Abstract:Caloric restriction and genetic disruption of growth hormone signaling have been shown to counteract aging in mice. The effects of these interventions on aging are examined through age-dependent survival or through the increase in age-dependent mortality rates on a logarithmic scale fitted to the Gompertz model. However, these methods have limitations that impede a fully comprehensive disclosure of these effects. Here we examine the effects of these interventions on murine aging through the increase in age-dep… Show more
“…These patterns are consistent with the effects on lifespan and survival discussed above. Moreover, these effects of GH are consistent with the effect of reduced GH signaling in other mutant mice, which have aging rates that increase at the advanced ages to a higher level relative to control mice (Koopman et al, 2016). 10.7554/eLife.24059.005Figure 3.Age-dependent aging rates of the groups of mice in the first week ( A ) and the second week ( B ) GH treatment groups.The aging rates describe the increases in the mortality rates with age and are expressed in deaths per 10,000 mice per day, which equals the change in mortality rate per day.…”
Section: Resultssupporting
confidence: 78%
“…We employed a non-parametric method, explained and applied previously (Koopman et al, 2016). In the first week GH treatment protocol (between postnatal first and seventh week), GH treated dwarf mice had aging rates that increased at younger ages to a lower level relative to saline-treated dwarf mice (Figure 3A).…”
Life-long lack of growth hormone (GH) action can produce remarkable extension of longevity in mice. Here we report that GH treatment limited to a few weeks during development influences the lifespan of long-lived Ames dwarf and normal littermate control mice in a genotype and sex-specific manner. Studies in a separate cohort of Ames dwarf mice show that this short period of the GH exposure during early development produces persistent phenotypic, metabolic and molecular changes that are evident in late adult life. These effects may represent mechanisms responsible for reduced longevity of dwarf mice exposed to GH treatment early in life. Our data suggest that developmental programming of aging importantly contributes to (and perhaps explains) the well documented developmental origins of adult disease.DOI:
http://dx.doi.org/10.7554/eLife.24059.001
“…These patterns are consistent with the effects on lifespan and survival discussed above. Moreover, these effects of GH are consistent with the effect of reduced GH signaling in other mutant mice, which have aging rates that increase at the advanced ages to a higher level relative to control mice (Koopman et al, 2016). 10.7554/eLife.24059.005Figure 3.Age-dependent aging rates of the groups of mice in the first week ( A ) and the second week ( B ) GH treatment groups.The aging rates describe the increases in the mortality rates with age and are expressed in deaths per 10,000 mice per day, which equals the change in mortality rate per day.…”
Section: Resultssupporting
confidence: 78%
“…We employed a non-parametric method, explained and applied previously (Koopman et al, 2016). In the first week GH treatment protocol (between postnatal first and seventh week), GH treated dwarf mice had aging rates that increased at younger ages to a lower level relative to saline-treated dwarf mice (Figure 3A).…”
Life-long lack of growth hormone (GH) action can produce remarkable extension of longevity in mice. Here we report that GH treatment limited to a few weeks during development influences the lifespan of long-lived Ames dwarf and normal littermate control mice in a genotype and sex-specific manner. Studies in a separate cohort of Ames dwarf mice show that this short period of the GH exposure during early development produces persistent phenotypic, metabolic and molecular changes that are evident in late adult life. These effects may represent mechanisms responsible for reduced longevity of dwarf mice exposed to GH treatment early in life. Our data suggest that developmental programming of aging importantly contributes to (and perhaps explains) the well documented developmental origins of adult disease.DOI:
http://dx.doi.org/10.7554/eLife.24059.001
“…Both Ames dwarf and GHR−/− mice are remarkably long‐lived, with increases in longevity ranging from some 20% to over 60% depending on the diet, gender, and genetic background of the animal (Brown‐Borg et al ., ; Coschigano et al ., ; Bartke et al ., ). The enhancement of longevity in these mice is associated with maintenance of youthful levels of cognitive and neuromuscular function, and other phenotypic characteristics into advanced age (Bartke et al ., ), delayed onset, and reduced incidence of cancer and other age‐related pathological changes (Ikeno et al ., ; Bartke et al ., ), and a reduced rate of aging (Koopman et al ., ). We have previously proposed that the activation of BAT and increased metabolic rate in these long‐lived mice represent responses to increased radiational heat loss in these diminutive animals (Westbrook, ; Darcy et al ., ).…”
SummaryIt was recently reported that the extragonadal actions of follicle‐stimulating hormone (FSH) include regulation of brown and white adipose tissue function and thermogenesis. Based on these findings and on our evidence for reduced FSH levels and enhanced thermogenesis in long‐lived growth hormone (GH)‐deficient mice and GH‐resistant mice, we suggest that FSH may have a role in the control of aging and longevity. We speculate that alterations in FSH secretion may represent one of the mechanisms of trade‐offs between reproduction and aging.
“…The conclusion that the biological process of aging is indeed slower in the absence of GH signals is supported by the evidence that the age-related changes in cognitive and musculoskeletal function, glucose homeostasis and risk of cancer are delayed and/or diminished in GH-related mutants compared to normal animals from the same strain [reviewed in 43, 44–49]. Recent analysis of survival curves of GHR−/− and GHRH−/− mice revealed that their mortality rate (arguably the most meaningful measure of aging) is lower in these mutants than in the normal mice, and that its age-related acceleration is correspondingly delayed [50]. …”
Section: Evidence That Gh Can Accelerate Agingmentioning
Interrelationships of growth hormone (GH) actions and aging are complex and incompletely understood. The very pronounced age-related decline in GH secretion together with benefits of GH therapy in individuals with congenital or adult GH deficiency (GHD) prompted interest in GH as an anti-aging agent. However, the benefits of treatment of normal elderly subjects with GH appear to be marginal and counterbalanced by worrisome side effects.
In laboratory mice, genetic GH deficiency or resistance leads to a remarkable extension of longevity accompanied by signs of delayed and/or slower aging. Mechanisms believed to contribute to extended longevity of GH-related mutants include improved anti-oxidant defenses, enhanced insulin sensitivity and reduced insulin levels, reduced inflammation and cell senescence, major shifts in mitochondrial function and energy metabolism and greater stress resistance. Negative association of the somatotropic signaling and GH/insulin-like growth factor 1 (IGF-1)-dependent traits with longevity was also shown in other mammalian species. In humans, syndromes of GH resistance or deficiency have no consistent effect on longevity, but can provide striking protection from cancer, diabetes and atherosclerosis. More subtle variations in various steps of GH and IGF-1 signaling are associated with reduced old-age mortality, particularly in women and with improved chances of attaining extremes of lifespan. Epidemiological studies raise a possibility that the relationship of IGF-1 and perhaps also GH levels with human healthy aging and longevity may be biphasic. However, the impact of somatotropic signaling on neoplastic disease is difficult to separate from its impact on aging and IGF-1 levels exhibit opposite associations with different chronic, age-related diseases.
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