Calorie restriction suppresses aging alpha cell pro-inflammatory signaling

Area of Science:

• Metabolic health
• Aging research
• Immunology

Background:

• Aging increases risk for insulin resistance and type 2 diabetes, linked to declining pancreatic beta cell function.
• Early-life calorie restriction (CR) benefits metabolic health, but its effects when initiated later in life are unknown.

Purpose of the Study:

• To investigate the impact of late-life CR on glucose homeostasis and beta cell function in aged mice.
• To explore the molecular mechanisms underlying CR's effects on aging islets and immune cell interactions.

Main Methods:

• A two-month, 20% CR intervention was applied to 72-week-old male mice.
• In vivo glucose homeostasis was assessed via meal tolerance tests.
• Single cell RNA-sequencing and confocal microscopy were used to analyze beta and alpha cell function and islet immune cell density.

Main Results:

• CR improved glucose tolerance and insulin sensitivity in aged mice.
• CR reduced glucose-stimulated insulin secretion and enhanced beta cell proteostasis by downregulating ER stress.
• CR reprogrammed alpha cell transcriptome, suppressing antigen presentation and MHC-I signaling, correlating with reduced CD8+ T cells in islets.

Conclusions:

• Late-life CR beneficially remodels aging alpha and beta cells, modulating immune cell interactions.
• CR mitigates age-related islet inflammation and immune activation.
• Findings suggest CR as a potential strategy to combat age-related metabolic and inflammatory decline in pancreatic islets.