Challenging a “Cushy” Life: Potential Roles of Thermogenesis and Adipose Tissue Adaptations in Delayed Aging of Ames and Snell Dwarf Mice

Laboratory mouse models with genetically altered growth hormone (GH) signaling and subsequent endocrine disruptions, have longer lifespans than control littermates. As such, these mice are commonly examined to determine the role of the somatotropic axis as it relates to healthspan and longevity in mammals. The two most prominent mouse mutants in this context are the genetically dwarf Ames and Snell models which have been studied extensively for over two decades. However, it has only been proposed recently that both white and brown adipose tissue depots may contribute to their delayed aging. Here we review the current state of the field and supplement it with recent data from our labs.

On the biochemical associations of FoxO3a and SirT1 with the stress resistance of cells from the slow senescing Snell dwarf Mouse

Tailskin fibroblasts from multiple genotypes of slow aging mice have been shown to be resistant to a broad spectrum of toxicants. The molecular determinants for this in vitro effect, as well as for the delayed/ decelerated senescence of these mice, are uncertain. Here, we have extended this phenomenon of in vitro cellular stress resistance to neurons derived from the cerebral cortex of the Snell Dwarf Mouse. We further investigated the role of the transcription factor FoxO3a and the protein deacetylase SirT1, proteins known to positively mediate cellular stress-resistance, in this paradigm. We found that Snell Dwarfs have a greater proportion of nuclear-localized FoxO3a within their cerebrums than their littermate controls and that the same is true for their unstressed fibroblasts in vitro; yet, Snell Dwarf fibroblasts did not differ in FoxO3a properties in response to the application of three different concentrations of two disparate stresses. Similar results were obtained for SirT1, although SirT1 content did increase under the mild cellular stress of serum deprivation. Taken together, these results depict stress resistance in non-fibroblast cell types of incontrovertible physiological import explanted from slow aging mice. Also, these results strongly suggest that neither FoxO3a nor SirT1 robustly regulate the stress-resistance of Snell Dwarf Mouse cells in vitro, and thus might not play a role in other slow aging mammalian in vitro models in which stress resistance has been documented. That cerebral neurons ex vivo and unstressed fibroblasts in vitro display FoxO3a concentrations suggestive of increased activity introduce the possibility that FoxO3a might partially mediate the in vivo retardation of senescence of these mice.

On the biochemical associations of FoxO3a and SirT1 with the stress resistance of cells from the slow senescing Snell dwarf Mouse

Tailskin fibroblasts from multiple genotypes of slow aging mice have been shown to be resistant to a broad spectrum of toxicants. The molecular determinants for this in vitro effect, as well as for the delayed/ decelerated senescence of these mice, are uncertain. Here, we have extended this phenomenon of in vitro cellular stress resistance to neurons derived from the cerebral cortex of the Snell Dwarf Mouse. We further investigated the role of the transcription factor FoxO3a and the protein deacetylase SirT1, proteins known to positively mediate cellular stress-resistance, in this paradigm. We found that Snell Dwarfs have a greater proportion of nuclear-localized FoxO3a within their cerebrums than their littermate controls and that the same is true for their unstressed fibroblasts in vitro; yet, Snell Dwarf fibroblasts did not differ in FoxO3a properties in response to the application of three different concentrations of two disparate stresses. Similar results were obtained for SirT1, although SirT1 content did increase under the mild cellular stress of serum deprivation. Taken together, these results depict stress resistance in non-fibroblast cell types of incontrovertible physiological import explanted from slow aging mice. Also, these results strongly suggest that neither FoxO3a nor SirT1 robustly regulate the stress-resistance of Snell Dwarf Mouse cells in vitro, and thus might not play a role in other slow aging mammalian in vitro models in which stress resistance has been documented. That cerebral neurons ex vivo and unstressed fibroblasts in vitro display FoxO3a concentrations suggestive of increased activity introduce the possibility that FoxO3a might partially mediate the in vivo retardation of senescence of these mice.

Regulation of mTOR Activity in Snell Dwarf and GH Receptor Gene-Disrupted Mice

The involvement of mammalian target of rapamycin (mTOR) in lifespan control in invertebrates, calorie-restricted rodents, and extension of mouse lifespan by rapamycin have prompted speculation that diminished mTOR function may contribute to mammalian longevity in several settings. We show here that mTOR complex-1 (mTORC1) activity is indeed lower in liver, muscle, heart, and kidney tissue of Snell dwarf and global GH receptor (GHR) gene-disrupted mice (GHR−/−), consistent with previous studies. Surprisingly, activity of mTORC2 is higher in fasted Snell and GHR−/− than in littermate controls in all 4 tissues tested. Resupply of food enhanced mTORC1 activity in both controls and long-lived mutant mice but diminished mTORC2 activity only in the long-lived mice. Mice in which GHR has been disrupted only in the liver do not show extended lifespan and also fail to show the decline in mTORC1 and increase in mTORC2 seen in mice with global loss of GHR. The data suggest that the antiaging effects in the Snell dwarf and GHR−/− mice are accompanied by both a decline in mTORC1 in multiple organs and an increase in fasting levels of mTORC2. Neither the lifespan nor mTOR effects appear to be mediated by direct GH effects on liver or by the decline in plasma IGF-I, a shared trait in both global and liver-specific GHR−/− mice. Our data suggest that a more complex pattern of hormonal effects and intertissue interactions may be responsible for regulating both lifespan and mTORC2 function in these mouse models of delayed aging.

Nrf2 Signaling, a Mechanism for Cellular Stress Resistance in Long-Lived Mice

ABSTRACT Transcriptional regulation of the antioxidant response element (ARE) by Nrf2 is important for the cellular adaptive response to toxic insults. New data show that primary skin-derived fibroblasts from the long-lived Snell dwarf mutant mouse, previously shown to be resistant to many toxic stresses, have elevated levels of Nrf2 and of multiple Nrf2-sensitive ARE genes. Dwarf-derived fibroblasts exhibit many of the traits associated with enhanced activity of Nrf2/ARE, including higher levels of glutathione and resistance to plasma membrane lipid peroxidation. Treatment of control cells with arsenite, an inducer of Nrf2 activity, increases their resistance to paraquat, hydrogen peroxide, cadmium, and UV light, rendering these cells as stress resistant as untreated cells from dwarf mice. Furthermore, mRNA levels for some Nrf2-sensitive genes are elevated in at least some tissues of Snell dwarf mice, suggesting that the phenotypes observed in culture may be mirrored in vivo. Augmented activity of Nrf2 and ARE-responsive genes may coordinate many of the stress resistance traits seen in cells from these long-lived mutant mice.