(OR22-02-25) Intermittent Fasting Improves Aging Immunity by Reprogramming Systemic Myeloid Lineage and Tissue Inflammation

Objectives: The rapidly growing aging population has made aging-associated diseases a global challenge, underscoring the critical need for healthy aging interventions. Calorie restriction is known to have health benefits, but long-term compliance is extremely challenging. Intermittent fasting (IF) has recently emerged as a more sustainable alternative to calorie restriction. Chronic low-grade inflammation, also known as “inflammaging,” is a hallmark of aging, underpinning many age-related diseases. While the metabolic benefits of IF in obesity have been elucidated, the effects of IF on aging immunity and inflammation remain unclear.

Methods: In this study, we subjected young (3-month-old) and old (20-month-old) mice to an IF regimen of alternate-day fasting and feeding for 12 weeks. As expected, IF improved body composition and glycemic homeostasis in both young and old mice. Next, we investigated the effects of IF on inflammaging by studying myeloid cells, including bone marrow hematopoietic stem and progenitor cells (HSPC), peripheral blood mononuclear cells (PBMC), peritoneal macrophages (PM), and tissue macrophages.

Results: In the bone marrow, the age-associated increase in myeloid-biased multipotent progenitor 3 (MPP3) was decreased by IF, suggesting a remodeling of the myeloid lineage. Consistently, IF decreased the age-associated increase in Ly6C^High monocytes in PBMC and reduced the expression of pro-inflammatory markers and intrinsic cytokine expression in PM. Intriguingly, IF-induced suppression of macrophage pro-inflammatory activation was only shown in the liver, not in the brain, heart, or white adipose tissue. Mechanistically, fasting activates autophagy in macrophages, rescuing aging-associated autophagy impairments and reducing macrophage pro-inflammatory activation.

Conclusions: Our results suggest IF effectively regulates myeloid lineage differentiation and reprogramming, reducing systemic inflammation and preferentially suppressing hepatic inflammation. IF offers significant benefits for metabolism and immunity in aging and may serve as a promising intervention to prevent or treat inflammaging, particularly by protecting the liver and improving healthspan.

Funding Sources: This study was supported by NIH/NIDDK, NIH/NIA, P30, and Texas A&M AgriLife Institute for Advancing Health through Agriculture.