Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

In theManuscript entitled “Conserved Pathways, Divergent Outcomes: A Cross-Species Genomic Perspective on the Cancer–Neurodegeneration Paradox” the authors develop an ambitious and intellectually rigorous synthesis of evolutionary biology, genomics, cancer biology, and neurodegeneration. By integrating antagonistic pleiotropy, Peto’s paradox, immune trade-offs, and cross-species comparative genomics, the authors develop a unifying conceptual framework that explains the inverse epidemiological relationship between cancer and neurodegenerative diseases. The review is comprehensive, mechanistically detailed, and highly timely.

The article is particularly strong in linking conserved pathways (p53, mTOR, PIN1, ATM, autophagy, immune signaling) to divergent cellular fates in proliferative versus post-mitotic tissues, supported by compelling examples from long-lived species such as elephants, bowhead whales, naked mole-rats, bats, and birds .

Overall, this is a high-quality, publishable review that makes a significant conceptual contribution.

Some points are important to address:

1. Excessive length and redundancy
   Several concepts (e.g., antagonistic pleiotropy, immune trade-offs, mTOR and p53 duality) are reiterated across multiple sections with overlapping explanations, which could be streamlined.
2. Limited visual synthesis
   Although Figure 1 is mentioned, the manuscript would strongly benefit from additional integrative schematics summarizing:

1. Pathway duality (cancer vs neurodegeneration)
2. Cross-species evolutionary tuning
3. Immune trade-off axes

1. Therapeutic implications underdeveloped
   While the evolutionary framework is strong, translation into actionable therapeutic strategies (e.g., how to selectively modulate mTOR, NRF2, immune checkpoints, autophagy in different tissues) remains largely conceptual.

Minor points

1. Occasional grammatical and typographical inconsistencies should be corrected.
2. Some long paragraphs (especially in Sections 2 and 4) would benefit from sub-structuring or condensation.

Recommendations

1. Moderate condensation of overlapping evolutionary and pathway discussions (10–15% reduction).
2. Add 2–3 summary figures illustrating:

1. Antagonistic pleiotropy across tissues
2. Pathway tuning across species
3. Immune–neuro–cancer axis

1. Expand the final section to include precision-medicine implications, emphasizing tissue- and age-specific pathway modulation.

Accept after minor revision

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

This is a comprehensive and intellectually ambitious review that brings together cancer biology and neurodegeneration under the notion that the same conserved molecular pathways can lead to either uncontrolled cell growth or cell loss, depending on context. The manuscript shows deep knowledge of the field, excellent literature background, and an interestingl evolutionary and systems-level perspective. The breadth of pathways covered and the integration of comparative biology and multi-omics approaches are clear strengths and make the review potentially of interest.

However, the manuscript would significantly benefit from greater clarity and focus. Much of the text is very dense, with long paragraphs that introduce at same time many pathways, multiple species examples, and disease links. Breaking these sections into shorter paragraphs, adding brief “take-home” sentences at the end of subsections, and using simpler sentence structures would make the arguments easier to follow without reducing scientific appropriateness.

There are also many repetitions of central concepts (i.e. context-dependent effects of conserved pathways). Tightening these summaries or merging overlapping points would improve flow and keep readers engaged. Also, in spite of its comprehensiveness, it is often descriptive rather than critical.

The authors could strengthen the manuscript by more clearly stating where evidence is incomplete, where findings are contradictory, or where proposed mechanisms remain speculative. For example, explicitly noting unresolved questions or debates around PIN1, NRF2, or autophagy would increase credibility.

Finally, for the translational implications the manuscript would benefit from more specific indications, such as: which pathways are most promising (or risky) to target therapeutically, what types of cell-type or temporal specificity might be feasible in practice, why previous attempts to target these conserved pathways have failed.

Overall, with simpler language, reduced redundancy, clearer critical evaluation, and more concrete translational examples, this review would increase its impact and provide a significant contribution in the field.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

the manuscript in the revised version is more clear and accessible to the potential readers