Hypothesis

Hormetic interventions such as cold exposure, fasting, low-dose radiation or exercise do not extend lifespan by activating a dedicated longevity program. Instead they provoke a transient, regulated increase in mosaic chromosomal alterations (mCAs) that serve as a stress‑signal to downstream survival pathways. When the DNA damage response (DDR) is intact, this wave of mCAs is kept below a pathogenic threshold and is rapidly resolved, thereby coupling the perception of threat to protective transcriptional programs (e.g., FOXO, NRF2, HSPs). With advancing age, declining DDR fidelity and reduced clearance of abnormal clones allow the hormesis‑induced mCAs to persist, expand, and eventually drive clonal hematopoiesis and cancer.

Mechanistic reasoning

1. Stress‑induced DNA lesions as signaling intermediates – Low‑level stressors generate reactive oxygen species and replication stress that produce double‑strand breaks (DSBs) and micronuclei. These lesions activate ATM/ATR, which in turn phosphorylate histone H2AX and recruit repair complexes. Recent work shows that sub‑lethal DSBs can alter chromatin topology without triggering apoptosis, influencing gene expression (1).

2. Transient mCA formation as a read‑out of DSB repair fidelity – In young cells, homologous recombination (HR) and non‑homologous end joining (NHEJ) efficiently repair DSBs, but a small fraction of repair events results in copy‑number neutral or small‑scale CNVs that are segregated into a minority of daughter cells. These events are detectable as low‑frequency mCAs in blood and rise sharply after a hormetic challenge (2).

3. mCA‑dependent signaling to stress‑response pathways – Certain CNVs affect dosage of stress‑responsive genes (e.g., SOD2, GPX1, HSP70). A modest increase in copy number can boost transcript output, amplifying the hormetic signal. Conversely, loss of heterozygosity at tumor suppressor loci is kept rare by efficient mismatch repair and apoptosis of highly aberrant cells (3).

4. Age‑related breakdown of the threshold – With age, baseline DSB load rises, HR capacity declines, and the pool of senescent cells secretes SASP factors that inhibit DDR. Consequently, the same hormetic stress now yields a higher proportion of mCAs that escape clearance, expand clonally, and increase the likelihood of oncogenic events (4).

5. Link to clonal hematopoiesis – Expanded mCA clones affecting ≥10% of leukocytes predict hematologic cancer with hazard ratios >100 (5). If hormesis‑derived mCAs are the seed, then interventions that boost hormesis without improving DDR should increase cancer incidence in aged organisms.

Testable predictions

• Prediction 1: In young mice, a single bout of intermittent fasting or cold exposure will cause a transient, measurable rise in low‑frequency mCAs (detectable by single‑cell sequencing) within 6–24 h, returning to baseline by 72 h. Inhibition of ATM (using KU‑55933) will abolish both the mCA burst and the associated lifespan extension.

• Prediction 2: In aged mice, the same hormetic stimulus will produce a persistent increase in mCA frequency that correlates with enlarged clones of clonal hematopoiesis and a higher incidence of myeloid malignancies.

• Prediction 3: Pharmacologic enhancement of HR (e.g., via overexpression of BRCA1) in aged animals will reduce the hormesis‑induced mCA persistence and improve healthspan without altering the initial stress signal.

Falsifiability

If hormetic treatments do not produce any detectable increase in mCAs above background, or if blocking DDR does not affect the longevity benefit, the hypothesis is refuted. Likewise, if enhancing HR fails to mitigate age‑related clonal expansion despite preserving hormetic signaling, the proposed link between mCA dynamics and stress signaling would be unsupported.

Conclusion

By reframing hormesis as a generator of regulated genomic instability rather than a direct activator of longevity pathways, we connect the observed exponential accumulation of CNVs and mCAs with the biology of stress resistance. This positions genomic maintenance not as a passive damage‑control system but as a dynamic interface where transient mCAs encode threat information, and their dysregulation underlies the transition from adaptive hormesis to maladaptive clonal hematopoiesis and cancer.