Endogenous and exogenous viral reactivation as a driver of epigenetic drift and mitophagy failure in aging

Aging is increasingly understood as a multifactorial process involving mitochondrial dysfunction, epigenetic drift, and chronic inflammation. While many age-related pathologies have been linked to impaired mitophagy and transcriptional deregulation, the upstream mechanisms driving these phenomena remain elusive. Here, a unifying hypothesis is proposed: that the progressive reactivation of human endogenous retroviruses (HERVs), combined with latent viral infections acquired during life, imposes an escalating burden on the epigenetic regulatory system. This "virome pressure" demands continuous silencing via DNA methylation, histone deacetylation, and NAD⁺-dependent pathways. With age, these silencing mechanisms deteriorate, leading to HERV reactivation, disruption of key mitochondrial quality control genes, and activation of innate immune responses. This is likened to a molecular peat bog, a simmering threat buried beneath the surface, where silencing mechanisms struggle to contain viral elements until pressure builds and erupts as the organism ages. This model integrates virology, epigenetics, and mitochondrial biology to offer novel insights into the aging process and suggests new targets for therapeutic intervention research.