Substrate-Specific Autophagy Failure Generates Predictable CNV Signatures that Drive Age-Related Cancer Risk and Can Be Modified by Enhancing Selective Adaptors

We propose that the hierarchical order of substrate degradation in autophagy determines which classes of copy number variations (CNVs) accumulate during aging, and that rescuing specific steps in this hierarchy will preferentially reduce corresponding CNV types and lower cancer risk. According to the substrate‑specific model, mitophagy defects elevate mitochondrial ROS and promote deletions, aggrephagy loss leads to proteotoxic stress‑driven amplifications, and nucleophagy impairment results in nuclear DNA‑repair deficits that favor tandem duplications. We further hypothesize that these CNV signatures are not random byproducts of general autophagy decline but are encoded by the selective engagement of autophagy adaptor proteins (e.g., BNIP3 for mitophagy, p62/SQSTM1 for aggrephagy, and HMGB1 for nucleophagy).

Testable predictions arise from this mechanistic link:

1. In aged murine hematopoietic stem cells, genetic or pharmacologic enhancement of mitophagy (via overexpression of BNIP3 or treatment with urolithin A) will specifically reduce the burden of small‑scale deletions (<50 kb) without affecting amplification rates, whereas aggrephagy enhancement (via TFEB activation) will preferentially curb focal amplifications.
2. Single‑cell whole‑genome sequencing of longitudinally sampled human peripheral blood will reveal that individuals with elevated plasma mitophagy biomarkers (e.g., circulating mitochondrial DNA fragments) show a higher ratio of deletions to amplifications in clonal hematopoiesis–associated CNVs, while those with elevated aggrephagy markers (e.g., ubiquitinated protein aggregates) display the inverse pattern.
3. CRISPR‑mediated knockdown of the nucleophagy adaptor HMGB1 in human epithelial organoids will increase the frequency of tandem duplications at fragile sites, a signature observable in premalignant lesions.
4. Combining low‑dose rapamycin (to partially stimulate global autophagy) with adaptor‑specific agonists will produce a synergistic reduction in total CNV load compared with either intervention alone, supporting the notion that hierarchy, not flux, is the critical determinant.

Falsifiable outcomes include: (a) failure of mitophagy enhancement to alter deletion frequencies; (b) absence of correlation between adaptor‑specific biomarkers and CNV subtype ratios in human cohorts; or (c) observation that global autophagy upregulation reduces all CNV classes equally, indicating that substrate selectivity is not a dominant factor. Each outcome can be assessed using established assays—mitochondrial ROS flow cytometry, ubiquitin‑aggregate immunostaining, γH2AX foci for nuclear damage, and low‑pass whole‑genome sequencing for CNV profiling.

If validated, this hypothesis reframes autophagy decline as a misregulated "cannibalism ritual" where the order of substrate consumption writes a mutagenic script. It opens precision‑prevention strategies that target specific adaptor pathways to rewrite the script before malignant clonal expansion takes hold.