Hypothesis

Telomeric chromatin functions as a redox‑sensitive information hub where oxidative lesions increase the Shannon entropy of telomeric DNA. This entropy change alters the phase‑separation behavior of the shelterin complex, promoting recruitment of DNA damage response factors and driving senescence in quiescent cardiac progenitor cells (CPCs) independent of telomere length.

Mechanistic Rationale

• Oxidative stress generates 8‑oxoguanine and other base lesions at telomeres, increasing molecular disorder and thus informational entropy.
• Elevated telomeric entropy destabilizes the liquid‑like condensates formed by TRF2 and associated shelterin proteins, shifting them toward a more solid, aggregation‑prone state.
• This conformational switch exposes telomeric DNA to ATM/ATR kinases, generating telomere‑induced foci (TIFs) that activate p21/p16 pathways even when repeat length remains long.
• The process is amplified in aged hearts because mitochondrial dysfunction raises ROS, while declining NAD+ limits PARP‑mediated chromatin relaxation, further trapping entropy‑rich telomeres in a damage‑prone state.

Testable Predictions

1. Entropy measurement – Quantitative profiling of oxidative telomeric lesions (e.g., via oxidative‑damage‑specific sequencing) will correlate with senescence markers (p16, SA‑β‑gal) across individual CPCs better than telomere length alone.
2. NAD+ rescue – Pharmacological elevation of NAD+ (using NR or NMN) will reduce telomeric entropy, restore shelterin condensate fluidity, lower TIF frequency, and improve CPC proliferative capacity without altering telomere repeat number.
3. Shelterin phase‑separation mutant – Expression of a TRF2 variant that cannot undergo phase separation (e.g., deletion of its basic‑rich domain) will suppress senescence induction under high oxidative stress, even when telomeric entropy is high.
4. Antioxidant specificity – Mitochondria‑targeted antioxidants (MitoQ) will decrease telomeric entropy and TIFs more effectively than cytosolic antioxidants, linking mitochondrial ROS directly to telomeric information decay.

Falsifiability

If oxidative lesion mapping shows no correlation between telomeric entropy and senescence, or if NAD+ supplementation fails to reduce TIFs despite improving mitochondrial function, the hypothesis would be refuted. Likewise, if forcing shelterin into a liquid state does not rescue CPC function under high entropy conditions, the mechanistic link between phase separation and entropy‑driven damage would be invalidated.

Broader Implications

Framing telomeres as an informational entropy sensor unifies the observation of long‑telomere, senescent CPCs with the broader concept of biological computation limits. It suggests that aging in post‑mitotic compartments may be driven by the accumulation of informational noise at specialized chromatin loci, offering a new avenue for interventions that target chromatin material properties rather than telomere length per se.

[1] https://doi.org/10.15252/embj.2018100492 [2] https://www.ahajournals.org/doi/10.1161/circresaha.114.302500 [3] https://doi.org/10.1111/acel.12931