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1.
Aging Cell ; 20(11): e13500, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34713968

RESUMO

Dietary restriction (DR) was reported to either have no effect or reduce the lifespan of the majority of the 41-recombinant inbred (RI) lines studied by Liao et al. (Aging Cell, 2010, 9, 92). In an appropriately power longevity study (n > 30 mice/group), we measured the lifespan of the four RI lines (115-RI, 97-RI, 98-RI, and 107-RI) that were reported to have the greatest decrease in lifespan when fed 40% DR. DR increased the median lifespan of female RI-115, 97-RI, and 107-RI mice and male 115-RI mice. DR had little effect (<4%) on the median lifespan of female and male 98-RI mice and male 97-RI mice and reduced the lifespan of male 107-RI mice over 20%. While our study was unable to replicate the effect of DR on the lifespan of the RI mice (except male 107-RI mice) reported by Liao et al. (Aging Cell, 2010, 9, 92), we found that the genotype of a mouse had a major impact on the effect of DR on lifespan, with the effect of DR ranging from a 50% increase to a 22% decrease in median lifespan. No correlation was observed between the changes in either body composition or glucose tolerance induced by DR and the changes observed in lifespan of the four RI lines of male and female mice. These four RI lines of mice give the research community a unique resource where investigators for the first time can study the anti-aging mechanism of DR by comparing mice in which DR increases lifespan to mice where DR has either no effect or reduces lifespan.


Assuntos
Envelhecimento/genética , Dietoterapia/métodos , Genótipo , Longevidade/genética , Recombinação Genética , Animais , Composição Corporal , Feminino , Teste de Tolerância a Glucose , Estimativa de Kaplan-Meier , Masculino , Camundongos , Camundongos Endogâmicos
2.
PLoS One ; 16(9): e0237199, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34587168

RESUMO

Nutritional manipulations early in life have been shown to influence growth rate and elicit long lasting effects which in turn has been found to impact lifespan. Therefore, we studied the long-term effects of pre-weaning dietary restriction implemented by litter expansion (4, 6, 8, 10, and 12 pups per dam: LS4, LS6, LS8, LS10, LS12) on male and female C57BL/6J mice. After weaning, these mice were fed ad libitum a commercial lab chow for the 15-month duration of the study. The male mice from large litter size (LS12) were significantly leaner and had reduced total fat mass compared to the normal size litters (LS 6) starting from weaning through to 15 months of age. Male LS10 & 12 mice also showed significant reduction in their fat depot masses at 15 months of age: gonadal, subcutaneous, and brown fat whereas the females did not mimic these findings. At 9 months of age, only male LS12 mice showed improved glucose tolerance and male LS12 mice also showed improved insulin tolerance starting at 5 months of age. In addition, we found that the male LS8, 10 & 12 mice at 15 months of age showed significantly reduced IGF-1 levels in the serum and various other organs (liver, gastrocnemius and brain cortex). Interestingly, the female LS8, 10, 12 mice showed a different pattern with reduced IGF-1 levels in serum, liver and gastrocnemius but not in the brain cortex. Similarly, the litter expanded mice showed sex specific response to levels of FGF21 and adiponectin with only the male mice showing increased FGF21 and adiponectin levels at 15 months of age. In summary, our data show that, litter expansion results in long-lasting metabolic changes that are age and sex dependent with the male mice showing an early and robust response compared to female mice.


Assuntos
Homeostase , Tamanho da Ninhada de Vivíparos , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Desmame
3.
Exp Gerontol ; 150: 111387, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-33957263

RESUMO

Researchers studying the effect of folate restriction on rodents have resorted to the use of the antibiotic succinylsulfathiazole (SST) in the folate depleted diet to induce a folate deficient status. SST has been used extensively in rodent studies since the 1940s. Its localized effect on the gut bacteria as well as its effectiveness in reducing folate producing species is well documented. The possible overlap between the pathways affected by folate depletion and SST could potentially produce a confounding variable in such studies. In our novel study, we analyzed the effect of SST on folate levels in c57Bl/6 male mice fed folate supplemented and deficient diets. We did not observe any significant difference on growth and weight gain at 21 weeks. SST did not significantly affect folate levels in the plasma, liver and colon tissues; however, it did alter energy metabolism and expression of key genes in the mTOR signaling pathway in the liver. This research sheds light on a possible confounding element when using SST to study folate depletion due to the potential overlap with multiple critical pathways such as mTOR. SUMMARY: The antibiotic succinylsulfathiazole (SST) is used to reduce folate producing bacteria in rodent folate depletion studies. SST can modulate critical energy and nutrient sensing pathways converging onto mTOR signaling, and potentially confounding cancer studies.


Assuntos
Deficiência de Ácido Fólico , Ácido Fólico , Animais , Dieta , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais , Sulfatiazóis , Serina-Treonina Quinases TOR/metabolismo
4.
Aging (Albany NY) ; 13(5): 6298-6329, 2021 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-33744869

RESUMO

The effect of calorie restriction (CR) on the microbiome, fecal metabolome, and colon transcriptome of adult and old male mice was compared. Life-long CR increased microbial diversity and the Bacteroidetes/Firmicutes ratio and prevented the age-related changes in the microbiota, shifting it to a younger microbial and fecal metabolite profile in both C57BL/6JN and B6D2F1 mice. Old mice fed CR were enriched in the Rikenellaceae, S24-7 and Bacteroides families. The changes in the microbiome that occur with age and CR were initiated in the cecum and further modified in the colon. Short-term CR in adult mice had a minor effect on the microbiome but a major effect on the transcriptome of the colon mucosa. These data suggest that CR has a major impact on the physiological status of the gastrointestinal system, maintaining it in a more youthful state, which in turn could result in a more diverse and youthful microbiome.


Assuntos
Restrição Calórica , Microbioma Gastrointestinal , Envelhecimento , Animais , Mucosa Intestinal/microbiologia , Camundongos Endogâmicos C57BL
5.
Nutrients ; 14(1)2021 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-35010891

RESUMO

Diet plays a crucial role in the development of colorectal cancer (CRC). Of particular importance, folate, present in foods and supplements, is a crucial modulator of CRC risk. The role of folate, and, specifically, the synthetic variant, folic acid, in the primary prevention of CRC has not been fully elucidated. Animal studies varied considerably in the timing, duration, and supplementation of folates, leading to equivocal results. Our work attempts to isolate these variables to ascertain the role of folic acid in CRC initiation, as we previously demonstrated that folate restriction conferred protection against CRC initiation in a ß-pol haploinsufficient mouse model. Here we demonstrated that prior adaptation to folate restriction altered the response to carcinogen exposure in wild-type C57BL/6 mice. Mice adapted to folate restriction for 8 weeks were protected from CRC initiation compared to mice placed on folate restriction for 1 week, irrespective of antibiotic supplementation. Through analyses of mTOR signaling, DNA methyltransferase, and DNA repair, we have identified factors that may play a critical role in the differential responses to folate restriction. Furthermore, the timing and duration of folate restriction altered these pathways differently in the absence of carcinogenic insult. These results represent novel findings, as we were able to show that, in the same model and under controlled conditions, folate restriction produced contrasting results depending on the timing and duration of the intervention.


Assuntos
Carcinogênese/efeitos dos fármacos , Neoplasias Colorretais/prevenção & controle , Dieta , Ácido Fólico/uso terapêutico , Animais , Antibacterianos/uso terapêutico , Reparo do DNA , Ácido Fólico/metabolismo , Deficiência de Ácido Fólico/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Fatores de Tempo
6.
Elife ; 92020 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-33289482

RESUMO

Metabolic dysfunction underlies several chronic diseases, many of which are exacerbated by obesity. Dietary interventions can reverse metabolic declines and slow aging, although compliance issues remain paramount. 17α-estradiol treatment improves metabolic parameters and slows aging in male mice. The mechanisms by which 17α-estradiol elicits these benefits remain unresolved. Herein, we show that 17α-estradiol elicits similar genomic binding and transcriptional activation through estrogen receptor α (ERα) to that of 17ß-estradiol. In addition, we show that the ablation of ERα completely attenuates the beneficial metabolic effects of 17α-E2 in male mice. Our findings suggest that 17α-E2 may act through the liver and hypothalamus to improve metabolic parameters in male mice. Lastly, we also determined that 17α-E2 improves metabolic parameters in male rats, thereby proving that the beneficial effects of 17α-E2 are not limited to mice. Collectively, these studies suggest ERα may be a drug target for mitigating chronic diseases in male mammals.


Assuntos
Estradiol/fisiologia , Receptor alfa de Estrogênio/fisiologia , Longevidade , Animais , Feminino , Regulação da Expressão Gênica/fisiologia , Hipotálamo/metabolismo , Hipotálamo/fisiologia , Resistência à Insulina/fisiologia , Fígado/metabolismo , Fígado/fisiologia , Longevidade/fisiologia , Masculino , Camundongos , Camundongos Knockout , Ratos
7.
J Gerontol A Biol Sci Med Sci ; 75(1): 4-13, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30854544

RESUMO

Since the initial suggestion that rapamycin, an inhibitor of target of rapamycin (TOR) nutrient signaling, increased lifespan comparable to dietary restriction, investigators have viewed rapamycin as a potential dietary restriction mimetic. Both dietary restriction and rapamycin increase lifespan across a wide range of evolutionarily diverse species (including yeast, Caenorhabditis elegans, Drosophila, and mice) as well as reducing pathology and improving physiological functions that decline with age in mice. The purpose of this article is to review the research comparing the effect of dietary restriction and rapamycin in mice. The current data show that dietary restriction and rapamycin have different effects on many pathways and molecular processes. In addition, these interventions affect the lifespan of many genetically manipulated mouse models differently. In other words, while dietary restriction and rapamycin may have similar effects on some pathways and processes; overall, they affect many pathways/processes quite differently. Therefore, rapamycin is likely not a true dietary restriction mimetic. Rather dietary restriction and rapamycin appear to be increasing lifespan and retarding aging largely through different mechanisms/pathways, suggesting that a combination of dietary restriction and rapamycin will have a greater effect on lifespan than either manipulation alone.


Assuntos
Envelhecimento/fisiologia , Restrição Calórica/métodos , Longevidade/efeitos dos fármacos , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/efeitos dos fármacos , Envelhecimento/efeitos dos fármacos , Animais , Humanos , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
8.
Pharmacol Ther ; 195: 172-185, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30419258

RESUMO

Recent research suggests that epigenetics, especially DNA methylation, plays a mechanistic role in aging. Epigenetic clocks, which measure changes in a few hundred specific CpG sites, can accurately predict chronological age in a variety of species, including humans. These clocks are currently the best biomarkers for predicting mortality in humans. Additionally, several studies have characterized the effects of aging across the methylome in a wide variety of tissues from humans and mice. A small fraction (~2%) of the CpG sites show age-related changes, either hypermethylation or hypomethylation with aging. Evaluation of non-CpG site methylation has only been examined in a few studies, with about ~0.5% of these sites showing a change with age. Therefore, while only a small fraction of cytosines in the genome show changes in DNA methylation with age, this represents 2 to 3 million cytosines in the genome. Importantly, the only study to compare the effect of aging on DNA methylation in male and female mice and humans found that >95% of the age-related changes in DNA methylation in the hippocampus were sexually divergent, i.e., the methylation did not differ between males and females at young age but age-related changes occurred in one sex but not the other. The age-related changes in DNA methylation tend to be enriched and under-represented in specific genomic contexts, with some commonalities between tissues and species that require further investigation. The strongest evidence that the age-related changes in DNA methylation play a role in aging comes from studies of anti-aging interventions (e.g., caloric restriction, dwarfism, and rapamycin treatment) in mice. These anti-aging interventions deaccelerate the epigenetic clocks and reverse/prevent 20 to 40% of the age-related changes in DNA methylation. It will be important in the future to demonstrate that at least some of the age-related changes in DNA methylation directly lead to alterations in the transcriptome of cells/tissues that could potentially contribute to aging.


Assuntos
Metilação de DNA , Epigênese Genética , Envelhecimento/genética , Animais , Epigenômica , Humanos
9.
Neurobiol Aging ; 67: 53-66, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29631215

RESUMO

Brain aging is marked by cognitive decline and susceptibility to neurodegeneration. Calorie restriction (CR) increases neurogenesis, improves memory function, and protects from age-associated neurological disorders. Epigenetic mechanisms, including DNA methylation, are vital to normal central nervous system cellular and memory functions and are dysregulated with aging. The beneficial effects of CR have been proposed to work through epigenetic processes, but this is largely unexplored. We therefore tested whether life long CR prevents age-related hippocampal DNA methylation changes. Hippocampal DNA from young (3 months) and old (24 months) male mice fed ad libitum and 24-month-old mice fed a 40% calorie-restricted diet from 3 months of age were examined by genome-wide bisulfite sequencing to measure methylation with base specificity. Over 27 million CG and CH (non-CG) sites were examined. Of the ∼40,000 differentially methylated CG and ∼80,000 CH sites with aging, >1/3 were prevented by CR and were found across genomic regulatory regions and gene pathways. CR also caused alterations to CG and CH methylation at sites not differentially methylated with aging, and these CR-specific changes demonstrated a different pattern of regulatory element and gene pathway enrichment than those affected by aging. CR-specific DNA methyltransferase 1 and Tet methylcytosine dioxygenase 3 promoter hypermethylation corresponded to reduced gene expression. These findings demonstrate that CR attenuates age-related CG and CH hippocampal methylation changes, in combination with CR-specific methylation that may also contribute to the neuroprotective effects of CR. The prevention of age-related methylation alterations is also consistent with the prolongevity effects of CR working through an epigenetic mechanism.


Assuntos
Envelhecimento/genética , Envelhecimento/metabolismo , Restrição Calórica , Metilação de DNA , Hipocampo/metabolismo , Neuroproteção , Animais , Envelhecimento Cognitivo , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Metilação de DNA/genética , Dioxigenases/metabolismo , Epigênese Genética , Expressão Gênica , Masculino , Memória , Camundongos Endogâmicos C57BL , Doenças do Sistema Nervoso/etiologia , Doenças do Sistema Nervoso/prevenção & controle , Neurogênese
10.
Aging Cell ; 17(4): e12770, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29696779

RESUMO

Necroptosis is a newly identified programmed cell death pathway that is highly proinflammatory due to the release of cellular components that promote inflammation. To determine whether necroptosis might play a role in inflammaging, we studied the effect of age and dietary restriction (DR) on necroptosis in the epididymal white adipose tissue (eWAT), a major source of proinflammatory cytokines. Phosphorylated MLKL and RIPK3, markers of necroptosis, were increased 2.7- and 1.9-fold, respectively, in eWAT of old mice compared to adult mice, and DR reduced P-MLKL and P-RIPK3 to levels similar to adult mice. An increase in the expression of RIPK1 (1.6-fold) and MLKL (2.7-fold), not RIPK3, was also observed in eWAT of old mice, which was reduced by DR in old mice. The increase in necroptosis was paralleled by an increase in 14 inflammatory cytokines, including the pro-inflammatory cytokines IL-6 (3.9-fold), TNF-α (4.7-fold), and IL-1ß (5.1-fold)], and 11 chemokines in old mice. DR attenuated the expression of IL-6, TNF-α, and IL-1ß as well as 85% of the other cytokines/chemokines induced with age. In contrast, inguinal WAT (iWAT), which is less inflammatory, did not show any significant increase with age in the levels of P-MLKL and MLKL or inflammatory cytokines/chemokines. Because the changes in biomarkers of necroptosis in eWAT with age and DR paralleled the changes in the expression of pro-inflammatory cytokines, our data support the possibility that necroptosis might play a role in increased chronic inflammation observed with age.


Assuntos
Apoptose , Restrição Calórica , Inflamação/metabolismo , Necrose/metabolismo , Fatores Etários , Animais , Camundongos
11.
Geroscience ; 40(2): 139-149, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29455275

RESUMO

Over the past 50 years, dietary restriction (DR) has been shown to extend the life span of a wide variety of organisms. A hallmark feature of DR is improved glucose homeostasis resulting in increased glucose tolerance and insulin sensitivity of animals ranging from rodents to humans. In this study, we demonstrate the early effects of varying levels of DR on glucose tolerance. Within 10 days of 40% DR, glucose tolerance was significantly improved and by 120 days; 10 and 20% DR also showed enhanced glucose tolerance. All three levels of DR showed reduced adiposity, increased expression of genes involved in fat turnover, and a reduction in the expression for markers of inflammation. Studies have shown that mice fed a DR diet retained metabolic memory in terms of improved glucose tolerance even after DR is discontinued. We show that 40% DR not only has an early effect on glucose tolerance but also maintained it after DR was discontinued for 2 months. Therefore, improvement in glucose tolerance is brought about by all three levels of DR but the metabolic memory is not dose responsive.


Assuntos
Restrição Calórica/métodos , Homeostase/genética , Homeostase/fisiologia , Redes e Vias Metabólicas/genética , Obesidade/fisiopatologia , Animais , Glicemia/metabolismo , Composição Corporal/genética , Índice de Massa Corporal , Metabolismo dos Carboidratos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Reação em Cadeia da Polimerase em Tempo Real/métodos , Sensibilidade e Especificidade
12.
Geroscience ; 40(1): 11-29, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29327208

RESUMO

As geroscience research extends into the role of epigenetics in aging and age-related disease, researchers are being confronted with unfamiliar molecular techniques and data analysis methods that can be difficult to integrate into their work. In this review, we focus on the analysis of DNA modifications, namely cytosine methylation and hydroxymethylation, through next-generation sequencing methods. While older techniques for modification analysis performed relative quantitation across regions of the genome or examined average genome levels, these analyses lack the desired specificity, rigor, and genomic coverage to firmly establish the nature of genomic methylation patterns and their response to aging. With recent methodological advances, such as whole genome bisulfite sequencing (WGBS), bisulfite oligonucleotide capture sequencing (BOCS), and bisulfite amplicon sequencing (BSAS), cytosine modifications can now be readily analyzed with base-specific, absolute quantitation at both cytosine-guanine dinucleotide (CG) and non-CG sites throughout the genome or within specific regions of interest by next-generation sequencing. Additional advances, such as oxidative bisulfite conversion to differentiate methylation from hydroxymethylation and analysis of limited input/single-cells, have great promise for continuing to expand epigenomic capabilities. This review provides a background on DNA modifications, the current state-of-the-art for sequencing methods, bioinformatics tools for converting these large data sets into biological insights, and perspectives on future directions for the field.


Assuntos
Envelhecimento/genética , Metilação de DNA/genética , Epigenômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Envelhecimento/fisiologia , Animais , Epigênese Genética , Feminino , Humanos , Masculino , Sensibilidade e Especificidade , Análise de Sequência de DNA/métodos
13.
Ann N Y Acad Sci ; 1418(1): 69-79, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29363785

RESUMO

The genomic hypomethylation hypothesis of aging proposes that an overall decrease in global DNA methylation occurs with age, and it has been argued that the decrease in global DNA methylation could be an important factor in aging, resulting in the relaxation of gene expression regulation and abnormal gene expression. Since it was initially observed that DNA methylation decreased with age in 1974, 16 articles have been published describing the effect of age on global DNA methylation in various tissues from rodents and humans. We critically reviewed the publications on the effect of age on DNA methylation and the expression of the enzymes involved in DNA methylation to evaluate the validity of the hypomethylation hypothesis of aging. On the basis of the current scientific literature, we conclude that a decrease in the global methylation of the genome occurs in most if not all tissues/cells as an animal ages. However, age-related changes in DNA methylation in specific regions or at specific sites in the genome occur even though the global DNA methylation does not change.


Assuntos
Envelhecimento/genética , Metilação de DNA , Genômica , Animais , Enzimas/metabolismo , Regulação da Expressão Gênica , Humanos , Camundongos , Ratos
14.
Aging Cell ; 16(6): 1342-1352, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28948711

RESUMO

DNA methylation is a central regulator of genome function, and altered methylation patterns are indicative of biological aging and mortality. Age-related cellular, biochemical, and molecular changes in the hippocampus lead to cognitive impairments and greater vulnerability to neurodegenerative disease that varies between the sexes. The role of hippocampal epigenomic changes with aging in these processes is unknown as no genome-wide analyses of age-related methylation changes have considered the factor of sex in a controlled animal model. High-depth, genome-wide bisulfite sequencing of young (3 month) and old (24 month) male and female mouse hippocampus revealed that while total genomic methylation amounts did not change with aging, specific sites in CG and non-CG (CH) contexts demonstrated age-related increases or decreases in methylation that were predominantly sexually divergent. Differential methylation with age for both CG and CH sites was enriched in intergenic and intronic regions and under-represented in promoters, CG islands, and specific enhancer regions in both sexes, suggesting that certain genomic elements are especially labile with aging, even if the exact genomic loci altered are predominantly sex-specific. Lifelong sex differences in autosomal methylation at CG and CH sites were also observed. The lack of genome-wide hypomethylation, sexually divergent aging response, and autosomal sex differences at CG sites was confirmed in human data. These data reveal sex as a previously unappreciated central factor of hippocampal epigenomic changes with aging. In total, these data demonstrate an intricate regulation of DNA methylation with aging by sex, cytosine context, genomic location, and methylation level.


Assuntos
Envelhecimento/genética , Metilação de DNA , Hipocampo/fisiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Caracteres Sexuais , Adulto Jovem
15.
Geroscience ; 39(3): 331-345, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28477138

RESUMO

An important facet of dietary restriction (DR) that has been largely overlooked is that DR can have early effects that create a cellular memory, which persists even when DR is discontinued. The goal of this study was to determine if DNA methylation played a role in the cellular memory of DR by examining the effect of short-term DR on gene expression and DNA methylation and determining if the changes in expression and DNA methylation persist when DR is discontinued and mice returned to ad libitum (AL) feeding. We show that DR can induce substantial changes in gene expression within 1 month of its implementation in various tissues, and more interestingly, ~19-50% of these changes in gene expression persist across the tissues even when DR is discontinued. We then determined whether DR induced changes in DNA methylation in the promoter of three candidate genes identified from our gene expression analysis (Pomc, Hsph1, and Nts1) that correlated with the changes in the expression of these genes. Decreased methylation at three specific CG sites in the promoter of the Nts1 gene encompassing the distal consensus AP-1 site was correlated with increased Nts1 expression. Both the promoter hypomethylation and increased Nts1 expression persisted even after DR was discontinued and mice fed AL, supporting our hypothesis that DNA methylation could play a role in the memory effect of DR. The changes in DNA methylation in the Nts1 gene are likely to occur in intestinal stem cells and could play a role in preserving the intestinal stem cell pool in DR mice.


Assuntos
Restrição Calórica , Metilação de DNA , Regulação da Expressão Gênica , Animais , Restrição Calórica/efeitos adversos , Alimentos , Camundongos , Modelos Animais , Regiões Promotoras Genéticas
16.
Free Radic Biol Med ; 108: 704-714, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28455142

RESUMO

White adipose tissue (WAT) mitochondrial dysfunction is linked to the pathogenesis of obesity driven insulin resistance. Dietary conditions that alter fat mass are known to affect white adipocyte mitochondrial function, however, the impact of high calorie diets on white adipocyte mitochondria is not fully understood. The aim of this study is to assess the effect of a diet rich in saturated or polyunsaturated fat on mitochondrial unfolded protein response (UPRmt), a retrograde signaling response that maintains mitochondrial homeostasis, in epididymal WAT (eWAT). Mice were fed a low fat diet (LFD), saturated fat diet (SFD) or fish oil (unsaturated fat diet, UFD) and assessed changes in eWAT mitochondria. Compared to mice fed a LFD, SFD-fed mice have reduced mitochondrial biogenesis markers, mitochondrial fatty acid oxidation enzymes and TCA cycle enzymes, suggesting an impaired mitochondrial function that could contribute to increased fat mass. In contrast, isocaloric UFD-fed mice have increased expression of mitochondrial uncoupling protein 1 (UCP1) and peroxisomal fatty acid oxidation enzymes suggesting that elevated mitochondrial uncoupling and peroxisomal fatty acid oxidation could contribute to the reduction in fat mass. Interestingly, expression of UPRmt-associated proteins caseinolytic peptidase (ClpP) and heat shock protein 60 (Hsp60) are induced by UFD, whereas SFD reduced the expression of ClpP. Based on our data, we propose that induction of UPRmt helps to preserve a functional mitochondria and efficient utilization of fat by UFD whereas a dampened UPRmt response might impair mitochondrial function and promote fat accumulation by SFD. Thus, our findings suggest a potential role of UPRmt in mediating the beneficial effects of fish oil.


Assuntos
Tecido Adiposo Branco/metabolismo , Epididimo/patologia , Óleos de Peixe/uso terapêutico , Mitocôndrias/metabolismo , Obesidade/terapia , Tecido Adiposo Branco/patologia , Animais , Biomarcadores/metabolismo , Dieta Hiperlipídica , Ácidos Graxos/metabolismo , Ácidos Graxos Insaturados/metabolismo , Resistência à Insulina , Metabolismo dos Lipídeos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Resposta a Proteínas não Dobradas
17.
Redox Biol ; 11: 30-37, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27846439

RESUMO

In contrast to other mouse models that are deficient in antioxidant enzymes, mice null for Cu/Zn-superoxide dismutase (Sod1-/- mice) show a major decrease in lifespan and several accelerated aging phenotypes. The goal of this study was to determine if cell senescence might be a contributing factor in the accelerated aging phenotype observed in the Sod1-/- mice. We focused on kidney because it is a tissue that has been shown to a significant increase in senescent cells with age. The Sod1-/- mice are characterized by high levels of DNA oxidation in the kidney, which is attenuated by DR. The kidney of the Sod1-/- mice also have higher levels of double strand DNA breaks than wild type (WT) mice. Expression (mRNA and protein) of p16 and p21, two of the markers of cellular senescence, which increased with age, are increased significantly in the kidney of Sod1-/- mice as is ß-gal staining cells. In addition, the senescence associated secretory phenotype was also increased significantly in the kidney of Sod1-/- mice compared to WT mice as measured by the expression of transcripts for IL-6 and IL-1ß. Dietary restriction of the Sod1-/- mice attenuated the increase in DNA damage, cellular senescence, and expression of IL-6 and IL-1ß. Interestingly, the Sod1-/- mice showed higher levels of circulating cytokines than WT mice, suggesting that the accelerated aging phenotype shown by the Sod1-/- mice could result from increased inflammation arising from an accelerated accumulation of senescent cells. Based on our data with Sod1-/- mice, we propose that various bouts of increased oxidative stress over the lifespan of an animal leads to the accumulation of senescent cells. The accumulation of senescent cells in turn leads to increased inflammation, which plays a major role in the loss of function and increased pathology that are hallmark features of aging.


Assuntos
Envelhecimento/genética , Senescência Celular/genética , Interleucina-1beta/genética , Interleucina-6/genética , Superóxido Dismutase-1/genética , Envelhecimento/patologia , Animais , Inibidor p16 de Quinase Dependente de Ciclina/genética , Quebras de DNA de Cadeia Dupla , Dano ao DNA/genética , Humanos , Inflamação/genética , Inflamação/patologia , Rim/metabolismo , Rim/patologia , Camundongos , Camundongos Knockout , Oxirredução , Estresse Oxidativo/genética , Quinases Ativadas por p21/genética
18.
Artigo em Inglês | MEDLINE | ID: mdl-27413395

RESUMO

BACKGROUND: Changes to the epigenome with aging, and DNA modifications in particular, have been proposed as a central regulator of the aging process, a predictor of mortality, and a contributor to the pathogenesis of age-related diseases. In the central nervous system, control of learning and memory, neurogenesis, and plasticity require changes in cytosine methylation and hydroxymethylation. Although genome-wide decreases in methylation with aging are often reported as scientific dogma, primary research reports describe decreases, increases, or lack of change in methylation and hydroxymethylation and their principle regulators, DNA methyltransferases and ten-eleven translocation dioxygenases in the hippocampus. Furthermore, existing data are limited to only male animals. RESULTS: Through examination of the hippocampus in young, adult, and old male and female mice by antibody-based, pyrosequencing, and whole-genome oxidative bisulfite sequencing methods, we provide compelling evidence that contradicts the genomic hypomethylation theory of aging. We also demonstrate that expression of DNA methyltransferases and ten-eleven translocation dioxygenases is not differentially regulated with aging or between the sexes, including the proposed cognitive aging regulator DNMT3a2. Using oxidative bisulfite sequencing that discriminates methylation from hydroxymethylation and by cytosine (CG and non-CG) context, we observe sex differences in average CG methylation and hydroxymethylation of the X chromosome, and small age-related differences in hydroxymethylation of CG island shores and shelves, and methylation of promoter regions. CONCLUSION: These findings clarify a long-standing misconception of the epigenomic response to aging and demonstrate the need for studies of base-specific methylation and hydroxymethylation with aging in both sexes.

19.
Ann N Y Acad Sci ; 1363: 11-7, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26695614

RESUMO

Although it is well documented that dietary restriction (DR) increases the life span of rodents and other animals, this increase is observed at relatively high levels of DR, in which rodents are typically fed 40% less than that consumed by rodents fed ad libitum. It is generally assumed that lower levels of DR will have a lesser impact on life span; however, there are very little published data on the effect of low levels of DR on life span. In this study, we show that 10% DR increased life span to almost the same extent as 40% DR. While both 10% and 40% DR resulted in similar changes in non-neoplastic lesions, 10% DR had no significant effect on the incidence of neoplasia (except for pituitary adenoma), and 40% DR resulted in a significant reduction (40%) in neoplasia. These data clearly demonstrate that the life span of F344 rats does not increase linearly with the level of DR; rather, even a low level of DR can substantially affect life span. This rodent study has important translational implications because it suggests that a modest reduction in calories might have significant health benefits for humans.


Assuntos
Restrição Calórica , Dieta , Expectativa de Vida , Animais , Peso Corporal , Causas de Morte , Masculino , Ratos
20.
Aging (Albany NY) ; 6(8): 645-60, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25133314

RESUMO

Coordinate control of gene activity is critical for fitness and longevity of an organism. The SIN3 histone deacetylase (HDAC) complex functions as a transcriptional repressor of many genes. SIN3-regulated genes include those that encode proteins affecting multiple aspects of mitochondrial function, such as energy production and stress responsiveness, important for health maintenance. Here we used Drosophila melanogaster as a model organism to examine the role of SIN3 in the regulation of fitness and longevity. Adult flies with RNA interference (RNAi) induced knockdown expression of Sin3A have reduced climbing ability; an activity that likely requires fully functional mitochondria. Additionally, compared to wild type, adult Sin3A knockdown flies were more sensitive to oxidative stress. Interestingly, media supplementation with the antioxidant glutathione largely restored fly tolerance to oxidative stress. Although Sin3A knockdown flies exhibited decreased longevity compared to wild type, no significant changes in expression of many well-categorized aging genes were observed. We found, however, that Sin3A knockdown corresponded to a significant reduction in expression of genes encoding proteins involved in the de novo synthesis of glutathione. Taken together, the data support a model whereby SIN3 regulates a gene expression program required for proper mitochondrial function and effective stress response during adulthood.


Assuntos
Proteínas de Drosophila/metabolismo , Longevidade/fisiologia , Estresse Oxidativo/fisiologia , Complexo Correpressor Histona Desacetilase e Sin3/metabolismo , Estresse Fisiológico/fisiologia , Animais , Comportamento Animal/fisiologia , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Atividade Motora/fisiologia , Interferência de RNA , Complexo Correpressor Histona Desacetilase e Sin3/genética
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