Older men display elevated levels of senescence-associated exercise-responsive CD28null angiogenic T cells compared with younger men.

Aging is associated with elevated cardiovascular disease risk. As a result of aging, endothelial dysfunction develops, partly due to a reduction in vascular regenerative ability. CD31+ T cells (angiogenic T cells; TANG ) possess highly angiogenic capabilities; however, these cells are significantly reduced in older populations. In addition, older populations possess significantly higher senescent and highly differentiated T-cell levels in circulation, and these are reported to be highly exercise responsive. We investigated whether older adults display greater levels of circulating senescent (CD28null ) TANG cells and whether these cells were more exercise responsive than CD28+ TANG cells. Young (18-25 years; n = 9) and older (60-75 years; n = 10) healthy men undertook a 30-min cycling bout at 70% V˙O2 peak, with circulating TANG cells (CD3+  CD31+  CD28+/null ; including CD4+ and CD8+ subsets) measured preexercise, postexercise, and 1 h post exercise by flow cytometry. Older adults displayed reduced basal levels of TANG cells (mean ± SEM: 410 ± 81 vs. 784 ± 118 cells·µL, P = 0.017), despite a greater proportion of these cells being CD28null (26.26 ± 5.08 vs. 13.36 ± 2.62%, P = 0.044). Exercise significantly increased the circulating number of TANG cells in both young and older men. However, in older men alone, exercise preferentially mobilized CD28null CD8+ TANG cells compared with CD28+ TANG cells (time × phenotype interaction: P = 0.022; Δ74 ± 29 vs. Δ27 ± 15 cells·µL, P = 0.059), with no such difference observed between these phenotypes in the young population. In conclusion, this is the first study to demonstrate that despite observing lower circulating numbers of TANG cells, older adults display greater levels of senescent TANG cells in comparison with younger individuals, and these cells are more exercise responsive than CD28+ TANG cells. Lower number of circulating TANG and greater levels of senescent-associated CD28null TANG may contribute to greater CVD risk with advancing age.

Lower resting and exercise-induced circulating angiogenic progenitors and angiogenic T cells in older men.

Aging is associated with a dysfunctional endothelial phenotype as well as reduced angiogenic capabilities. Exercise exerts beneficial effects on the cardiovascular system, possibly by increasing/maintaining the number and/or function of circulating angiogenic cells (CACs), which are known to decline with age. However, the relationship between cardiorespiratory fitness (CRF) and age-related changes in the frequency of CACs, as well as the exercise-induced responsiveness of CACs in older individuals, has not yet been determined. One-hundred seven healthy male volunteers, aged 18-75 yr, participated in study 1. CRF was estimated using a submaximal cycling ergometer test. Circulating endothelial progenitor cells (EPCs), angiogenic T cells (TANG), and their chemokine (C-X-C motif) receptor 4 (CXCR4) cell surface receptor expression were enumerated by flow cytometry using peripheral blood samples obtained under resting conditions before the exercise test. In study 2, 17 healthy men (8 young men, 18-25 yr; 9 older men, 60-75 yr) were recruited, and these participants undertook a 30-min cycling exercise bout at 70% maximal O2 consumption, with CACs enumerated before and immediately after exercise. Age was inversely associated with both CD34+ progenitor cells ( r2 = -0.140, P = 0.000) and TANG ( r2 = -0.176, P = 0.000) cells as well as CXCR4-expressing CACs (CD34+: r2 = -0.167, P = 0.000; EPCs: r2 = -0.098, P = 0.001; TANG: r2 = -0.053, P = 0.015). However, after correcting for age, CRF had no relationship with either CAC subset. In addition, older individuals displayed attenuated exercise-induced increases in CD34+ progenitor cells, TANG, CD4+, TANG, and CD8+CXCR4+ TANG cells. Older men display lower CAC levels, which may contribute to increased risk of cardiovascular disease, and older adults display an impaired exercise-induced responsiveness of these cells. NEW & NOTEWORTHY Older adults display lower circulating progenitor cell and angiogenic T cell counts compared with younger individuals independently of cardiometabolic risk factors and cardiorespiratory fitness. Older adults also display impaired exercise-induced mobilization of these vasculogenic cells.

A 10 km time trial running bout acutely increases the number of angiogenic T cells in the peripheral blood compartment of healthy males.

What is the central question of the study? Are CD31+ angiogenic T (TANG ) cells preferentially mobilized in response to acute exercise? What is the main finding and its importance? Our study reveals that TANG cells are redistributed into the circulation in response to acute strenuous exercise, but to a lesser extent than CD31- T cells. Of the TANG cells mobilized, TANG cells expressing CXCR4 show greater redistribution compared with CXCR4- TANG cells. Stromal-derived factor 1-α does not appear to play a role in the redistribution of TANG cells expressing CXCR4. The results suggest that a single bout of strenuous exercise might provide a short vasculogenic window, which could benefit the vascular system by redistributing CD31+ TANG cells. CD31+ T cells have been documented to possess vasculogenic properties and have been termed 'angiogenic T cells' (TANG cells). No study to date has fully characterized the effect of acute exercise on TANG cells. Twelve male participants aged 24-45 years undertook a running 10 km time trial, with peripheral blood samples taken before, immediately after and 1 h postexercise for quantification of TANG cells and subsequent CXCR4 cell surface expression by flow cytometry. The TANG cells demonstrated a 102% increase in number in the peripheral circulation immediately postexercise compared with pre-exercise levels, followed by a large egress (50%) from the circulation in total TANG cells 1 h postexercise. This was due to changes in both CD4+ and CD8+ TANG cells, with CD8+ TANG cells displaying greater ingress (123%) and egress (52%) compared with CD4+ TANG cells (ingress, 83%; egress, 37%). The cell surface expression intensity of CXCR4 was affected only on CD8+ TANG cells, with a significant increase in cell surface expression immediately postexercise versus pre-exercise levels. The CD31- T cells displayed greater redistribution than CD31+ TANG cells (119 versus 102%). CXCR4-expressing TANG cells showed greater response to acute exercise than CXCR4- cells, which was accompanied by large changes in CXCR4 ligand SDF-1α. The results show that acute exercise increases TANG cells in the circulation in response to an acute exercise stressor. Additionally, CXCR4 cell surface expression appears to be increased in response to exercise, which may result from the direct upregulation of CXCR4 on the T-cell surface or could be due to CD31+ T cells being redistributed into the blood expressing greater levels of CXCR4.

Sleep disruption and its effect on lymphocyte redeployment following an acute bout of exercise.

Sleep disruption and deprivation are common in contemporary society and have been linked with poor health, decreased job performance and increased life-stress. The rapid redeployment of lymphocytes between the blood and tissues is an archetypal feature of the acute stress response, but it is not known if short-term perturbations in sleep architecture affect lymphocyte redeployment. We examined the effects of a disrupted night sleep on the exercise-induced redeployment of lymphocytes and their subtypes. 10 healthy male cyclists performed 1h of cycling at a fixed power output on an indoor cycle ergometer, following a night of undisrupted sleep (US) or a night of disrupted sleep (DS). Blood was collected before, immediately after and 1h after exercise completion. Lymphocytes and their subtypes were enumerated using direct immunofluorescence assays and 4-colour flow cytometry. DS was associated with elevated concentrations of total lymphocytes and CD3(-)/CD56(+) NK-cells. Although not affecting baseline levels, DS augmented the exercise-induced redeployment of CD8(+) T-cells, with the naïve/early differentiated subtypes (KLRG1(-)/CD45RA(+)) being affected most. While the mobilisation of cytotoxic lymphocyte subsets (NK cells, CD8(+) T-cells γδ T-cells), tended to be larger in response to exercise following DS, their enhanced egress at 1h post-exercise was more marked. This occurred despite similar serum cortisol and catecholamine levels between the US and DS trials. NK-cells redeployed with exercise after DS retained their expression of perforin and Granzyme-B indicating that DS did not affect NK-cell 'arming'. Our findings indicate that short-term changes in sleep architecture may 'prime' the immune system and cause minor enhancements in lymphocyte trafficking in response to acute dynamic exercise.

Senescent T-lymphocytes are mobilised into the peripheral blood compartment in young and older humans after exhaustive exercise.

Senescent T-lymphocytes are antigen-experienced cells that express the killer-cell lectin-like receptor G1 (KLRG1) and/or CD57; fail to clonally expand following further antigenic stimulation and prevail in the resting blood of older adults compared to the young. Physical exercise mobilises T-lymphocytes into the bloodstream and is therefore a model with which to compare age-related phenotypes of blood-resident T-cells with those T-cells entering the blood from peripheral lymphoid compartments. Eight young (Y; Age: 21+/-3 years) and 8 older (O; Age: 56+/-3 years) healthy males completed a maximal treadmill exercise protocol. Blood lymphocytes isolated before, immediately after and 1h after exercise were assessed for cell surface expression of KLRG1, CD57, CD28, CD45RA, CD45RO, CD62L and lymphocyte subset markers using three-colour flow cytometry. Lymphocyte subset numbers (CD3+, CD3+/CD4+, CD3+/CD8 and CD3-/CD56+) increased with exercise (p<0.05) but were not different between Y and O. At rest and immediately after exercise, the percentage of CD3+/CD8+ T-lymphocytes expressing KLRG1 and CD45RO was greater in O than Y, whereas Y had a greater expression of CD45RA and CD62L than O. The percentage of all CD3+/CD8+ and CD3+/CD4+ T-lymphocytes expressing KLRG1 and CD57 increased after exercise, but the magnitude of change was not age-dependent. In conclusion, there is a greater proportion of senescent CD3+/CD8+ T-lymphocytes in the blood of older adults compared to young at rest and immediately after exhaustive exercise, indicating that the greater frequency of KLRG1+/CD8+ T-lymphocytes in older humans is ubiquitous and not localised to the peripheral blood.