Hypothesis

Telomere-associated protein interaction networks encode aging information as Shannon entropy, independent of telomere length.

Mechanistic Basis

Shelterin complexes dynamically remodel telomere chromatin and recruit factors that influence proteostasis, mitochondrial signaling, and epigenetic states [2]. We propose that each telomere functions as a noisy communication hub where the variability of its protein‑binding pattern reflects cumulative informational stress from oxidative damage and metabolic fluctuations. As cells age, stochastic alterations in post‑translational modifications and competing binding events increase the disorder of the interaction map, raising its Shannon entropy. This entropy rises even if telomere repeat number remains unchanged, making it a true informational clock.

Predictions and Experimental Design

1. Quantitative interactome mapping – Perform affinity‑purification mass spectrometry of telomere‑bound proteins in human fibroblasts at defined population doublings (early, mid, late) and in replicatively senescent cells. Compute the degree distribution, clustering coefficient, and betweenness of the telomere‑centric network, then calculate Shannon entropy of the edge‑weight distribution.
2. Independent variable – Measure telomere length by qPCR or Southern blot in the same samples.
3. Outcome variable – Determine remaining replicative capacity via cumulative population doublings until senescence.
4. Statistical test – Use multiple regression to assess whether network entropy predicts remaining lifespan after controlling for telomere length. A significant positive coefficient for entropy supports the hypothesis; a non‑significant coefficient falsifies it.
5. Mechanistic perturbation – Overexpress the mitochondrial antioxidant SOD2 or the chaperone HSP70 in a subset of cultures. If entropy increase is driven by oxidative proteostatic stress, these manipulations should attenuate entropy rise without altering telomere shortening rate.

Potential Outcomes and Falsifiability

• Supportive result: Network entropy shows a strong, telomere‑length‑independent correlation with remaining doublings (p < 0.01). Antioxidant/chaperone overexpression blunts entropy accumulation and extends lifespan.
• Refutative result: Entropy does not add predictive power beyond telomere length (p > 0.1), or manipulations that lower oxidative stress fail to affect entropy despite extending lifespan, indicating that telomere interaction disorder is not a primary informational metric.

This framework directly tests whether telomeres function as information‑bearing networks whose entropy mirrors biological age, moving beyond the simple division‑counter view and linking telomere biology to proteostasis and redox homeostasis through quantifiable information theory.