We propose that short, repeated autophagy-inducing fasting pulses (12–36 h) augment epigenetic plasticity of hematopoietic stem cells, leading to a measurable increase in naïve T‑cell receptor diversity and myeloid lineage balance. This immune remodeling, rather than metabolic rate suppression, mediates the longevity advantage observed in calorie‑restricted mice that maintain body weight.

We argue that immune rejuvenation provides a mechanistic bridge between autophagy activation and extended healthspan, offering a biomarker‑driven strategy to personalize fasting regimens.

Mechanistic Rationale

• Fasting triggers AMPK‑ULK1 signaling, initiating autophagic clearance of damaged mitochondria and protein aggregates in HSCs.
• Reduced oxidative stress preserves NAD⁺ levels, supporting SIRT1‑dependent deacetylation of histone H3K9 at loci governing lymphoid versus myeloid fate.
• The resulting chromatin state favors balanced differentiation, expanding the naive T‑cell pool and enhancing clonal repertoire breadth, which correlates with youthful immune phenotypes described in recent biomarker studies [[https://onlinelibrary.wiley.com/doi/full/10.1111/acel.14482]].

Testable Predictions

1. In humans undergoing a 5‑day fasting‑mimicking diet repeated monthly for 3 months, flow‑cytometry of peripheral blood mononuclear cells will show a significant rise in CD45RA⁺CCR7⁺ naïve T‑cell frequency and Shannon entropy of TCRβ sequencing compared with an isocaloric continuous 20 % CR group.
2. Autophagy flux, quantified by LC3‑II/I ratio in isolated CD34⁺ progenitors before and after each fasting cycle, will peak during the 24‑h fasting window and correlate inversely with mitochondrial ROS measured by MitoSOX.
3. Subjects exhibiting the greatest increase in naïve T‑cell diversity will also display improved youthful red‑cell metrics (elevated reticulocyte volume, reduced oxidative hemoglobin adducts) independent of changes in resting metabolic rate or body‑weight loss.
4. Conversely, pharmacological inhibition of autophagy (e.g., chloroquine) during fasting periods will abolish the immune‑cell improvements, confirming causality.

Falsifiability

If repeated fasting pulses fail to increase naïve T‑cell receptor diversity or autophagy flux in HSCs, or if immune changes do not predict longevity‑associated biomarkers better than metabolic markers, the hypothesis is refuted.

Such an approach could refine clinical trials of fasting‑mimicking diets.