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1.
Aquat Toxicol ; 263: 106673, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37669601

RESUMO

Methylmercury (MeHg) is a pervasive environmental contaminant in aquatic ecosystems that can reach elevated concentrations in fish of high trophic levels, such as salmonids. The present study aims at investigating the individual and combined impacts of dietary MeHg and fatty acids on lipid metabolism in juvenile rainbow trout (Oncorhynchus mykiss) with a focus on two key organs, adipose tissue and liver. MeHg and fatty acids are both known to act on energy homeostasis although little is known about their interplay on lipid metabolism in fish. Fish were fed diets enriched in linoleic acid (LA, 18:2 n-6), α-linolenic acid (ALA, 18:3 n-3), eicosapentaenoic acid (EPA, 20:5 n-3) or docosahexaenoic acid (DHA, 22:6 n-3) for ten weeks, with the addition of MeHg to the diets during the last six weeks (0, 2.4 or 5.5 mg MeHg/kg dry matter). LA and ALA are polyunsaturated fatty acids (PUFA) typical of plant-derived oils whereas EPA and DHA are n-3 long chain PUFA largely found in fish oil, all used in feed formulation in aquaculture. The results showed that the LA-enriched diet induced a higher whole-body lipid content compared to the three other diets. On the contrary, the addition of MeHg led to a significant reduction of the whole-body lipid content, regardless of the diet. Interestingly, the adipocytes were larger both in presence of LA, compared to EPA and DHA, or MeHg, indicating a lipogenic effect of these two compounds. No effect was, however, observed on lipid accumulation per gram of adipose tissue. The fatty acid composition of adipose tissue and liver was significantly modified by the dietary lipids, reflecting both the fatty acid composition of the diets and the high bioconversion capacity of the rainbow trout. Exposure to MeHg selectively led to a release of n-6 PUFA from the hepatic membranes of fish fed the LA-enriched diet, showing a disruption of the pathways using n-6 PUFA. This study highlights the significant impact of MeHg exposure and dietary fatty acids on lipid metabolism in fish. Further investigation is needed to elucidate the underlying mechanisms and to explore the potential involvement of other organs.


Assuntos
Compostos de Metilmercúrio , Oncorhynchus mykiss , Poluentes Químicos da Água , Animais , Ácidos Graxos/metabolismo , Oncorhynchus mykiss/metabolismo , Compostos de Metilmercúrio/toxicidade , Compostos de Metilmercúrio/metabolismo , Metabolismo dos Lipídeos , Ecossistema , Poluentes Químicos da Água/toxicidade , Fígado , Dieta/veterinária , Ácidos Docosa-Hexaenoicos/farmacologia , Tecido Adiposo
2.
Cancers (Basel) ; 14(24)2022 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-36551658

RESUMO

Cancer research has benefited immensely from the use of animal models. Several genetic tools accessible in rodent models have provided valuable insight into cellular and molecular mechanisms linked to cancer development or metastasis and various lines are available. However, at the same time, it is important to accompany these findings with those from alternative or non-model animals to offer new perspectives into the understanding of tumor development, prevention, and treatment. In this review, we first discuss animals characterized by little or no tumor development. Cancer incidence in small animals, such as the naked mole rat, blind mole rat and bats have been reported as almost negligible and tumor development may be inhibited by increased defense and repair mechanisms, altered cell cycle signaling and reduced rates of cell migration to avoid tumor microenvironments. On the other end of the size spectrum, large animals such as elephants and whales also appear to have low overall cancer rates, possibly due to gene replicates that are involved in apoptosis and therefore can inhibit uncontrolled cell cycle progression. While it is important to determine the mechanisms that lead to cancer protection in these animals, we can also take advantage of other animals that are highly susceptible to cancer, especially those which develop tumors similar to humans, such as carnivores or poultry. The use of such animals does not require the transplantation of malignant cancer cells or use of oncogenic substances as they spontaneously develop tumors of similar presentation and pathophysiology to those found in humans. For example, some tumor suppressor genes are highly conserved between humans and domestic species, and various tumors develop in similar ways or because of a common environment. These animals are therefore of great interest for broadening perspectives and techniques and for gathering information on the tumor mechanisms of certain types of cancer. Here we present a detailed review of alternative and/or non-model vertebrates, that can be used at different levels of cancer research to open new perspectives and fields of action.

3.
Antioxidants (Basel) ; 11(9)2022 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-36139917

RESUMO

This study investigated the effect of the catechins profile on the antioxidant activity of green tea extracts (GTEs) by comparing the antioxidant activity of an EGC-rich GTE (GTE1, catechin content: 58% EGC, 30.1% EGCG, 7.9% EC, and 3.9% ECG) and an EGCG-rich GTE (GTE2, catechin content: 60.6% EGCG, 17.7% EGC, 11.8% ECG, and 9.8% EC) in a DHA-rich oil. The effects of the individual catechins (EGC, EC, EGCG, and ECG) and reconstituted catechins mixtures (CatMix), prepared to contain the same amount of major catechins as in the GTEs, were also measured. All treatments (GTE1, CatMix1, GTE2, CatMix2, EGC250, EC250, EGCG250, and ECG250), each containing epistructured catechins at a concentration of 250 ppm, as well as the control (oil with no added antioxidant), were stored at 30 °C for 21 days with sampling intervals of 7 days. The antioxidant activity was assessed by measuring the peroxide value (PV) and p-anisidine value (p-AV) of oils. Changes in fatty acid content and catechins content were also monitored. Both GTEs enhanced the oxidative stability of the DHA-rich oil, but GTE1 demonstrated a stronger antioxidant activity than GTE2. No significant difference was observed between the PV of treatments with GTE1 and CatMix1 during storage, whereas the PV of oil with GTE2 was significantly higher than that with CatMix2 after 21 days. Among the individual catechins, EGC was the strongest antioxidant. Overall, the antioxidant activities of the extracts and catechins were observed in the decreasing order GTE1 ≈ EGC250 ≈ CatMix1 > GTE2 > EGCG250 ≈ CatMix2 > ECG250 > EC250. A significant change in fatty acid content was observed for the control and EC250 samples, and the catechins were most stable in GTE1-supplemented oil. Our results indicate that the EGC-rich GTE is a more potent antioxidant in DHA-rich oil than the EGCG-rich GTE.

4.
Aging (Albany NY) ; 10(5): 1027-1052, 2018 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-29779018

RESUMO

Dietary restriction (DR) is the most widely studied non-genetic intervention capable of extending lifespan across multiple taxa. Modulation of genes, primarily within the insulin/insulin-like growth factor signalling (IIS) and the mechanistic target of rapamycin (mTOR) signalling pathways also act to extend lifespan in model organisms. For example, mice lacking insulin receptor substrate-1 (IRS1) are long-lived and protected against several age-associated pathologies. However, it remains unclear how these particular interventions act mechanistically to produce their beneficial effects. Here, we investigated transcriptional responses in wild-type and IRS1 null mice fed an ad libitum diet (WTAL and KOAL) or fed a 30% DR diet (WTDR or KODR). Using an RNAseq approach we noted a high correlation coefficient of differentially expressed genes existed within the same tissue across WTDR and KOAL mice and many metabolic features were shared between these mice. Overall, we report that significant overlap exists in the tissue-specific transcriptional response between long-lived DR mice and IRS1 null mice. However, there was evidence of disconnect between transcriptional signatures and certain phenotypic measures between KOAL and KODR, in that additive effects on body mass were observed but at the transcriptional level DR induced a unique set of genes in these already long-lived mice.


Assuntos
Restrição Calórica , Proteínas Substratos do Receptor de Insulina/deficiência , Longevidade/fisiologia , Transcrição Gênica/fisiologia , Animais , Camundongos , Camundongos Knockout
5.
Trends Endocrinol Metab ; 29(6): 389-399, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29665988

RESUMO

Insulin plays roles in lipid uptake, lipolysis, and lipogenesis, in addition to controlling blood glucose levels. Excessive circulating insulin is associated with adipose tissue expansion and obesity, yet a causal role for hyperinsulinemia in the development of mammalian obesity has proven controversial, with many researchers suggesting it as a consequence of insulin resistance. Recently, evidence that specifically reducing hyperinsulinemia can prevent and reverse obesity in animal models has been presented. Our experiments, and others in this field, question the current dogma that hyperinsulinemia is a response to obesity and/or insulin resistance. In this review, we discuss preclinical evidence in the context of the broader literature and speculate on the possibility of clinical translation of alternative approaches for treating obesity.


Assuntos
Glucose/metabolismo , Hiperinsulinismo/metabolismo , Obesidade/metabolismo , Animais , Homeostase , Humanos , Hiperinsulinismo/tratamento farmacológico , Insulina/uso terapêutico , Resistência à Insulina/fisiologia , Obesidade/tratamento farmacológico
6.
FASEB J ; 32(3): 1196-1206, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29122848

RESUMO

Excess circulating insulin is associated with obesity in humans and in animal models. However, the physiologic causality of hyperinsulinemia in adult obesity has rightfully been questioned because of the absence of clear evidence that weight loss can be induced by acutely reversing diet-induced hyperinsulinemia. Herein, we describe the consequences of inducible, partial insulin gene deletion in a mouse model in which animals have already been made obese by consuming a high-fat diet. A modest reduction in insulin production/secretion was sufficient to cause significant weight loss within 5 wk, with a specific effect on visceral adipose tissue. This result was associated with a reduction in the protein abundance of the lipodystrophy gene polymerase I and transcript release factor ( Ptrf; Cavin) in gonadal adipose tissue. RNAseq analysis showed that reduced insulin and weight loss also associated with a signature of reduced innate immunity. This study demonstrates that changes in circulating insulin that are too fine to adversely affect glucose homeostasis nonetheless exert control over adiposity.-Page, M. M., Skovsø, S., Cen, H., Chiu, A. P., Dionne, D. A., Hutchinson, D. F., Lim, G. E., Szabat, M., Flibotte, S., Sinha, S., Nislow, C., Rodrigues, B., Johnson, J. D. Reducing insulin via conditional partial gene ablation in adults reverses diet-induced weight gain.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Deleção de Genes , Homeostase , Insulina/fisiologia , Obesidade/prevenção & controle , Aumento de Peso/genética , Adiposidade , Animais , Peso Corporal , Masculino , Camundongos , Camundongos Knockout , Obesidade/etiologia , Obesidade/patologia
7.
J Physiol ; 595(20): 6383-6390, 2017 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-28718225

RESUMO

The global increase in life expectancy is creating significant medical, social and economic challenges to current and future generations. Consequently, there is a need to identify the fundamental mechanisms underlying the ageing process. This knowledge should help develop realistic interventions capable of combatting age-related disease, and thus improving late-life health and vitality. While several mechanisms have been proposed as conserved lifespan determinants, the loss of proteostasis - where proteostasis is defined here as the maintenance of the proteome - appears highly relevant to both ageing and disease. Several studies have shown that multiple proteostatic mechanisms, including the endoplasmic reticulum (ER)-induced unfolded protein response (UPR), the ubiquitin-proteasome system (UPS) and autophagy, appear indispensable for longevity in many long-lived invertebrate mutants. Similarly, interspecific comparisons suggest that proteostasis may be an important lifespan determinant in vertebrates. Over the last 20 years a number of long-lived mouse mutants have been described, many of which carry single-gene mutations within the growth-hormone, insulin/IGF-1 or mTOR signalling pathways. However, we still do not know how these mutations act mechanistically to increase lifespan and healthspan, and accordingly whether mechanistic commonality occurs between different mutants. Recent evidence supports the premise that the successful maintenance of the proteome during ageing may be linked to the increased lifespan and healthspan of long-lived mouse mutants.


Assuntos
Envelhecimento/metabolismo , Proteostase , Animais , Estresse do Retículo Endoplasmático , Humanos , Longevidade , Camundongos , Camundongos Mutantes , Resposta a Proteínas não Dobradas
8.
J Endocrinol ; 232(3): R173-R183, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28052999

RESUMO

Insulin modulates the biochemical pathways controlling lipid uptake, lipolysis and lipogenesis at multiple levels. Elevated insulin levels are associated with obesity, and conversely, dietary and pharmacological manipulations that reduce insulin have occasionally been reported to cause weight loss. However, the causal role of insulin hypersecretion in the development of mammalian obesity remained controversial in the absence of direct loss-of-function experiments. Here, we discuss theoretical considerations around the causal role of excess insulin for obesity, as well as recent studies employing mice that are genetically incapable of the rapid and sustained hyperinsulinemia that normally accompanies a high-fat diet. We also discuss new evidence demonstrating that modest reductions in circulating insulin prevent weight gain, with sustained effects that can persist after insulin levels normalize. Importantly, evidence from long-term studies reveals that a modest reduction in circulating insulin is not associated with impaired glucose homeostasis, meaning that body weight and lipid homeostasis are actually more sensitive to small changes in circulating insulin than glucose homeostasis in these models. Collectively, the evidence from new studies on genetic loss-of-function models forces a re-evaluation of current paradigms related to obesity, insulin resistance and diabetes. The potential for translation of these findings to humans is briefly discussed.


Assuntos
Hiperinsulinismo/complicações , Resistência à Insulina/fisiologia , Obesidade/etiologia , Animais , Dieta Hiperlipídica , Humanos , Hiperinsulinismo/metabolismo , Insulina/sangue , Obesidade/metabolismo
9.
Cell Metab ; 23(1): 179-93, 2016 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-26626461

RESUMO

Pancreatic ß cells are mostly post-mitotic, but it is unclear what locks them in this state. Perturbations including uncontrolled hyperglycemia can drive ß cells into more pliable states with reduced cellular insulin levels, increased ß cell proliferation, and hormone mis-expression, but it is unknown whether reduced insulin production itself plays a role. Here, we define the effects of ∼50% reduced insulin production in Ins1(-/-):Ins2(f/f):Pdx1Cre(ERT):mTmG mice prior to robust hyperglycemia. Transcriptome, proteome, and network analysis revealed alleviation of chronic endoplasmic reticulum (ER) stress, indicated by reduced Ddit3, Trib3, and Atf4 expression; reduced Xbp1 splicing; and reduced phospho-eIF2α. This state was associated with hyper-phosphorylation of Akt, which is negatively regulated by Trib3, and with cyclinD1 upregulation. Remarkably, ß cell proliferation was increased 2-fold after reduced insulin production independently of hyperglycemia. Eventually, recombined cells mis-expressed glucagon in the hyperglycemic state. We conclude that the normally high rate of insulin production suppresses ß cell proliferation in a cell-autonomous manner.


Assuntos
Proliferação de Células , Estresse do Retículo Endoplasmático , Células Secretoras de Insulina/fisiologia , Insulina/biossíntese , Animais , Células Cultivadas , Metaboloma , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Mapas de Interação de Proteínas , Proteoma/metabolismo , Transdução de Sinais , Transcriptoma
10.
Aging Cell ; 13(5): 962-4, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25059507

RESUMO

Reduced signalling through the insulin/insulin-like growth factor-1 signalling (IIS) pathway is a highly conserved lifespan determinant in model organisms. The precise mechanism underlying the effects of the IIS on lifespan and health is currently unclear, although cellular stress resistance may be important. We have previously demonstrated that mice globally lacking insulin receptor substrate 1 (Irs1(-/-) ) are long-lived and enjoy a greater period of their life free from age-related pathology compared with wild-type (WT) controls. In this study, we show that primary dermal fibroblasts and primary myoblasts derived from Irs1(-/-) mice are no more resistant to a range of oxidant and nonoxidant chemical stressors than cells derived from WT mice.


Assuntos
Fibroblastos/metabolismo , Proteínas Substratos do Receptor de Insulina/deficiência , Estresse Fisiológico/fisiologia , Animais , Feminino , Fibroblastos/efeitos dos fármacos , Proteínas Substratos do Receptor de Insulina/genética , Proteínas Substratos do Receptor de Insulina/metabolismo , Masculino , Camundongos , Camundongos Knockout , Estresse Oxidativo/fisiologia
11.
Age (Dordr) ; 35(3): 647-58, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22371226

RESUMO

Insulin receptor substrate-1 null (Irs1 (-/-)) mice are long lived and importantly they also demonstrate increased resistance to several age-related pathologies compared to wild type (WT) controls. Currently, the molecular mechanisms that underlie lifespan extension in long-lived mice are unclear although protection against oxidative damage may be important. Here, we determined both the activities of several intracellular antioxidants and levels of oxidative damage in brain, skeletal muscle, and liver of Irs1 (-/-) and WT mice at 80, 450, and 700 days of age, predicting that long-lived Irs1 (-/-) mice would be protected against oxidative damage. We measured activities of both intracellular superoxide dismutases (SOD); cytosolic (CuZnSOD) and mitochondrial (MnSOD), glutathione peroxide (GPx), glutathione reductase (GR), catalase (CAT), and reduced glutathione (GHS). Of these, only hepatic CAT was significantly altered (increased) in Irs1 (-/-) mice. In addition, the levels of protein oxidation (protein carbonyl content) and lipid peroxidation (4-hydroxynonenal) were unaltered in Irs1 (-/-) mice, although the hepatic GSH/GSSG ratio, indicating an oxidized environment, was significantly lower in long-lived Irs1 (-/-) mice. Overall, our results do not support the premise that lifespan extension in Irs1 (-/-) mice is associated with greater tissue antioxidant protection or reduced oxidative damage.


Assuntos
Envelhecimento/fisiologia , Antioxidantes/metabolismo , Proteínas Substratos do Receptor de Insulina/metabolismo , Longevidade/fisiologia , Estresse Oxidativo/fisiologia , Animais , Encéfalo/citologia , Encéfalo/metabolismo , Feminino , Líquido Intracelular/metabolismo , Fígado/citologia , Fígado/metabolismo , Camundongos , Camundongos Knockout , Músculo Esquelético/citologia , Músculo Esquelético/metabolismo
12.
Age (Dordr) ; 35(5): 1937-47, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22836712

RESUMO

Discovering key cellular and molecular traits that promote longevity is a major goal of aging and longevity research. One experimental strategy is to determine which traits have been selected during the evolution of longevity in naturally long-lived animal species. This comparative approach has been applied to lifespan research for nearly four decades, yielding hundreds of datasets describing aspects of cell and molecular biology hypothesized to relate to animal longevity. Here, we introduce a Comparative Cellular and Molecular Biology of Longevity Database, available at ( http://genomics.brocku.ca/ccmbl/ ), as a compendium of comparative cell and molecular data presented in the context of longevity. This open access database will facilitate the meta-analysis of amalgamated datasets using standardized maximum lifespan (MLSP) data (from AnAge). The first edition contains over 800 data records describing experimental measurements of cellular stress resistance, reactive oxygen species metabolism, membrane composition, protein homeostasis, and genome homeostasis as they relate to vertebrate species MLSP. The purpose of this review is to introduce the database and briefly demonstrate its use in the meta-analysis of combined datasets.


Assuntos
Biologia Celular , Longevidade , Biologia Molecular/métodos , Bases de Dados Factuais , Homeostase
13.
Mech Ageing Dev ; 133(1): 37-45, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22212415

RESUMO

Dietary restriction (DR) is suggested to induce mitochondrial biogenesis, although recently this has been challenged. Here we determined the impact of 1, 9 and 18 months of 30% DR in male C57BL/6 mice on key mitochondrial factors and on mitochondrial function in skeletal muscle, relative to age-matched ad libitum (AL) controls. We examined proteins and mRNAs associated with mitochondrial biogenesis and measured mitochondrial respiration in permeabilised myofibres using high resolution respirometry. 30% DR, irrespective of duration, had no effect on citrate synthase activity. In contrast, total and nuclear protein levels of PGC-1α, mRNA levels of several mitochondrial associated proteins (Pgc-1α, Nrf1, Core 1, Cox IV, Atps) and cytochrome c oxidase content were increased in skeletal muscle of DR mice. Furthermore, a range of mitochondrial respiration rates were increased significantly by DR, with DR partially attenuating the age-related decline in respiration observed in AL controls. Therefore, DR did not increase mitochondrial content, as determined by citrate synthase, in mouse skeletal muscle. However, it did induce a PGC-1α adaptive response and increased mitochondrial respiration. Thus, we suggest that a functionally 'efficient' mitochondrial electron transport chain may be a critical mechanism underlying DR, rather than any net increase in mitochondrial content per se.


Assuntos
Envelhecimento , Restrição Calórica , Mitocôndrias Musculares/metabolismo , Proteínas Mitocondriais/metabolismo , Músculo Esquelético/metabolismo , Consumo de Oxigênio , Animais , Transporte de Elétrons , Masculino , Camundongos
14.
Age (Dordr) ; 34(5): 1195-209, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21853261

RESUMO

Accumulation of DNA lesions compromises replication and transcription and is thus toxic to cells. DNA repair deficiencies are generally associated with cellular replicative senescence and premature aging syndromes, suggesting that efficient DNA repair is required for normal longevity. It follows that the evolution of increasing lifespan amongst animal species should be associated with enhanced DNA repair capacities. Although UV damage repair has been shown to correlate positively with mammalian species lifespan, we lack similar insight into many other DNA repair pathways, including base excision repair (BER). DNA is continuously exposed to reactive oxygen species produced during aerobic metabolism, resulting in the occurrence of oxidative damage within DNA. Short-patch BER plays an important role in repairing the resultant oxidative lesions. We therefore tested whether an enhancement of BER enzyme activities has occurred concomitantly with the evolution of increased maximum lifespan (MLSP). We collected brain and liver tissue from 15 vertebrate endotherm species ranging in MLSP over an order of magnitude. We measured apurinic/apyrimidinic (AP) endonuclease activity, as well as the rates of nucleotide incorporation into an oligonucleotide containing a single nucleotide gap (catalyzed by BER polymerase ß) and subsequent ligation of the oligonucleotide. None of these activities correlated positively with species MLSP. Rather, nucleotide incorporation and oligonucleotide ligation activities appeared to be primarily (and negatively) correlated with species body mass.


Assuntos
Encéfalo/enzimologia , DNA Polimerase beta/metabolismo , Reparo do DNA , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo , DNA/metabolismo , Fígado/enzimologia , Longevidade/genética , Animais , Sequência de Bases , Coturnix , Cricetinae , Dano ao DNA , Replicação do DNA , Cães , Equidae , Feminino , Gerbillinae , Cobaias , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oxirredução , Coelhos , Espécies Reativas de Oxigênio/metabolismo
15.
Mech Ageing Dev ; 132(6-7): 287-97, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21703294

RESUMO

Cellular stress resistance is generally associated with longevity, but the mechanisms underlying this phenotype are not clear. In invertebrate models there is a clear role for heat shock proteins (Hsps) and organelle-specific unfolded protein responses (UPR) in longevity. However, this has not been demonstrated in vertebrates. Some Hsp amino acid sequences are highly conserved amongst mammals and birds. We used antibodies recognizing conserved regions of Hsp60 (primarily mitochondrial), Hsp70 (primarily cytosolic), GRP78 (Bip) and GRP94 (endoplasmic reticulum) to measure constitutive levels of these proteins in brain, heart and liver of 13 mammalian and avian species ranging in maximum lifespan from 3 to 30 years. In all three tissues, the expression of these proteins was highly correlated with MLSP, indicating higher basal levels of Hsp expression are characteristic of longer-lived species. We also quantified the levels of Hsp60, Hsp70 and GRP78 in brain and heart tissue of young adult (6-7 month old) Snell dwarf mice and normal littermates. Snell dwarf mice are characterized by a single gene mutation that is associated with an ∼50% increase in lifespan. However, neither Hsp60, nor Hsp70, nor GRP78 levels were elevated in brain or heart tissue from Snell dwarf mice compared to normal littermates.


Assuntos
Tentilhões/metabolismo , Regulação da Expressão Gênica/fisiologia , Proteínas de Choque Térmico/metabolismo , Longevidade/fisiologia , Ovinos/metabolismo , Suínos/metabolismo , Animais , Bovinos , Cães , Chaperona BiP do Retículo Endoplasmático , Tentilhões/genética , Cobaias , Proteínas de Choque Térmico/genética , Camundongos , Mutação , Especificidade de Órgãos/fisiologia , Coelhos , Ratos , Ovinos/genética , Especificidade da Espécie , Suínos/genética
16.
Exp Neurol ; 228(2): 253-8, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21281628

RESUMO

Strong epidemiological and experimental evidence links folate deficiency and resultant hyperhomocysteinemia with cognitive decline and neurodegeneration. Here, we tested the hypothesis that uracil misincorporation contributes to mitochondrial pathology in aged brain following folate deprivation. In a 2 × 2 design, 14-month-old mice lacking uracil DNA glycosylase (Ung-/-) versus wild-type controls were subjected to a folate-deficient versus a regular diet for six weeks. Folate-deficient feeding significantly enhanced mtDNA content and overall abundance of the D-1 mtDNA deletion in brain of Ung-/-, but not of wild-type mice. Independent of folate status, the frequency of the D-1 mtDNA deletion in mtDNA was significantly increased in Ung-/- mice. The rate of mitochondrial biogenesis as assessed at six weeks of the experimental diet by mRNA expression levels of transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α and of mitochondrial transcription factor A (Tfam) was not affected by either Ung-/- genotype or short-term folate deficiency. Similarly, citrate synthase (CS) activity in the brain did not differ across experimental groups. By contrast, independent of genotype, lactate dehydrogenase (LDH) activity was significantly reduced in folate-deficient animals. Our results suggest that impaired uracil excision repair causes an increase in mitochondrial mutagenesis in aged brain along with a compensatory increase in mtDNA content in response to low folate status. Folate deficiency may contribute to neurodegeneration via mtDNA damage.


Assuntos
Envelhecimento/genética , Deficiência de Ácido Fólico/genética , Deleção de Genes , Doenças Mitocondriais/genética , Doenças Neurodegenerativas/genética , Uracila-DNA Glicosidase/deficiência , Uracila-DNA Glicosidase/genética , Envelhecimento/metabolismo , Animais , Encefalopatias/complicações , Encefalopatias/enzimologia , Encefalopatias/genética , DNA Mitocondrial/genética , Regulação para Baixo/genética , Deficiência de Ácido Fólico/complicações , Deficiência de Ácido Fólico/diagnóstico , Camundongos , Camundongos Knockout , Doenças Mitocondriais/complicações , Doenças Mitocondriais/enzimologia , Doenças Neurodegenerativas/enzimologia , Doenças Neurodegenerativas/etiologia , Uracila-DNA Glicosidase/biossíntese
17.
Age (Dordr) ; 33(1): 33-47, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20567926

RESUMO

Previous studies have shown that longevity is associated with enhanced cellular stress resistance. This observation supports the disposable soma theory of aging, which suggests that the investment made in cellular maintenance will be proportional to selective pressures to extend lifespan. Maintenance of protein homeostasis is a critical component of cellular maintenance and stress resistance. To test the hypothesis that enhanced protein repair and recycling activities underlie longevity, we measured the activities of the 20S/26S proteasome and two protein repair enzymes in liver, heart and brain tissues of 15 different mammalian and avian species with maximum lifespans (MLSP) ranging from 3 to 30 years. The data set included Snell dwarf mice, in which lifespan is increased by ∼50% compared to their normal littermates. None of these activities in any of the three tissues correlated positively with MLSP. In liver, 20S/26S proteasome and thioredoxin reductase (TrxR) activities correlated negatively with body mass. In brain tissue, TrxR was also negatively correlated with body mass. Glutaredoxin (Grx) activity in brain was negatively correlated with MLSP and this correlation remained after residual analysis to remove the effects of body mass, but was lost when the data were analysed using Felsenstein's independent contrasts. Snell dwarf mice had marginally lower 20S proteasome, TrxR and Grx activities than normal controls in brain, but not heart tissue. Thus, increased longevity is not associated with increased protein repair or proteasomal degradation capacities in vertebrate endotherms.


Assuntos
Envelhecimento/metabolismo , Homeostase , Longevidade , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas/metabolismo , Animais , Vertebrados
18.
Mech Ageing Dev ; 131(9): 591-8, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20736031

RESUMO

In mammals, insulin-like growth factor-1 (IGF-1) is positively correlated with adult body mass, in comparisons made within a given species. In mice, IGF-1 deficiency is associated with dwarfism, whereas IGF-1 overproduction in transgenic animals causes gigantism. Surprisingly, the opposite is true in an inter-species context. We collected published plasma total IGF-1 data for adults of 36 mammalian species and analyzed it with respect to body mass. In contrast to the intra-species observation, this analysis revealed a significant negative correlation of plasma IGF-1 with body mass. Interestingly, IGF-1 is negatively correlated with longevity, and suppression of IGF-1 signalling in worms, flies and mice increases lifespan. Smaller mouse strains, for example, tend to have lower plasma IGF-1 levels and to be longer-lived. However, when plasma total IGF-1 was analyzed relative to the maximum lifespans of the 36 species examined here, there was no statistically significant correlation. Low plasma IGF-1 levels in larger mammalian species may be physiologically significant, considering the roles of this hormone in metabolism, tissue regeneration, and cancer incidence.


Assuntos
Fator de Crescimento Insulin-Like I/biossíntese , Fator de Crescimento Insulin-Like I/metabolismo , Animais , Composição Corporal , Índice de Massa Corporal , Peso Corporal , Feminino , Humanos , Longevidade , Masculino , Camundongos , Filogenia , Regeneração , Especificidade da Espécie , Fatores de Tempo
19.
Age (Dordr) ; 32(2): 255-70, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20431992

RESUMO

The free radical theory of ageing posits that accrual of oxidative damage underlies the increased cellular, tissue and organ dysfunction and failure associated with advanced age. In support of this theory, cellular resistance to oxidative stress is highly correlated with life span, suggesting that prevention or repair of oxidative damage might indeed be essential for longevity. To test the hypothesis that the prevention of oxidative damage underlies longevity, we measured the activities of the five major intracellular antioxidant enzymes in brain, heart and liver tissue of 14 mammalian and avian species with maximum life spans (MLSPs) ranging from 3 years to over 100 years. Our data set included Snell dwarf mice in which life span is increased by approximately 50% compared to their normal littermates. We found that CuZn superoxide dismutase, the major cytosolic superoxide dismutase, showed no correlation with MLSP in any of the three organs. Similarly, neither glutathione peroxidase nor glutathione reductase activities correlated with MLSP. MnSOD, the sole mitochondrial superoxide dismutase in mammals and birds, was positively correlated with MLSP only for brain tissue. This same trend was observed for catalase. For all correlational data, effects of body mass and phylogenetic relatedness were removed using residual analysis and Felsenstein's phylogenetically independent contrasts. Our results are not consistent with a causal role for intracellular antioxidant enzymes in longevity, similar to recent reports from studies utilising genetic modifications of mice (Pérez et al., Biochim Biophys Acta 1790:1005-1014, 2009). However, our results indicate a specific augmentation of reactive oxygen species neutralising activities in brain associated with longevity.


Assuntos
Antioxidantes/metabolismo , Longevidade , Vertebrados/fisiologia , Animais , Encéfalo/metabolismo , Catalase/metabolismo , Radicais Livres , Glutationa/metabolismo , Cobaias , Fígado/metabolismo , Miocárdio/metabolismo , Especificidade de Órgãos , Coelhos , Ratos , Especificidade da Espécie , Superóxido Dismutase/metabolismo , Suínos
20.
Mech Ageing Dev ; 131(4): 242-52, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20219522

RESUMO

Mitochondrial redox metabolism has long been considered to play important roles in mammalian aging and the development of age-related pathologies in the major oxidative organs. Both genetic and dietary manipulations of mitochondrial redox metabolism have been associated with the extension of lifespan. Here we provide a broad overview of the circumstantial evidence showing associations between mitochondrial reactive oxygen species (ROS) metabolism, aging and longevity. We address most aspects of mitochondrial ROS metabolism, from superoxide production, to ROS detoxification and the repair/removal of ROS-mediated macromolecular damage. Finally, we discuss the effects of dietary manipulations (e.g. caloric restriction, methionine restriction), dietary deficiencies (e.g. folate) and dietary supplementation (e.g. resveratrol) on mitochondrial ROS metabolism and lifespan.


Assuntos
Envelhecimento/metabolismo , Metionina/metabolismo , Metionina/farmacologia , Mitocôndrias/metabolismo , Envelhecimento/efeitos dos fármacos , Envelhecimento/genética , Animais , Restrição Calórica , Dieta , Suplementos Nutricionais , Longevidade/efeitos dos fármacos , Longevidade/genética , Metionina/genética , Mitocôndrias/genética , Oxirredução , Ratos , Espécies Reativas de Oxigênio/metabolismo
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