-
[show abstract]
[hide abstract]
ABSTRACT: Dietary restriction (DR) extends lifespan in a wide range of animal models. A major obstacle to understanding how DR modulates lifespan and aging-related dysfunction is the multiplicity of physiological and molecular changes associated with DR. Unraveling their importance to the longevity effect of DR remains a major challenge. In this Perspective, we review the marked genetic variation in the response to DR of multiple recombinant inbred (RI) mouse strains. We illustrate how this genetic variation can be exploited to probe the mechanisms mediating lifespan extension by DR, as well as uncover its limits as an intervention. RI strains exhibit marked variation in their lifespan as well as physiological responses to DR. Quantitative genetic and statistical tools can use this phenotypic variation to probe the importance of physiological and molecular changes that have been hypothesized to play roles in DR-mediated lifespan extension.
Experimental gerontology 04/2013; · 3.34 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Interference in insulin and/or insulin-like growth factor 1 (IGF-1) signaling can extend invertebrate life span, and interference in IGF-1 signaling can extend murine life span. Whether interference with murine insulin signaling, which can be diabetogenic and pathological, is also life-extending is controversial. We therefore measured life span in 3 murine strains genetically modified to reduce or increase insulin sensitivity. Mice with reduced insulin sensitivity were hemizygous for a null mutation in the insulin receptor (insulin receptor knockout mice; IRKO(+/-)). Mice with increased insulin sensitivity either had a null mutation of protein tyrosine phosphatase 1B (PTP-1B(-/-)) or overexpressed Peroxisome proliferator-activated receptor-α coactivator (PGC)-1α (PGC-1α(TG)). Life span of insulin insensitive IRKO(+/) mice was increased (males) or unaffected (females). Life spans of mice with increased insulin sensitivity were shortened overall (PTP-1B(-/-) mice) or partially (PGC-1α(TG): survival at the 25th percentile was reduced). These results show that insulin sensitivity in some murine genotypes is inversely related to longevity and provide further evidence for evolutionary conservation of this pathway as a modulator of longevity.
The Journals of Gerontology Series A Biological Sciences and Medical Sciences 10/2012; · 4.60 Impact Factor
-
Randy Strong,
Richard A Miller,
Clinton M Astle,
Joseph A Baur,
Rafael de Cabo,
Elizabeth Fernandez,
Wen Guo,
Martin Javors,
James L Kirkland, James F Nelson,
David A Sinclair,
Bruce Teter,
David Williams,
Nurulain Zaveri,
Nancy L Nadon,
David E Harrison
[show abstract]
[hide abstract]
ABSTRACT: The National Institute on Aging Interventions Testing Program (ITP) was established to evaluate agents that are hypothesized to increase life span and/or health span in genetically heterogeneous mice. Each compound is tested in parallel at three test sites. It is the goal of the ITP to publish all results, negative or positive. We report here on the results of lifelong treatment of mice, beginning at 4 months of age, with each of five agents, that is, green tea extract (GTE), curcumin, oxaloacetic acid, medium-chain triglyceride oil, and resveratrol, on the life span of genetically heterogeneous mice. Each agent was administered beginning at 4 months of age. None of these five agents had a statistically significant effect on life span of male or female mice, by log-rank test, at the concentrations tested, although a secondary analysis suggested that GTE might diminish the risk of midlife deaths in females only.
The Journals of Gerontology Series A Biological Sciences and Medical Sciences 03/2012; · 4.60 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Dietary restriction (DR), one of the most robust life-extending manipulations, is usually associated with reduced adiposity. This reduction is hypothesized to be important in the life-extending effect of DR, because excess adiposity is associated with metabolic and age-related disease. Previously, we described remarkable variation in the lifespan response of 41 recombinant inbred strains of mice to DR, ranging from life extension to life shortening. Here, we used this variation to determine the relationship of lifespan modulation under DR to fat loss. Across strains, DR life extension correlated inversely with fat reduction, measured at midlife (males, r= -0.41, P<0.05, n=38 strains; females, r= -0.63, P<0.001, n=33 strains) and later ages. Thus, strains with the least reduction in fat were more likely to show life extension, and those with the greatest reduction were more likely to have shortened lifespan. We identified two significant quantitative trait loci (QTLs) affecting fat mass under DR in males but none for lifespan, precluding the confirmation of these loci as coordinate modulators of adiposity and longevity. Our data also provide evidence for a QTL previously shown to affect fuel efficiency under DR. In summary, the data do not support an important role for fat reduction in life extension by DR. They suggest instead that factors associated with maintaining adiposity are important for survival and life extension under DR.
Aging cell 03/2011; 10(4):629-39. · 7.55 Impact Factor
-
Richard A Miller,
David E Harrison,
C M Astle,
Joseph A Baur,
Angela Rodriguez Boyd,
Rafael de Cabo,
Elizabeth Fernandez,
Kevin Flurkey,
Martin A Javors, James F Nelson,
Carlos J Orihuela,
Scott Pletcher,
Zelton Dave Sharp,
David Sinclair,
Joseph W Starnes,
J Erby Wilkinson,
Nancy L Nadon,
Randy Strong
[show abstract]
[hide abstract]
ABSTRACT: Rapamycin was administered in food to genetically heterogeneous mice from the age of 9 months and produced significant increases in life span, including maximum life span, at each of three test sites. Median survival was extended by an average of 10% in males and 18% in females. Rapamycin attenuated age-associated decline in spontaneous activity in males but not in females. Causes of death were similar in control and rapamycin-treated mice. Resveratrol (at 300 and 1200 ppm food) and simvastatin (12 and 120 ppm) did not have significant effects on survival in male or female mice. Further evaluation of rapamycin's effects on mice is likely to help delineate the role of the mammalian target of rapamycin complexes in the regulation of aging rate and age-dependent diseases and may help to guide a search for drugs that retard some or all of the diseases of aging.
The Journals of Gerontology Series A Biological Sciences and Medical Sciences 10/2010; 66(2):191-201. · 4.60 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Dietary restriction (DR) has been used for decades to retard aging in rodents, but its mechanism of action remains an enigma. A principal roadblock has been that DR affects many different processes, making it difficult to distinguish cause and effect. To address this problem, we applied a quantitative genetics approach utilizing the ILSXISS series of mouse recombinant inbred strains. Across 42 strains, mean female lifespan ranged from 380 to 1070days on DR (fed 60% of ad libitum [AL]) and from 490 to 1020days on an AL diet. Longevity under DR and AL is under genetic control, showing 34% and 36% heritability, respectively. There was no correlation between lifespans on DR and AL; thus different genes modulate longevity under the two regimens. DR lifespans are significantly correlated with female fertility after return to an AL diet after various periods of DR (R=0.44, P=0.006). We assessed fuel efficiency (FE, ability to maintain growth and body weight independent of absolute food intake) using a multivariate approach and found it to be correlated with longevity and female fertility, suggesting possible causality. We found several quantitative trait loci responsible for these traits, mapping to chromosomes 7, 9, and 15. We present a metabolic model in which the anti-aging effects of DR are consistent with the ability to efficiently utilize dietary resources.
Experimental gerontology 05/2010; 45(9):691-701. · 3.34 Impact Factor
-
Aging cell 03/2010; · 7.55 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Chronic dietary restriction (DR) is considered among the most robust life-extending interventions, but several reports indicate that DR does not always extend and may even shorten lifespan in some genotypes. An unbiased genetic screen of the lifespan response to DR has been lacking. Here, we measured the effect of one commonly used level of DR (40% reduction in food intake) on mean lifespan of virgin males and females in 41 recombinant inbred strains of mice. Mean strain-specific lifespan varied two to threefold under ad libitum (AL) feeding and 6- to 10-fold under DR, in males and females respectively. Notably, DR shortened lifespan in more strains than those in which it lengthened life. Food intake and female fertility varied markedly among strains under AL feeding, but neither predicted DR survival: therefore, strains in which DR shortened lifespan did not have low food intake or poor reproductive potential. Finally, strain-specific lifespans under DR and AL feeding were not correlated, indicating that the genetic determinants of lifespan under these two conditions differ. These results demonstrate that the lifespan response to a single level of DR exhibits wide variation amenable to genetic analysis. They also show that DR can shorten lifespan in inbred mice. Although strains with shortened lifespan under 40% DR may not respond negatively under less stringent DR, the results raise the possibility that life extension by DR may not be universal.
Aging cell 10/2009; 9(1):92-5. · 7.55 Impact Factor
-
David E Harrison,
Randy Strong,
Zelton Dave Sharp, James F Nelson,
Clinton M Astle,
Kevin Flurkey,
Nancy L Nadon,
J Erby Wilkinson,
Krystyna Frenkel,
Christy S Carter,
Marco Pahor,
Martin A Javors,
Elizabeth Fernandez,
Richard A Miller
[show abstract]
[hide abstract]
ABSTRACT: Inhibition of the TOR signalling pathway by genetic or pharmacological intervention extends lifespan in invertebrates, including yeast, nematodes and fruitflies; however, whether inhibition of mTOR signalling can extend lifespan in a mammalian species was unknown. Here we report that rapamycin, an inhibitor of the mTOR pathway, extends median and maximal lifespan of both male and female mice when fed beginning at 600 days of age. On the basis of age at 90% mortality, rapamycin led to an increase of 14% for females and 9% for males. The effect was seen at three independent test sites in genetically heterogeneous mice, chosen to avoid genotype-specific effects on disease susceptibility. Disease patterns of rapamycin-treated mice did not differ from those of control mice. In a separate study, rapamycin fed to mice beginning at 270 days of age also increased survival in both males and females, based on an interim analysis conducted near the median survival point. Rapamycin may extend lifespan by postponing death from cancer, by retarding mechanisms of ageing, or both. To our knowledge, these are the first results to demonstrate a role for mTOR signalling in the regulation of mammalian lifespan, as well as pharmacological extension of lifespan in both genders. These findings have implications for further development of interventions targeting mTOR for the treatment and prevention of age-related diseases.
Nature 08/2009; 460(7253):392-5. · 36.28 Impact Factor
-
Randy Strong,
Richard A Miller,
Clinton M Astle,
Robert A Floyd,
Kevin Flurkey,
Kenneth L Hensley,
Martin A Javors,
Christiaan Leeuwenburgh, James F Nelson,
Ennio Ongini,
Nancy L Nadon,
Huber R Warner,
David E Harrison
[show abstract]
[hide abstract]
ABSTRACT: The National Institute on Aging's Interventions Testing Program was established to evaluate agents that are purported to increase lifespan and delay the appearance of age-related disease in genetically heterogeneous mice. Up to five compounds are added to the study each year and each compound is tested at three test sites (The Jackson Laboratory, University of Michigan, and University of Texas Health Science Center at San Antonio). Mice in the first cohort were exposed to one of four agents: aspirin, nitroflurbiprofen, 4-OH-alpha-phenyl-N-tert-butyl nitrone, or nordihydroguaiaretic acid (NDGA). Sample size was sufficient to detect a 10% difference in lifespan in either sex,with 80% power, using data from two of the three sites. Pooling data from all three sites, a log-rank test showed that both NDGA (p=0.0006) and aspirin (p=0.01) led to increased lifespan of male mice. Comparison of the proportion of live mice at the age of 90% mortality was used as a surrogate for measurement of maximum lifespan;neither NDGA (p=0.12) nor aspirin (p=0.16) had a significant effect in this test. Measures of blood levels of NDGA or aspirin and its salicylic acid metabolite suggest that the observed lack of effects of NDGA or aspirin on life span in females could be related to gender differences in drug disposition or metabolism. Further studies are warranted to find whether NDGA or aspirin, over a range of doses,might prove to postpone death and various age-related outcomes reproducibly in mice.
Aging cell 10/2008; 7(5):641-50. · 7.55 Impact Factor
-
Richard A Miller,
David E Harrison,
Clinton M Astle,
Robert A Floyd,
Kevin Flurkey,
Kenneth L Hensley,
Martin A Javors,
Christiaan Leeuwenburgh, James F Nelson,
Ennio Ongini,
Nancy L Nadon,
Huber R Warner,
Randy Strong
[show abstract]
[hide abstract]
ABSTRACT: The National Institute on Aging's Interventions Testing Program (ITP) has developed a plan to evaluate agents that are considered plausible candidates for delaying rates of aging. Key features include: (i) use of genetically heterogeneous mice (a standardized four-way cross), (ii) replication at three test sites (the Jackson Laboratory, TJL; University of Michigan, UM; and University of Texas, UT), (iii) sufficient statistical power to detect 10% changes in lifespan, (iv) tests for age-dependent changes in T cell subsets and physical activity, and (v) an annual solicitation for collaborators who wish to suggest new interventions for evaluation. Mice in the first cohort were exposed to one of four agents: aspirin, nitroflurbiprofen (NFP), 4-OH-alpha-phenyl-N-tert-butyl nitrone (4-OH-PBN), or nordihydroguiaretic acid (NDGA). An interim analysis was conducted using survival data available on the date at which at least 50% of the male control mice had died at each test site. Survival of control males was significantly higher, at the interim time-point, at UM than at UT or TJL; all three sites had similar survival of control females. Males in the NDGA group had significantly improved survival (P = 0.0004), with significant effects noted at TJL (P < 0.01) and UT (P < 0.04). None of the other agents altered survival, although there was a suggestion (P = 0.07) of a beneficial effect of aspirin in males. More data will be needed to determine if any of these compounds can extend maximal lifespan, but the current data show that NDGA reduces early life mortality risks in genetically heterogeneous mice at multiple test sites.
Aging Cell 09/2007; 6(4):565-75. · 6.26 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: This study examined the effect of housing density on the longevity-extending and disease-delaying actions of calorie restriction (CR). Singly or multiply housed (four per cage) mice were either fed ad libitum (AL) or were on CR beginning at 2 months. All CR mice were fed 40% less food than were multiply housed AL mice. CR increased median longevity by 19%, and housing density had no effect on this increase. CR also reduced neoplastic lesions in both housing groups, but lymphoma, the most common neoplasm, was reduced more in singly than in multiply housed mice. Singly housed AL mice ate 40% more food than did multiply housed AL mice, but weighed the same and lived as long as multiply housed AL mice. These results indicate that CR can extend life span as effectively in multiply as in singly housed mice, even though housing density can differentially affect the cancer-reducing effect of CR.
The Journals of Gerontology Series A Biological Sciences and Medical Sciences 01/2006; 60(12):1510-7. · 4.60 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Research with invertebrates over the past 10 years has suggested that alterations in insulin and/or insulin-like growth factor I (IGF-I) signalling result in increased lifespan and retard ageing. In this chapter, we describe the current research in mammalian systems with respect to the role of insulin or IGF-I in ageing. Using rodent models of caloric restriction and genetic mouse models, e.g. the Ames and Snell dwarf mice, fat-specific insulin receptor knockout mice (FIRKO) and mice that are heterozygous for the IGF-I receptor (Igf1r+/-), investigators have shown that a reduction in plasma levels of insulin and/or IGF-I or reductions in insulin/IGF-I signalling appear to be correlated with increased longevity and retarded ageing.
Bailliè re s Best Practice and Research in Clinical Endocrinology and Metabolism 10/2004; 18(3):393-406. · 4.12 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We have undertaken a series of experiments to examine several issues that directly affect design of gene expression studies using Affymetrix GeneChip arrays: probe-level analysis, need for technical replication, relative contribution of various sources of variability, and utility of pooling RNA from different samples. Probe-level data were analyzed by Affymetrix MAS 5.0, and three model-based methods, PM-MM and PM-only models by dChip, and the RMA model by Bioconductor, with the latter two providing the best performance. We found that replicate chips of the same RNA have limited value in reducing total variability, and for relatively highly expressed genes in this biologically homogeneous animal model of aging, about 11% of total variation is due to day effects and the remainder is approximately equally split between sample and residual sources. We also found that pooling samples is neither advantageous nor detrimental. Finally we suggest a strategy for sample size calculations using formulas appropriate when coefficients of variation are known, target effects are expressed as fold changes, and data can be assumed to be approximately lognormally distributed.
The Journals of Gerontology Series A Biological Sciences and Medical Sciences 05/2004; 59(4):306-15. · 4.60 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: To determine whether reduced caloric intake affects the susceptibility of nigrostriatal dopamine (DA) neurons to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity, 1-year-old male C57BL6 mice were offered food ad libitum or were given only 60% of the normal dietary intake. After 3 months, both groups were treated with low cumulative doses of 0, 10, 15, or 20 mg/kg MPTP. One week later, the striata were collected and DA, dihydroxyphenylalanine (DOPAC), and norepinephrine (NE) were measured. Treatment with MPTP had no effect on striatal NE but produced a dose-related depletion of DA and DOPAC in both the ad libitum-fed and the dietary-restricted mice. The MPTP-induced depletions of DA and DOPAC were not ameliorated in the dietary-restricted versus the ad libitum-fed mice. Baseline DA levels and those observed after treatment with the 15-mg/kg dose of MPTP were lower in the dietary-restricted mice compared with the ad libitum-fed mice. Overall, these results suggest that, at least in 1-year-old mice, dietary restriction for 3 months does not protect nigral DA nerve terminals from low toxic dosages of MPTP.
The Journals of Gerontology Series A Biological Sciences and Medical Sciences 06/2003; 58(5):B394-9. · 4.60 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The efficacy of dietary restriction in retarding tumor growth is well established in rodents. However, gene and cell lineage specificity of dietary restriction effects is far less defined. Mice with a single copy of the retinoblastoma susceptibility gene (Rb) develop a well-established syndrome of mouse neuroendocrine neoplasia associated with Rb deficiency. Thus, if DR represses tumor growth in this model, it should be unambiguously attributed to the Rb defect in neuroendocrine cell lineages. To address this possibility, Rb(+/-) mice were entered into a diet restriction study. Surprisingly, 40-50% reductions in dietary intake, relative to an ad libitum group, started on either postnatal day 28 or 42 had little to no effect on either the frequency or growth of pituitary tumors either during the latency period (postnatal day 224) or at the time of their natural death. Consistent with cross-section data, survival of 65 diet restricted Rb(+/-) mice was almost identical to that of 67 Rb(+/-) mice fed ad libitum (AL); median life span was 414 and 436 days for AL and DR groups, respectively. These findings indicate that diet restriction provides no significant benefit in delaying growth and progression of neuroendocrine tumors exhibiting loss of RB function. They also introduce the possibility that RB is required for the tumor-repressive effects of DR.
Carcinogenesis 03/2003; 24(2):179-83. · 5.70 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The aim of this study was to determine if long-term treatment with melatonin (MEL), a purported anti-aging agent, was as effective as calorie restriction (CR) in modulating immune parameters in aging Fischer 344 male rats. Splenic lymphocytes were isolated from 17-month-old rats that, beginning at 6 weeks of age, were treated with MEL (4 or 16 microg/ml in drinking water) and from 17-month-old rats fed ad libitum (AL) or rats fed a CR diet (55% of AL intake). The number of splenic T cell populations and T cell subsets was measured by flow cytometry, the proliferative response of splenocytes to Concanavalin A (Con A) and lipopolysaccharide (LPS) was measured by [(3)H]thymidine incorporation, and the induction of cytokine production (IL-2 and IFN-gamma) was measured by ELISA assay. In addition, the level of the natural killer (NK) cell activity was assessed by fluorimetric assay. CR rats had a higher number of lymphocytes expressing the naïve T cell marker (CD3 OX22) than AL rats (P < 0.05). CR rats also showed greater induction of proliferative response, IL-2 and IFN-gamma levels following Con A simulation, and NK cell activity than AL rats (P < 0.05). MEL-treated rats did not differ from AL rats in any of these parameters or in any other measurement. These results indicate that MEL treatment is unable to modulate immune function in a manner comparable with that of CR.
Experimental Biology and Medicine 03/2002; 227(3):201-7. · 2.64 Impact Factor
-
ILAR journal / National Research Council, Institute of Laboratory Animal Resources 02/1997; 38(3):125-136. · 2.33 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Since 1996, seven genetic mouse models have been reported to show increased lifespan: Ames and Snell dwarf mice, the ‘little mouse’ (Ghrhrlit/lit), mice null for either growth hormone receptor/binding protein (GHR/BP−/−) or p66shc (p66shc−/−), mice heterozygous for the IGF-I receptor (Igf1r+/−), and fat-specific insulin receptor knockout mice. In this article, we describe and evaluate these mouse models with respect to their relevance for aging studies. While these seven genetic models all show a significant increase in lifespan, issues of sample size and animal husbandry procedures require further evaluation before firm conclusions can be drawn on the reproducibility of life extension in most of these mouse models. Because data on the age-related pathology and physiological functions are lacking for all of the models, except the dwarf mice, it is too early to conclude that aging is retarded in these mouse models. However, these mouse models are already providing new information about the mechanism underlying mammalian aging.
Experimental Gerontology.
-
[show abstract]
[hide abstract]
ABSTRACT: Since 1996, seven genetic mouse models have been reported to show increased lifespan: Ames and Snell dwarf mice, the 'little mouse' (Ghrhr(lit/lit)), mice null for either growth hormone receptor/binding protein (GHR/BP(-/-)) or p66(shc) (p66(shc-/-)), mice heterozygous for the IGF-I receptor (Igf1r(+/-)), and fat-specific insulin receptor knockout mice. In this article, we describe and evaluate these mouse models with respect to their relevance for aging studies. While these seven genetic models all show a significant increase in lifespan, issues of sample size and animal husbandry procedures require further evaluation before firm conclusions can be drawn on the reproducibility of life extension in most of these mouse models. Because data on the age-related pathology and physiological functions are lacking for all of the models, except the dwarf mice, it is too early to conclude that aging is retarded in these mouse models. However, these mouse models are already providing new information about the mechanism underlying mammalian aging.
Experimental Gerontology 38(11-12):1353-64. · 3.74 Impact Factor
