Review of 'Integrating the environmental and genetic architectures of aging and mortality'

Major comments:

1. In paragraph 1 of the introduction, the authors state that no large-scale exposome-wide studies have accounted for the correlation structure across the exposome to identify exposures independently associated with aging and mortality. I am glad and it is admirable that the authors addressed this gap, it would benefit from clearly explaining why previous studies were unable to overcome this challenge. A detailed discussion on methodological barriers (e.g., issues with confounding, multicollinearity) and how the current study's approach (e.g., hierarchical clustering, sensitivity analyses) successfully navigated these obstacles would strengthen the manuscript. The authors should consider including this context to fully appreciate the novelty and rigor of the pipeline deployed.

2. The study utilizes XWAS and PheWAS to robustly screen and validate environmental exposures linked to aging and mortality, exciting! But, the authors did not reveal how confunded exposures were filtered or better still how the thresholds for removing confounded exposures were determined.

MInor comments:

3. Although this only occured once, I would like for the authors to clarify whether external exposome and exposome can be used interchangeably in the field or better still, the authors can use one consistently.

4. I would be interested to know the opinion of the authors on how the methods deployed in this study would potentially benefit or be adapted to study specific neurodegenerative outcomes. Also, beyond cautioning against false positives in gene-environment interaction studies, the authors should also highlight potential benefits to encourage further research in this area.

This manuscript offers a comprehensive and methodologically sound investigation into how environmental and genetic factors contribute to aging and mortality. With suggested refinements, the manuscript will make a substantial contribution to the literature on aging biology and environmental epidemiology.