Accelerated aging of giant transgenic mice is associated with elevated free radical processes

Rollo, C. David; Carlson, John C.; Sawada, Masaaki

doi:10.1139/z96-070

Cited by 94 publications

(73 citation statements)

References 75 publications

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“…Superoxide generation has been shown to be significantly elevated in rodents overexpressing GH (66). In the current study, we found that GH transgenic mice exhibited elevated levels of oxidative protein damage to both liver and brain at different ages compared to their normal counterparts.…”

Section: Discussionsupporting

confidence: 56%

“…No differences in the amount of oxidized DNA (8OHdG) were detected between GH transgenic and normal mice. Lipid peroxidation was not measured in this study as previous reports indicated that indices of lipid peroxidation were significantly higher in animals with high plasma GH compared to controls (66).…”

Section: Discussionmentioning

confidence: 85%

“…Importantly, evidence presented by Krzisnik and coworkers (74) shows increased longevity in hypopituitary patients with mutations at the Prop-1 locus, the same gene that is mutated in the Ames dwarf. In sharp contrast, mice overexpressing G H live significantly shortened lives, exhibit increased indices of free radical processes (66), decreased antioxidative defenses (14,67), signs of accelerated aging including reduced replicative potential of cells in vitro (75), and signs of premature central nervous system aging including reduced catecholamine turnover, increased astrogliosis, and impaired learning and memory (19,76,77). In addition, these animals typically reach sexual maturation earlier and cessation of reproduction sooner than wild type siblings (21,78).…”

Section: Discussionmentioning

confidence: 94%

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Mitochondrial oxidant generation and oxidative damage in Ames dwarf and GH transgenic mice

Brown‐Borg

Johnson

Rakoczy

et al. 2001

AGE

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Aging is associated with an accumulation of oxidative damage to proteins, lipids and DNA. Cellular mechanisms designed to prevent oxidative damage decline with aging and in diseases associated with aging. A long-lived mouse, the Ames dwarf, exhibits growth hormone deficiency and heightened antioxidative defenses. In contrast, animals that over express GH have suppressed antioxidative capacity and live half as long as wild type mice. In this study, we examined the generation of H202 from liver mitochondria of Ames dwarf and wild type mice and determined the level of oxidative damage to proteins, lipids and DNA in various tissues of these animals. Dwarf liver mitochondria (24 months) produced less H202 than normal liver in the presence of succinate (p<0.03) andADP (p<0.003). Levels of oxidative DNA damage (8OHdG) were variable and dependent on tissue and age in dwarf and normal mice. Forty-seven percent fewer protein carbonyls were detected in 24-month old dwarf liver tissue compared to controls (p<0.04). Forty percent more (p<0.04) protein carbonyls were detected in liver tissue (3-month old) of GH transgenic mice compared to wild types while 12 month old brain tissue had 53% more protein carbonyls compared to controls (p<0.005). Levels of liver malonaldehyde (lipid peroxidation) were not different at 3 and 12 months of age but were greater in Ames dwarf mice at 24 months compared to normal mice. Previous studies indicate a strong negative correla-

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Section: Discussionsupporting

confidence: 56%

Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 94%

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Mitochondrial oxidant generation and oxidative damage in Ames dwarf and GH transgenic mice

Brown‐Borg

Johnson

Rakoczy

et al. 2001

AGE

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“…We previously found that longevity of mice was negatively associated with oxidative and nitrosative stress (Rollo et al 1996;Aksenov et al 2013;Long et al 2012). Lipid peroxidation in the heart or brain of transgenic growth hormone mice expressing doubled growth rates explained~89 % of variation in maximal longevity associated with genotype, sex, and diet (Rollo et al 1996).…”

Section: Hydrogen Peroxidementioning

confidence: 99%

“…Lipid peroxidation in the heart or brain of transgenic growth hormone mice expressing doubled growth rates explained~89 % of variation in maximal longevity associated with genotype, sex, and diet (Rollo et al 1996). If free radicals do not impact aging, some are strongly associated.…”

Section: Hydrogen Peroxidementioning

confidence: 99%

Impacts of metformin and aspirin on life history features and longevity of crickets: trade-offs versus cost-free life extension?

Hans

Lone

Aksenov

et al. 2015

AGE

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We examined the impacts of aspirin and metformin on the life history of the cricket Acheta domesticus (growth rate, maturation time, mature body size, survivorship, and maximal longevity). Both drugs significantly increased survivorship and maximal life span. Maximal longevity was 136 days for controls, 188 days (138 % of controls) for metformin, and 194 days (143 % of controls) for aspirin. Metformin and aspirin in combination extended longevity to a lesser degree (163 days, 120 % of controls). Increases in general survivorship were even more pronounced, with low-dose aspirin yielding mean longevity 234 % of controls (i.e., health span). Metformin strongly reduced growth rates of both genders (<60 % of controls), whereas aspirin only slightly reduced the growth rate of females and slightly increased that of males. Both drugs delayed maturation age relative to controls, but metformin had a much greater impact (>140 % of controls) than aspirin (~118 % of controls). Crickets maturing on low aspirin showed no evidence of a trade-off between maturation mass and life extension. Remarkably, by 100 days of age, aspirin-treated females were significantly larger than controls (largely reflecting egg complement). Unlike the reigning dietary restriction paradigm, low aspirin conformed to a paradigm of Beat more, live longer.^In contrast, metformin-treated females were only~67 % of the mass of controls. Our results suggest that hormetic agents like metformin may derive significant trade-offs with life extension, whereas health and longevity benefits may be obtained with less cost by agents like aspirin that regulate geroprotective pathways.

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A multi‐ingredient dietary supplement abolishes large‐scale brain cell loss, improves sensory function, and prevents neuronal atrophy in aging mice

Lemon

Aksenov

Samigullina

et al. 2016

Environ and Mol Mutagen

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Transgenic growth hormone mice (TGM) are a recognized model of accelerated aging with characteristics including chronic oxidative stress, reduced longevity, mitochondrial dysfunction, insulin resistance, muscle wasting, and elevated inflammatory processes. Growth hormone/IGF-1 activate the Target of Rapamycin known to promote aging. TGM particularly express severe cognitive decline. We previously reported that a multi-ingredient dietary supplement (MDS) designed to offset five mechanisms associated with aging extended longevity, ameliorated cognitive deterioration and significantly reduced age-related physical deterioration in both normal mice and TGM. Here we report that TGM lose more than 50% of cells in midbrain regions, including the cerebellum and olfactory bulb. This is comparable to severe Alzheimer's disease and likely explains their striking age-related cognitive impairment. We also demonstrate that the MDS completely abrogates this severe brain cell loss, reverses cognitive decline and augments sensory and motor function in aged mice. Additionally, histological examination of retinal structure revealed markers consistent with higher numbers of photoreceptor cells in aging and supplemented mice. We know of no other treatment with such efficacy, highlighting the potential for prevention or amelioration of human neuropathologies that are similarly associated with oxidative stress, inflammation and cellular dysfunction. Environ. Mol. Mutagen. 57:382-404, 2016. © 2016 Wiley Periodicals, Inc.

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Accelerated aging of giant transgenic mice is associated with elevated free radical processes

Cited by 94 publications

References 75 publications

Mitochondrial oxidant generation and oxidative damage in Ames dwarf and GH transgenic mice

Mitochondrial oxidant generation and oxidative damage in Ames dwarf and GH transgenic mice

Impacts of metformin and aspirin on life history features and longevity of crickets: trade-offs versus cost-free life extension?

A multi‐ingredient dietary supplement abolishes large‐scale brain cell loss, improves sensory function, and prevents neuronal atrophy in aging mice

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