Hypothesis

A twelve‑month regimen that combines daily time‑restricted feeding (TRF), moderate‑intensity aerobic exercise, and a specific prebiotic fiber blend will produce greater improvements in thymic output and systemic inflammation than either rapamycin or anti‑IL‑6 monoclonal antibody monotherapy in adults aged 65‑80.

Mechanistic Rationale

• TRF and exercise raise NAD⁺ levels, activating SIRT1 in thymic epithelial cells (TECs). SIRT1 deacetylates FOXN1, driving its transcription and promoting TEC differentiation, which expands naïve T‑cell output【https://pmc.ncbi.nlm.nih.gov/articles/PMC12711513/】.
• Exercise‑induced irisin shifts macrophage polarization toward M2 and upregulates Foxp3 in regulatory T cells, while the accompanying IL‑6 transient differs from chronic inflammatory IL‑6 signaling【https://pmc.ncbi.nlm.nih.gov/articles/PMC12784853/】.
• Prebiotic fiber fermentation yields butyrate, which binds GPR109A on hematopoietic stem cells (HSCs), biasing lymphoid lineage commitment and limiting expansion of pro‑inflammatory myeloid cells【https://pmc.ncbi.nlm.nih.gov/articles/PMC12711513/】.
• The three interventions concurrently hit SASP‑driven inflammation, HSC lineage skewing, thymic involution, and metabolic dysregulation, breaking the self‑reinforcing loop where chronic inflammation impairs immunity and weakened immunity fails to clear senescent cells.

Predictions

1. Thymic output (measured by circulating T‑cell receptor excision circles) will increase ≥30 % in the combination arm, versus <10 % in each monotherapy arm.
2. Plasma inflammaging markers (IL‑6, TNF‑α, CRP) will drop ≥25 % in the combination arm, while monotherapies show ≤10 % change.
3. Flow cytometric analysis of bone marrow will reveal a higher lymphoid‑to‑myeloid HSC ratio only in the combination group.

Experimental Design

• Randomized, double‑blind, placebo‑controlled trial with four arms: (1) TRF + exercise + prebiotic fiber, (2) rapamycin low‑dose, (3) anti‑IL‑6 antibody, (4) placebo.
• Primary endpoints: TREC concentration and composite inflammaging score at baseline, 6 months, and 12 months.
• Secondary endpoints: thymic MRI fat fraction, VO₂ max, fecal short‑chain fatty acid profiles, and adverse event monitoring.

Falsifiability

If after 12 months the combination arm does not show a statistically significant superiority (p < 0.05) over both monotherapies in either thymic output or inflammaging reduction, the hypothesis is falsified. Conversely, meeting both superiority criteria would support the mechanistic claim that simultaneous NAD⁺‑SIRT1 activation, irisin‑mediated immune modulation, and butyrate‑driven HSC biasing are necessary for maximal immune rejuvenation in aging.