Lifespan extension in female mice by early, transient exposure to adult female olfactory cues
Curation statements for this article:-
Curated by eLife
eLife assessment
This valuable study provides solid evidence for a new intervention, exposure to male vs. female olfactory cues, with an impact on female mouse lifespan. This is interesting to the field of aging research, especially since most described pro-longevity interventions to date tend to work better in male mice. Although the data broadly support the claims, additional analyses showing all probed phenotypes are needed to support all claims.
This article has been Reviewed by the following groups
Listed in
- Evaluated articles (eLife)
- Evolutionary Biology (eLife)
Abstract
Several previous lines of research have suggested, indirectly, that mouse lifespan is particularly susceptible to endocrine or nutritional signals in the first few weeks of life, as tested by manipulations of litter size, growth hormone levels, or mutations with effects specifically on early-life growth rate. The pace of early development in mice can also be influenced by exposure of nursing and weanling mice to olfactory cues. In particular, odors of same-sex adult mice can in some circumstances delay maturation. We hypothesized that olfactory information might also have a sex-specific effect on lifespan, and we show here that the lifespan of female mice can be increased significantly by odors from adult females administered transiently, that is from 3 days until 60 days of age. Female lifespan was not modified by male odors, nor was male lifespan susceptible to odors from adults of either sex. Conditional deletion of the G protein Gαo in the olfactory system, which leads to impaired accessory olfactory system function and blunted reproductive priming responses to male odors in females, did not modify the effect of female odors on female lifespan. Our data provide support for the idea that very young mice are susceptible to influences that can have long-lasting effects on health maintenance in later life, and provide a potential example of lifespan extension by olfactory cues in mice.
Article activity feed
-
-
Author Response
Reviewer #3 (Public Review):
Garratt et al. investigated that transient exposure of young mice during their first two months of life with olfactory cues from con-specific adults would have long-lasting effects on their late-life health and lifespan. They find that the olfactory cues have sex-specific effects on lifespan, which only the lifespan of young females can be extended by odours from adult females but no other combinations, neither young females with adult males nor young males with either sex. Interestingly, their data also suggested that depletion of G protein Gαo in the olfactory system played no role in the lifespan extension, indicating it might be another unknown factor(s) mediating this sex-specific effect on longevity in mice. While the conclusions of this study are well supported by the data, there …
Author Response
Reviewer #3 (Public Review):
Garratt et al. investigated that transient exposure of young mice during their first two months of life with olfactory cues from con-specific adults would have long-lasting effects on their late-life health and lifespan. They find that the olfactory cues have sex-specific effects on lifespan, which only the lifespan of young females can be extended by odours from adult females but no other combinations, neither young females with adult males nor young males with either sex. Interestingly, their data also suggested that depletion of G protein Gαo in the olfactory system played no role in the lifespan extension, indicating it might be another unknown factor(s) mediating this sex-specific effect on longevity in mice. While the conclusions of this study are well supported by the data, there are some issues with parts of the data analysis and presentation that would need to be clarified and extended.
- The authors suggested that the G protein Gαo played no role in lifespan extension in the case that transient exposure of young females with olfactory cues from female adults, as they showed in Figure 1. However, it is not clear if the depletion of G Gαo (Gαo mutant) itself has effects on lifespan, compared to its wild type. It would be important to show the lifespan curves from wild type and Gαo mutant individually alongside the pooled lifespan curves, as well as regarding data in a table, followed with a proper discussion.
Data for genotypes is now shown individually.
- Regarding the functional tests, the authors showed that there was only a small fraction of experiments showed differences between treatments, which were all in figure 2. However, it is necessary to also show the data with no differences, particularly since the conclusion of the study suggested the underlying mechanisms are not clear yet. In my opinion, body weight, plasma glucose, and body temperature all deserve to have their figures individually with all data points.
This data is now shown.
- As the authors mentioned in the Introduction, the age at sexual maturity correlates positively with the median lifespan across mice strains (Yuan et al. 2012, Wang et al. 2018). Also, young female mice that were exposed to male odours during their developmental stage accelerated sexual maturity (Drickamer 1983), and the same happened to young males that were exposed to the odours from the opposite sex (Vandenbergh 1971). It is, therefore, surprising to see in this study, the exposure of young females or young males to the olfactory information from their opposite sex had no effects on lifespan. One of the solutions to solve this disparity is to measure the sexual maturity of the mice in this study. The authors should seek the possibility to check the record of when the first litter of pups was born between treatments (Shindyapina et al. 2022) or examine preputial separation and vaginal opening (Hoffmann 2018), for instance.
The animals used in the lifespan experiment were not allowed to breed so as not to interfere with the lifespan assessment. Similarly, we did not check animals within the lifespan experiment for sexual maturity as we wanted to minimize the handling of animals after weaning, and this requires daily handling and/or vaginal swabbing.
We conducted a preliminary experiment prior to the main lifespan experiment (in UM-Het3 mice) to test whether sexual maturity was modulated in the expected directions with the odour exposure protocol we planned to impose. This experiment showed that the odor manipulation we applied has the expected effects on sexual maturity. We have now outlined this experiment and its results in the methods section of the paper to justify the odor treatment protocol.
-
eLife assessment
This valuable study provides solid evidence for a new intervention, exposure to male vs. female olfactory cues, with an impact on female mouse lifespan. This is interesting to the field of aging research, especially since most described pro-longevity interventions to date tend to work better in male mice. Although the data broadly support the claims, additional analyses showing all probed phenotypes are needed to support all claims.
-
Reviewer #1 (Public Review):
In this manuscript, Garratt and collaborators describe exposure to male vs. female olfactory cues as an intervention modulating mouse lifespan. They use urine exposure (early life) and soiled bedding exposure (after weaning) to determine the impact of sex-specific olfactory cues on lifespan. They use wild-type and Gnao1 neural-specific mutants to determine potential dependency on vomeronasal function as well. They also recorded information about body temperature, body weight, glucose levels, grip strength, and balance. Overall, they identify female-olfactory cues as increasing the lifespan of female but not male mice, regardless of genotype.
This study reports an intriguing new intervention with an impact on mouse lifespan (with a female-specific effect). However, some of the data with negative results are …
Reviewer #1 (Public Review):
In this manuscript, Garratt and collaborators describe exposure to male vs. female olfactory cues as an intervention modulating mouse lifespan. They use urine exposure (early life) and soiled bedding exposure (after weaning) to determine the impact of sex-specific olfactory cues on lifespan. They use wild-type and Gnao1 neural-specific mutants to determine potential dependency on vomeronasal function as well. They also recorded information about body temperature, body weight, glucose levels, grip strength, and balance. Overall, they identify female-olfactory cues as increasing the lifespan of female but not male mice, regardless of genotype.
This study reports an intriguing new intervention with an impact on mouse lifespan (with a female-specific effect). However, some of the data with negative results are not plotted/shown, and although all experiments were performed in wild-type and mutant background, all the shown data is pooled and not split by genotype. Overall, this study will be valuable to the field provided that a few analytical points are addressed for clarity and reproducibility and that all methodological details are included.
-
Reviewer #2 (Public Review):
In this study, the authors were attempting to determine if early life exposure to specific olfactory cues leads to changes in lifespan. They exposed young mice to urine from male or female adult mice, or no urine for the control groups. They were also interested in determining if the Gao gene was responsible for any effect they found due to its impact on olfaction. They found that females exposed to female urine lived longer than control or male-exposed female mice, and there was no effect of exposure on male lifespan. These effects were found to be completely independent of the Gao gene.
I felt the overall methods were good, and they had sufficient power to look at the lifespan effects. However, the authors used spent bedding from male and female mice as the source of the smell exposure, and I would worry …
Reviewer #2 (Public Review):
In this study, the authors were attempting to determine if early life exposure to specific olfactory cues leads to changes in lifespan. They exposed young mice to urine from male or female adult mice, or no urine for the control groups. They were also interested in determining if the Gao gene was responsible for any effect they found due to its impact on olfaction. They found that females exposed to female urine lived longer than control or male-exposed female mice, and there was no effect of exposure on male lifespan. These effects were found to be completely independent of the Gao gene.
I felt the overall methods were good, and they had sufficient power to look at the lifespan effects. However, the authors used spent bedding from male and female mice as the source of the smell exposure, and I would worry that spent bedding would have traces of fecal matter in it. This could suggest that any effect they see would be due to microbiome differences from the bedding exposure, not the smell of urine.
While the results are interesting, I'm not sure they will have a huge impact on the field. Early life exposures have previously been shown to affect aging and lifespan, and there were overall very minor effects seen of these olfactory exposures in female mice.
-
Reviewer #3 (Public Review):
Garratt et al. investigated that transient exposure of young mice during their first two months of life with olfactory cues from con-specific adults would have long-lasting effects on their late-life health and lifespan. They find that the olfactory cues have sex-specific effects on lifespan, which only the lifespan of young females can be extended by odours from adult females but no other combinations, neither young females with adult males nor young males with either sex. Interestingly, their data also suggested that depletion of G protein Gαo in the olfactory system played no role in the lifespan extension, indicating it might be another unknown factor(s) mediating this sex-specific effect on longevity in mice. While the conclusions of this study are well supported by the data, there are some issues with …
Reviewer #3 (Public Review):
Garratt et al. investigated that transient exposure of young mice during their first two months of life with olfactory cues from con-specific adults would have long-lasting effects on their late-life health and lifespan. They find that the olfactory cues have sex-specific effects on lifespan, which only the lifespan of young females can be extended by odours from adult females but no other combinations, neither young females with adult males nor young males with either sex. Interestingly, their data also suggested that depletion of G protein Gαo in the olfactory system played no role in the lifespan extension, indicating it might be another unknown factor(s) mediating this sex-specific effect on longevity in mice. While the conclusions of this study are well supported by the data, there are some issues with parts of the data analysis and presentation that would need to be clarified and extended.
The authors suggested that the G protein Gαo played no role in lifespan extension in the case that transient exposure of young females with olfactory cues from female adults, as they showed in Figure 1. However, it is not clear if the depletion of G Gαo (Gαo mutant) itself has effects on lifespan, compared to its wild type. It would be important to show the lifespan curves from wild type and Gαo mutant individually alongside the pooled lifespan curves, as well as regarding data in a table, followed with a proper discussion.
Regarding the functional tests, the authors showed that there was only a small fraction of experiments showed differences between treatments, which were all in figure 2. However, it is necessary to also show the data with no differences, particularly since the conclusion of the study suggested the underlying mechanisms are not clear yet. In my opinion, body weight, plasma glucose, and body temperature all deserve to have their figures individually with all data points.
As the authors mentioned in the Introduction, the age at sexual maturity correlates positively with the median lifespan across mice strains (Yuan et al. 2012, Wang et al. 2018). Also, young female mice that were exposed to male odours during their developmental stage accelerated sexual maturity (Drickamer 1983), and the same happened to young males that were exposed to the odours from the opposite sex (Vandenbergh 1971). It is, therefore, surprising to see in this study, the exposure of young females or young males to the olfactory information from their opposite sex had no effects on lifespan. One of the solutions to solve this disparity is to measure the sexual maturity of the mice in this study. The authors should seek the possibility to check the record of when the first litter of pups was born between treatments (Shindyapina et al. 2022) or examine preputial separation and vaginal opening (Hoffmann 2018), for instance.
In sum, this is a great piece of work suggesting the importance of sex differences on olfactory cues mediated lifespan and pointing out some directions for future works.
-
-
-
-