A mathematical model that predicts human biological age from physiological traits identifies environmental and genetic factors that influence aging

Reviewer #1 (Public Review):

Summary:

In this study, the authors developed a mathematical model to predict human biological ages using physiological traits. This model provides a way to identify environmental and genetic factors that impact aging and lifespan.

Strengths:

1. The topic addressed by the authors - human age predication using physiological traits - is an extremely interesting, important, and challenging question in the aging field. One of the biggest challenges is the lack of well-controlled data from a large number of humans. However, the authors took this challenge and tried their best to extract useful information from available data.

2. Some of the findings can provide valuable guidelines for future experimental design for human and animal studies. For example, it was found that this mathematical model can best predict age when all different organ and physiological systems are sampled. This finding makes sense in general but can be, and has been, neglected when people use molecular markers to predict age. Most of those studies have used only one molecular trait or different traits from one tissue.

Weaknesses:

1. As I mentioned above, the Biobank data used here are not designed for this current study, so there are many limitations for model development using these data, e.g., missing data points and irrelevant measurements for aging. This is a common caveat for human studies and has been discussed by the authors.

2. There is no validation dataset to verify the proposed model. The authors suggested that human biological age can be predicted with high accuracy using 12 simple physiological measurements. It will be super useful and convincing if another biobank dataset containing those 12 traits can be applied to the current model.

Reviewer #2 (Public Review):

In this manuscript, Libert et al. develop a model to predict an individual's age using physiological traits from multiple organ systems. The difference between the predicted biological age and the chronological age -- ∆Age, has an effect equivalent to that of a chronological year on Gompertz mortality risk. By conducting GWAS on ∆Age, the authors identify genetic factors that affect aging and distinguish those associated with age-related diseases. The study also uncovers environmental factors and employs dropout analysis to identify potential biomarkers and drivers for ∆Age. This research not only reveals new factors potentially affecting aging but also shows promise for evaluating therapeutics aimed at prolonging a healthy lifespan. This work represents a significant advancement in data-driven understanding of aging and provides new insights into human aging. Addressing the points raised would enhance its scientific validity and broaden its implications.

Major points:

1. Enhance the description and clarity of model evaluation.

The manuscript requires additional details regarding the model's evaluation. The authors have stated "To develop a model that predicts age, we experimented with several algorithms, including simple linear regression, Gradient Boosting Machine (GBM) and Partial Least Squares regression (PLS). The outcomes of these approaches were almost identical". It is currently unclear whether the 'almost identical outcomes' mentioned refer to the similarity in top contribution phenotypes, the accuracy of age prediction, or both. To resolve this ambiguity, it would be beneficial to include specific results and comparisons from each of these models.

Furthermore, the authors mention "to test for overfitting, a PLS model had been generated on randomly selected 90% of individuals and tested on the remaining 10% with similar results". To comprehensively assess the model's performance, it is crucial to provide detailed results for both the test and validation datasets. This should at least include metrics such as correlation coefficients and mean squared error for both training and test datasets.

2. External validation and generalization of results

To enhance the robustness and generalizability of the study's findings, it is crucial to perform external validation using an independent population. Specifically, conducting validation with the participants of the 'All of Us' research program offers a unique opportunity. This diverse and extensive cohort, distinct from the initial study group, will serve as an independent validation set, providing insights into the applicability of the study's conclusions across varied demographics.