Hypothesis

Attenuated TOR and IGF-1 signaling not only slows stochastic DNA damage but actively enhances homologous recombination (HR) repair in hematopoietic stem cells (HSCs), thereby lowering the rate of mosaic chromosomal alterations (mCAs). This posits a mechanistic link where the same pathways that embody antagonistic pleiotropy also regulate the choice between error‑prone non‑homologous end joining (NHEJ) and high‑fidelity HR during double‑strand break (DSB) repair.

Predictions

• Individuals with genetically reduced TOR/IGF-1 activity (e.g., heterozygous loss‑of‑function variants in MTOR or IGF1R) will show a higher ratio of HR‑mediated to NHEJ‑mediated repair markers in purified HSCs ex vivo.
• Pharmacologic inhibition of TOR (rapamycin) or IGF-1R (OSI‑906) in young human HSC cultures will increase RAD51 foci formation and decrease 53BP1 foci after irradiation, indicating a shift toward HR.
• In longitudinal cohorts, the incidence of new autosomal mCAs over a 5‑year interval will be inversely proportional to the magnitude of HR activity measured at baseline, independent of age.

Experimental Approach

1. Collect peripheral blood from volunteers stratified by genotype (MTOR rs2536, IGF1R rs2229765) and treat CD34⁺ HSCs with/without rapamycin or IGF‑1R inhibitor.
2. Induce DSBs with 2 Gy γ‑irradiation, fix at 0.5 h and 6 h, immunostain for RAD51 (HR) and 53BP1 (NHEJ). Quantify foci per nucleus via flow‑imaging.
3. Perform single‑cell whole‑genome sequencing after 4‑week culture to detect de novo mCAs; compare frequencies across conditions.
4. In the LonGenity cohort, measure baseline HR capacity (RAD51 foci after ex vivo irradiation) and follow for mCA emergence using array‑based detection over 5 years.

Falsifiability If TOR/IGF-1 inhibition fails to shift DSB repair toward HR, or if HR activity does not predict lower mCA accrual, the hypothesis is refuted. Conversely, a consistent increase in HR and concomitant drop in mCAs would support the idea that longevity‑associated signaling pathways actively preserve genome integrity, rather than merely delaying damage.

Implications This reframes antagonistic pleiotropy: the pathways that boost early growth also tune DSB repair toward faster, error‑prone NHEJ to meet rapid proliferation demands. Their attenuation in later life—whether genetically or pharmacologically—reverts HSCs to a high‑fidelity HR mode, reducing mCA accumulation and contributing to the lower mCA burden observed in centenarians[2]. Thus, aging‑associated genomic instability is not a passive by‑product but a tractable output of signaling‑controlled repair pathway choice.

References [1] https://pmc.ncbi.nlm.nih.gov/articles/PMC6276058/ [2] https://scholars.duke.edu/publication/1663145 [3] https://pubmed.ncbi.nlm.nih.gov/20724817/ [4] https://www.fightaging.org/archives/2025/08/in-search-of-antagonistic-pleiotropy-in-human-data/ [5] https://www.genome.gov/27548594/2012-release-scientists-find-that-chromosomal-abnormalities-are-associated-with-aging-and-cancer