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PubMed2005

Peroxisome proliferator-activated receptor gamma coactivator 1 in caloric restriction and other models of longevity.

Dietary restriction of calories (caloric restriction [CR]) increases longevity in phylogenetically diverse species. CR retards or prevents age-dependent deterioration of tissues and an array of spontaneous and chemically induced diseases associated with obesity including cardiovascular disease, diabetes, and cancer. An understanding of the molecular mechanisms that underlie the beneficial effects of CR will help identify novel dietary, pharmacological, and lifestyle strategies for slowing the rate of aging and preventing these diseases as well as identify factors which modulate chemical toxicity. Here, we review the involvement of transcriptional coactivator proteins, peroxisome proliferator-activated receptor (PPAR) gamma coactivator 1 (PGC-1) alpha and beta, and regulated nuclear receptors (NR) in mediating the phenotypic changes found in models of longevity which include rodent CR models and mouse mutants in which insulin and/or insulin-like growth factor-I signaling is attenuated. PGC-1alpha is transcriptionally or posttranslationally regulated in mammals by: 1) forkhead box "other" (FoxO) transcription factors through an insulin/insulin-like growth factor-I -dependent pathway, 2) glucagon-stimulated cellular AMP (cAMP) response element binding protein, 3) stress-activated kinase signaling through p38 mitogen-activated protein kinase, and 4) the deacetylase and longevity factor sirtuin 1 (SIRT1). PGC-1alpha and PGC-1beta regulate the ligand-dependent and -independent activation of a large number of NR including PPARalpha and constitutive activated receptor (CAR). These NR regulate genes involved in nutrient and xenobiotic transport and metabolism as well as resistance to stress. CR reverses age-dependent decreases in PGC-1alpha, PPARalpha, and regulated genes. Strategies that target one or multiple PGC-1-regulated NR could be used to mimic the beneficial health effects found in models of longevity.

Animals↗
PubMed2004

Long-lived growth hormone receptor knockout mice: interaction of reduced insulin-like growth factor i/insulin signaling and caloric restriction.

Reduced IGF-I/insulin signaling and caloric restriction (CR) are known to extend the life span and delay age-related diseases. To address the interaction of these two interventions, we subjected normal (N) and long-lived GH receptor knockout (GHRKO) mice to CR for 20 months starting at weaning. We also used bovine GH transgenic (bGH Tg) mice, which overexpress GH and are short-lived and insulin resistant, for comparison. Circulating insulin and IGF-I levels were reduced by CR in N animals, whereas GHRKO animals exhibited very low insulin and undetectable IGF-I. Consistently, hepatic Akt phosphorylation was reduced by CR and was very low in GHRKO mice. bGH Tg mice exhibited increased active Akt. The forkhead box O1 (Foxo1) transcription factor was additively increased by CR and GHRKO at the mRNA level. However, Foxo1 protein levels were only elevated in GHRKO mice. The coactivator peroxisome proliferator-activated receptor-gamma coactivator 1alpha was increased at both gene and protein levels in GHRKO mice. N-CR and GHRKO mice also exhibited increased phosphorylated cAMP response element-binding protein and active p38 compared with the N ad libitum-fed mice, and the levels of these proteins were greatly diminished in bGH Tg mice. The protein levels of the deacetylase sirtuin 1 (SIRT1) were elevated in the two CR groups and, unexpectedly, also in bGH Tg mice. These results suggest a major role for the Akt/Foxo1 pathway in the regulation of longevity in rodents. An activated gluconeogenic pathway and increased fat metabolism may be involved in mediating the effects of reduced somatotropic and insulin signaling on longevity. These results also add to the evidence that targeted disruption of the GH receptor/GH-binding protein gene and CR act via overlapping, but distinct, mechanisms.

Adenylate Kinase↗
PubMed2005

Multiple mechanisms induce transcriptional silencing of a subset of genes, including oestrogen receptor alpha, in response to deacetylase inhibition by valproic acid and trichostatin A.

Valproate (VPA) and trichostatin A (TSA), inhibitors of zinc-dependent deacetylase activity, induce reduction in the levels of mRNA encoding oestrogen receptor-alpha (ERalpha), resulting in subsequent clearance of ERalpha protein from breast and ovarian cell lines. Inhibition of oestrogen signalling may account for the endocrine disorders, menstrual abnormalities, osteoporosis and weight gain that occur in a proportion of women treated with VPA for epilepsy or for bipolar mood disorder. Transcriptome profiling revealed that VPA and TSA also modulate the expression of, among others, key regulatory components of the cell cycle. Meta-analysis of genes directly responsive to oestrogen indicates that VPA and TSA have a generally antioestrogenic profile in ERalpha positive cells. Concomitant treatment with cycloheximide prevented most of these changes in gene expression, including downregulation of ERalpha mRNA, indicating that a limited number of genes signal a hyperacetylated state within cells. Three members of the NAD-dependent deacetylases, the sirtuins, are upregulated by VPA and by TSA and sirtuin activity contributes to loss of ERalpha expression. However, prolonged inhibition of the sirtuins by sirtinol also induces loss of ERalpha from cells. Mechanistically, we show that VPA invokes reversible promoter shutoff of the ERalpha, pS2 and cyclin D1 promoters, by inducing recruitment of methyl cytosine binding protein 2 (MeCP2) with concomitant exclusion of the maintenance methylase DNMT1. Furthermore, we demonstrate that, in the presence of VPA, local DNA methylation, deacetylation and demethylation of activated histones and recruitment of inhibitory complexes occurs on the pS2 promoter.

Base Sequence↗
PubMed2026

Sechium edule: Phytochemistry, Biological Activities, Potential Health Effects, Food-Industry Applications, and Future Perspectives.

Sechium edule (Jacq.) Sw. (chayote), a neglected and underutilized Cucurbitaceae crop widely cultivated across tropical and subtropical regions, has drawn growing interest as a source of health-promoting food components. This review critically synthesizes studies published between 2000 and 2026 on its botanical features, genome characterization, nutritional value, phytochemistry, bioactivities, safety, and food-industry applications, based on literature retrieved from PubMed, Scopus, Web of Science, ScienceDirect, and the Cochrane Library. Different plant parts (fruits, leaves, seeds, tuberous roots, and peels) contain diverse bioactive compounds, including flavonoids, phenolic acids, cucurbitacins, pectin polysaccharides, and carotenoids. Reported bioactivities include antioxidant, anti-inflammatory, hypoglycemic, cardioprotective, antiproliferative, and geroprotective effects, mediated in part through Nrf2-mediated antioxidant signaling and sirtuin (SIRT1/3/5/6) upregulation. Notably, a systematic meta-analysis demonstrated a significant reduction in serum glucose (MD = -20.56; 95% CI: -29.35 to -11.77) and HbA1c following three months of chayote intake in patients with metabolic syndrome and type 2 diabetes. Industrially, chayote has been developed into fermented products, starch- and peel-derived bioactive films, ultrasound-extracted pectin, α-amylase inhibitory seed protein isolates, and probiotic encapsulation systems. Recent genomic work has further revealed a chromosome-level genome assembly, whole-genome duplication events, and a domestication history tracing to Mexico's Oaxaca region. Collectively, this evidence positions chayote as a promising underutilized resource for food, nutraceutical, and biomedical use, while highlighting key gaps: the need for standardized clinical trials, bioavailability studies, and comprehensive safety evaluation.

Sechium edule↗
PubMed2006

Cell cycle and checkpoint regulation of histone H3 K56 acetylation by Hst3 and Hst4.

Histone modifications, including H3 K56 acetylation, have been implicated in DNA damage tolerance. Here, we present evidence that Hst3 and Hst4, two paralogues of the histone deacetylase Sir2, target the cell cycle-regulated acetylation of H3 on K56 and are downregulated during DNA damage in a checkpoint-dependent manner. We show that Hst3 and Hst4 are themselves cell cycle regulated and that their misexpression affects H3 K56-Ac. Moreover, a histone H3 K56R mutation is epistatic to all phenotypes caused by HST3/4 deletion or HST3 overexpression, suggesting that H3K56-Ac is the major target of these histone deacetylases. On examining 18 members of the "Clb2 cluster" of cell cycle-regulated proteins to which Hst3 belongs, we find that two others, Ynl058c and Alk1, are significantly downregulated on DNA damage. Taken together, our data show that Hst3/Hst4 are negative regulators of H3 K56-Ac and that HST3 downregulation by a checkpoint-mediated transcriptional repression system is essential for surviving DNA damage.

Acetylation↗
PubMed2003

Histone deacetylases in fungi: novel members, new facts.

Acetylation is the most prominent modification on core histones that strongly affects nuclear processes such as DNA replication, DNA repair and transcription. Enzymes responsible for the dynamic equilibrium of histone acetylation are histone acetyltransferases (HATs) and histone deacetylases (HDACs). In this paper we describe the identification of novel HDACs from the filamentous fungi Aspergillus nidulans and the maize pathogen Cochliobolus carbonum. Two of the enzymes are homologs of Saccharomyces cerevisiae HOS3, an enzyme that has not been identified outside of the established yeast systems until now. One of these homologs, HosB, showed intrinsic HDAC activity and remarkable resistance against HDAC inhibitors like trichostatin A (TSA) when recombinant expressed in an Escherichia coli host system. Phylo genetic analysis revealed that HosB, together with other fungal HOS3 orthologs, is a member of a separate group within the classical HDACs. Immunological investigations with partially purified HDAC activities of Aspergillus showed that all classical enzymes are part of high molecular weight complexes and that a TSA sensitive class 2 HDAC constitutes the major part of total HDAC activity of the fungus. However, further biochemical analysis also revealed an NAD(+)-dependent activity that could be separated from the other activities by different types of chromatography and obviously represents an enzyme of the sirtuin class.

Amino Acid Sequence↗
PubMed2006

In vino veritas: a tale of two sirt1s?

Resveratrol increases life span in lower organisms by activating the NAD(+)-dependent histone deacetylase Sirt1. Studies by and now show that resveratrol promotes longevity and improves glucose homeostasis in mice by stimulating the Sirt1-mediated deacetylation of the transcriptional coactivator PGC-1alpha.

Acetylation↗
PubMed2005

Increased dosage of mammalian Sir2 in pancreatic beta cells enhances glucose-stimulated insulin secretion in mice.

Sir2 NAD-dependent deacetylases connect transcription, metabolism, and aging. Increasing the dosage or activity of Sir2 extends life span in yeast, worms, and flies and promotes fat mobilization and glucose production in mammalian cells. Here we show that increased dosage of Sirt1, the mammalian Sir2 ortholog, in pancreatic beta cells improves glucose tolerance and enhances insulin secretion in response to glucose in beta cell-specific Sirt1-overexpressing (BESTO) transgenic mice. This phenotype is maintained as BESTO mice age. Pancreatic perfusion experiments further demonstrate that Sirt1 enhances insulin secretion in response to glucose and KCl. Microarray analyses of beta cell lines reveal that Sirt1 regulates genes involved in insulin secretion, including uncoupling protein 2 (Ucp2). Isolated BESTO islets also have reduced Ucp2, increased ATP production, and enhanced insulin secretion during glucose and KCl stimulation. These findings establish the importance of Sirt1 in beta cell function in vivo and suggest therapeutic interventions for type 2 diabetes.

Animals↗
PubMed2006

The LXXLL motif of murine forkhead transcription factor FoxO1 mediates Sirt1-dependent transcriptional activity.

The forkhead transcription factor FoxO1 has been identified as a negative regulator of insulin/IGF-1 signaling. Its function is inhibited by phosphorylation and nuclear exclusion through a PI3K-dependent pathway. However, the structure/function relationship of FoxO1 has not been elucidated completely. In this study, we carried out mutation analysis of the FoxO1 coactivator-interacting LXXLL motif (amino acids 459-463). Expression of a 3A/LXXAA mutant, in which 3 Akt phosphorylation sites (T24, S253, and S316) and 2 leucine residues in the LXXLL motif (L462 and L463) were replaced by alanine, decreased both Igfbp-1 and G6Pase promoter activity and endogenous Igfbp-1 and G6Pase gene expression in simian virus 40-transformed (SV40-transformed) hepatocytes. Importantly, mutagenesis of the LXXLL motif eliminated FoxO1 interaction with the nicotinamide adenine dinucleotide-dependent (NAD-dependent) deacetylase sirtuin 1 (Sirt1), sustained the acetylated state of FoxO1, and made FoxO1 nicotinamide and resveratrol insensitive, supporting a role for this motif in Sirt1 binding. Furthermore, intravenous administration of adenovirus encoding 3A/LXXAA FoxO1 into Lepr db/db mice decreased fasting blood glucose levels and improved glucose tolerance and was accompanied by reduced G6Pase and Igfbp-1 gene expression and increased hepatic glycogen content. In conclusion, the LXXLL motif of FoxO1 may have an important role for its transcriptional activity and Sirt1 binding and should be a target site for regulation of gene expression of FoxO1 target genes and glucose metabolism in vivo.

1-Methyl-3-isobutylxanthine↗
PubMed2005

Suppression of FOXO1 activity by FHL2 through SIRT1-mediated deacetylation.

Forkhead box class O (FOXO) proteins are transcription factors that function downstream of the PTEN tumor suppressor and directly control the expression of genes involved in apoptosis, cell cycle progression, and stress responses. In the present study, we show that FOXO1 interacts with four and a half LIM 2 (FHL2) in prostate cancer cells. This interaction occurred in the nucleus and was enhanced by lysophosphatic acid. FHL2 decreased the transcriptional activity of FOXO1 and the expression of known FOXO target genes and inhibited FOXO1-induced apoptosis. Interestingly, SIRT1, a mammalian homolog of yeast Sir2, bound to and deacetylated FOXO1 and inhibited its transcriptional activity. FHL2 enhanced the interaction of FOXO1 and SIRT1 and the deacetylation of FOXO1 by Sirtuin-1 (SIRT1). Overall, our data show that FHL2 inhibits FOXO1 activity in prostate cancer cells by promoting the deacetylation of FOXO1 by SIRT1.

Acetylation↗
PubMed2006

SIRT1 regulates adiponectin gene expression through Foxo1-C/enhancer-binding protein alpha transcriptional complex.

Adiponectin is an adipose-derived hormone that plays an important role in maintaining energy homeostasis. Adiponectin gene expression is diminished in both obesity and type 2 diabetes. However, the mechanism underlying the impaired adiponectin gene expression remains poorly understood. Recent studies have indicated that forkhead transcription factor O1 (Foxo1) and silent information regulator 2 mammalian ortholog SIRT1 are involved in adipogenesis. Here we have shown that Foxo1 up-regulates adiponectin gene transcription through a Foxo1-responsive region in the mouse adiponectin promoter that contains two adjacent Foxo1 binding sites. Foxo1 interacts with CCAAT/enhancer-binding protein alpha (C/EBPalpha) to form a transcription complex at the mouse adiponectin promoter and up-regulates adiponectin gene transcription. Our study has revealed that C/EBPalpha accesses the adiponectin promoter through two Foxo1 binding sites and acts as a co-activator. Further, SIRT1 increases adiponectin transcription in adipocytes by activating Foxo1 and enhancing Foxo1 and C/EBPalpha interaction. Importantly, both Foxo1 and SIRT1 protein levels were significantly lower in epididymal fat tissues from db/db and high fat diet-induced obese mice compared with normal mice. We propose that low expression of SIRT1 and Foxo1 leads to impaired Foxo1-C/EBPalpha complex formation, which contributes to the diminished adiponectin expression in obesity and type 2 diabetes.

3T3-L1 Cells↗
PubMed2005

Gene expression profiling reveals a signaling role of glutathione in redox regulation.

Proteins can form reversible mixed disulfides with glutathione (GSH). It has been hypothesized that protein glutathionylation may represent a mechanism of redox regulation, in a fashion similar to that mediated by protein phosphorylation. We investigated whether GSH has a signaling role in the response of HL60 cells to hydrogen peroxide (H2O2), in addition to its obvious antioxidant role. We identified early changes in gene expression induced at different times by H2O2 treatment, under conditions that increase protein glutathionylation and minimal toxicity. We then investigated the effect of prior GSH depletion by buthionine sulfoximine and diethylmaleate on this response. The analysis revealed 2,016 genes regulated by H2O2. Of these, 215 genes showed GSH-dependent expression changes, classifiable into four clusters displaying down- or up-regulation by H2O2, either potentiated or inhibited by GSH depletion. The modulation of 20 selected genes was validated by real-time RT-PCR. The biological process categories overrepresented in the largest cluster (genes whose up-regulation was inhibited by GSH depletion) were NF-kappaB activation, transcription, and DNA methylation. This cluster also included several cytokine and chemokine ligands and receptors, the redox regulator thioredoxin interacting protein, and the histone deacetylase sirtuin. The cluster of genes whose up-regulation was potentiated by GSH depletion included two HSPs (HSP40 and HSP70) and the AP-1 transcription factor components Fos and FosB. This work demonstrates that GSH, in addition to its antioxidant and protective function against oxidative stress, has a specific signaling role in redox regulation.

Gene Expression↗
PubMed2006

Aberrant expression of cytoskeleton proteins in hippocampus from patients with mesial temporal lobe epilepsy.

Mesial temporal lobe epilepsy (MTLE), the most common form of epilepsy, is characterised by cytoarchitectural abnormalities including neuronal cell loss and reactive gliosis in hippocampus. Determination of aberrant cytoskeleton protein expression by proteomics techniques may help to understand pathomechanism that is still elusive. We searched for differential expression of hippocampal proteins by an analytical method based on two-dimensional gel electrophoresis (2-DE) coupled with mass spectrometry unambiguously identifying 77 proteins analysed in eight control and eight MTLE hippocampi. Proteins were quantified and we observed 18 proteins that were altered in MTLE. Cytoskeleton proteins tubulin alpha-1 chain, beta-tubulin, profilin II, neuronal tropomodulin were significantly reduced and one actin spot was missing, whereas ezrin and vinculin were significantly increased in MTLE. Proteins of several classes as e.g. antioxidant proteins (peroxiredoxins 3 and 6), chaperons (T-complex protein 1-alpha, stress-induced-phosphoprotein 1), signaling protein MAP kinase kinase 1, synaptosomal proteins (synaptotagmin I, alpha-synuclein), NAD-dependent deacetylase sirtuin-2 and 26S protease regulatory subunit 7 protein, neuronal-specific septin 3 were altered in MTLE. Taken together, the findings may represent or lead to cytoskeletal impairment; aberrant antioxidant proteins, chaperons, MAP kinase kinase 1 and NAD-dependent deacetylase sirtuin-2 may have been involved in pathogenetic mechanisms and altered synaptosomal protein expression possibly reflects synaptic impairment in MTLE.

Adult↗
PubMed2005

A forkhead in the road to longevity: the molecular basis of lifespan becomes clearer.

OBJECTIVE: Although the quest for longevity is as old as civilization itself, only recently have technical and conceptual advances in genomics research brought us to the point of understanding the precise molecular events that make us age. This heralds an era when manipulations of these will enable us to live longer, healthier lives. The present review describes how recent experimental strategies have identified key genes and intracellular pathways that are responsible for ageing and longevity. FINDINGS: In diverse species transcription factors belonging to the forkhead/winged helix box gene, group O (FOXO) subfamily have been found to be crucial in downstream suppression of the life-shortening effects of insulin/insulin-like growth factor-I receptor signalling pathways that, when upregulated, accelerate ageing by suppression of FOXO. The various adverse processes activated upon FOXO suppression include increased generation of reactive oxygen species (ROS). ROS are pivotal for the onset of various common conditions, including hypertension, atherosclerosis, type 2 diabetes, cancer and Alzheimer's disease, each of which shortens lifespan. In humans, FOXO3a, as well as FOXO1 and -4, and their downstream effectors, could hold the key to counteracting ageing and common diseases. An understanding of the processes controlled by these FOXOs should permit development of novel classes of agents that will more directly counteract or prevent the damage associated with diverse life-threatening conditions, and so foster a life of good health to a ripe old age. Just like caloric restriction, lifespan can be increased in various species by plant-derived polyphenols, such as resveratrol, via activation of sirtuins in cells. Sirtuins, such as SIRT1 in mammals, utilize FOXO and other pathways to achieve their beneficial effects on health and lifespan. CONCLUSION: Lifespan is tractable and basic mechanisms are now known. Longevity research complements and overlaps research in most major medical disciplines. Current progress bodes well for an ever-increasing length of healthy life for those who adapt emerging knowledge personally (so-called 'longevitarians').

Aging↗
PubMed2005

Increase in activity during calorie restriction requires Sirt1.

Sir2 (silent information regulator 2) is a nicotinamide adenine dinucleotide-dependent deacetylase required for longevity due to calorie restriction in yeast and Drosophila. In mammals, calorie restriction induces a complex pattern of physiological and behavioral changes. Here we report that the mammalian Sir2 ortholog, Sirt1, is required for the induction of a phenotype by calorie restriction in mice.

Animals↗
PubMed2005

FoxO1 protects against pancreatic beta cell failure through NeuroD and MafA induction.

Diabetes causes pancreatic beta cell failure through hyperglycemia-induced oxidative stress, or "glucose toxicity." We show that the forkhead protein FoxO1 protects beta cells against oxidative stress by forming a complex with the promyelocytic leukemia protein Pml and the NAD-dependent deacetylase Sirt1 to activate expression of NeuroD and MafA, two Insulin2 (Ins2) gene transcription factors. Using acetylation-defective and acetylation-mimicking mutants, we demonstrate that acetylation targets FoxO1 to Pml and prevents ubiquitin-dependent degradation. We show that hyperglycemia suppresses MafA expression in vivo and that MafA inhibition can be prevented by transgenic expression of constitutively nuclear FoxO1 in beta cells. The findings provide a mechanism linking glucose- and growth factor receptor-activated pathways to protect beta cells against oxidative damage via FoxO proteins.

Acetylation↗
PubMed2003

Linking chromatin function with metabolic networks: Sir2 family of NAD(+)-dependent deacetylases.

Chromatin remodeling enzymes rely on coenzymes derived from metabolic pathways, suggesting a tight synchronization among apparently diverse cellular processes. A unique example of this link is the recently described NAD(+)-dependent protein and/or histone deacetylases. The founding member of this family - yeast silent information regulator 2 (ySir2) - is involved in gene silencing, chromosomal stability and ageing. Sir2-like enzymes catalyze a reaction in which the cleavage of NAD(+)and histone and/or protein deacetylation are coupled to the formation of O-acetyl-ADP-ribose, a novel metabolite. The dependence of the reaction on both NAD(+) and the generation of this potential second messenger offers new clues to understanding the function and regulation of nuclear, cytoplasmic and mitochondrial Sir2-like enzymes.

Catalysis↗