Precision Gerontometry: Introduction, Fundamentals and Areas of Application

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This opinion article proposes “precision gerontometry” as a metabolomics-based approach for measuring short-term changes in biological age. The topic is timely and potentially relevant for the evaluation of geroprotective and gerotoxic interventions. The manuscript is clearly motivated by an important problem: existing biological clocks often lack sufficient resolution to assess short-term intervention effects. However, the current version is too selective in its treatment of the existing literature and makes several strong claims that require more balanced discussion and clearer qualification.

My main concern is that the article discusses “metabolomic clocks” as a broad category but does not sufficiently address the existing literature on NMR/metabonomics-based metabolic age scores and NMR-derived metabolic clocks. This is particularly important because NMR metabolomics has been one of the most reproducible and scalable approaches for blood metabolic phenotyping, and several NMR-based metabolic age or health scores have already been proposed. At minimum, the authors should explicitly discuss NMR metabolic clocks, their strengths and limitations, and how the proposed mass-spectrometry-based precision gerontometry differs from or improves upon them.

Also, Figure 1 compares clinical, epigenetic, transcriptomic, proteomic, metabolomic, and “precise metabolomic” clocks using broad MAE ranges. This is useful as a conceptual figure, but the comparison risks being misleading because different clocks are trained on different populations, biospecimens, age ranges, platforms, and outcomes. Chronological-age prediction error is also not the same as sensitivity to biological aging or responsiveness to interventions. The authors should make this distinction more explicit.

In line with this, the manuscript uses “accuracy” in several contexts, including correlation with chronological age, MAE, minimum detectable change, and the ability to detect short-term within-person change. These are related but not equivalent. A method may be precise within an individual but not necessarily accurate as a biological aging measure. Conversely, a clock may predict chronological age well without being useful for intervention studies.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

This article introduces the concept of "Precision Gerontometry," a metabolomics-based framework aimed at measuring biological age changes with high temporal resolution. The topic is timely and relevant because the development of sensitive biomarkers of aging remains a major challenge in geroscience and preventive medicine. The manuscript is generally well structured, clearly written, and provides an interesting perspective on how metabolomics may contribute to the assessment of aging trajectories and anti-aging interventions.

The concept is innovative and may stimulate further discussion within the aging research community. However, several statements throughout the manuscript are presented with a level of certainty that is not fully supported by the current literature. Since this is an opinion article, the authors are entitled to present a forward-looking perspective, but a more balanced discussion of existing limitations, competing approaches, and unresolved challenges is necessary.

Major Comments

1. Balance between opinion and evidence

The manuscript frequently presents precision gerontometry as a mature solution to the problem of biological age measurement. However, much of the supporting evidence originates from the authors' own publications. The article would benefit from a clearer distinction between established findings and the authors' proposed vision for future development.

2. Discussion of alternative aging clocks

The review provides a useful overview of clinical, epigenetic, transcriptomic, proteomic, and metabolomic clocks. However, recent developments in multi-omics clocks, pace-of-aging measurements, and integrated biological age models should be discussed in greater depth. This would provide a more comprehensive overview of the field.

3. One-month precision claim

The repeated assertion that biological age changes can be measured with approximately one-month precision is central to the manuscript. Because this claim exceeds the performance of most currently available aging biomarkers, the authors should acknowledge that broader validation remains necessary and discuss potential limitations more explicitly.

4. Reproducibility and standardization

The proposed approach appears highly dependent on specific analytical platforms, laboratory procedures, and data-processing pipelines. Additional discussion regarding reproducibility, standardization, and inter-laboratory implementation would strengthen the article.

5. Potential confounding factors

Although diet and microbiome influences are addressed, other important determinants of metabolomic variability should also be discussed, including medication use, physical activity, circadian rhythms, acute illness, and environmental exposures.

Minor Comments

• A dedicated section discussing limitations of precision gerontometry would improve the balance of the manuscript.
• Figure 1 would benefit from a more detailed explanation of how the MAE values for different biological clocks were selected and compared.
• The term "gerovolunteer" should be more clearly defined when first introduced.
• Some sections, particularly the application scenarios in Table 1, contain speculative statements that should be presented more cautiously.
• Several sentences could be shortened to improve readability.
• The manuscript would benefit from additional references covering recent advances in multi-omics and pace-of-aging biomarkers.

Conclusion       

This manuscript presents an interesting and potentially valuable conceptual framework for aging research. The topic is appropriate for Metabolites and will likely be of interest to readers working in metabolomics and geroscience. However, the article would be strengthened by a more balanced discussion of limitations, validation requirements, and competing approaches in the field.

Recommendation: Major Revision.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

I appreciate the authors' careful and comprehensive revision of the manuscript. The point-by-point responses adequately address the concerns raised during the previous review. The manuscript has been substantially improved through the inclusion of additional discussion on multi-omics and pace-of-aging approaches, a more balanced presentation of the proposed concept, expanded consideration of methodological limitations and confounding factors, and improved clarity throughout the text. The authors have also strengthened the discussion regarding reproducibility, standardization, and future validation requirements.

Overall, the manuscript is well organized, scientifically sound, and provides an interesting perspective on precision gerontometry. I have no further major comments and believe the manuscript is suitable for publication in its current form.

Recommendation: Accept for publication.