The Hypothesis

Neural progenitor cells accumulate mosaic chromosomal alterations (mCAs) as we age, and these changes may create what I'm calling a circulating "genomic instability field" that speeds up mutation accumulation in distant tissues—especially the gastrointestinal epithelium. If this holds up, it flips the prevailing gut-to-brain aging paradigm on its head, positioning central nervous system genomic mosaicism as an upstream driver of peripheral tissue decline rather than a downstream consequence.

Mechanistic Framework

Three observations form the backbone of this model. First, mCAs show up in both blood and brain as we age, but we still don't know which tissue initiates these changes or how they spread 1. Second, large chromosomal deletions, duplications, and loss-of-heterozygosity accumulate in normal human colon crypts over time 2. Third, clonal hematopoiesis of indeterminate potential (CHIP) drives systemic inflammation that accelerates aging across multiple organs 3.

What ties these together? I'm proposing that neural mCAs might work analogously to CHIP—releasing secreted factors like exosomes containing genomic DNA fragments, inflammatory cytokines, or metabolically altered cerebrospinal fluid that "precondition" peripheral tissues for faster mutation accumulation.

This model makes a specific prediction: people with high CNS mCA burden should show accelerated gut epithelial CNV accumulation regardless of their gut microbiome composition. That directly challenges the unidirectional gut-to-brain framework that dominates aging research right now 4.

Testable Predictions

1. In aged human cohorts, neural-derived mCA burden—assessed via single-nucleus sequencing of postmortem brain tissue—will correlate positively with colonic crypt CNV burden, even after controlling for gut microbiome diversity and systemic inflammation markers.

2. In mouse models, inducible neural progenitor cell-specific CNV induction (using CRISPR-based chromosomal engineering) will accelerate mutation rates in gut epithelial organoids transplanted into these animals, compared to controls—demonstrating a circulating factor effect.

3. CSF from high-mCA human donors will increase DNA damage response activation in cultured gut epithelial cells relative to low-mCA CSF controls.

Falsification Criteria

This hypothesis would fall apart if: (a) neural and gut CNV burdens show no correlation in human tissue cohorts; (b) neural-specific CNV induction fails to accelerate gut mutation rates in vivo; or (c) parabiosis experiments isolating circulation don't transfer the acceleration effect.

Significance

This framework rethinks CNS aging as a potential "mutation radiator" rather than just a downstream receiver of peripheral inflammatory signals. It offers a mechanistic explanation for why interventions targeting brain health alone can influence systemic aging trajectories 5. More practically, it gives the field a concrete, genomics-based experimental roadmap—something desperately needed in a research landscape currently dominated by correlative microbiome studies.