Review Reports

Round 1

Reviewer 1 Report

The authors review the premise that "Excessive production of reactive oxygen and nitrogen species, combined with declining antioxidant defenses, contributes to lipid peroxidation, mitochondrial dysfunction, chronic inflammation, complement activation, cellular senescence, and impaired cellular stress responses in both the retina and the vascular system." While there are many coincidental possibilities and common mechanistic overlaps between age-related macular degeneration (AMD) and cardiovascular diseases in general, the authors do a good job in detailing likely mechanisms defined in their premise for both AMD and CVD, acknowledging that the coincidence of these pathologies may be confounded by tissue specificity, genetics, confluence of environmental factors (diet, smoking history), age and other as yet unknown processes. The authors took "a structured qualitative approach with elements of critical appraisal.... to enhance transparency and interpretability of the evidence." This is reasonable given the often-broad definitions and details of oxidative stress (reactive oxygen and nitrogen species), mitochondrial functions, AMD and CVD disease, patient specific clinical data, and different epidemiological study designs in the published literature. The discussion is balanced and fairly presents data for both associations and lack of association from studies of the natural history and progression of both diseases. Given the many mechanisms underlying vascular endothelial damage, lipid oxidation, mitochondrial function and risks of aging and environmental influences, the common finding of oxidative stress is likely central to progression of AMD and CVD, though causality remains a difficult milestone. The sections on shared specific molecular features of the diseases are important to the premise and even though causality and co-morbidity may not always link both diseases, the hope is that this discussion may lead to discovery of a few early dysfunctional elements as targets for novel therapies in the treatment of either or both diseases. Table 1 is useful in that aspect. Overall, the review is comprehensive and a useful thought process for scientists and clinicians working with these pathologies, and a reminder that complex disease processes may utilize overlapping biological pathways to converge on common pathways producing related pathologies in different tissues. 

Minor comments:

1. Line 108, do you mean extracted or subtracted?
2. Should line 110 be the second sentence of that paragraph, simply to keep the timeline of AMD progression in sequence?
3. Line 158, do you mean "influence" or "may be influenced by"? The use of systemic in the next sentence suggests the latter terms as to suggested direction of the influence.
4. Line 215, have you previously defined RONS?  

 

Author Response

Please see attached.

Author Response File: Author Response.pdf

Reviewer 2 Report

This is a timely, well-organized narrative review that synthesizes epidemiological associations, overlapping molecular pathways, biomarkers, and therapeutic implications of oxidative stress as a potential mechanistic bridge between AMD and CVD.

The strengths include 1. clear conceptual framing and logical flow from epidemiology; 2. effective integration of lipid peroxidation/oxLDL–drusen parallels, mitochondrial DAMPs/NLRP3, complement, senescence/SASP, and NRF2/autophagy decline; 3. Balanced treatment of mixed epidemiological data, confounding by age/smoking, and the failure of generic antioxidant trials versus more targeted approaches; 4. Recent literature (through 2025–2026) is included; limitations of a narrative approach are stated.

The weaknesses include: 1. Search strategy is described but remains qualitative; no PRISMA-style flow or formal risk-of-bias assessment, which is acceptable for a perspective review but should be stated more explicitly; 2. Some typos need to be corrected.

 

1. The caption for Fig. 1 should be moved to below the figure.
2. What is “RONS” in Line 193, 215, other places?
3. There should be a brief explanation for redox or redox imbalance before Fig. 2.

Author Response

Please see attached.

Author Response File: Author Response.pdf