# Lower CD8+ T‐cell Senescence Partially Mediates the Neuroprotection of Higher Aerobic Fitness

## TL;DR

Higher aerobic fitness in older adults may protect the brain by reducing the aging of immune cells linked to Alzheimer's risk.

## Contribution

This study shows that reduced CD8+ T-cell senescence partially explains the cognitive benefits of aerobic fitness in older African Americans.

## Key findings

- Higher aerobic fitness was associated with fewer generalization errors, a marker of Alzheimer's risk.
- Reduced CD8+ T-cell senescence explained 15% of the neuroprotective benefits of aerobic fitness.
- The remaining 85% of the effect may involve other immune or inflammatory factors.

## Abstract

Immunosenescence––age‐related changes in immunity––may exacerbate the pathologic processes of Alzheimer's disease. Compartments of the adaptive immune system (e.g., cytotoxic CD8+ T‐cells) show the most significant decline in later life. Fortunately, a higher level of aerobic fitness is linked to both lower age‐related accumulation of senescent T‐cells and reduced Alzheimer's risk. However, it remains unclear whether this association between higher aerobic fitness and decreased Alzheimer's risk is mediated by lower proportions of T‐cell senescence. In a cohort of older African Americans, this study aimed to: 1) examine the relationship between aerobic fitness and generalization (a sensitive cognitive marker of Alzheimer's risk) and 2) investigate whether CD8+ T‐cell senescence mediates this relationship.

231 older African American participants from the Pathways to Healthy Aging in African Americans cohort study (M
age=70.74 years, SD = 6.40; M
education=14.02 years, SD = 2.25) responded to demographic, health, and lifestyle questionnaires; completed a cognitive battery including a generalization task (Concurrent Discrimination and Transfer Task); underwent an anthropometric and physical performance battery; and provided a blood sample for T‐cell senescence characterization. Using the blood specimens, peripheral blood mononuclear cells were isolated and analyzed for senescence‐associated ß‐Galactosidase activity as a measure of proportions of cytotoxic CD8+ T‐cell senescence. Aerobic fitness (VO2peak) was estimated from the Six‐Minute Walk Test. Covariates included age, sex, education, and waist‐to‐hip ratio.

Higher aerobic fitness was significantly associated with fewer generalization errors. The direction of the paths indicated that higher aerobic fitness was associated with lower CD8+ T‐cell senescence ( = ‐0.29, p = .03), which was subsequently associated with a decrease in generalization errors ( = 0.15, p = .01). Overall, reduced T‐cell senescence may explain 15% of the neuroprotective benefits of exercise.

One pathway by which higher aerobic fitness is associated with lower Alzheimer's risk in older African Americans is through lower proportions of CD8+ T‐cell senescence. The remaining 85% of the effect could include other immune, inflammatory, or other cellular phenotypes associated with age and physical function. These results highlight the immune and cognitive function benefits of a physically active lifestyle.