Endogenous and Exogenous ViralReactivation as a Driver of Epigenetic Driftand Mitophagy Failure in Aging

Abstract

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, we propose a unifying hypothesis: 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 such as PINK1 and Parkin, and
activation of innate immune responses. We liken this to a molecular peat bog, where silencing
resources are gradually consumed in a futile effort to contain viral elements. This model integrates
virology, epigenetics, and mitochondrial biology to offer novel insights into the aging process and
suggests new targets for therapeutic intervention.