Evening Blue Light Alters Gut‑Derived Short‑Chain Fatty Acid Signaling to Peripheral Clocks, Amplifying Circadian‑Driven Aging

Evening exposure to blue‑rich light (460‑480 nm) suppresses melatonin via ipRGCs, shifting circadian phase and increasing oxidative stress【https://www.chronobiologyinmedicine.org/m/journal/view.php?number=167】. We hypothesize that this light‑induced melatonin drop also reduces gut‑derived short‑chain fatty acid (SCFA) production, weakening SCFA signaling to peripheral clocks and accelerating aging phenotypes. Specifically, blue light‑mediated circadian disruption lowers colonic fermentation of fiber, decreasing acetate, propionate and butyrate that normally entrain liver, muscle and adipose clocks through GPR41/43 activation and HDAC inhibition【https://pmc.ncbi.nlm.nih.gov/articles/PMC12996223】. The resulting desynchrony between central and peripheral oscillators amplifies inflammatory NF‑κB signaling and mitochondrial ROS, driving the aging cascade linked to cardiovascular disease, insulin resistance and cognitive decline【https://www.frontiersin.org/journals/aging/articles/10.3389/fragi.2025.1646794/full】. Thus, evening blue light acts as a dual hit: directly dampening melatonin and indirectly eroding the gut‑brain‑clock axis, together hastening biological aging.

Mechanism

1. Blue light activates ipRGCs → ↓ melatonin secretion → ↓ MT1/MT2 receptor signaling in enterochromaffin cells.
2. Reduced melatonin diminishes ileal motility and mucus secretion, slowing transit time and altering substrate availability for saccharolytic bacteria.
3. Microbiota shift toward proteolytic taxa, lowering SCFA yields (acetate, propionate, butyrate) as shown in fiber‑feeding studies【https://pmc.ncbi.nlm.nih.gov/articles/PMC12996223】.
4. Lower SCFA levels decrease activation of GPR41/43 on vagal afferents and peripheral tissues, blunting peripheral clock entrainment via cAMP‑CREB and PPARγ pathways.
5. Peripheral clocks fall out of phase with the suprachiasmatic nucleus, leading to mistimed expression of metabolic genes (e.g., Pparα, Bmal1) and heightened NF‑κB‑driven inflammation.
6. Chronic low‑grade inflammation and ROS accumulation accelerate telomere shortening and senescence, hallmarks of accelerated aging.

Testable Predictions

• Individuals using blue‑blocking glasses after 19:00 will show higher fecal SCFA concentrations (acetate, propionate, butyrate) compared with controls after two weeks.
• In a crossover study, melatonin‑rich snack (tart cherry juice) given before bedtime will partially rescue SCFA levels only when blue light exposure is limited, indicating interaction between melatonin and gut microbiota.
• PER3^5/5 genotype carriers will exhibit a larger decrease in SCFA production under blue light than PER3^4/4 carriers, linking genetic vulnerability to gut‑clock disruption.
• Administration of a SCFA‑producing probiotic (e.g., Faecalibacterium prausnitzii + inulin) will attenuate blue‑light‑induced elevation of plasma IL‑6 and CRP, suggesting a protective gut‑brain‑clock axis.

Experimental Approach

• Recruit 120 healthy adults aged 30‑50, stratify by PER3 genotype.
• Four‑week parallel arms: (1) standard evening LED exposure (480 nm peak), (2) blue‑blocking glasses, (3) blue‑blocking + tart cherry juice, (4) blue‑blocking + SCFA‑producing probiotic.
• Collect saliva melatonin (dim‑light melatonin onset), fecal SCFA (GC‑MS), peripheral clock gene expression from blood (qPCR of Bmal1, Rev‑erbα), and plasma inflammatory markers (IL‑6, TNF‑α, CRP).
• Primary outcome: change in fecal butyrate concentration; secondary outcomes: melatonin amplitude, peripheral clock phase, inflammatory score.
• Statistical analysis: mixed‑effects model with time, intervention, and genotype as fixed effects; participant as random effect.

If blue light exacerbates aging via gut‑derived SCFA loss, then interventions preserving or boosting SCFA should mitigate melatonin‑independent aging markers even under circadian stress. Failure to observe SCFA changes or protective effects would falsify the hypothesis.