Evening blue light triggers retinal exosome‑mediated miRNA transfer that accelerates peripheral epigenetic aging

Evening blue light (400‑500 nm) suppresses melatonin via ipRGC‑SCN signaling, delaying circadian phase by ~1.1 h after 2 h exposure (Evening blue light suppresses melatonin). Chronic exposure fragments rhythms, reduces amplitude and is linked to cognitive decline, metabolic disease and immunosenescence (Circadian disruption and aging). We hypothesize that the same ipRGC activation that drives melatonin suppression also triggers the release of exosomes enriched in specific microRNAs (e.g., miR‑182, miR‑92a) from retinal ganglion cells. These exosomes enter the bloodstream, reach peripheral tissues such as liver, adipose and hippocampus, and deliver their cargo to resident cells. Inside target cells, miR‑182 and miR‑92a bind to the 3′‑UTR of core clock genes BMAL1 and PER2, reducing their transcription and dampening the amplitude of peripheral circadian oscillators. Simultaneously, exosomal transfer induces low‑level mitochondrial ROS production, which accelerates DNA methylation drift at CpG sites associated with epigenetic clocks, thereby increasing biological age independent of chronological age. This provides a mechanistic bridge between acute light‑induced circadian disruption and the progressive aging phenotypes observed in long‑term misalignment.

The hypothesis is testable through three complementary approaches. First, expose human participants to controlled evening blue light (2 h at 30 lux) versus dim light controls and collect serum exosomes at 0, 2 and 6 h post‑exposure; quantify miR‑182 and miR‑92a levels by qPCR (Exosome isolation methods). Second, administer isolated exosomes from blue‑light‑exposed donors to cultured human fibroblasts or mouse hepatocytes and measure BMAL1/PER2 expression (luciferase reporters) and mitochondrial ROS (MitoSOX fluorescence). Third, conduct a longitudinal crossover trial where participants wear blue‑light blocking glasses after sunset for 8 weeks; assess changes in peripheral epigenetic age (Horvath clock), serum exosomal miRNA profiles, and markers of circadian amplitude (actigraphy‑derived interdaily stability). A significant reduction in exosomal miRNA load, restored clock gene amplitude, and slowed epigenetic aging in the blocking condition would falsify the null hypothesis that evening blue light affects aging solely through central SCN pathways. Conversely, persistence of epigenetic acceleration despite blocked central melatonin suppression would support the exosome‑mediated mechanism.