output.

Figure 1

The impact of maintained physical activity on T‐cell subset distribution. Immunostaining of PBMCs shows (a) the percentage of CD3^+ve T cells. Further analysis of the CD3^+ve T cell population shows the frequency of (b) naïve CD8^+ve CD45RA ^+ve T cells and (c) memory CD8^+ve CD45RA ^−ve T cells in the CD8 T cell pool, (d) naïve CD4^+ve CD45RA ^+ve T cells and (e) memory CD4^+ve CD45RA ^−ve T cells in the CD4 pool. The solid bar represents the mean value. *p < .05, **p < .005, ***p < .001

Figure 2

The impact of maintained physical activity on memory T‐cell subsets. Immunostaining of PBMCs shows (a) CD8 central memory (CM) characterized as CD45RA ^−ve CCR7 ^+ve, (b) CD8 effector memory (EM) as CD45RA ^−ve CCR7^−ve, (c) CD8 EMRA as CD45RA ^+ve CCR7^–ve, (d) CD4 central memory (CM) characterized as CD45RA ^−ve CCR7 ^+ve, (e) CD4 effector memory (EM) as CD45RA ^−ve CCR7^−ve, (f) CD4 EMRA as CD45RA ^+ve CCR7^–ve, (g) CD28^−ve CD57^+ve CD4 T cells in the CD4 pool, (h) CD28^−ve CD57^+ve CD8 T cells in the CD8 pool, in healthy young donors (n = 55), healthy sedentary old donors (n = 75) and master cyclists (n = 118). The solid bar represents the mean value. *p < .05, **p < .005, ***p < .001

Figure 3

The impact of maintained physical activity on B‐cell subset distribution. (a) Representative flow cytometric plot showing the gating strategy used to identify B‐cell subsets via expression of IgD and CD27. (b) Immunostaining of PBMCs shows the frequency of CD19^+ve B cells. Further analysis of the B‐cell population shows the frequency of (c) naïve IgD^+ve CD27^−ve CD19^+ve B cells, (d) switched IgD^−ve CD27^+ve CD19^+ve B cells, (e) unswitched IgD^+ve CD27^+ve CD19^+ve B cells and (f) IgD^−ve CD27^−ve CD19^+ve B cells in the B‐cell pool, in healthy young donors (n = 55), sedentary healthy old donors (n = 75) and master cyclists (n = 108). The solid bar represents the mean value. *p < .05, **p < .005, ***p < .001

Figure 4

The impact of maintained physical activity on recent thymic emigrants. Immunostaining of the T‐cell population shows the frequency of (a) PTK7^+ve CD45RA ^+ve CD4 T cells in the CD4 pool, (b) CD103^+ve CD45RA ^+ve CD8 T cells in the CD8 pool, (c) CD34^+ve CD10^+ve CD19^−ve CD3^−ve CD14^−ve cells in the PBMC pool, in healthy young donors (n = 55), sedentary healthy old donors (n = 75) and master cyclists (n = 118). The solid bar represents the mean value. *p < .05, **p < .005, ***p < .001

Figure 5

Possible mechanisms underlying maintained thymic output in cyclists. (a) Serum IL‐6 levels in master cyclists (n = 105), sedentary healthy old donors (n = 70) and young donors (n = 50). (b) Serum cortisol levels (ug/ml) in master cyclists (n = 117), sedentary healthy old donors (n = 75) and young donors (n = 52). (c) Serum IL‐7 levels in master cyclists (n = 119), sedentary healthy old donors (n = 75) and young donors (n = 50). (d) Serum KGF levels (pg/ml) in master cyclists (n = 119), sedentary healthy old donors (n = 75) and young donors (n = 50). (e) Serum IL‐15 levels in master cyclists (n = 119), sedentary healthy old donors (n = 65) and young donors (n = 52). In A‐E, data are mean ± SEM. (f) Serum IL‐15 levels were plotted against peripheral CD4 naïve T‐cell frequency (%) in master cyclists (n = 87). *p < .05, **p < .005, ***p < .001

Figure 6

Impact of physical activity on Th1, Th2 and Th17 cell differentiation. PBMCs isolated from master cyclists, healthy young and sedentary older adults were stimulated via PMA and ionomycin for 4 hr and stained for surface expression of CD3, CD4 and intracellularly for IFNγ, IL‐4 or IL‐17. Scatter plot shows the frequency in master cyclists (n = 103), sedentary healthy old donors (n = 66) and healthy young donors (n = 50) of (a) IFNγ‐positive cells within the CD4 T cell subset, (b) IL‐4‐positive cells within the CD4 T cell subset, (c) shows the Th1/Th2 ratio in the same groups. (d) The frequency of IL‐17‐positive cells within the CD4 T cell subset in master cyclists (n = 96), healthy old donors (n = 70) and healthy young donors (n = 50). *p < .05, **p < .005, ***p < .001

Figure 7

Impact of physical activity on immune regulatory cells. Immunostaining of CD4^+ve T cells shows the frequency of (a) CD4^+ve CD25^hi Foxp3^+ve T cells in healthy young donors (n = 52), sedentary healthy old donors (n = 72) and master cyclists (n = 120); (b) IL‐10‐positive T cells in master cyclists (n = 96), sedentary healthy old donors (n = 66) and healthy young donors (n = 45). Immunostaining of B cells shows the frequency (c) CD24^hi CD38^hi B cells in healthy young donors (n = 52), sedentary healthy old donors (n = 75) and master cyclists (n = 110), (d) IL‐10‐positive CD19^+ve CD24^hi CD38^hi B cells after 72‐hr stimulation in healthy young donors (n = 50), sedentary healthy old donors (n = 70) and master cyclists (n = 93). *p < .05, **p < .005, ***p < .001