Autophagy-Mediated Clearance of Cytoplasmic Chromatin Fragments Resets the cGAS-STING Inflammaging Clock and Reverses Epigenetic Age Acceleration in Rheumatic Disease
Background: Cytoplasmic chromatin fragments (CCFs) accumulate in senescent and stressed cells, chronically activating the cGAS-STING pathway and driving type I interferon-mediated inflammaging. This process is markedly accelerated in systemic autoimmune diseases (SLE, RA), where patients show 5-15 years of epigenetic age acceleration on Horvath/GrimAge clocks.
Hypothesis: Pharmacological induction of selective autophagy targeting CCFs — via TFEB activation with trehalose or synthetic TFEB mRNA — will reduce cytoplasmic DNA burden by >60%, suppress tonic cGAS-STING signaling, lower circulating CXCL10 and IFN-alpha levels, and produce measurable reversal of epigenetic age acceleration (>=2 years on GrimAge2) within 12 weeks, without requiring direct senolytic clearance of the host cell.
Testable Predictions
- Cross-sectional correlation: CCF-positive cell fraction (anti-dsDNA/gamma-H2AX co-staining in PBMCs) correlates with GrimAge2 acceleration (r > 0.5) in RA/SLE patients vs. age-matched healthy controls (n >= 80).
- In vitro clearance: TFEB agonist treatment (100 mM trehalose, 72h) in replicatively senescent human fibroblasts reduces CCF burden >60%, cGAS dimer formation >50%, and SASP secretion (IL-6, IL-8, TNF-alpha) >40% vs. vehicle.
- In vivo reversal: In a murine collagen-induced arthritis model, 8-week trehalose supplementation (2% drinking water) reduces joint inflammation scores, lowers serum IFN-alpha, and reverses ribosomal DNA methylation age by >=1 murine epigenetic year equivalent.
- Mechanistic specificity: DNase II knockout (blocking lysosomal DNA digestion post-autophagy) abolishes the anti-inflammaging effect of TFEB activation, confirming the pathway requires complete CCF degradation, not merely sequestration.
Significance
This hypothesis proposes a mechanistic link between autophagy failure, innate immune chronicity, and biological aging that is specifically amplified in rheumatic diseases. Rather than wholesale senolysis (which risks tissue depletion in already immunocompromised patients), targeting CCF clearance via TFEB-autophagy-DNase II offers a more precise geroprotective strategy. If validated, it would establish CCF burden as a druggable biomarker bridging geroscience and clinical rheumatology.
Key References
- Dou et al. (2017) Nature 550:402-406 — CCFs activate cGAS-STING in senescence
- Ivanov et al. (2013) J Cell Biol 202:407-419 — Lysosomal processing of chromatin in senescence
- Lu et al. (2023) Nat Aging — GrimAge2 clock validation
- Controlled autophagy induction with trehalose: Sarkar et al. (2007) J Biol Chem 282:5641