Cumulative physiological stress is associated with age-related changes to peripheral T lymphocyte subsets in healthy humans

Authors: Snodgrass, Ryan; Jiang, Xiaowen; Stephensen, Charles; Laugero, Kevin

Submitted to: Immunity & Ageing
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/17/2023
Publication Date: 6/23/2023
Citation: Snodgrass, R.G., Jiang, X., Stephensen, C.B., Laugero, K.D. 2023. Cumulative physiological stress is associated with age-related changes to peripheral T lymphocyte subsets in healthy humans. Immunity & Ageing. 20. Article 29. https://doi.org/10.1186/s12979-023-00357-5.
DOI: https://doi.org/10.1186/s12979-023-00357-5

Interpretive Summary: Progressive age-associated change in frequencies and functional capacities of immune cells is known as immunosenescence. Despite data linking chronic environmental, physiological, and psychosocial stressors with accelerated aging, how stress contributes to immunosenesence is not well characterized. To help delineate the contribution of cumulative physiological stress on immunosensence we assessed relationships between a composite measurement of cumulative physiological stress, reflecting the functioning of the hypothalamic-pituitary-adrenal axis, sympathetic nervous system, cardiovascular system, and metabolic processes, with immune cell changes typically affiliated with aging in a cohort of healthy volunteers ranging from 18-66 y. The cumulative physiological stress, or physiological stress load, positively correlated with subject age in the study cohort and was significantly higher in adults 50-66 y compared to adults 18-33 y and 34-49 y. Using physiological stress load, we identified a significant age-dependent association between stress load and frequencies of circulating immune cells known as regulatory T lymphocytes (Tregs). Tregs contribute to immune homeostasis by suppressing exaggerated immune responses. Frequencies of these cells were higher in younger participants, but only in participants exhibiting low physiological stress load. As stress load increased, frequencies of Tregs decreased in young participants to levels similar to older participants. However, frequency of Tregs were unchanged with increasing stress load in middle and older age individuals. A follow-up analysis of stress load components indicated lower circulating DHEA-S, a steroid hormone abundantly secreted from the adrenal gland, and higher urinary norepinephrine, a neurotransmitter and hormone important in the body’s “fight-or-flight” stress response, as the primary contributors to the influence of total stress load on Treg frequency in younger subjects. We also identified an inverse association between stress load and frequencies of immature Tregs and a positive association between stress load and frequencies of activated Tregs. Those associations did not depend on whether the participants were young, middle age, or older. Waist circumference and blood pressure appeared to be the primary factors of stress load mediating those age-independent associations. In summary, our study results suggest that, in younger people, physiological stress load may diminish regulatory T cell frequencies to levels seen in older persons. Furthermore, independent of age, stress load may contribute to contraction of the immature Treg pool and accumulation of activated Treg cells.

Technical Abstract: Background: Progressive age-associated change in frequencies and functional capacities of immune cells is known as immunosenescence. Despite data linking chronic environmental, physiological, and psychosocial stressors with accelerated aging, how stress contributes to immunosenesence is not well characterized. Objective: To help delineate the contribution of cumulative physiological stress on immunosensence we assessed relationships between a composite measurement of cumulative physiological stress, reflecting the functioning of the hypothalamic-pituitary-adrenal axis, sympathetic nervous system, cardiovascular system, and metabolic processes, and lymphocyte changes typically affiliated with aging in a cohort of healthy volunteers ranging from 18-66 y. Results: Physiological stress load positively correlated with subject age in the study cohort and was significantly higher in adults 50-66 y compared to adults 18-33 y and 34-49 y. Using physiological stress load, we identified a significant age-dependent association between stress load and frequencies of circulating regulatory T lymphocytes (Tregs). Frequencies were higher in younger participants, but only in participants exhibiting low physiological stress load. As stress load increased, frequencies of Tregs decreased in young participants but were unchanged with increasing stress load in middle and older age individuals. A follow-up analysis of stress load components indicated lower circulating DHEA-S and higher urinary norepinephrine as the primary contributors to the effects of total stress load on Tregs. In addition, we identified an age-independent inverse association between stress load and frequencies of naïve Tregs and a positive association between stress load and frequencies of memory Tregs. These associations were primarily driven by stress load components waist circumference and systolic and diastolic blood pressure. In summary, our study results suggest that, in younger people, physiological stress load may diminish regulatory T cell frequencies to levels seen in older persons. Furthermore, independent of age, stress load may contribute to contraction of the naïve Treg pool and accumulation of memory Treg cells.