Exploratory study links habitual activity to adrenergic regulation in aging T cells

An exploratory human study found that habitual physical activity was associated with how circulating CD8+ T cells responded to short, exercise-like adrenergic stimulation, particularly in terms of glucose-transporter expression. Investigators compared six young adults aged 18–35 years with 12 healthy adults aged 65 or older, including six classified as highly physically active and six as moderately active. Across these small groups, age-related impairment of CD8+ T-cell activation persisted, while greater habitual activity was linked to differences in how β-adrenergic stimulation affected metabolism-related markers. The authors cautioned that the cross-sectional, laboratory-based experiment cannot show that physical activity caused the observed differences or that the cellular patterns translate into better vaccine responses, infection resistance or tumor control.

The researchers isolated peripheral blood mononuclear cells and examined CD4+ and CD8+ T cells from the three participant groups. To mimic the short increase in adrenaline associated with acute exercise, they exposed cells to the β-adrenergic agonist isoproterenol for 30 minutes. Selected cultures also received ICI-118,551, a selective β2-adrenergic receptor blocker, allowing the investigators to distinguish effects that depended on β2 signaling from effects that remained when that pathway was inhibited. After a one-hour rest, cells were stimulated for four hours with phorbol 12-myristate 13-acetate, or PMA, and ionomycin. These compounds induce rapid T-cell activation through protein kinase C activation and intracellular calcium flux, bypassing recognition of antigen by the T-cell receptor. This approach was chosen because its rapid kinetics helped separate short-term responses to isoproterenol from longer-term adaptations that could desensitize adrenergic signaling.

Age-related differences were clearest in CD8+ T cells. Following PMA and ionomycin stimulation, the early activation marker CD69 increased significantly only in the young group. Young participants consequently displayed greater CD8+ activation than both older groups, including the highly active older adults, with reported comparisons of p < 0.001 against the highly active group and p = 0.003 against the moderately active group. Blocking β2-adrenergic receptors during adrenergic stimulation also reduced CD8+ activation, and this condition effect was significant at p = 0.011. CD4+ cells behaved differently: PMA and ionomycin increased CD69 expression, but there was no significant group-by-condition interaction showing that age or habitual activity altered that response. In the activated CD8+ population, adrenergic stimulation itself did not improve CD69 expression, while adding the β2 blocker reduced activation relative to adrenergic stimulation alone. The findings therefore identify a selective age-related vulnerability in the CD8+ subset that was not visibly restored by higher habitual activity under the tested conditions.

Metabolic measurements suggested that habitual activity was associated more clearly with glucose-transporter regulation than with recovery of CD8+ activation. Surface expression of glucose transporter 1, or Glut1, increased after PMA and ionomycin in both CD4+ and CD8+ T cells, with condition effects of p = 0.002 and p < 0.001, respectively. In unstimulated CD8+ cells, combining β2-receptor blockade with isoproterenol increased Glut1 expression in every group relative to adrenergic stimulation alone, with p < 0.001 in each comparison. The increase was significantly greater in highly active older adults than in moderately active older adults at p = 0.043. The difference between the highly active older and young groups showed a nonsignificant trend at p = 0.073. Among activated CD8+ cells, β2 blockade also produced a larger Glut1 increase than stimulation alone. Because blocking β2 did not eliminate the metabolic response, the measured metabolic effect of isoproterenol could not be attributed solely to β2-adrenergic receptors.

That result complicates a simple model in which β2 signaling uniformly improves T-cell metabolism. The authors proposed that residual or opposing adrenergic effects might involve β1-adrenergic receptors, although the study did not directly test that mechanism. This possibility is compatible with the observation that β2 blockade reduced rather than enhanced CD8+ activation in some conditions. It indicates that the balance among receptor subtypes may depend on whether cells are resting or activated and on the duration and context of stimulation. The investigators specifically called for future experiments that distinguish β1 from β2 effects. Their hypothesis is also consistent with earlier mouse work cited by the authors, in which β-adrenergic blockade improved aspects of exhausted CD8+ T-cell function, but that animal research does not establish what occurred in the present human participants.

Neither age nor habitual activity altered the measured abundance of ADRB2 messenger RNA in CD4+ or CD8+ T cells. The researchers also found no group differences in intracellular cyclic AMP, or cAMP, after a two-minute exposure to 10 micromolar isoproterenol. Isoproterenol did significantly raise cAMP overall, at p = 0.0027, showing that the treatment engaged a functional intracellular signaling response. Nevertheless, the similar cAMP responses across groups argue against gross differences in β2-receptor transcription or canonical cAMP responsiveness as the explanation for the activation and Glut1 patterns. They do not rule out subtler changes in receptor protein abundance, cell-surface density, receptor sensitivity, downstream signaling or post-transcriptional regulation. Quantitative reverse-transcription polymerase chain reaction provided only an indirect indication of receptor expression rather than a direct measurement of receptor protein abundance or surface density.

Direct measurements of fuel use and lipid storage were less decisive than the Glut1 results. A fluorescent glucose analogue, 2-NBDG, showed a nonsignificant trend toward increased uptake after activation in CD4+ cells from the moderately active older group, at p = 0.088, but there was no corresponding effect in CD8+ cells and no significant group difference. Lipid accumulation measured with BODIPY did not increase with activation in CD4+ cells, while PMA and ionomycin reduced lipid accumulation in CD8+ cells as a condition effect at p = 0.010. The authors cautioned that 2-NBDG is an imperfect surrogate for glucose metabolism in T cells and that elevated surface Glut1 does not necessarily demonstrate increased glycolytic flux. Actual glucose use also depends on transporter localization, co-stimulatory signaling, nutrient availability and downstream metabolic pathways. A four-hour activation window may also have been too short to produce substantial changes in glucose utilization or lipid accumulation, while the study lacked a true positive control for those two assays.

The study design limits how broadly its associations can be interpreted. Habitual activity among the older participants was measured objectively for seven days with accelerometry. Highly active older adults accumulated a mean 149.5 ± 22.9 minutes per day of moderate-to-vigorous physical activity, compared with 71.5 ± 29.1 minutes per day among moderately active older adults; both groups met physical-activity recommendations. Young participants’ activity was instead estimated through a general-health questionnaire that was not validated, so the comparison across the age boundary was less rigorous. The sample included only six participants per group and no physically inactive older adults. It also lacked sex balance, omitted direct analysis of naïve, memory and senescent T-cell proportions, and could not fully account for hormones, inflammatory signals, blood-flow changes and other physiological conditions present during real exercise. Only one blocker concentration was tested, limiting validation of its selectivity in T cells, while α-adrenergic receptors and other simultaneous exercise signals were not included in the model.

The results should therefore be treated as hypothesis-generating rather than evidence of a causal effect of exercise. Although highly active older adults retained the age-related deficit in CD8+ activation, their CD8+ cells showed a different pattern of Glut1 regulation during adrenergic stimulation, including a stronger response to β2 blockade than was seen in moderately active older adults. The experiment also followed one brief isoproterenol exposure, whereas repeated or sustained adrenergic signaling may produce different immune effects. PMA and ionomycin provide controlled pharmacological activation but do not reproduce antigen presentation, physiological stress or the full neuroendocrine environment of exercise. No result in this study demonstrated that more active older adults had stronger vaccine responses, controlled tumors more effectively or experienced fewer infections. What the data show is narrower: in an in vitro model of acute adrenergic stimulation, habitual activity level was associated with how CD8+ T cells integrated signals affecting glucose-transporter expression, while the age-related impairment of CD8+ activation remained. Larger studies incorporating more physiological stimulation, direct metabolic measurements and separate tests of β1 and β2 receptors will be needed to determine the biological meaning of these associations.

Subject of Research: Associations among habitual physical activity, aging, adrenergic signaling and human T-cell activation and metabolism

Article Title: Impact of habitual physical activity and age on T cell metabolism and activation via β2-adrenergic receptor modulation

Article References: Sardeli, A. V., Ramkrapes, A., Boyes-Jensen, J., Hazeldine, J., Batatinha, H., Duggal, N. A., Calebiro, D., & Turner, J. E. (2026). Impact of habitual physical activity and age on T cell metabolism and activation via β2-adrenergic receptor modulation. Frontiers in Aging, 7, Article 1869552. https://doi.org/10.3389/fragi.2026.1869552

Image Credits: AI Generated

DOI: 10.3389/fragi.2026.1869552

Keywords: habitual physical activity, immune aging, CD8+ T cells, adrenergic signaling, β2-adrenergic receptor, T-cell activation, cellular metabolism, Glut1, immunosenescence, exploratory human study, Impact, habitual