Genes That Prolong Life: Relationships of Growth Hormone and Growth to Aging and Life Span

Bartke, Andrzej; Coschigano, Karen T.; Kopchick, John J.; Chandrashekar, Varadaraj; Mattison, Julie A.; Kinney, Beth; Hauck, Steven

doi:10.1093/gerona/56.8.b340

Cited by 154 publications

(114 citation statements)

References 80 publications

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“…These findings also differ from the results obtained in long-lived Ames dwarfs, which share many phenotypic characteristics with GHRKO mice and were exposed to an identical CR protocol in an earlier study in our laboratory (6). Both GHRKO and Ames dwarf mice are characterized by extremely low levels of IGF-I in peripheral circulation, reduced postnatal growth, delayed puberty, diminished body size (19), reduced plasma insulin and glucose, and enhanced sensitivity to injected insulin (20,21). Because normal siblings of GHRKO mice exhibited a robust longevity response to CR in the present study, it appears exceedingly unlikely that differences in the responses of Ames dwarf and GHRKO mice to CR are due to distinct genetic backgrounds or differences in some hard-to-define environmental factors between studies conducted several years apart.…”

Section: Discussioncontrasting

confidence: 56%

“…Phenotypic differences between GHRKO and Ames dwarf mice include opposite alterations in prolactin levels; varying degrees of suppression of thyroid hormone levels and body core temperature; major differences in reproductive status, particularly in females; and differences in body composition, antioxidant enzymes, and end-of-life pathology (19,22). From the present data, we cannot conclude which of these differences may have contributed to their divergent responses to 30% CR.…”

Section: Discussionmentioning

confidence: 57%

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Targeted disruption of growth hormone receptor interferes with the beneficial actions of calorie restriction

Bonkowski¹,

Rocha²,

Masternak³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

295

259

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Reduced intake of nutrients [calorie restriction (CR)] extends longevity in organisms ranging from yeast to mammals. Mutations affecting somatotropic, insulin, or homologous signaling pathways can increase life span in worms, flies, and mice, and there is considerable evidence that reduced secretion of insulin-like growth factor I and insulin are among the mechanisms that mediate the effects of CR on aging and longevity in mammals. In the present study, mice with targeted disruption of the growth hormone (GH) receptor [GH receptor͞GH-binding protein knockout (GHRKO) mice] and their normal siblings were fed ad libitum (AL) or subjected to 30% CR starting at 2 months of age. In normal females and males, CR produced the expected increases in overall, average, median, and maximal life span. Longevity of normal mice subjected to CR resembles that of GHRKO animals fed AL. In sharp contrast to its effects in normal mice, CR failed to increase overall, median, or average life span in GHRKO mice and increased maximal life span only in females. In a separate group of animals, CR for 1 year improved insulin sensitivity in normal mice but failed to further enhance the remarkable insulin sensitivity in GHRKO mutants. These data imply that somatotropic signaling is critically important not only in the control of aging and longevity under conditions of unlimited food supply but also in mediating the effects of CR on life span. The present findings also support the notion that enhanced sensitivity to insulin plays a prominent role in the actions of CR and GH resistance on longevity.insulin-like growth factor I ͉ insulin ͉ longevity ͉ aging ͉ dietary restriction M utations affecting somatotropic and͞or insulin signaling can produce a marked increase of longevity in mice. Genes related to homologous signaling pathways in the yeast Saccharomyces cerevisiae, the worm Caenorhabditis elegans, and the f ly Drosophila melanogaster play a key role in the control of aging in these species (1-3). A moderate reduction in the intake of nutrients [also known as calorie restriction (CR)] is extremely effective in delaying aging and increasing longevity in organisms ranging from yeast to mammals (3-5). We have previously reported that CR produces an additional increase in the life span of a long-lived hypopituitary mutant mouse, the Ames dwarf, and alters the slope of its survival curve similarly to the effects of CR in normal mice (6). This result was counterintuitive because both Ames dwarfs and normal animals subjected to CR have reduced insulin-like growth factor I (IGF-I) and insulin levels and share other phenotypic characteristics. Although C. elegans with a mutation in the insulin͞IGF-I homologous signaling pathway Daf 16͞FOXO lived longer when subjected to CR (7,8), CR failed to further increase longevity in D. melanogaster with a chico mutation that interferes with insulin͞IGF-I signaling and prolongs life (9). Interpretation of the findings obtained in Ames dwarf mice is complicated by the fact that in addition to growth hormone (GH...

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Section: Discussioncontrasting

confidence: 56%

Section: Discussionmentioning

confidence: 57%

Targeted disruption of growth hormone receptor interferes with the beneficial actions of calorie restriction

Bonkowski¹,

Rocha²,

Masternak³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

295

259

View full text Add to dashboard Cite

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“…Low levels of serum IGF-I and T4 are seen in calorically restricted rodents (Weindruch et al ., 1988), as well as in the long-lived Snell and Ames dwarf mice. Low levels of IGF-I are also seen in two other long-lived mutant mouse stocks lit / lit (Donahue & Beamer, 1993) and GHR-BP-knockout (Bartke et al ., 2001). The small size of pituitary dwarf mice can be restored by a programme of injections of growth hormone (a stimulus for IGF-I production) in the first few months of life, and the rate and extent of this induced growth is increased still further by simultaneous administration of thyroid hormones (Bartke, 1965).…”

Section: Figmentioning

confidence: 94%

Big mice die young: early life body weight predicts longevity in genetically heterogeneous mice

et al. 2002

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SummarySmall body size has been associated with long life span in four stocks of mutant dwarf mice, and in two varieties of dietary restriction in rodents. In this study, small body size at ages 2-24 months was shown to be a significant predictor of life span in a genetically heterogeneous mouse population derived from four common inbred mouse strains. The association was strongest for weights measured early in adult life, and somewhat weaker, though still statistically significant, at later ages. The effect was seen both in males and females, and was replicated in an independent population of the same genetic background. Body size at ages 2-4 months was correlated with levels of serum leptin in both males and females, and with levels of IGF-I and thyroid hormone in females only. A genome scan showed the presence of polymorphic alleles on chromosomes 2, 6, 7 and 15 with significant effects on body weight at 2-4 months, at 10 -12 months, or at both age ranges, showing that weight gain trajectory in this stock is under complex genetic control. Because it provides the earliest known predictor of life span, body weight may be usefully included in screens for induced mutations that alter aging. The evidence that weight in 2-month-old mice is a significant predictor of life span suggests that at least some of the lethal diseases of old age can be timed by factors that influence growth rate in juvenile rodents.

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“…This initial study did not assess potential effects of gender and reproductive activity, which could affect life span (Reznick et al, 2001). The life span of outbred zebrafish is thus at least 50% longer than that of commonly used mouse strains, and is slightly longer than long-lived mouse mutants (Bartke et al, 2001).…”

Section: The Origins Of Zebrafish As a Gerontological Modelmentioning

confidence: 98%

“…However, several mutations that result in a dwarf phenotype, i.e. the Ames dwarf (Prop1 df/df ) and Snell dwarf (Pit1 dw/dw ) mice can increase life span by over 50% (Bartke et al, 2001). The growth abnormalities are due to multiple hormonal deficiencies, including the growth hormone/insulin-like growth factor-1 pathway, suggesting potential common regulatory aspects of life span determination across a wide range of species.…”

Section: Zebrafish Versus Lab Mice-50 Times Smaller Yet Live 50% Longermentioning

confidence: 99%

Comparative aspects of zebrafish (Danio rerio) as a model for aging research

Gerhard

2003

Experimental Gerontology

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Genes That Prolong Life: Relationships of Growth Hormone and Growth to Aging and Life Span

Cited by 154 publications

References 80 publications

Targeted disruption of growth hormone receptor interferes with the beneficial actions of calorie restriction

Targeted disruption of growth hormone receptor interferes with the beneficial actions of calorie restriction

Big mice die young: early life body weight predicts longevity in genetically heterogeneous mice

Comparative aspects of zebrafish (Danio rerio) as a model for aging research

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