The HPA stress axis shapes aging rates in long-lived, social mole-rats

  1. Arne Sahm
  2. Steve Hoffmann
  3. Philipp Koch
  4. Yoshiyuki Henning
  5. Martin Bens
  6. Marco Groth
  7. Hynek Burda
  8. Sabine Begall
  9. Saskia Ting
  10. Moritz Goetz
  11. Paul Van Daele
  12. Magdalena Staniszewska
  13. Jasmin Klose
  14. Pedro Fragoso Costa
  15. Matthias Platzer
  16. Karol Szafranski
  17. Philip Dammann

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Abstract

Sexual activity and/or reproduction doubles life expectancy in the long-lived rodent genus Fukomys . To investigate the molecular mechanisms underlying this phenomenon, we analyzed a total of 636 RNA-seq samples across 15 tissues. This analysis suggests that the differences in life expectancy between reproductive and non-reproductive mole-rats are mainly caused by critical changes in the regulation of the hypothalamic-pituitary-adrenal stress axis, which we further substantiate with a series of independent evidence. In accordance with previous studies, the up-regulation of the proteasome and several so-called “anti-aging molecules”, such as DHEA, is also linked with enhanced life expectancy. On the other hand, several our results oppose crucial findings in short-lived model organisms. For example, we found the up-regulation of the IGF1/GH axis and several other anabolic processes to be compatible with a considerable lifespan prolongation. These contradictions question the extent to which findings from short-lived species can be transferred to longer-lived ones.

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  1. eLife

    ###Reviewer #3:

    The manuscript by Sahm et al. describes the transcriptomic comparison of breeders and non-breeders in two species of mole rats from genus Fukomys. The remarkable aspect of Fukomys mole rats is that the breeders live significantly longer than workers. The authors produced new breeder couples by pairing animals from different family groups and then compared their transcriptomes to non-breeders of the same age from the original colonies.

    There were very few differences identified between breeders and non-breeders. Most transcriptomic changes were confined to gonads and endocrine glands. This is somewhat unsurprising and these organs become active for breeding. The pathways that became activated were related to ribosome biogenesis, protein translation, and MYC signaling, which all reflect physiological activation of these tissues in breeders.

    Interestingly, some activation of these signaling pathways was also observed in non-gonadal tissues, which contradicts the common dogma that downregulation of these pathways is associated with lifespan extension. This is a remarkable result that suggests that short-lived model organisms may not correctly reflect signaling effects required for longevity in long-lived species. The authors also point out to higher glucocorticoid levels in workers and speculate that that may be showing Cushing's like syndrome.

    Overall, this is an important study of high interest.

    Items to address:

    1. It is not clear how long were the animals maintained in a breeder status prior to analysis.

    2. Figure 3A, the rationale for the comparison of changes in young breeder versus non breeder animals to changes that occur with age over time is unclear.

    3. Figure 4, were the changes driven by gonads mainly? How many were non-gonadal? For example, in Figure 2, muscle showed 0 DEGs by status, but in pathway analysis we see upregulation of pathways. Please explain.

    4. Table 2: TOR is downregulated in breeders while ribosome processes are upregulated, please explain.

    5)The finding of Cushing's syndrome needs more support. Please consider comparing Cushing's related transcriptome changes as a whole to the changes observed in mole rats, otherwise this conclusion may need to be toned down.

  2. eLife

    ###Reviewer #2:

    Sahm et al. have analyzed gene expression of 22 samples across 15 tissues of Fukomys mole rat, and with these resources, they try to explain why breeders and non-breeders have different lifespans in those species. Below I highlight key aspects of the approach (and related conclusions, or lack thereof) that I believe represent serious issues. One positive note, again, the questions and data of this paper that I believe are highly interesting and important if the author can pursue it in a more focused and solid way.

    1. First, in my opinion, the discussion of the paper is not well synthesized, and the content does not help the reader for the aim of study and of what is discussed in the title (e.g., HPA) and abstract. While the entire discussion fails to build logics between HPA stress and aging in mole rats, it tells the story of intervention and hypothesis testing instead, with the last of the results immediately jumping into comparisons of positive selection genes and DEG (It is unclear why it is relevant even one gene is found under positive selection).

    2. Given hundreds of samples have been sequenced in the paper, there is no extensive examination of batch effect, which could ultimately, in its present form, put all the results (e.g., DEG analysis, pathways enrichment, multifactors analysis) and conclusions at high risk. Particularly, the PCA analysis has indicated the species, tissue, and the combination of both variables accounted for 98.4 % of the total variance in the data set--it becomes more important to know how the authors have organized the sequencing strategy.

    3. Unsophisticated use of enrichment analysis on pathways likely leads to misleading conclusions - a large portion of the analyses presented use an unreasonable approach to identify genes with expression shift across tissues and species to make conclusions that I believe are largely misleading about genes important for longevity. The authors identify pathways that have overall (gene-wide) changes in gene expression as p values looks like a potential indication of expression shift. While this approach MAY be lucky enough to catch a few of these 'true positives", the VAST majority of what it will identify will be pathways with global accumulated changes (which is what the point would be), but rather small pathways or pathways fully of with wired p values or undetectable expression (and thus perhaps some of the least important genes). Then, the extension of these approaches to pathways further muddies the waters of any discussions. The approaches for detecting affected global pathways have been the subject of a very large body of literature, and there are well developed hierarchical/empirical models for testing these hypotheses that the authors have not referred to. And, of course, it is strongly encouraged that the authors formulate a new model/index to reevaluate pathways analysis as the data and experimental design is unique compared to other studies.

    4. Last but not the least, small KEGG set, i.e., KEGG, that with very few genes could also be confusing such whole categories analysis. The author should check this potential bias using random sampling 'pseudo-KEGG set' with the same gene number and/or identify a threshold to filter each true KEGG category considered.

  3. eLife

    ###Reviewer #1:

    This is a primarily descriptive study reporting gene expression differences between breeding and non-breeding individuals of two long-lived Fukomys species. These mole rat species are interesting for this type of analysis because it has been previously shown that breeders live ~2-fold longer than non-breeders. Thus, it may be possible to learn about mechanisms that determine longevity by studying differences between breeders and non-breeders. Although the manuscript is primarily descriptive, there is value in observational data sets such as this, which can be hypothesis generating and can spur future, more mechanistic studies. A lot of analyses are presented - with many different comparisons of differentially expressed genes, GO terms, etc. - but they have not yet produced a lot in terms of true biological insight. As it was largely limited to gene expression, it is also a bit one-dimensional. The data will likely be of interest and value to scientists who study the comparative biology of aging and systems biology of aging, but without additional biological insights derived from the data, the manuscript will probably not capture the interest of a broad scientific audience or even the broader gerontology community.

    My largest concerns with the content of this manuscript are related to interpretation of the data. While this type of comparative gene expression analysis can generate hypotheses, it cannot strongly support or refute causal relationships without additional experimentation. The authors repeatedly appear to interpret correlative observations with causation and make claims that overreach the data. The title itself is a good example of this where the authors claim "the HPA stress axis shapes aging rates". There is no direct evidence to support this claim or others similar in nature throughout the manuscript.

    Another area of overinterpretation is with respect to the relevance of these findings as a test of the validity of prior aging theories or mechanisms. It seems very likely that this is a somewhat unique evolutionary case where upon the switch from non-breeder to breeder there is a dramatic rewiring of physiology at many levels (transcriptional, translational, post-translational, metabolome, epigenome, etc.). Simply because this switch does not match patterns seen in longevity interventions such as caloric restriction, reduced GH/IGF-1 signaling, or mTOR inhibition does not refute or call into question literature describing potential mechanisms for how those interventions act. It likely simply reflects that this is a different path to achieve longevity.

    Specific comments:

    • The title is problematic as described above.
    • The first sentence in the abstract is problematic as it implies causality between sexual activity/reproduction and longevity. Sexual activity/reproduction are associated with life expectancy. It is interesting to consider whether these two things could perhaps be uncoupled in this animal, as has been shown for reduced fecundity and longevity in invertebrate models.
    • The phrase "oppose crucial findings" in the abstract is also problematic. First, the word "crucial" does not seem to make sense in this context. What makes them crucial? Second, it is intuitive and expected, indeed perhaps required, that reproduction would be associated with anabolic processes, and this study does not show causality between the observed changes in these processes and longevity, so it does not actually "oppose" the prior findings in genetic models with reduced IGF-1/GH signaling where lifespan is extended.
    • I have a problem with the premise that it is possible to "confirm or falsify" results from cross-species or intra-species studies through the type of approach taken here as implied in line 47. Confirming or falsifying results implies something about the quality of the prior data itself. I assume what the authors mean is confirming or falsifying the underlying hypotheses or assumptions. Even that is questionable, however, since the mechanisms by which longevity are determined could simply be different within species versus across species versus cases like this where you have dramatically different life expectancies in breeders versus non-breeders.
    • I thought the discussion of the GH/IGF-1 results was fairly balanced, but I would encourage the authors to consider more deeply the within species versus across species observations in the literature. The evidence for reduced GH/IGF-1 increasing lifespan comes from within species studies and appears to hold true from worms to dogs and likely in humans as well, although the correlation between body size and lifespan is a bit more complicated in humans for obvious reasons. Within species, smaller individuals who have reduced GH/IGF-1 tend to live longer - that's a correlation. In worms, flies, and mice a reduction in growth signaling has been shown to be sufficient - and very likely causal - for enhanced longevity through genetic and pharmacological studies. The comment that these interventions are all performed during development is not exactly true - in mice rapamycin at least works in adulthood and even when only given transiently or intermittently in adulthood. Across species, larger species tend to live longer. Perhaps the mechanisms going from non-breeders to breeders more resemble the evolutionary longevity strategies that have been taken at the species level rather than the mechanism that appear to determine longevity within species. Personally, I don't see this as a contradiction or a controversy within the field.
    • I find the "short-lived" versus "long-lived" species argument to be overly speculative and arbitrary. Interventions such as CR, mTOR inhibition, reduced IGF-1, etc. extend lifespan at least from worms to mice, which is a >50-fold difference in lifespan. Mice to people is ~30-fold. Compared to mice, worms are shorter-lived (by a fold difference metric) than mice are compared to humans.
    • The authors state that breeders and non-breeders have "massively diverging aging rates", but I think it is important to keep in mind that differences in lifespan do not necessarily imply differences in aging rate. Especially going from the long-lived state to the short-lived state. Perhaps there is good evidence that functional and molecular declines and diseases/pathologies of aging are accelerated in the non-breeders and delayed in the breeders, which would support this assertion, but this is unclear from the manuscript.
    • The phrase "unilaterally described as harmful" in the conclusion is simply not true. GH/IGF-1 signaling limits lifespan in worms, flies, and mice but none of the papers cited unilaterally claim that it is harmful. In fact, some of those same papers note that high GH/IGF-1 signaling often confers a selective advantage in terms of faster maturation and reproduction. So, at the species level, this is beneficial. Even at the individual level, high GH/IGF-1 may be associated with better outcomes in the wild where predation is a factor. High GF/IGF-1 in these species is detrimental (only?) in the context of aging/longevity in a relatively safe laboratory environment at the individual level.
  4. eLife

    ##Preprint Review

    This preprint was reviewed using eLife’s Preprint Review service, which provides public peer reviews of manuscripts posted on bioRxiv for the benefit of the authors, readers, potential readers, and others interested in our assessment of the work. This review applies only to version 2 of the manuscript.

    ###Summary

    Mole-rats live in social colonies that contain two breeders and many non-breeding workers. This study looks at gene expression between breeding and non-breeding individuals of two long-lived mole-rat species in the genus Fukomys. The large lifespan difference between breeders and non-breeders has made these animals an important model system for the study of aging, and the data collection reported in this manuscript is very impressive. The paper is descriptive data, with limited data analyses and experimental support for the conclusions. However, given the scale and rarity of the dataset, it will be a valuable resource for the aging research community once the quality and physiological relevance of the data are demonstrated by additional bioinformatic analyses and experimental validations.

  5. Version published to 10.1101/2020.02.22.961011v2 on bioRxiv
  6. Version published to 10.1101/2020.02.22.961011v1 on bioRxiv