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  1. Reviewer #3 (Public Review):

    Rosenberg and colleagues provide a thorough and comprehensive paper on an aging-associated biological phenomenon: greying. They are the first to show that pigment production can be switched of and on within one growth phase of the human hair follicle and that meaningful omics can be performed on pigmented versus non-pigmented hair and sections of hair. In addition, they provide evidence that greying episodes can be linked to stressfull periods in life. Overall, the authors describe a new method for the assessment of effects of stress and life style factors as well as biological strains on aging that can be used as outcomes in real world studies as well as randomized controlled therapeutic studies.

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  2. Reviewer #2 (Public Review):

    The authors have taken an 'omics' 'bioinformatics' approach to understand the process of human hair greying. Using a wide range of techniques including mass spec they have developed methods to investigate proteins expressed in pigmented and unpigmented (white) hairs plus those that are intermediate (grey).

    They have also investigated the process of loss of pigmentation along the length of individual hair fibres. From these data they have developed models of hair greying and loss of pigmentation.

    They have shown in very elegant experiments that loss of pigment can occur suddenly in the same hair fibre. That loss of pigment is associated very closely with changes in proteins associated with metabolism and especially carbohydrate metabolism-glycolysis, TCA and oxidative phosphorylation. They have also shown close association with changes in hair pigmentation associated with stress and the parameters above

    The major strength of this study is it is clearly a true interdisciplinary collaboration between dermatologists, hair biologists, bioinformaticians and computational biologists.

    The data are striking and set a very clear set of parameters associated with loss of pigment in the hair fibre. The process of isolating proteins other than hair keratins is to be commended. The hair fibre is notoriously reluctant to give up its proteins (other than hair keratins). The broad range but also specificity of proteins and pathways identified suggest this method is broad in its scope and not selective to specific chemical moieties.

    The data generated are robust and clearly identify pathways known to be altered in ageing with loss of pigmentation in the hair fibre in a relatively young population. The predictive models developed from this data demonstrate the strength of the data and also point to further studies not the least to follow up in older participants >40 years although it is important out point out that loss of pigment is seen in much of the population from late 20's to early 30's. Also to follow up in hair diseases such as alopecia areata will be of real interest.

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  3. Reviewer #1 (Public Review):

    This is an interesting and informative study reporting on the molecular features of reversible hair graying in humans and the connection with psychological stress. The study appears to have been very well conducted and the interpretations are generally supported by the data. While the results are primarily correlative at this stage, this work will set the stage for future more mechanistic studies and represents an important conceptual and methodological advance.

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  4. Evaluation Summary:

    This is an interesting and informative study reporting on the molecular features of reversible hair graying in humans and the connection with psychological stress. The study appears to have been very well conducted and the interpretations are generally supported by the data. While the results are primarily correlative at this stage, this work will set the stage for future more mechanistic studies and represents an important conceptual and methodological advance.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their names with the authors.)

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  5. Excerpt

    I guess we were responsible for our parents’ gray hairs after all…but there’s some good news. A new study shows that hair graying can be induced by stress, albeit in a reversible manner.

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