Gut-derived metabolic reprogramming drives immune aging and tissue degeneration

Area of Science:

• Aging research
• Immunology
• Metabolism
• Ophthalmology

Background:

• Aging involves gut microbiome alterations, metabolic imbalance, and chronic inflammation, contributing to tissue degeneration.
• The integration of these factors in driving age-related diseases like age-related macular degeneration (AMD) is not fully understood.

Purpose of the Study:

• To investigate the link between diet, gut microbiome, metabolism, immune aging, and retinal degeneration using AMD as a model.
• To identify key molecular mechanisms and potential therapeutic targets.

Main Methods:

• Utilized mouse models fed a high-fat, cholesterol-enriched (HFC) diet to study gut microbiome and metabolic changes.
• Analyzed plasma histidine levels in mice and AMD patients.
• Investigated immune cell reprogramming and infiltration into the retina.
• Employed *C. elegans* to explore IGF1R/AKT2 signaling in diet-induced aging.
• Examined retinal pigment epithelium (RPE) in a mouse AMD model, focusing on histidine transporter SLC7A5 and MIF/CD74 signaling.
• Tested histidine supplementation and AKT2 modulation as interventions.

Main Results:

• HFC diet induced gut barrier dysfunction, microbiome changes, and reduced circulating histidine in mice.
• Lower histidine levels were observed in AMD patients and correlated inversely with BMI in controls.
• Diet-induced changes promoted innate immune reprogramming, with increased inflammatory neutrophils and monocytes infiltrating the retina.
• IGF1R/AKT2 signaling was identified as a regulator of epigenetic remodeling and immune aging in *C. elegans*.
• RPE cells in AMD mice showed reduced SLC7A5, linking metabolic stress to inflammatory signaling.
• Histidine supplementation or AKT2 modulation reduced immune activation and rescued retinal degeneration.

Conclusions:

• A diet-induced metabolic-immune axis, mediated by histidine dysregulation, connects gut microbiome changes, metabolic stress, and immune aging to retinal degeneration.
• Targeting the histidine axis offers a potential therapeutic strategy for AMD and other age-related diseases.