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2.
Cells ; 10(9)2021 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-34572007

RESUMO

Health and lifespan are influenced by dietary nutrients, whose balance is dependent on the supply or demand of each organism. Many studies have shown that an increased carbohydrate-lipid intake plays a critical role in metabolic dysregulation, which impacts longevity. Caenorhabditis elegans has been successfully used as an in vivo model to study the effects of several factors, such as genetic, environmental, diet, and lifestyle factors, on the molecular mechanisms that have been linked to healthspan, lifespan, and the aging process. There is evidence showing the causative effects of high glucose on lifespan in different diabetic models; however, the precise biological mechanisms affected by dietary nutrients, specifically carbohydrates and lipids, as well as their links with lifespan and longevity, remain unknown. Here, we provide an overview of the deleterious effects caused by high-carbohydrate and high-lipid diets, as well as the molecular signals that affect the lifespan of C. elegans; thus, understanding the detailed molecular mechanisms of high-glucose- and lipid-induced changes in whole organisms would allow the targeting of key regulatory factors to ameliorate metabolic disorders and age-related diseases.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/metabolismo , Carboidratos da Dieta/metabolismo , Lipídeos/fisiologia , Longevidade/fisiologia , Envelhecimento/metabolismo , Envelhecimento/fisiologia , Animais , Dieta/métodos , Humanos
3.
Nat Chem Biol ; 17(10): 1027-1036, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34552221

RESUMO

Aging is an inevitable biochemical process that adversely affects personal health and poses ever-increasing challenges to society. Recent research has revealed the crucial role of metabolism in regulating aging and longevity. During diverse metabolic processes, the host organism and their symbiotic partners-the microbiota-produce thousands of chemical products (metabolites). Emerging studies have uncovered specific metabolites that act as signaling molecules to actively regulate longevity. Here we review the latest progress in understanding the molecular mechanisms by which metabolites from the host and/or microbiota promote longevity. We also highlight state-of-the-art technologies for discovering, profiling and imaging aging- and longevity-regulating metabolites and for deciphering the molecular basis of their actions. The broad application of these technologies in aging research, together with future advances, will foster the systematic discovery of aging- and longevity-regulating metabolites and their signaling pathways. These metabolite signals should provide promising targets for developing new interventions to promote longevity and healthy aging.


Assuntos
Envelhecimento/fisiologia , Metabolismo Energético/fisiologia , Interações entre Hospedeiro e Microrganismos/fisiologia , Microbiota/fisiologia , Animais , Biomarcadores/metabolismo , Humanos , Longevidade/fisiologia
4.
Int J Mol Sci ; 22(17)2021 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-34502551

RESUMO

The evolutionarily conserved c-Jun N-terminal kinase (JNK) signaling pathway is a critical genetic determinant in the control of longevity. In response to extrinsic and intrinsic stresses, JNK signaling is activated to protect cells from stress damage and promote survival. In Drosophila, global JNK upregulation can delay aging and extend lifespan, whereas tissue/organ-specific manipulation of JNK signaling impacts lifespan in a context-dependent manner. In this review, focusing on several tissues/organs that are highly associated with age-related diseases-including metabolic organs (intestine and fat body), neurons, and muscles-we summarize the distinct effects of tissue/organ-specific JNK signaling on aging and lifespan. We also highlight recent progress in elucidating the molecular mechanisms underlying the tissue-specific effects of JNK activity. Together, these studies highlight an important and comprehensive role for JNK signaling in the regulation of longevity in Drosophila.


Assuntos
Envelhecimento/fisiologia , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/fisiologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Longevidade/fisiologia , Sistema de Sinalização das MAP Quinases/fisiologia , Animais , Encéfalo/citologia , Encéfalo/enzimologia , Drosophila melanogaster/enzimologia , Corpo Adiposo/enzimologia , Modelos Biológicos , Neurônios/enzimologia
5.
Nature ; 598(7880): 353-358, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34588695

RESUMO

Time-restricted feeding (TRF) has recently gained interest as a potential anti-ageing treatment for organisms from Drosophila to humans1-5. TRF restricts food intake to specific hours of the day. Because TRF controls the timing of feeding, rather than nutrient or caloric content, TRF has been hypothesized to depend on circadian-regulated functions; the underlying molecular mechanisms of its effects remain unclear. Here, to exploit the genetic tools and well-characterized ageing markers of Drosophila, we developed an intermittent TRF (iTRF) dietary regimen that robustly extended fly lifespan and delayed the onset of ageing markers in the muscles and gut. We found that iTRF enhanced circadian-regulated transcription and that iTRF-mediated lifespan extension required both circadian regulation and autophagy, a conserved longevity pathway. Night-specific induction of autophagy was both necessary and sufficient to extend lifespan on an ad libitum diet and also prevented further iTRF-mediated lifespan extension. By contrast, day-specific induction of autophagy did not extend lifespan. Thus, these results identify circadian-regulated autophagy as a critical contributor to iTRF-mediated health benefits in Drosophila. Because both circadian regulation and autophagy are highly conserved processes in human ageing, this work highlights the possibility that behavioural or pharmaceutical interventions that stimulate circadian-regulated autophagy might provide people with similar health benefits, such as delayed ageing and lifespan extension.


Assuntos
Autofagia/fisiologia , Ritmo Circadiano/fisiologia , Drosophila melanogaster/fisiologia , Comportamento Alimentar/fisiologia , Longevidade/fisiologia , Envelhecimento/genética , Envelhecimento/efeitos da radiação , Animais , Autofagia/genética , Biomarcadores , Relógios Circadianos/efeitos da radiação , Ritmo Circadiano/genética , Ritmo Circadiano/efeitos da radiação , Escuridão , Drosophila melanogaster/genética , Drosophila melanogaster/efeitos da radiação , Comportamento Alimentar/efeitos da radiação , Feminino , Longevidade/genética , Longevidade/efeitos da radiação , Masculino , Fatores de Tempo
6.
Nat Commun ; 12(1): 5073, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34417467

RESUMO

The contents of numerous membrane lipids change upon ageing. However, it is unknown whether and how any of these changes are causally linked to lifespan regulation. Acyl chains contribute to the functional specificity of membrane lipids. In this study, working with C. elegans, we identified an acyl chain-specific sphingolipid, C22 glucosylceramide, as a longevity metabolite. Germline deficiency, a conserved lifespan-extending paradigm, induces somatic expression of the fatty acid elongase ELO-3, and behenic acid (22:0) generated by ELO-3 is incorporated into glucosylceramide for lifespan regulation. Mechanistically, C22 glucosylceramide is required for the membrane localization of clathrin, a protein that regulates membrane budding. The reduction in C22 glucosylceramide impairs the clathrin-dependent autophagic lysosome reformation, which subsequently leads to TOR activation and longevity suppression. These findings reveal a mechanistic link between membrane lipids and ageing and suggest a model of lifespan regulation by fatty acid-mediated membrane configuration.


Assuntos
Caenorhabditis elegans/fisiologia , Ácidos Graxos não Esterificados/metabolismo , Glicoesfingolipídeos/metabolismo , Homeostase , Longevidade/fisiologia , Lisossomos/metabolismo , Animais , Proteínas de Caenorhabditis elegans/metabolismo , Ceramidas/metabolismo , Colesterol/metabolismo , Clatrina/metabolismo , Mutação em Linhagem Germinativa/genética , Proteínas de Fluorescência Verde/metabolismo , Larva/metabolismo , Modelos Biológicos , Interferência de RNA , Estresse Fisiológico
7.
Biomolecules ; 11(8)2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34439857

RESUMO

Improvement of longevity is an eternal dream of human beings. The accumulation of protein damages is considered as a major cause of aging. Here, we report that the injection of exogenous recombinant mouse serum albumin (rMSA) reduced the total damages of serum albumin in C57BL/6N mice, with higher level of free-thiols, lower levels of carbonyls and advanced glycation end-products as well as homocysteines in rMSA-treated mice. The healthspan and lifespan of C57BL/6N mice were significantly improved by rMSA. The grip strength of rMSA-treated female and male mice increased by 29.6% and 17.4%, respectively. Meanwhile, the percentage of successful escape increased 23.0% in rMSA-treated male mice using the Barnes Maze test. Moreover, the median lifespan extensions were 17.6% for female and 20.3% for male, respectively. The rMSA used in this study is young and almost undamaged. We define the concept "young and undamaged" to any protein without any unnecessary modifications by four parameters: intact free thiol (if any), no carbonylation, no advanced glycation end-product, and no homocysteinylation. Here, "young and undamaged" exogenous rMSA used in the present study is much younger and less damaged than the endogenous serum albumin purified from young mice at 1.5 months of age. We predict that undamaged proteins altogether can further improve the healthspan and lifespan of mice.


Assuntos
Envelhecimento/efeitos dos fármacos , Envelhecimento/fisiologia , Longevidade/efeitos dos fármacos , Longevidade/fisiologia , Albumina Sérica/administração & dosagem , Fatores Etários , Animais , Feminino , Força da Mão/fisiologia , Injeções Intravenosas , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Recombinantes/administração & dosagem
8.
Nutrients ; 13(7)2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34371855

RESUMO

Aging is a biological process determined by multiple cellular mechanisms, such as genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication, that ultimately concur in the functional decline of the individual. The evidence that the old population is steadily increasing and will triplicate in the next 50 years, together with the fact the elderlies are more prone to develop pathologies such as cancer, diabetes, and degenerative disorders, stimulates an important effort in finding specific countermeasures. Calorie restriction (CR) has been demonstrated to modulate nutrient sensing mechanisms, inducing a better metabolic profile, enhanced stress resistance, reduced oxidative stress, and improved inflammatory response. Therefore, CR and CR-mimetics have been suggested as powerful means to slow aging and extend healthy life-span in experimental models and humans. Taking into consideration the difficulties and ethical issues in performing aging research and testing anti-aging interventions in humans, researchers initially need to work with experimental models. The present review reports the major experimental models utilized in the study of CR and CR-mimetics, highlighting their application in the laboratory routine, and their translation to human research.


Assuntos
Envelhecimento/fisiologia , Materiais Biomiméticos/farmacologia , Restrição Calórica , Modelos Teóricos , Pesquisa Médica Translacional/métodos , Envelhecimento/efeitos dos fármacos , Animais , Senescência Celular/efeitos dos fármacos , Senescência Celular/fisiologia , Humanos , Longevidade/efeitos dos fármacos , Longevidade/fisiologia
9.
PLoS One ; 16(8): e0254779, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34407083

RESUMO

The unprecedented population aging brings profound influences to the social values of longevity. The individual attitudes toward the expended life time deserves scrutiny, as it reflects the impacts of social networks and social welfare on people's life and wellbeing. This study aims to examine whether and how gender disparity is affecting the individual anticipation to longevity among Japanese citizen. We used the dataset of National Survey on Social Security and Peoples Life implemented in 2017 to calculate the odds ratios (OR) of the individual anticipation to longevity. Besides gender, other demographic characteristics, physical and mental health, the experience of nursing care for the elderly, financial conditions and social networks are examined by performing the multilevel mixed-effects logistic regression analysis. The results indicate the robust effects of gender disparity on the individual aspiration for longevity. The proportion of those who inclined the positive statement on longevity was estimated to be 69.7% (95% CI: 68.6% - 70.9%) in the whole population, and 70.9% (95% CI: 69.4% - 72.5%) and 68.7% (95% CI: 67.1% - 70.2%) in male and female, respectively. Besides gender, independent factors significantly affecting the individual valuation of longevity include age, annual household income, the experience of nursing care, household saving, having a conversation with others and the availability of reliable partner(s) for relevant supports; while the common factors affecting the outcome variable were self-perceived health status and mental distress measured by K6. The interaction of gender and these significant factors were determined as well. In conclusion, with relevant representativeness and quality of data source, this analysis adds knowledge on gender disparity in the individual anticipation on longevity. The findings are suggestive to reform the social security system in the super aged society.


Assuntos
Grupo com Ancestrais do Continente Asiático , Longevidade/fisiologia , Sexismo , Inquéritos e Questionários , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Razão de Chances , Adulto Jovem
10.
Nat Commun ; 12(1): 4568, 2021 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-34315882

RESUMO

Insulin/IGF-1 Signaling (IIS) is known to constrain longevity by inhibiting the transcription factor FOXO. How phosphorylation mediated by IIS kinases regulates lifespan beyond FOXO remains unclear. Here, we profile IIS-dependent phosphorylation changes in a large-scale quantitative phosphoproteomic analysis of wild-type and three IIS mutant Caenorhabditis elegans strains. We quantify more than 15,000 phosphosites and find that 476 of these are differentially phosphorylated in the long-lived daf-2/insulin receptor mutant. We develop a machine learning-based method to prioritize 25 potential lifespan-related phosphosites. We perform validations to show that AKT-1 pT492 inhibits DAF-16/FOXO and compensates the loss of daf-2 function, that EIF-2α pS49 potently inhibits protein synthesis and daf-2 longevity, and that reduced phosphorylation of multiple germline proteins apparently transmits reduced DAF-2 signaling to the soma. In addition, an analysis of kinases with enriched substrates detects that casein kinase 2 (CK2) subunits negatively regulate lifespan. Our study reveals detailed functional insights into longevity.


Assuntos
Caenorhabditis elegans/fisiologia , Insulina/metabolismo , Longevidade/fisiologia , Transdução de Sinais , Algoritmos , Sequência de Aminoácidos , Animais , Proteínas de Caenorhabditis elegans/química , Proteínas de Caenorhabditis elegans/metabolismo , Células Germinativas/metabolismo , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Modelos Biológicos , Mutação/genética , Fosfoproteínas/metabolismo , Fosforilação , Proteoma/metabolismo , Proteômica
12.
Neurobiol Aging ; 106: 80-94, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34256190

RESUMO

Healthy aging is accompanied by reduced cognitive control and widespread alterations in the underlying brain networks; but the extent to which large-scale functional networks in older age show reduced specificity across different domains of cognitive control is unclear. Here we use cov-STATIS (a multi-table multivariate technique) to examine similarity of functional connectivity during different domains of cognitive control-inhibition, initiation, shifting, and working memory-across the adult lifespan. We report two major findings: (1) Functional connectivity patterns during initiation, inhibition, and shifting were more similar in older ages, particularly for control and default networks, a pattern consistent with dedifferentiation of the neural correlates associated with cognitive control; and (2) Networks exhibited age-related reconfiguration such that frontal, default, and dorsal attention networks were more integrated whereas sub-networks of somato-motor system were more segregated in older age. Together these findings offer new evidence for dedifferentiation and reconfiguration of functional connectivity underlying different aspects of cognitive control in normal aging.


Assuntos
Encéfalo/fisiologia , Desdiferenciação Celular/fisiologia , Cognição/fisiologia , Envelhecimento Saudável/fisiologia , Longevidade/fisiologia , Rede Nervosa/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/fisiologia , Envelhecimento/psicologia , Encéfalo/diagnóstico por imagem , Feminino , Envelhecimento Saudável/psicologia , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Rede Nervosa/diagnóstico por imagem , Desempenho Psicomotor/fisiologia , Adulto Jovem
13.
Sci Rep ; 11(1): 15090, 2021 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-34301962

RESUMO

The klotho gene encodes a transmembrane protein αKlotho that interacts with a fibroblast growth factor (FGF) receptor in renal tubular epithelial cells and functions as a co-receptor for FGF23, which is an osteocytes-derived hormone. This bone-to-kidney signal promotes urinary phosphate excretion. Interestingly, αKlotho knockout mice show an accelerated aging and a shortened life span. Similarly, C. elegans lacking the αklotho homologue showed a short life span. However, the physiological basis of aging-related function of αklotho remain unclear. The αklotho-deficient vertebrate animals other than mice have been awaited as an alternative model of premature aging. We here employed zebrafish in our study and revealed that αklotho mutant zebrafish appeared to be normal at 3 months postfertilization (mpf) but eventually underwent premature death by 9 mpf, while normal zebrafish is known to survive for 42 months. We also assessed the motor ability of zebrafish in a forced swimming assay and found that αklotho mutant zebrafish displayed reduced swimming performance before their survival declined. A recent study also reported a similar finding that αklotho-deficient zebrafish exhibited a short life span and reduced spontaneous movements. Taken together, these results suggest that αKlotho mutant zebrafish show premature aging and are useful to investigate aging in vertebrates.


Assuntos
Glucuronidase/metabolismo , Longevidade/fisiologia , Peixe-Zebra/metabolismo , Envelhecimento/metabolismo , Animais , Osso e Ossos/metabolismo , Caenorhabditis elegans/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Humanos , Rim/metabolismo , Camundongos , Camundongos Knockout
14.
Commun Biol ; 4(1): 725, 2021 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-34117367

RESUMO

Methionine metabolism arises as a key target to elucidate the molecular adaptations underlying animal longevity due to the negative association between longevity and methionine content. The present study follows a comparative approach to analyse plasma methionine metabolic profile using a LC-MS/MS platform from 11 mammalian species with a longevity ranging from 3.5 to 120 years. Our findings demonstrate the existence of a species-specific plasma profile for methionine metabolism associated with longevity characterised by: i) reduced methionine, cystathionine and choline; ii) increased non-polar amino acids; iii) reduced succinate and malate; and iv) increased carnitine. Our results support the existence of plasma longevity features that might respond to an optimised energetic metabolism and intracellular structures found in long-lived species.


Assuntos
Longevidade/fisiologia , Metionina/sangue , Animais , Carnitina/metabolismo , Gatos , Bovinos , Colina/sangue , Colina/metabolismo , Colina/fisiologia , Cistationina/sangue , Cistationina/metabolismo , Cistationina/fisiologia , Cães , Cromatografia Gasosa-Espectrometria de Massas , Cobaias , Cavalos , Humanos , Malatos/sangue , Malatos/metabolismo , Metionina/metabolismo , Metionina/fisiologia , Camundongos , Filogenia , Coelhos , Ratos , Ovinos , Ácido Succínico/sangue , Ácido Succínico/metabolismo , Suínos
16.
Aging (Albany NY) ; 13(12): 16873-16894, 2021 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-34156973

RESUMO

Female reproductive aging is, in a way, a biological phenomenon that develops along canonical molecular pathways; however, it has particular features. Recent studies revealed complexity of the interconnections between reproductive aging and aging of other systems, and even suggested a cause-effect uncertainty between them. It was also shown that reproductive aging can impact aging processes in an organism at the level of cells, tissues, organs, and systems. Women at the end of their reproductive lives are characterized by the accelerated incidence of age-related diseases. Timing of the onset of menarche and menopause and variability in the duration of reproductive life carry a latent social risk: not having enough information about the reproductive potential, women keep on postponing childbirth. Identification and use of the most accurate and sensitive aging biomarkers enable the prediction of menopause timing and quantification of the true biological and reproductive ages of an organism. We discuss current views on reproductive aging and peculiarities of using available biomarkers of aging. We also consider latest advances in the search for potential genetic markers of reproductive aging. Finally, we posit the importance of determining the female biological age and highlight potential research directions in this area.


Assuntos
Biomarcadores/metabolismo , Longevidade/fisiologia , Reprodução/fisiologia , Relógios Circadianos , Feminino , Marcadores Genéticos , Humanos , Mitocôndrias/metabolismo
17.
Aging (Albany NY) ; 13(12): 16527-16540, 2021 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-34160365

RESUMO

INTRODUCTION: Falls are a leading cause of death among Chinese oldest olds. However, studies on Chinese community-dwelling older adults are lacking. We aimed to identify the associations of falls and severe falls with blood pressure and frailty among Chinese community-dwelling oldest olds. METHODS: Cross-sectional analyses were conducted with 6,595 community-dwelling oldest olds (aged ≥80 years) from 22 Chinese provinces from the Chinese Longitudinal Health and Longevity Study (CLHLS). Systolic BP (SBP) and diastolic BP (DBP) were measured twice at participants' homes, and a 38-item frailty index was used to assess the frailty status of participants. Falls and severe falls were confirmed through face-to-face interviews. Multivariate logistic regression was used to investigate the associations of BP and frailty with falls and severe falls. RESULTS: The mean participant age was 91.0 years, and 56.1% were female. In total, 24.2% participants had a history of fall and 8.3% had a history of severe falls. The multivariate-adjusted odds ratio (OR) for falls among the oldest old with SBP ≥140 mm Hg compared to those with an SBP of 120-129 mm Hg was 1.20 (95% confidence interval [CI], 1.01-1.44). The adjusted OR for falls among frail participants compared to robust participants was 1.39 (95% CI, 1.02-1.89). DBP and pre-frailty were not associated with falls after multivariate adjustment. SBP, DBP, and frailty status were not associated with severe falls after multivariate adjustment. CONCLUSIONS: SBP and frailty but not DBP and pre-frailty are associated with increased odds of falls among Chinese community-dwelling oldest olds.


Assuntos
Acidentes por Quedas , Grupo com Ancestrais do Continente Asiático , Pressão Sanguínea/fisiologia , Fragilidade/fisiopatologia , Vida Independente , Longevidade/fisiologia , Idoso de 80 Anos ou mais , Diástole/fisiologia , Feminino , Humanos , Estudos Longitudinais , Masculino , Razão de Chances , Sístole/fisiologia
18.
Nat Commun ; 12(1): 3486, 2021 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-34108489

RESUMO

The metabolome represents a complex network of biological events that reflects the physiologic state of the organism in health and disease. Additionally, specific metabolites and metabolic signaling pathways have been shown to modulate animal ageing, but whether there are convergent mechanisms uniting these processes remains elusive. Here, we used high resolution mass spectrometry to obtain the metabolomic profiles of canonical longevity pathways in C. elegans to identify metabolites regulating life span. By leveraging the metabolomic profiles across pathways, we found that one carbon metabolism and the folate cycle are pervasively regulated in common. We observed similar changes in long-lived mouse models of reduced insulin/IGF signaling. Genetic manipulation of pathway enzymes and supplementation with one carbon metabolites in C. elegans reveal that regulation of the folate cycle represents a shared causal mechanism of longevity and proteoprotection. Such interventions impact the methionine cycle, and reveal methionine restriction as an underlying mechanism. This comparative approach reveals key metabolic nodes to enhance healthy ageing.


Assuntos
Carbono/metabolismo , Ácido Fólico/metabolismo , Longevidade/fisiologia , Redes e Vias Metabólicas , Animais , Caenorhabditis elegans , Insulina/metabolismo , Longevidade/genética , Redes e Vias Metabólicas/genética , Metaboloma , Metionina/metabolismo , Camundongos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Mutação , Peptídeos/metabolismo , Transdução de Sinais , Tetra-Hidrofolato Desidrogenase/genética , Tetra-Hidrofolato Desidrogenase/metabolismo , Tetra-Hidrofolatos/metabolismo , Timidilato Sintase/genética , Timidilato Sintase/metabolismo
19.
Expert Opin Investig Drugs ; 30(7): 749-758, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34081543

RESUMO

Introduction:Several pharmacological drugs have shown proof of concept for longevity in animal models. I aimed to identify and review those longevity drug candidates that are undergoing clinical trials.Areas covered:Recent (post-2017) longevity clinical trials were found in US and EU clinical trial registries. Longevity drug candidates are the antidiabetic drugs metformin and acarbose, and the immunosuppressant rapamycin. These medicinal drugs are tested on biochemical and clinical markers of aging. In addition, vitamin D supplementation is being investigated in two mega-trials (sample size> 5000) for its efficacy in reducing all-cause mortality.Expert opinion:Anti-aging effects of longevity drug candidates suggest, but do not demonstrate that they prolong life. The two megatrials with vitamin D supplementation make it possible to detect differences in life expectancy between vitamin D and placebo. Therefore, a protocol similar to that for vitamin D could be used to demonstrate pro-longevity effects of metformin, acarbose, and rapamycin.


Assuntos
Envelhecimento/efeitos dos fármacos , Drogas em Investigação/farmacologia , Longevidade/efeitos dos fármacos , Acarbose/farmacologia , Envelhecimento/fisiologia , Animais , Humanos , Longevidade/fisiologia , Metformina/farmacologia , Nutrientes/farmacologia , Sirolimo/farmacologia
20.
Aging (Albany NY) ; 13(10): 13474-13495, 2021 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-34091442

RESUMO

The medicinal fungus Ganoderma lucidum is used as a dietary supplement and health tonic, but whether it affects longevity remains unclear. We show here that a water extract of G. lucidum mycelium extends lifespan of the nematode Caenorhabditis elegans. The G. lucidum extract reduces the level of fibrillarin (FIB-1), a nucleolar protein that correlates inversely with longevity in various organisms. Furthermore, G. lucidum treatment increases expression of the autophagosomal protein marker LGG-1, and lifespan extension is abrogated in mutant C. elegans strains that lack atg-18, daf-16, or sir-2.1, indicating that autophagy and stress resistance pathways are required to extend lifespan. In cultured human cells, G. lucidum increases concentrations of the LGG-1 ortholog LC3 and reduces levels of phosphorylated mTOR, a known inhibitor of autophagy. Notably, low molecular weight compounds (<10 kDa) isolated from the G. lucidum water extract prolong lifespan of C. elegans and the same compounds induce autophagy in human cells. These results suggest that G. lucidum can increase longevity by inducing autophagy and stress resistance.


Assuntos
Autofagia , Caenorhabditis elegans/citologia , Caenorhabditis elegans/fisiologia , Longevidade/fisiologia , Reishi/química , Animais , Proteínas de Caenorhabditis elegans/metabolismo , Linhagem Celular Tumoral , Humanos , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo
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