Hypoxia Preserves Chromatin Integrity and Delays Cellular Senescence through Epigenetic Regulation

Abstract

Hypoxia is a physiologically relevant microenvironment in both normal and diseased tissues and has emerged as a potent modu-lator of cellular senescence and organismal longevity. This review synthesizes evidence that hypoxia delays senescence across diverse experimental systems and species, and highlights mechanisms by which hypoxia rewires chromatin states during se-nescence-associated transitions. We focus on oxygen-and α-ketoglutarate–dependent epigenetic regulators, particularly his-tone lysine demethylases, whose catalytic activities are limited under hypoxia. Consequently, histone methylation increases and higher-order chromatin organization is stabilized. Using oncogene-induced senescence as an experimentally tractable framework, we discuss recent findings showing that hypoxia suppresses senescence-associated histone clipping, preserves nuclear lamina integrity, and restrains large-scale heterochromatin reorganization while leaving canonical cell-cycle arrest largely intact. We further consider emerging links among DNA damage, epigenetic instability, and aging phenotypes, and propose that senescence can be viewed as a breakdown of coordinated epigenetic homeostasis. By integrating these concepts, we position hypoxia and hypoxia-mimetic interventions as promising strategies to modulate aging-associated cellular states and to explore therapeutic opportunities in age-related pathologies.