Decision letter | Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice

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Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice

Decision letter

Affiliation details

University of Washington, United States; Fred Hutchinson Cancer Research Center, United States; University of Missouri, United States
Amy J Wagers, Reviewing editor, Harvard University, United States

In the interests of transparency, eLife includes the editorial decision letter and accompanying author responses. A lightly edited version of the letter sent to the authors after peer review is shown, indicating the most substantive concerns; minor comments are not usually included.

Thank you for submitting your article "Transient rapamycin treatment increases lifespan and healthspan in middle-aged mice" for consideration by eLife. Your article has been reviewed by three peer reviewers, one of whom, Amy Wagers, is a member of our Board of Reviewing Editors, and the evaluation has been overseen by Kevin Struhl as the Senior Editor.

The reviewers have discussed the reviews with one another and the Reviewing Editor has drafted this decision to help you prepare a revised submission.

Summary:

The manuscript by Kaeberlein and colleagues investigates the impact on lifespan of transient exposure of older mice to rapamycin (via injection or as a dietary supplement). Assessment of some healthspan metrics (grip strength and rotorod performance) is also included. The authors present intriguing data showing sex-specific differences with high dose rapamycin in terms of lifespan extension and effect on cancer development, and congruent effects on longevity in both sexes with lower dose, oral administration. Finally, they report differences in the composition of gut microbiota that are associated with rapamycin administration. Reviewers agreed that the manuscript has a number of strengths, but also several weaknesses.

In particular, reviewers appreciated the careful assessment of lifespan and cause of death in both sexes, the relatively novel approach of transient rapamycin administration in pre-senescent mice, and the evaluation of rapamycin at different doses and via different routes of administration, which reveal novel information regarding the potential benefits and possible toxicities of rapamycin administration for the treatment of age-associated dysfunctions. Furthermore, the association with changes in microbiota composition present some intriguing potential explanations for rapamycin's effects. Yet, this aspect of the study also represents its major limitation, as the authors do not provide any direct link between SFB colonization and lifespan extension. This issue is exacerbated by the fact that the aged mice used for analysis of SFB colonization and lifespan studies derive from different animal colonies. The inclusion of additional data that strengthen the connection between SFB, rapamycin and lifespan regulation is needed. In addition, it is essential to assess plasma levels of rapamycin achieved by the different dosing regimens in male vs. female mice.

Essential revisions:

1) The major problem in this study is the lack of compelling support for the importance of microbiota for the rapamycin-induced healthspan extension. The association of short-term Rapa treatment with increased SFB is interesting, but the authors have not provided a causal link between the increase in this organism and any of the phenotypes observed. A direct link should be demonstrated experimentally through addition of new experiments, e.g. fecal transfer from SFB monoassociated mice and/or intervention to specifically deplete SFB (if possible).

2) An additional concern is that the aged mice used for analysis of SFB colonization and lifespan studies derive from different animal colonies (see Methods), making the connection between these observations more tenuous. Confirmation of SFB differences in NIA mice should be added to the manuscript to validate the inferences made in the text.

3) For Figure 6, it is unclear if the rapa treatment group represents injected or fed rapamycin, and if males and females are separately analyzed. Please clarify the text on this point. Also, as dietary intake of eRAPA could have distinct effects on microbiota compared to ip injection, the authors should add to the manuscript a comparison of microbiota analyses between these two administration methods.

4) Since plasma rapamycin levels following oral administration differed between males and females in the Intervention Testing Program, it is important to know the plasma levels achieved following the oral and ip doses given in the current study. This could be part of the reason for the sex effect observed. The authors should add analysis of plasma levels achieved by oral or ip dosing in males and females in the study. Also, as differences in food intake or physical activity/energy expenditure could also provide a possible explanation, measurements of these variables should be added to the manuscript for the two different administration methods.

5) What were major causes of death in males ip-injected with rapamycin and in both males and females administered with eRAPA orally? Were there any particular causes of death in each cohort? The authors should add this information to the manuscript.

6) Changes in rotarod performance over time are not adequate to support the improvement in memory formation by transient rapamycin treatment. The authors should tone down their description or conduct appropriate experiments.

7) Some figures are inaccurately referenced in the text. The authors should check these carefully to ensure accuracy.

[Editors' note: further revisions were requested prior to acceptance, as described below.]

Thank you for resubmitting your work entitled "Transient rapamycin treatment increases lifespan and healthspan in middle-aged mice" for further consideration at eLife. Your revised article has been favorably evaluated by Kevin Struhl (Senior editor) and a Reviewing editor.

The manuscript has been improved, and most issues have been addressed by new data, revision/clarification of the text, or by explaining why these issues cannot be addressed at the present time. However, there are some remaining issues that need to be addressed before acceptance, as outlined below:

1) Please edit the title. Since lifespan increases are shown to be sex- and dose-variant in this study, the title should be changed to "Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice". This will help to emphasize the very important points the authors raise in their discussion about evaluating potential risks and side effects of drug interventions for lifespan regulation.

2) In the new data added in Figure 1—figure supplement 2 or Figure 2—figure supplement 2, why are there no error bars?

DOI: http://dx.doi.org/10.7554/eLife.16351.030