Immune Surveillance Limits Mosaic Chromosomal Alteration Burden in Extreme Longevity
Hypothesis: Immune-mediated clearance curbs mCA accumulation in centenarians
Core proposition In individuals who achieve exceptional longevity, heightened innate immune surveillance specifically eliminates hematopoietic stem and progenitor cells harboring mosaic chromosomal alterations (mCAs), thereby producing the observed plateau in mCA prevalence after age 102 and the reduced burden in familial longevity cohorts.
Mechanistic rationale
- mCA‑bearing clones display increased surface stress ligands (e.g., MICA/B, ULBP2) due to genomic imbalance, rendering them susceptible to NK‑cell activation via the NKG2D receptor【1】(https://scholars.duke.edu/publication/1663145).
- Centenarians exhibit elevated circulating IL‑15 and IL‑12, cytokines that potentiate NK cytotoxicity and are linked to superior antiviral defense【2】(https://pmc.ncbi.nlm.nih.gov/articles/PMC10460554).
- Enhanced NK activity reduces the proliferative advantage of mCA‑driven clonal hematopoiesis, lowering the risk of progression to hematologic malignancy and attenuating inflammaging‑associated cardiovascular mortality【3】(https://www.genome.gov/27548594/2012-release-scientists-find-that-chromosomal-abnormalities-are-associated-with-aging-and-cancer).
- Conversely, APOE ε4 carriers show reduced IL‑15 signaling and higher mCA incidence, providing a mechanistic bridge between Alzheimer’s risk and genomic instability【4】(https://aacrjournals.org/cebp/article/32/6/776/726569/Somatic-Mosaic-Chromosomal-Alterations-and-Death).
Testable predictions
- Peripheral blood NK‑cell cytotoxic activity (measured by CD107a degranulation against K562 targets) will be significantly higher in centenarians (≥100 y) than in age‑matched septuagenarians, after adjusting for CMV serostatus.
- mCA‑positive hematopoietic progenitors isolated from centenarians will show increased surface expression of NKG2D ligands compared with those from non‑longeagenarians.
- Blocking NKG2D in vitro will rescue the colony‑forming unit‑granulocyte/macrophage (CFU‑GM) capacity of mCA‑bearing cells from centenarian samples, confirming dependence on NK‑like surveillance.
- Longitudinal cohorts (e.g., UK Biobank) with genotyped APOE ε4 status will demonstrate that carriers who maintain high IL‑15 levels (via genotype or supplementation) have a blunted increase in mCA prevalence over time, falsifying the notion that APOE ε4 solely drives mCA accrual.
Falsifiability If NK‑cell activity and ligand expression are not elevated in centenarians, or if NK blockade does not affect mCA‑clone fitness, the hypothesis would be refuted, pointing to alternative mechanisms such as cell‑intrinsic DNA‑repair upregulation or selective clonal extinction.
Broader implications Demonstrating immune‑mediated restraint of mCAs would suggest that immunomodulatory strategies—exogenous IL‑15, NKG2D agonism, or senolytic‑NK combinations—could delay clonal hematopoiesis‑associated morbidity in the general aging population.