Circulating factors induced by time-restricted eating drive metabolic reprogramming in endothelial cells

Area of Science:

• Neuroscience
• Metabolic Health
• Vascular Biology

Background:

• Age-related endothelial dysfunction in cerebral microcirculation contributes to vascular cognitive impairment and dementia (VCID).
• Time-restricted eating (TRE) shows promise for metabolic and vascular health, but its brain microvasculature effects are unclear.
• The role of TRE-induced circulating factors in endothelial function needs investigation.

Purpose of the Study:

• To test if circulating factors from TRE practitioners protect human cerebromicrovascular endothelial cells.
• To investigate the molecular mechanisms of TRE's influence on brain microvasculature.

Main Methods:

• Serum transfer bioassay using human cerebromicrovascular endothelial cells.
• Transcriptomic profiling of cells treated with serum from aged individuals with or without TRE.
• Gene set enrichment analysis and upstream regulator analysis.

Main Results:

• TRE-associated serum reprogrammed endothelial cells, activating stress-responsive pathways (ISR/ATF4) and suppressing anabolic programs (mTORC1).
• TRE serum induced GDF15 and altered mitochondrial gene expression, indicating stress adaptation.
• Key transcription factors (ATF4, FOXO, KLF) were activated, while anabolic regulators (SREBF1/2) were inhibited.

Conclusions:

• Circulating factors induced by TRE promote a unique endothelial phenotype of metabolic reprogramming and stress adaptation.
• This study provides mechanistic insights into how TRE influences cerebrovascular aging.
• TRE-induced circulating factors may mediate the link between systemic metabolism and endothelial function in the brain.