Rapamycin Does Not Interact Favorably with Growth Hormone Receptor Knockout
The scientific community is, on the whole, very focused on exploring the effects and understanding the mechanisms of single interventions. Studies that investigate potential synergies between two or more interventions are comparatively rare. This need not be the case; it seems to be a cultural thing, a product of many various influences on funding, planning, and development. There are numerous well-established methods of slowing aging in mice, and it would be interesting to learn how they interact, whether they stack or not, even though these are largely not useful roads to greatly enhanced human longevity. Accordingly, here is one of the rare studies to examine the combined effect on life span of two interventions at once. In this case it is found that they work against one another, which at least has the potential to extend our understanding of the biochemistry of both.
Mechanistic target of rapamycin (mTOR) plays central roles in growth, metabolism, and aging. It acts via two distinct complexes: mTORC1 and mTORC2, defined by Raptor and Rictor, respectively. Rapamycin, an inhibitor of mTOR, inhibits mTORC1, and longer rapamycin treatment also inhibits mTORC2. Rapamycin was the first drug shown to extend longevity in a mammal. The effects of rapamycin on longevity were accounted for by mTORC1 inhibition, whereas information on mTORC2 is generally lacking. However, it seems that many of the negative adverse effects of rapamycin treatment are mediated by inhibition of mTORC2.
Rictor has positive effects on a variety of functions involved in whole-body homeostasis. Although at this time, the role of mTORC2 in the regulation of longevity is uncertain, several lines of evidence imply that mTORC2 may have opposite effects on aging compared with mTORC1. For instance, Rictor loss-of-function mutants in Caenorhabditis elegans had decreased life spans by 24-43% on a standard diet. Interestingly, transcriptional down-regulation of mTORC1 and transcriptional up-regulation of mTORC2 was reported to be associated with human longevity. It is vital to understand how mTORC2 regulates aging in a mammal.
mTORC2 is regulated by growth hormone (GH)-dependent growth factors. GH is essential for growth and metabolism and is involved in the control of aging. It binds and signals through GH receptor (GHR). Therefore, deletion of GHR eliminates GH signaling and its biological functions. GHR-KO (GHR knockout) mice have been a valuable tool to study GH functions, including its relationship to longevity. GHR-KO mice are dwarf, extremely insulin sensitive, and have their life span extended up to 40%. Importantly, compared with their normal littermates, GHR-KO and several other long-lived mice have decreased mTORC1 and increased mTORC2 signaling, which may play a role in their extended longevity. Therefore, we decided to examine how prolonged rapamycin treatment alters mTORC1 and mTORC2 signaling in GHR-KO mice.
In long-lived GHR-KO mice, prolonged rapamycin treatment did not further extend, but unexpectedly shortened, life span. One possible reason could be that prolonged rapamycin treatment further decreases the already low levels of mTORC1 signaling in these animals, which could adversely affect the benefits of mTORC1 inhibition. However, mTORC1 signaling was not further reduced in three key metabolic tissues of GHR-KO mice with prolonged rapamycin treatment compared with control GHR-KO mice. We cannot explain why prolonged rapamycin treatment did not further decrease mTORC1 signaling in these animals, and also cannot rule out the possibility that mTORC1 signaling may have been further reduced in other tissues.
In contrast, a significant reduction of mTORC2 signaling was evident in each of the examined tissues of GHR-KO mice treated with rapamycin. Decreased mTORC2 signaling and impaired whole-body homeostasis (which could result from reduced mTORC2 signaling) in rapamycin-treated GHR-KO mice might have contributed to the effect of prolonged rapamycin treatment on the life span of GHR-KO mice. Thus, our data indicated that mTORC2 may play a beneficial role in longevity via improving or maintaining whole-body homeostasis. Based on our data and data from previous studies, we propose the following concept: if whole-body homeostasis is impaired (which was associated with the significant reduction of mTORC2 in our study), life span could be shortened, and if mTORC2 signaling is unaltered or enhanced, inhibition of mTORC1 will lead to extension of life span. The effects of altered mTOR signaling on longevity would thus reflect a balance between inhibition of mTORC1 and enhancement, or maintenance, of mTORC2.