Holistic Immune Rejuvenation via Combined Metabolic, Microbiome, and STING Modulation Outperforms Monotherapy in Human Aging

Hypothesis

In a randomized, controlled trial of middle‑aged to older adults, a combined intervention consisting of (1) time‑restricted eating (16:8 intermittent fasting), (2) a high‑fiber diet designed to elevate circulating short‑chain fatty acids (SCFAs), and (3) a low‑dose, selective STING inhibitor will produce a greater increase in naïve T‑cell output and a larger reduction in systemic SASP biomarkers than any single component alone or a standard care control after six months.

Rationale

The mechanistic landscape of immunosenescence reveals three interlocking nodes:

• Mitochondrial DNA efflux from senescent cells activates cGAS‑STING, amplifying SASP secretion [1];
• Defective T‑cell mitochondria drive chronic inflammation and accelerate aging [2];
• Skewed hematopoiesis and thymic involution restrict naïve T‑cell replenishment [3].

Each node can be attenuated by distinct lifestyle or pharmacologic levers:

• Intermittent fasting improves mitochondrial bioenergetics, reduces mitochondrial DNA release, and expands thymic epithelial cells, thereby boosting naïve T‑cell production [3];
• High‑fiber intake raises colonic SCFA production, which inhibits myeloid bias in hematopoietic stem cells and promotes lymphopoiesis [3];
• Low‑dose STING inhibition blunt the inflammatory feedback loop without completely abolishing pathogen sensing, preserving host defense while curbing SASP [1].

Isolated targeting of any single node yields partial benefit but fails to break the feedback loops because compensatory pathways remain active. For example, STING inhibition lowers SASP but does not correct mitochondrial dysfunction in T cells or myeloid skewing; fasting improves thymic output yet may not sufficiently suppress cGAS‑STING signaling if microbial metabolites remain low; SCFA enrichment shifts hematopoiesis but does not directly mitigate existing senescent cell burden.

We hypothesize that simultaneous modulation creates a synergistic metabolic‑immune milieu: fasting‑driven NAD+ replenishment enhances STING inhibitor efficacy, SCFAs promote a tolerant mucosal environment that reduces basal IFN‑β production, and reduced STING signaling diminishes senescence‑associated mitochondrial stress, together allowing hematopoietic stem cells to regain lymphoid potential and the thymus to export more naïve T cells.

Predictions and Falsifiability

• Primary outcome: Flow‑cytometric quantification of circulating CD45RA⁺CCR7⁺ naïve CD4⁺ and CD8⁺ T cells will show a ≥25% greater increase in the combination arm versus the best single‑agent arm (p<0.05).
• Secondary outcomes: Serum IL‑6, IFN‑β, and CXCL10 (SASP markers) will decrease by ≥30% relative to baseline in the combination arm, exceeding changes seen with any monotherapy.
• Exploratory: Metabolomic profiling will reveal elevated circulating β‑hydroxybutyrate (fasting), acetate/propionate (SCFAs), and reduced mitochondrial DNA in plasma.

If the combination fails to outperform the most effective monotherapy on both primary and secondary endpoints, the hypothesis is falsified, indicating that the purported synergy does not translate to human immunosenescence under the tested conditions.