Journal Article Review Ppublish
PubMed: 42580558 DOI: 10.1016/j.mad.2026.112235
Epigenetic drift and LINE-1 activation in aging brain: Implications for neurodegenerative disease.
Mech Ageing Dev 233:112235
Authors: Alkinoos A Armoundas, Christina Piperi
Affiliations
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
Abstract
Brain aging and age-associated neurological diseases, such as Alzheimer's Disease (AD), Parkinson's Disease (PD), and Amyotrophic Lateral Sclerosis (ALS), are largely attributed to epigenetic drift which is characterized by the gradual accumulation of alterations in neural cell methylation patterns over time. These methylation changes are particularly evident in transposable element (TE)-derived sequences such as Long interspersed element-1 (LINE-1) which comprises approximately 17% of the human genome. During aging, LINE-1 elements gradually lose their methylation, as well as the regulatory safeguard mechanisms that usually keep them inactive. This repression loss can lead to LINE-1 reactivation, contributing to harmful effects including genomic instability, neuroinflammation, and more. Together these findings indicate that impaired epigenetic maintenance, especially in repetitive genome regions, plays a key role in biological aging of neurons and glial cells. In this narrative review, we discuss the methylation dynamics and regulatory mechanisms of LINE-1 retrotransposons, their activation processes during aging, and contribution to age-associated neurological diseases. We also highlight the potential of targeting LINE-1 methylation to restore methylation homeostasis, epigenetic stability and delay brain aging.
MeSH
Cells, Growth, Biochemistry, Aging, Brain, Genome, Neurodegenerative Diseases