Endocrine regulation of heat shock protein mRNA levels in long-lived dwarf mice

Swindell, William R.; Masternak, Michał M.; Kopchick, John J.; Conover, Cheryl A.; Bartke, Andrzej; Miller, Richard A.

doi:10.1016/j.mad.2009.03.004

Cited by 48 publications

(37 citation statements)

References 61 publications

(118 reference statements)

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“…While this between-species immunodetection approach requires validation for conservation of amino acid sequence, it is nonetheless in agreement with the observation that HSP70 levels are also lower in stress-resistant fibroblasts of long-lived Snell dwarf mice compared to those from normal littermates (Maynard and Miller 2006). A further study examining several different heat shock protein mitochondrial RNAs (mRNAs) in Snell dwarf mice found no coordinated elevation of heat shock proteins (HSPs) in Snell dwarf tissues or fibroblasts (Swindell et al 2009). These latter mRNA data may not reflect protein levels, as changes in gene transcript levels often do not parallel changes in corresponding protein levels, even for transcriptionally regulated proteins (see for example Ideker et al 2001;Le Naour et al 2001).…”

Section: Discussionmentioning

confidence: 53%

Enhanced protein repair and recycling are not correlated with longevity in 15 vertebrate endotherm species

Salway

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Faure

et al. 2010

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Previous studies have shown that longevity is associated with enhanced cellular stress resistance. This observation supports the disposable soma theory of aging, which suggests that the investment made in cellular maintenance will be proportional to selective pressures to extend lifespan. Maintenance of protein homeostasis is a critical component of cellular maintenance and stress resistance. To test the hypothesis that enhanced protein repair and recycling activities underlie longevity, we measured the activities of the 20S/26S proteasome and two protein repair enzymes in liver, heart and brain tissues of 15 different mammalian and avian species with maximum lifespans (MLSP) ranging from 3 to 30 years. The data set included Snell dwarf mice, in which lifespan is increased by ∼50% compared to their normal littermates. None of these activities in any of the three tissues correlated positively with MLSP. In liver, 20S/26S proteasome and thioredoxin reductase (TrxR) activities correlated negatively with body mass. In brain tissue, TrxR was also negatively correlated with body mass. Glutaredoxin (Grx) activity in brain was negatively correlated with MLSP and this correlation remained after residual analysis to remove the effects of body mass, but was lost when the data were analysed using Felsenstein's independent contrasts. Snell dwarf mice had marginally lower 20S proteasome, TrxR and Grx activities than normal controls in brain, but not heart tissue. Thus, increased longevity is not associated with increased protein repair or proteasomal degradation capacities in vertebrate endotherms.

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Section: Discussionmentioning

confidence: 53%

Enhanced protein repair and recycling are not correlated with longevity in 15 vertebrate endotherm species

Salway

Page

Faure

et al. 2010

AGE

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“…Tissues of 4-to 6-month-old dwarf and control mice were prepared by RNeasy kit preparation, as previously described (100).…”

Section: Animalsmentioning

confidence: 99%

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

Leiser

Miller

2010

Molecular and Cellular Biology

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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.The discovery of single gene mutations that extend life span, first in invertebrates (43,48,60) and then in mice (9, 14, 19), has provided new momentum for defining the molecular mechanisms that control the aging process. Since Harman first proposed the free radical theory of aging (23), many lines of evidence have suggested that oxidative stress plays an important role in aging. In roundworms (Caenorhabditis elegans) (44, 52) and fruit flies (Drosophila melanogaster) (7, 67, 109), mutations resulting in resistance to toxic stresses, both oxidative and otherwise, tend to result in increases in longevity. The relative importance of oxidation damage as a regulator of life span is more controversial. Longevity is often associated with resistance to oxidative injury within and among species, but most attempts to retard aging by antioxidant treatments have failed to show beneficial effects, and mutations that promote oxidative damage in mice have often had little impact on life span (25,72,81,86,96). Utilizing cells from the Snell dwarf mouse, a model of extended longevity, we are attempting to find the mechanism behind cellular stress resistance in hopes of relating this resistance to the delayed aging of the Snell dwarf animal.Snell dwarf mice are homozygous for a mutation at the Pit-1 locus which causes improper development of the anterior pituitary, leading to low levels of growth hormone, thyroid stimulating hormone, and prolactin in young and adult mice (10, 30). These pituitary defects lead to diminished circulating levels of insulin-like growth factor 1 (IGF-1) and thyroxine, which in turn result in reduced size and hypothermia. Snell dwarf mice, like the closely related Prop1 mutant Ames dwarf (9), live approximately 40% longer than littermate controls on several different background stocks (19,20) and show delay in many forms of aging-related pathologies (1,3,19).Previous work has shown that pr...

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“…The levels of mRNAs for multiple heat-shock proteins were reduced in the liver, kidney and heart of Snell dwarfs (GH-deficient mutants with endocrine phenotype identical to Ames dwarfs) and in GHRKO mice, while expression of other heat-shock proteins was elevated in tissues from Snell dwarfs only (41). In both Snell and Ames dwarf mice, the expression of Nrf-2-sensitive genes was elevated in various organs (42). Moreover, the responses of Ames dwarf and normal mice to treatment with diquat, a known hepatotoxin, differed in terms of activation of stress responsive pathways including ERK, JNK, p38MAPK, ERK-dependent and Nrf2-dependent genes, as well as Nrf2 protein (43).…”

Section: Mechanisms Linking Reduced Gh Signaling With Extended Longevitymentioning

confidence: 99%

Pleiotropic effects of growth hormone signaling in aging

Bartke

2011

Trends in Endocrinology & Metabolism

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Summary Growth hormone (GH) affects somatic growth, sexual maturation, body composition and metabolism, as well as aging and longevity. Mice lacking GH or GH receptor outlive their normal siblings and exhibit symptoms of delayed aging associated with improved insulin signaling and increased stress resistance. Beneficial effects of eliminating the actions of GH are counterintuitive but conform to the concept of antagonistic pleiotropy. Evolutionary selection for traits promoting early life fitness and reproductive success may account for detrimental effects post-reproductively. Reciprocal relationships between GH signaling and longevity discovered in mutant mice apply also to normal mice, other mammalian species, and perhaps humans. This review summarizes the present understanding of the multifaceted relationship between somatotropic signaling and mammalian aging.

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Endocrine regulation of heat shock protein mRNA levels in long-lived dwarf mice

Cited by 48 publications

References 61 publications

Enhanced protein repair and recycling are not correlated with longevity in 15 vertebrate endotherm species

Enhanced protein repair and recycling are not correlated with longevity in 15 vertebrate endotherm species

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

Pleiotropic effects of growth hormone signaling in aging

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