Dynamics of Human Endogenous Retroviruses Expression, Proviral Load and Systemic Inflammatory Status Modulated by Physical Exercise and Aging

Human endogenous retroviruses (HERVs), remnants of ancient germline infections, constitute ~8% of the human genome. Although mostly silenced, these elements can be expressed and play physiological or pathological roles. We investigated HERV expression dynamics, proviral load, and systemic inflammatory status in young and older adults, as well as the impact of regular physical exercise. PBMC and serum samples were collected from 30 young controls (YC), 30 inactive older adults (INAC) and 30 regularly exercising older adults (REG). Expression of HERV-W, -K, -H, Syncytin-1 and -2 was assessed by qPCR using the −2ΔΔCt method, and proviral load (HERV-W, -K, -H) was estimated by relative copy number. Serum cytokines (IL-1β, IL-6, IL-17, TNF-α, IFN-γ, IL-10) were quantified by ELISA. Statistical significance was set at p < 0.05. INAC participants showed higher proviral load of HERV-K, -W and -H compared to YC (p = 0.025), but overall lower HERV expression, except for HERV-K. REG presented increased expression of HERV-W (~1.5-fold, p < 0.0001), HERV-H (~1.8-fold, p < 0.0001; higher than YC p = 0.01), HERV-K (vs. YC p = 0.02) and Syncytin-1 (~1.4-fold vs. INAC and YC, p < 0.01). HERV-K was the most upregulated element in INAC. HERV-W and HERV-H expression were strongly correlated in all groups. INAC showed a pro-inflammatory profile, with elevated IL-6/IL-10, IL-1β/IL-10, and IFN-γ/IL-10 ratios. Older adults exhibit higher HERV proviral load, suggesting possible age-related insertions. Regular physical exercise modulates HERV expression, whereas inactivity is associated with reduced expression and increased inflammation. HERV-W and HERV-H maintain coordinated expression across ages, indicating interplay between inflammatory balance, aging, and retroviral activity.