Alterations in xenobiotic metabolism in the long‐lived Little mice

Amador‐Noguez, Daniel; Dean, Adam; Huang, Wendong; Setchell, Kenneth D.R.; Moore, David D.; Darlington, Gretchen

doi:10.1111/j.1474-9726.2007.00300.x

Cited by 118 publications

(114 citation statements)

References 65 publications

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“…However, it has also been suggested that induction of genes linked to xenobiotic metabolism plays a significant role in longevity assurance in animals. [59][60][61] Interestingly, the induction of hepatic P450 genes after 18 months of supplementation was largely abrogated, although as we examined only two time-points, we do not know exactly when this actually occurred. However, by 18 months of supplementation, a significant upregulation of several genes associated with the cyclin dependent kinase inhibitor 1A (Cdki1a/p21) signaling pathway was observed, with p38 Mapk up 92%, Mdm2 up 89%, and p21 upregulated 554% (5.5-fold).…”

Section: Discussionmentioning

confidence: 98%

Lifelongα-Tocopherol Supplementation Increases the Median Life Span of C57BL/6 Mice in the Cold but Has Only Minor Effects on Oxidative Damage

Selman

McLaren

Mayer

et al. 2008

Rejuvenation Research

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. (2008) Lifelongα-tocopherol supplementation increases the median life span of C57BL/6 mice in the cold but has only minor effects on oxidative damage. Rejuvenation Research, 11 (1 ABSTRACTThe effects of dietary antioxidant supplementation on oxidative stress and life span are confused. We maintained C57BL/6 mice at 7 ؎ 2°C and supplemented their diet with ␣-tocopherol from 4 months of age. Supplementation significantly increased (p ‫؍‬ 0.042) median life span by 15% (785 days, n ‫؍‬ 44) relative to unsupplemented controls (682 days, n ‫؍‬ 43) and also increased maximum life span (oldest 10%, p ‫؍‬ 0.028). No sex or sex by treatment interaction effects were observed on life span, with treatment having no effect on resting or daily metabolic rate. Lymphocyte and hepatocyte oxidative DNA damage and hepatic lipid peroxidation were unaffected by supplementation, but hepatic oxidative DNA damage increased with age. Using a cDNA macroarray, genes associated with xenobiotic metabolism were significantly upregulated in the livers of female mice at 6 months of age (2 months supplementation). At 22 months of age (18 months supplementation) this response had largely abated, but various genes linked to the p21 signaling pathway were upregulated at this time. We suggest that ␣-tocopherol may initially be metabolized as a xenobiotic, potentially explaining why previous studies observe a life span extension generally when lifelong supplementation is initiated early in life. The absence of any significant effect on oxidative damage suggests that the life span extension observed was not mediated via any antioxidant properties of ␣-tocopherol. We propose that the life span extension observed following ␣-tocopherol supplementation may be mediated via upregulation of cytochrome p450 genes after 2 months of supplementation and/or upregulation of p21 signaling genes after 18 months of supplementation. However, these signaling pathways now require further investigation to establish their exact role in life span extension following ␣-tocopherol supplementation. 83

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Section: Discussionmentioning

confidence: 98%

Lifelongα-Tocopherol Supplementation Increases the Median Life Span of C57BL/6 Mice in the Cold but Has Only Minor Effects on Oxidative Damage

Selman

McLaren

Mayer

et al. 2008

Rejuvenation Research

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show abstract

“…Importantly, we showed that, at least for the three xenobiotics that we tested, the increased xenobiotic resistance and lifespan of IIS mutants are independently mediated traits with no direct, causal connection between them. Increased expression of genes involved in xenobiotic metabolism together with xenobiotic resistance are, nonetheless, common correlates of lifespan extension (7,10,11,(13)(14)(15), raising the question of why this association is so frequent. Interestingly, genes involved in xenobiotic metabolism are indirectly activated by toxic by-products of microbes and pathogens, through the cellular surveillance-activated detoxification and defense (cSADD) system (40), which senses xenobiotics through the dysfunction in cellular processes that they cause, including decreased host translation and altered metabolism (41).…”

Section: Discussionmentioning

confidence: 99%

“…Genome-wide transcript profiles from long-lived animals, including IIS mutant worms and flies (9, 10), long-lived mutant Ames and Little dwarf mice (11), and mice from crowded litters, subjected to dietary restriction or treated with rapamycin (12) all show increased expression of genes involved in phase 1 and 2 drug and xenobiotic metabolism (13). Little mice are also resistant to toxicity from xenobiotic compounds (14), indicating that the gene expression profiles are physiologically relevant. The link between increased lifespan and xenobiotic metabolism has led to the "Green Theory," which suggests that aging results from an accumulation of xenobiotic and endobiotic toxicity as a consequence of a declining detoxification response with age (15).…”

mentioning

confidence: 99%

Nuclear hormone receptor DHR96 mediates the resistance to xenobiotics but not the increased lifespan of insulin-mutant Drosophila

Afschar

Toivonen

Hoffmann

et al. 2016

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

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Lifespan of laboratory animals can be increased by genetic, pharmacological, and dietary interventions. Increased expression of genes involved in xenobiotic metabolism, together with resistance to xenobiotics, are frequent correlates of lifespan extension in the nematode worm Caenorhabditis elegans, the fruit fly Drosophila, and mice. The Green Theory of Aging suggests that this association is causal, with the ability of cells to rid themselves of lipophilic toxins limiting normal lifespan. To test this idea, we experimentally increased resistance of Drosophila to the xenobiotic dichlordiphenyltrichlorethan (DDT), by artificial selection or by transgenic expression of a gene encoding a cytochrome P450. Although both interventions increased DDT resistance, neither increased lifespan. Furthermore, dietary restriction increased lifespan without increasing xenobiotic resistance, confirming that the two traits can be uncoupled. Reduced activity of the insulin/Igf signaling (IIS) pathway increases resistance to xenobiotics and extends lifespan in Drosophila, and can also increase longevity in C. elegans, mice, and possibly humans. We identified a nuclear hormone receptor, DHR96, as an essential mediator of the increased xenobiotic resistance of IIS mutant flies. However, the IIS mutants remained long-lived in the absence of DHR96 and the xenobiotic resistance that it conferred. Thus, in Drosophila IIS mutants, increased xenobiotic resistance and enhanced longevity are not causally connected. The frequent co-occurrence of the two traits may instead have evolved because, in nature, lowered IIS can signal the presence of pathogens. It will be important to determine whether enhanced xenobiotic metabolism is also a correlated, rather than a causal, trait in long-lived mice.lifespan | xenobiotic resistance | IIS | nuclear hormone receptor | DHR96

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“…Amador‐Noguez et al ., 2007). Moreover, in a clinical trial UDCA prevented colorectal adenoma recurrence (Alberts et al ., 2005).…”

Section: Introductionmentioning

confidence: 99%

Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α‐glucosidase inhibitor or a Nrf2‐inducer

et al. 2016

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SummaryThe National Institute on Aging Interventions Testing Program (ITP) evaluates agents hypothesized to increase healthy lifespan in genetically heterogeneous mice. Each compound is tested in parallel at three sites, and all results are published. We report the effects of lifelong treatment of mice with four agents not previously tested: Protandim, fish oil, ursodeoxycholic acid (UDCA) and metformin – the latter with and without rapamycin, and two drugs previously examined: 17‐α‐estradiol and nordihydroguaiaretic acid (NDGA), at doses greater and less than used previously. 17‐α‐estradiol at a threefold higher dose robustly extended both median and maximal lifespan, but still only in males. The male‐specific extension of median lifespan by NDGA was replicated at the original dose, and using doses threefold lower and higher. The effects of NDGA were dose dependent and male specific but without an effect on maximal lifespan. Protandim, a mixture of botanical extracts that activate Nrf2, extended median lifespan in males only. Metformin alone, at a dose of 0.1% in the diet, did not significantly extend lifespan. Metformin (0.1%) combined with rapamycin (14 ppm) robustly extended lifespan, suggestive of an added benefit, based on historical comparison with earlier studies of rapamycin given alone. The α‐glucosidase inhibitor, acarbose, at a concentration previously tested (1000 ppm), significantly increased median longevity in males and 90th percentile lifespan in both sexes, even when treatment was started at 16 months. Neither fish oil nor UDCA extended lifespan. These results underscore the reproducibility of ITP longevity studies and illustrate the importance of identifying optimal doses in lifespan studies.

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Alterations in xenobiotic metabolism in the long‐lived Little mice

Abstract: Summary

Cited by 118 publications

References 65 publications

Lifelongα-Tocopherol Supplementation Increases the Median Life Span of C57BL/6 Mice in the Cold but Has Only Minor Effects on Oxidative Damage

Lifelongα-Tocopherol Supplementation Increases the Median Life Span of C57BL/6 Mice in the Cold but Has Only Minor Effects on Oxidative Damage

Nuclear hormone receptor DHR96 mediates the resistance to xenobiotics but not the increased lifespan of insulin-mutant Drosophila

Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α‐glucosidase inhibitor or a Nrf2‐inducer

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