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1.
Gene ; 850: 146955, 2023 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-36220447

RESUMO

The present research aims to evaluate the effect of swimming exercise and chitosan-coated l-arginine on mitochondrial oxidation, BCL2 Interacting Protein 3 (Bnip3), NIP-like protein × (Nix), B-cell lymphoma-extra-large (Bcl-xL) and autophagy-related protein light chain 3(LC3) expression in soleus muscle of aging rats. In this experimental research, 25 male Wistar rats were assigned into five groups randomly: young, old, old + Nano l-arginine (Nano L-a), old + exercise (Ex), and old + Nano l-arginine (Nano L-a) + exercise (Ex) (n = 5 in each). They performed a swimming exercise program five days a week for six weeks. To determine the relative strength for rats before and after performing these interventions, the 1repetition maximum (1RM) test was done as a pre and post-test. The exercise program started with 20 min and after four sessions, gradually increased to 60 min and this time was maintained until the completion of the training period. l-arginine coated with chitosan nanoparticles was given to the rats in the l-arginine-supplemented group via gavage at a dosage of 500 mg/kg/day, five days a week, for six weeks. Additionally, the rats in all groups were fed a normal diet (2.87 kcal/g and 15 % energy from fat). Upon the completion of the protocol implementation, the rats were sacrificed and the soleus muscle was fixed and frozen to determine hematoxylin and eosin (H&E) staining, immunohistochemistry (IHC), gene expression analysis, levels of reactive oxygen species (ROS), and total antioxidant capacity (TAC). The results from the present research indicated that swimming exercise and Nano l-arginine improve the strength and histology of muscle tissue in old rats (p < 0.05). Aging significantly increased the expression of Nix and Bnip3 (p < 0.05) and reduced the Bcl-xL gene expression (p < 0.05). The expression of LC3 protein also increased with aging (p < 0.05). Therapeutic interventions, such as combined treatment (old + Nano L-a + Ex) for old animals, reduced the amount of this protein in soleus muscle (p < 0.05). The ROS values also showed a significant reduction only in the old + Nano L-a + Ex group compared to the old group. Moreover, TAC values show a significant decrease in the old and old + Ex groups in comparison to the young group. The use of arginine supplement, especially in nano form, along with swimming exercise seems to reduce the oxidative damage to the elderly muscle tissue, which has a positive effect on the structure and function of the soleus muscle. Since these interventions only had a significant effect on LC3 protein, further studies with more diverse measurement methods for autophagy are suggested.


Assuntos
Quitosana , Condicionamento Físico Animal , Animais , Masculino , Ratos , Envelhecimento/metabolismo , Antioxidantes/farmacologia , Arginina/farmacologia , Arginina/metabolismo , Autofagia , Proteínas Relacionadas à Autofagia/metabolismo , Quitosana/farmacologia , Suplementos Nutricionais , Amarelo de Eosina-(YS)/metabolismo , Amarelo de Eosina-(YS)/farmacologia , Hematoxilina/metabolismo , Hematoxilina/farmacologia , Músculo Esquelético/metabolismo , Estresse Oxidativo , Condicionamento Físico Animal/fisiologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Natação
2.
Biomolecules ; 12(11)2022 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-36358900

RESUMO

The study of aging is an important topic in contemporary research. Considering the demographic changes and the resulting shifts towards an older population, it is of great interest to preserve youthful physiology in old age. For this endeavor, it is necessary to choose an appropriate model. One such model is the nematode Caenorhabditis elegans (C. elegans), which has a long tradition in aging research. In this review article, we explore the advantages of using the nematode model in aging research, focusing on bioenergetics and the study of secondary plant metabolites that have interesting implications during this process. In the first section, we review the situation of aging research today. Conventional theories and hypotheses about the ongoing aging process will be presented and briefly explained. The second section focuses on the nematode C. elegans and its utility in aging and nutrition research. Two useful genome editing methods for monitoring genetic interactions (RNAi and CRISPR/Cas9) are presented. Due to the mitochondria's influence on aging, we also introduce the possibility of observing bioenergetics and respiratory phenomena in C. elegans. We then report on mitochondrial conservation between vertebrates and invertebrates. Here, we explain why the nematode is a suitable model for the study of mitochondrial aging. In the fourth section, we focus on phytochemicals and their applications in contemporary nutritional science, with an emphasis on aging research. As an emerging field of science, we conclude this review in the fifth section with several studies focusing on mitochondrial research and the effects of phytochemicals such as polyphenols. In summary, the nematode C. elegans is a suitable model for aging research that incorporates the mitochondrial theory of aging. Its living conditions in the laboratory are optimal for feeding studies, thus enabling bioenergetics to be observed during the aging process.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Humanos , Caenorhabditis elegans/metabolismo , Envelhecimento/metabolismo , Mitocôndrias/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Compostos Fitoquímicos/metabolismo
3.
Biomolecules ; 12(11)2022 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-36358944

RESUMO

BACKGROUND: The process of aging and metabolism are intricately linked, thus rendering the identification of reliable biomarkers related to metabolism crucial for delaying the aging process. However, research of reliable markers that reflect aging profiles based on machine learning is scarce. METHODS: Serum samples were obtained from aged mice (18-month-old) and young mice (3-month-old). LC-MS was used to perform a comprehensive analysis of the serum metabolome and machine learning was used to screen potential aging-related biomarkers. RESULTS: In total, aging mice were characterized by 54 different metabolites when compared to control mice with criteria: VIP ≥ 1, q-value < 0.05, and Fold-Change ≥ 1.2 or ≤0.83. These metabolites were mostly involved in fatty acid biosynthesis, cysteine and methionine metabolism, D-glutamine and D-glutamate metabolism, and the citrate cycle (TCA cycle). We merged the comprehensive analysis and four algorithms (LR, GNB, SVM, and RF) to screen aging-related biomarkers, leading to the recognition of oleic acid. In addition, five metabolites were identified as novel aging-related indicators, including oleic acid, citric acid, D-glutamine, trypophol, and L-methionine. CONCLUSIONS: Changes in the metabolism of fatty acids and conjugates, organic acids, and amino acids were identified as metabolic dysregulation related to aging. This study revealed the metabolic profile of aging and provided insights into novel potential therapeutic targets for delaying the effects of aging.


Assuntos
Envelhecimento , Glutamina , Camundongos , Animais , Cromatografia Líquida , Espectrometria de Massas , Biomarcadores/metabolismo , Envelhecimento/metabolismo , Ácidos Oleicos
4.
Nature ; 611(7935): 358-364, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36323784

RESUMO

The accumulation of senescent cells is a major cause of age-related inflammation and predisposes to a variety of age-related diseases1. However, little is known about the molecular basis underlying this accumulation and its potential as a target to ameliorate the ageing process. Here we show that senescent cells heterogeneously express the immune checkpoint protein programmed death-ligand 1 (PD-L1) and that PD-L1+ senescent cells accumulate with age in vivo. PD-L1- cells are sensitive to T cell surveillance, whereas PD-L1+ cells are resistant, even in the presence of senescence-associated secretory phenotypes (SASP). Single-cell analysis of p16+ cells in vivo revealed that PD-L1 expression correlated with higher levels of SASP. Consistent with this, administration of programmed cell death protein 1 (PD-1) antibody to naturally ageing mice or a mouse model with normal livers or induced nonalcoholic steatohepatitis reduces the total number of p16+ cells in vivo as well as the PD-L1+ population in an activated CD8+ T cell-dependent manner, ameliorating various ageing-related phenotypes. These results suggest that the heterogeneous expression of PD-L1 has an important role in the accumulation of senescent cells and inflammation associated with ageing, and the elimination of PD-L1+ senescent cells by immune checkpoint blockade may be a promising strategy for anti-ageing therapy.


Assuntos
Envelhecimento , Antígeno B7-H1 , Fenótipo , Receptor de Morte Celular Programada 1 , Animais , Camundongos , Envelhecimento/imunologia , Envelhecimento/metabolismo , Envelhecimento/patologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Inflamação/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo , Análise de Célula Única , Hepatopatia Gordurosa não Alcoólica , Fígado , Rejuvenescimento
5.
Int J Mol Sci ; 23(21)2022 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-36361511

RESUMO

Autophagy is involved in the maintenance of cellular homeostasis and the removal of damaged proteins and organelles and is necessary to maintain cell metabolism in conditions of energy and nutrient deficiency. A decrease in autophagic activity plays an important role in age-related diseases. However, the metabolic response to autophagy modulation remains poorly understood. Here, we for the first time explored the effects of (1) autophagy activation by 48 h fasting, (2) inhibition by chloroquine (CQ) treatment, and (3) combined effects of fasting and CQ on the quantitative composition of metabolites in the blood serum of senescent-accelerated OXYS and control Wistar rats at the age of 4 months. By means of high-resolution 1H NMR spectroscopy, we identified the quantitative content of 55 serum metabolites, including amino acids, organic acids, antioxidants, osmolytes, glycosides, purine, and pyrimidine derivatives. Groups of 48 h fasting (induction of autophagy), CQ treatment (inhibition of autophagy), and combined effects (CQ + fasting) are clearly separated from control groups by principal component analysis. Fasting for 48 h led to significant changes in the serum metabolomic profile, primarily affecting metabolic pathways related to fatty acid metabolism, and led to metabolism of several amino acids. Under CQ treatment, the most affected metabolites were citrate, betaine, cytidine, proline, tryptophan, glutamate, and mannose. As shown by two-way ANOVA, for many metabolites the effects of autophagy modulation depend on the animal genotype, indicating a dysregulation of metabolome reactivity in OXYS rats. Thus, the metabolic responses to modulation of autophagy in OXYS rats and Wistar rats are different. Altered metabolites in OXYS rats may serve as potential biomarkers of the manifestation of the signs of accelerated aging. Metabolic signatures characteristic to fasting and CQ treatment revealed in this work might provide a better understanding of the connections between metabolism and autophagy.


Assuntos
Metabolômica , Soro , Animais , Ratos , Ratos Wistar , Envelhecimento/metabolismo , Autofagia/genética , Aminoácidos
6.
Int J Mol Sci ; 23(21)2022 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-36361845

RESUMO

Atherosclerosis is one of the main underlying causes of cardiovascular diseases (CVD). It is associated with chronic inflammation and intimal thickening as well as the involvement of multiple cell types including immune cells. The engagement of innate or adaptive immune response has either athero-protective or atherogenic properties in exacerbating or alleviating atherosclerosis. In atherosclerosis, the mechanism of action of immune cells, particularly monocytes, macrophages, dendritic cells, and B- and T-lymphocytes have been discussed. Immuno-senescence is associated with aging, viral infections, genetic predispositions, and hyperlipidemia, which contribute to atherosclerosis. Immune senescent cells secrete SASP that delays or accelerates atherosclerosis plaque growth and associated pathologies such as aneurysms and coronary artery disease. Senescent cells undergo cell cycle arrest, morphological changes, and phenotypic changes in terms of their abundances and secretome profile including cytokines, chemokines, matrix metalloproteases (MMPs) and Toll-like receptors (TLRs) expressions. The senescence markers are used in therapeutics and currently, senolytics represent one of the emerging treatments where specific targets and clearance of senescent cells are being considered as therapy targets for the prevention or treatment of atherosclerosis.


Assuntos
Aterosclerose , Senescência Celular , Humanos , Senescência Celular/genética , Envelhecimento/metabolismo , Citocinas/metabolismo , Inflamação/patologia
7.
Mol Cells ; 45(11): 763-770, 2022 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-36380728

RESUMO

Caenorhabditis elegans has been used as a major model organism to identify genetic factors that regulate organismal aging and longevity. Insulin/insulin-like growth factor 1 (IGF- 1) signaling (IIS) regulates aging in many species, ranging from nematodes to humans. C. elegans is a nonpathogenic genetic nematode model, which has been extensively utilized to identify molecular and cellular components that function in organismal aging and longevity. Here, we review the recent progress in the role of IIS in aging and longevity, which involves direct regulation of protein and RNA homeostasis, stress resistance, metabolism and the activities of the endocrine system. We also discuss recently identified genetic factors that interact with canonical IIS components to regulate aging and health span in C. elegans. We expect this review to provide valuable insights into understanding animal aging, which could eventually help develop anti-aging drugs for humans.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Humanos , Caenorhabditis elegans/genética , Fator de Crescimento Insulin-Like I/metabolismo , Insulina/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Longevidade/genética , Envelhecimento/metabolismo
8.
Exp Gerontol ; 169: 111976, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36244585

RESUMO

There is a need to characterize the potential susceptibility of older adults to toxicity from environmental chemical exposures. Liver xenobiotic metabolizing enzymes (XMEs) play important roles in detoxifying and eliminating xenobiotics. We examined global gene expression in the livers of young (21-45 years) and old (69+ years) men and women. Differentially expressed genes (DEG) were identified using two-way ANOVA (p ≤ 0.05). We identified 1437 and 1670 DEGs between young and old groups in men and women, respectively. Only a minor number of the total number of genes overlapped (146 genes). Aging increased or decreased pathways involved in inflammation and intermediary metabolism, respectively. Aging led to numerous changes in the expression of XME genes or genes known to control their expression (~90 genes). Out of 10 cytochrome P450s activities examined, there were increased activities of CYP1A2 and CYP2C9 enzymes in the old groups. We also identified sex-dependent genes that were more numerous in the young group (1065) than in the old group (202) and included changes in XMEs. These studies indicate that the livers from aging humans when compared to younger adults exhibit changes in XMEs that may lead to differences in the metabolism of xenobiotics.


Assuntos
Sistema Enzimático do Citocromo P-450 , Xenobióticos , Masculino , Humanos , Feminino , Idoso , Xenobióticos/metabolismo , Xenobióticos/toxicidade , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Fígado/metabolismo , Envelhecimento/genética , Envelhecimento/metabolismo , Expressão Gênica
9.
Biochem Soc Trans ; 50(5): 1389-1402, 2022 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-36305642

RESUMO

Advances in public health have nearly doubled life expectancy over the last century, but this demographic shift has also changed the landscape of human illness. Today, chronic and age-dependent diseases dominate the leading causes of morbidity and mortality worldwide. Targeting the underlying molecular, genetic and cell biological drivers of the aging process itself appears to be an increasingly viable strategy for developing therapeutics against these diseases of aging. Towards this end, one of the most exciting developments in cell biology over the last decade is the explosion of research into organelle contact sites and related mechanisms of inter-organelle communication. Identification of the molecular mediators of inter-organelle tethering and signaling is now allowing the field to investigate the consequences of aberrant organelle interactions, which frequently seem to correlate with age-onset pathophysiology. This review introduces the major cellular roles for inter-organelle interactions, including the regulation of organelle morphology, the transfer of ions, lipids and other metabolites, and the formation of hubs for nutrient and stress signaling. We explore how these interactions are disrupted in aging and present findings that modulation of inter-organelle communication is a promising avenue for promoting longevity. Through this review, we propose that the maintenance of inter-organelle interactions is a pillar of healthy aging. Learning how to target the cellular mechanisms for sensing and controlling inter-organelle communication is a key next hurdle for geroscience.


Assuntos
Envelhecimento , Organelas , Humanos , Envelhecimento/metabolismo , Longevidade , Membranas Mitocondriais , Organelas/metabolismo , Comunicação Celular
10.
Int J Mol Sci ; 23(19)2022 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-36232442

RESUMO

Cardiac aging is characterized by increased cardiomyocyte hypertrophy, myocardial stiffness, and fibrosis, which enhance cardiovascular risk. The receptor for advanced glycation end-products (RAGE) is involved in several age-related diseases. RAGE knockout (Rage-/-) mice show an acceleration of cardiac dimension changes and interstitial fibrosis with aging. This study identifies the age-associated cardiac gene expression signature induced by RAGE deletion. We analyzed the left ventricle transcriptome of 2.5-(Young), 12-(Middle age, MA), and 21-(Old) months-old female Rage-/- and C57BL/6N (WT) mice. By comparing Young, MA, and Old Rage-/- versus age-matched WT mice, we identified 122, 192, and 12 differently expressed genes, respectively. Functional inference analysis showed that RAGE deletion is associated with: (i) down-regulation of genes involved in antigen processing and presentation of exogenous antigen, adaptive immune response, and cellular responses to interferon beta and gamma in Young animals; (ii) up-regulation of genes related to fatty acid oxidation, cardiac structure remodeling and cellular response to hypoxia in MA mice; (iii) up-regulation of few genes belonging to complement activation and triglyceride biosynthetic process in Old animals. Our findings show that the age-dependent cardiac phenotype of Rage-/- mice is associated with alterations of genes related to adaptive immunity and cardiac stress pathways.


Assuntos
Envelhecimento , Transcriptoma , Envelhecimento/genética , Envelhecimento/metabolismo , Animais , Ácidos Graxos , Feminino , Fibrose , Produtos Finais de Glicação Avançada/genética , Produtos Finais de Glicação Avançada/metabolismo , Interferon beta/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor para Produtos Finais de Glicação Avançada/genética , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Triglicerídeos
11.
J Prev Alzheimers Dis ; 9(4): 580-588, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36281662

RESUMO

Alzheimer's Disease is a progressive manifestation of aging associated with accumulated Amyloid ß. It remains frustratingly unclear why this protein accumulates and how it contributes to Alzheimer's Disease pathology. In one recent hypothesis, Amyloid ß is suggested to function as an antimicrobial peptide in innate immune defense within the brain, where Amyloid ß gains toxicity when it becomes abundant. This essay proposes an evolutionary explanation for why Amyloid ß expression is regulated at an optimum based on its function as a defense and how this leads to disease. Among its potential physiological functions, Amyloid ß confers benefits to reduce direct pathogen damage while this simultaneously entails cellular cost of defense. Optimal Amyloid ß expression occurs when the gain in fitness from an incremental increase is balanced by the marginal cost of this increase. It proposes that natural selection acting upon the young favored systems to maintain Amyloid ß at an optimal level through mechanisms that induce the defense and repress its expression. With age, the force of natural selection declines and permits mechanisms of negative feedback repression to degenerate. Consequently, Amyloid ß is expressed beyond its optimum. Age also elevates cumulative pathogen exposure, reduces pathogen barriers and reactivates latent pathogens. The net effect is elevated, chronic induction of Amyloid ß in the brain. The model recommends attention to innate immune negative regulation in the brain to discover ways to restore these functions toward a youthful state in the elderly.


Assuntos
Doença de Alzheimer , Humanos , Idoso , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Envelhecimento/metabolismo , Imunidade Inata
12.
J Proteome Res ; 21(11): 2664-2686, 2022 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-36181456

RESUMO

Protein turnover maintains the proteome's functional integrity. Here, protein turnover efficiency over time in wild-type Caenorhabditis elegans was assessed using inverse [15N]-pulse labeling up to 7 days after the egg-laying phase at 20 °C. Isotopic analysis of some abundant proteins was executed favoring data quality over quantity for mathematical modeling. Surprisingly, isotopic enrichment over time reached an upper limit showing an apparent cessation of protein renewal well before death, with protein fractions inaccessible to turnover ranging from 14 to 83%. For life span modulation, worms were raised at different temperatures after egg laying. Mathematical modeling of isotopic enrichment points either to a slowdown of protein turnover or to an increasing protein fraction resistant to turnover with time. Most notably, the estimated time points of protein turnover cessation from our mathematical model were highly correlated with the observed median life span. Thrashing and pumping rates over time were linearly correlated with isotopic enrichment, therefore linking protein/tracer intake to protein turnover rate and protein life span. If confirmed, life span extension is possible by optimizing protein turnover rate through modulating protein intake in C. elegans and possibly other organisms. While proteome maintenance benefits from a high protein turnover rate, protein turnover is fundamentally energy-intensive, where oxidative stress contributes to damage that it is supposed to repair.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Proteoma/genética , Proteoma/metabolismo , Longevidade , Envelhecimento/metabolismo , Ingestão de Alimentos
13.
Arthritis Res Ther ; 24(1): 235, 2022 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-36258202

RESUMO

BACKGROUND: Animal models of spontaneous osteoarthritis (OA) are sparse and not well characterized. The purpose of the present study is to examine OA-related changes and mechanisms in senescence-accelerated mouse prone 8 (SAMP8) that displays a phenotype of accelerated aging.  METHODS: Knees of male SAMP8 and SAM-resistant 1 (SAMR1) mice as control from 6 to 33 weeks of age were evaluated by histological grading systems for joint tissues (cartilage, meniscus, synovium, and subchondral bone), and µCT analysis. Gene expression patterns in articular cartilage were analyzed by real-time PCR. Immunohistochemistry was performed for OA-related factors, senescence markers, and apoptosis. RESULTS: Starting at 14 weeks of age, SAMP8 exhibited mild OA-like changes such as proteoglycan loss and cartilage fibrillation. From 18 to 33 weeks of age, SAMP8 progressed to partial or full-thickness defects with exposure of subchondral bone on the medial tibia and exhibited synovitis. Histological scoring indicated significantly more severe OA in SAMP8 compared with SAMR1 from 14 weeks [median (interquartile range): SAMR1: 0.89 (0.56-1.81) vs SAMP8: 1.78 (1.35-4.62)] to 33 weeks of age [SAMR1: 1.67 (1.61-1.04) vs SAMP8: 13.03 (12.26-13.57)]. Subchondral bone sclerosis in the medial tibia, bone mineral density (BMD) loss of femoral metaphysis, and meniscus degeneration occurred much earlier than the onset of cartilage degeneration in SAMP8 at 14 weeks of age. CONCLUSIONS: SAMP8 are a spontaneous OA model that is useful for investigating the pathogenesis of primary OA and evaluating therapeutic interventions.


Assuntos
Cartilagem Articular , Osteoartrite , Camundongos , Animais , Masculino , Modelos Animais de Doenças , Osteoartrite/genética , Osteoartrite/patologia , Cartilagem Articular/patologia , Tíbia , Envelhecimento/metabolismo , Proteoglicanas
14.
Exp Gerontol ; 170: 111978, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36244586

RESUMO

The present study aimed to evaluate the anti-aging effect of the leaves of Scutellaria baicalensis Georgi (LSBG) and investigate its mechanisms. For this purpose, SD rats were received D-galactose (D-gal) subcutaneously (0.3 g/kg) and LSBG intragastrically (0.4 g/kg or 0.8 g/kg) for 7 weeks. Behavior tests were conducted to evaluate the cognitive function of all rats. Results showed that memory impairment was reversed by LSBG. Then, metabolomics of the cortex and hippocampus were used to investigate the potential mechanisms. 21 metabolites in the cortex and 22 metabolites in the hippocampus of aging rats were altered, respectively. Additionally, results showed that the content of key metabolites and activities of enzymes in glutamate metabolism and its downstream metabolism (glutathione metabolism) could be regulated by the LSBG. Additionally, proteins in the Nrf2 signaling pathway were analyzed by western blot. And the protein expression levels of Nrf2, GCLC, HO-1, NQO-1 were significantly regulated by the LSBG in the cortex and hippocampus. Above all, the anti-aging effects of the LSBG were involved in regulating the glutamate metabolism and Nrf2 signaling pathway.


Assuntos
Galactose , Scutellaria baicalensis , Animais , Ratos , Scutellaria baicalensis/metabolismo , Galactose/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Ratos Sprague-Dawley , Envelhecimento/metabolismo , Encéfalo/metabolismo , Estresse Oxidativo , Transdução de Sinais , Glutamatos/farmacologia
15.
Nature ; 611(7935): 374-379, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36289337

RESUMO

The dynamic turnover of actin filaments (F-actin) controls cellular motility in eukaryotes and is coupled to changes in the F-actin nucleotide state1-3. It remains unclear how F-actin hydrolyses ATP and subsequently undergoes subtle conformational rearrangements that ultimately lead to filament depolymerization by actin-binding proteins. Here we present cryo-electron microscopy structures of F-actin in all nucleotide states, polymerized in the presence of Mg2+ or Ca2+ at approximately 2.2 Å resolution. The structures show that actin polymerization induces the relocation of water molecules in the nucleotide-binding pocket, activating one of them for the nucleophilic attack of ATP. Unexpectedly, the back door for the subsequent release of inorganic phosphate (Pi) is closed in all structures, indicating that Pi release occurs transiently. The small changes in the nucleotide-binding pocket after ATP hydrolysis and Pi release are sensed by a key amino acid, amplified and transmitted to the filament periphery. Furthermore, differences in the positions of water molecules in the nucleotide-binding pocket explain why Ca2+-actin shows slower polymerization rates than Mg2+-actin. Our work elucidates the solvent-driven rearrangements that govern actin filament assembly and aging and lays the foundation for the rational design of drugs and small molecules for imaging and therapeutic applications.


Assuntos
Citoesqueleto de Actina , Actinas , Envelhecimento , Microscopia Crioeletrônica , Citoesqueleto de Actina/química , Citoesqueleto de Actina/metabolismo , Citoesqueleto de Actina/ultraestrutura , Actinas/química , Actinas/metabolismo , Actinas/ultraestrutura , Trifosfato de Adenosina/metabolismo , Hidrólise , Nucleotídeos/química , Nucleotídeos/metabolismo , Água/metabolismo , Envelhecimento/metabolismo , Magnésio , Cálcio , Aminoácidos , Fosfatos
16.
Ageing Res Rev ; 82: 101756, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36243357

RESUMO

Nuclear Factor-Erythroid Factor 2 (Nrf2) is an important transcription factor that regulates the expression of large number of genes in healthy and disease states. Nrf2 is made up of 605 amino acids and contains 7 conserved regions known as Nrf2-ECH homology domains. Nrf2 regulates the expression of several key components of oxidative stress, mitochondrial biogenesis, mitophagy, autophagy and mitochondrial function in all organs of the human body, in the peripheral and central nervous systems. Mounting evidence also suggests that altered expression of Nrf2 is largely involved in aging, neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's diseases, Amyotrophic lateral sclerosis, Stroke, Multiple sclerosis and others. The purpose of this article is to detail the essential role of Nrf2 in oxidative stress, antioxidative defense, detoxification, inflammatory responses, transcription factors, proteasomal and autophagic/mitophagic degradation, and metabolism in aging and neurodegenerative diseases. This article also highlights the Nrf2 structural and functional activities in healthy and disease states, and also discusses the current status of Nrf2 research and therapeutic strategies to treat aging and neurodegenerative diseases.


Assuntos
Doença de Alzheimer , Doenças Neurodegenerativas , Humanos , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Doenças Neurodegenerativas/metabolismo , Doença de Alzheimer/genética , Envelhecimento/metabolismo , Estresse Oxidativo/fisiologia
17.
Sci Rep ; 12(1): 17084, 2022 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-36224264

RESUMO

Slowing down age-related neurocognitive impairment has been a challenge. We evaluated the therapeutic effects of metformin in D-galactose-induced aging. Additionally, we studied the potential molecular mechanisms that could be responsible for metformin's anti-aging effects. Thirty male rats were equally divided into: 1-control group, which received saline solution, 2-D-galactose (D-gal) group, which received D-galactose (100 mg/kg/day) by gastric lavage for eight weeks, and 3-D-galactose + Metformin (D-gal + Met) treated group, which received D-galactose + metformin (200 mg/kg/day) by gastric lavage for eight weeks. Neurocognitive assessment was done. Measurement of inflammatory, oxidative stress, and BDNF biomarkers was performed. AMPK and PI3K genes expression were assessed. Hippocampal tissues were dissected for histopathological and immunohistochemical studies. D-gal resulted in neurocognitive impairments, elevation of inflammatory biomarkers, altered oxidative stress markers, decreased BDNF, decreased expression of synaptophysin and Bcl2 with increased expression of Caspase-3, and down-regulation of AMPK and PI3K genes. Neurodegenerative changes were present in the hippocampus. Metformin restored significantly D-gal induced neurodegenerative changes. We concluded that metformin could alleviate age-induced neurocognitive deficit via amelioration of neuroinflammation, attenuation of oxidative stress, reduction of apoptosis, as well as promotion of synaptic plasticity. These mechanisms could be mediated via the activation of the AMPK/BDNF/PI3K pathway.


Assuntos
Galactose , Metformina , Proteínas Quinases Ativadas por AMP/metabolismo , Envelhecimento/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Caspase 3/metabolismo , Galactose/farmacologia , Masculino , Metformina/farmacologia , Estresse Oxidativo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Solução Salina/farmacologia , Sinaptofisina/metabolismo
18.
Int J Mol Sci ; 23(19)2022 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-36233264

RESUMO

Age-associated loss of skeletal muscle mass and function is one of the main causes of the loss of independence and physical incapacitation in the geriatric population. This study used the D-galactose-induced C2C12 myoblast aging model to explore whether nobiletin (Nob) could delay skeletal muscle aging and determine the associated mechanism. The results showed that Nob intervention improved mitochondrial function, increased ATP production, reduced reactive oxygen species (ROS) production, inhibited inflammation, and prevented apoptosis as well as aging. In addition, Nob improved autophagy function, removed misfolded proteins and damaged organelles, cleared ROS, reduced mitochondrial damage, and improved skeletal muscle atrophy. Moreover, our results illustrated that Nob can not only enhance mitochondrial function, but can also enhance autophagy function and the protein synthesis pathway to inhibit skeletal muscle atrophy. Therefore, Nob may be a potential candidate for the prevention and treatment of age-related muscle decline.


Assuntos
Galactose , Mitocôndrias , Trifosfato de Adenosina/metabolismo , Idoso , Envelhecimento/metabolismo , Senescência Celular , Flavonas , Galactose/efeitos adversos , Galactose/metabolismo , Humanos , Mitocôndrias/metabolismo , Músculo Esquelético/metabolismo , Atrofia Muscular/induzido quimicamente , Atrofia Muscular/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo
19.
Ageing Res Rev ; 82: 101766, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36283617

RESUMO

INTRODUCTION: The protein Klotho (KL) was first discovered in KL-deficient mice, which developed a syndrome similar to premature aging in humans. Since then, KL has been implicated in multiple molecular signaling pathways and diseases. KL has been shown to have anti-aging, healthspan and lifespan extending, cognitive enhancing, anti-oxidative, anti-inflammatory, and anti-tumor properties. KL levels decrease with age and in many diseases. Therefore, it has been of great interest to develop a KL-boosting or restoring drug, or to supplement endogenous Klotho with exogenous Klotho genetic material or recombinant Klotho protein, and to use KL levels in the body as a marker for the efficacy of such drugs and as a biomarker for the diagnosis and management of diseases. OBJECTIVE: The goal of this study was to provide a comprehensive review of KL levels across age groups in individuals who are healthy or have certain health conditions, using four sources: blood, cerebrospinal fluid, urine, and whole biopsy/necropsy tissue. By doing so, baseline KL levels can be identified across the lifespan, in the absence or presence of disease. In turn, these findings can be used to guide the development of future KL-based therapeutics and biomarkers, which will heavily rely on an individual's baseline KL range to be efficacious. METHODS: A total of 65 studies were collected primarily using the PubMed database. Research articles that were published up to April 2022 were included. Statistical analysis was conducted using RStudio. RESULTS: Mean and median blood KL levels in healthy individuals, mean blood KL levels in individuals with renal conditions, and mean blood KL levels in individuals with metabolic or endocrine conditions were shown to decrease with age. Similarly, CSF KL levels in patients with AD also declined compared with age-matched controls. CONCLUSIONS: The present study confirms the trend that KL levels in blood decrease with age in humans, among those who are healthy, and even further among those with renal and endocrine/metabolic illnesses. Further, by drawing this trend from multiple published works, we were able to provide a general idea of baseline KL ranges, specifically in blood in these populations. These data add to the current knowledge on normal KL levels in the body and how they change with time and in disease, and can potentially support efforts to create KL-based treatments and screening tools to better manage aging, renal, and metabolic/endocrine diseases.


Assuntos
Senilidade Prematura , Glucuronidase , Humanos , Camundongos , Animais , Proteínas Klotho , Envelhecimento/metabolismo , Longevidade/genética , Biomarcadores
20.
J Physiol ; 600(21): 4633-4651, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36111692

RESUMO

Vascular dysfunction: develops progressively with ageing; increases the risk of cardiovascular diseases (CVD); and is characterized by endothelial dysfunction and arterial stiffening, which are primarily mediated by superoxide-driven oxidative stress and consequently reduced nitric oxide (NO) bioavailability and arterial structural changes. Interventions initiated before vascular dysfunction manifests may have more promise for reducing CVD risk than interventions targeting established dysfunction. Gut microbiome-derived trimethylamine N-oxide (TMAO) induces vascular dysfunction, is associated with higher CV risk, and can be suppressed by 3,3-dimethyl-1-butanol (DMB). We investigated whether DMB supplementation could prevent age-related vascular dysfunction in C57BL/6N mice when initiated prior to development of dysfunction. Mice received drinking water with 1% DMB or normal drinking water (control) from midlife (18 months) until being studied at 21, 24 or 27 months of age, and were compared to young adult (5 month) mice. Endothelial function [carotid artery endothelium-dependent dilatation (EDD) to acetylcholine; pressure myography] progressively declined with age in control mice, which was fully prevented by DMB via higher NO-mediated EDD and lower superoxide-related suppression of EDD (normalization of EDD with the superoxide dismutase mimetic TEMPOL). In vivo aortic stiffness (pulse wave velocity) increased progressively with age in controls, but DMB attenuated stiffening by ∼ 70%, probably due to preservation of endothelial function, as DMB did not affect aortic intrinsic mechanical (structural) stiffness (stress-strain testing) nor adventitial abundance of the arterial structural protein collagen. Our findings indicate that long-term DMB supplementation prevents/attenuates age-related vascular dysfunction, and therefore has potential for translation to humans for reducing CV risk with ageing. KEY POINTS: Vascular dysfunction, characterized by endothelial dysfunction and arterial stiffening, develops progressively with ageing and increases the risk of cardiovascular diseases (CVD). Interventions aimed at preventing the development of CV risk factors have more potential for preventing CVD relative to those aimed at reversing established dysfunction. The gut microbiome-derived metabolite trimethylamine N-oxide (TMAO) induces vascular dysfunction, is associated with higher CV risk and can be suppressed by supplementation with 3,3-dimethyl-1-butanol (DMB). In mice, DMB prevented the development of endothelial dysfunction and delayed and attenuated in vivo arterial stiffening with ageing when supplementation was initiated in midlife, prior to the development of dysfunction. DMB supplementation or other TMAO-suppressing interventions have potential for translation to humans for reducing CV risk with ageing.


Assuntos
Doenças Cardiovasculares , Água Potável , Doenças Vasculares , Rigidez Vascular , Camundongos , Humanos , Animais , Superóxidos/metabolismo , Vasodilatação , Análise de Onda de Pulso , Endotélio Vascular/metabolismo , Butanóis/metabolismo , Água Potável/metabolismo , Camundongos Endogâmicos C57BL , Envelhecimento/metabolismo , Doenças Vasculares/metabolismo , Óxido Nítrico/metabolismo
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