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1.
Lancet Healthy Longev ; 3(11): e789-e796, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36356628

RESUMO

Intrinsic capacity, a crucial concept in healthy ageing, is defined by WHO as "the composite of all the physical and mental capacities that an individual can draw on at any point in time". Vitality capacity is considered the underlying physiological determinant of intrinsic capacity. To advance the measurement and monitoring of vitality capacity, a working group of WHO staff members and twenty experts representing six WHO regions was convened to discuss and clarify the attributes of vitality capacity and to develop a clear working definition of the concept. Potential biomarkers to measure vitality capacity were identified, and the following consensual working definition was developed: vitality capacity is a physiological state (due to normal or accelerated biological ageing processes) resulting from the interaction between multiple physiological systems, reflected in (the level of) energy and metabolism, neuromuscular function, and immune and stress response functions of the body.


Assuntos
Envelhecimento Saudável , Longevidade , Humanos , Longevidade/fisiologia , Nível de Saúde , Envelhecimento/fisiologia , Organização Mundial da Saúde
2.
Nat Commun ; 13(1): 6554, 2022 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-36323683

RESUMO

The pathways that impact longevity in the wake of dietary restriction (DR) remain still ill-defined. Most studies have focused on nutrient limitation and perturbations of energy metabolism. We showed that the L-threonine was elevated in Caenorhabditis elegans under DR, and that L-threonine supplementation increased its healthspan. Using metabolic and transcriptomic profiling in worms that were fed with RNAi to induce loss of key candidate mediators. L-threonine supplementation and loss-of-threonine dehydrogenaseincreased the healthspan by attenuating ferroptosis in a ferritin-dependent manner. Transcriptomic analysis showed that FTN-1 encoding ferritin was elevated, implying FTN-1 is an essential mediator of longevity promotion. Organismal ferritin levels were positively correlated with chronological aging and L-threonine supplementation protected against age-associated ferroptosis through the DAF-16 and HSF-1 pathways. Our investigation uncovered the role of a distinct and universal metabolite, L-threonine, in DR-mediated improvement in organismal healthspan, suggesting it could be an effective intervention for preventing senescence progression and age-induced ferroptosis.


Assuntos
Proteínas de Caenorhabditis elegans , Ferroptose , Animais , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Treonina/metabolismo , Ferritinas/genética , Ferritinas/metabolismo , Restrição Calórica , Transdução de Sinais , Longevidade/fisiologia
3.
J Diabetes Complications ; 36(11): 108320, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36201892

RESUMO

AIMS: To determine the relationship between renal hemodynamic function and neuropathy in adults with ≥50-years of type 1 diabetes (T1D) compared to nondiabetic controls. METHODS: Glomerular filtration rate (GFR, inulin), effective renal plasma flow (ERPF, p-aminohippurate), modified Toronto Clinical Neuropathy Score (mTCNS), corneal confocal microscopy, nerve conduction, and heart rate variability (autonomic function) were measured; afferent (RA) and efferent (RE) arteriolar resistances were estimated using the Gomez equations in 74 participants with T1D and in 75 controls. Diabetic kidney disease (DKD) non-resistors were defined by eGFRMDRD < 60 ml/min/1.73 m2 or 24-h urine albumin excretion >30 mg/day. Linear regression was applied to examine the relationships between renal function (dependent variable) and neuropathy measures (independent variable), adjusted for age, sex, HbA1c, systolic blood pressure, low density lipoprotein cholesterol, and 24-h urine albumin to creatinine ratio. RESULTS: Higher mTCNS associated with lower renal blood flow (ß ± SE:-9.29 ± 4.20, p = 0.03) and greater RE (ß ± SE:32.97 ± 15.43, p = 0.04) in participants with T1D, but not in controls. DKD non-resistors had a higher mTCNS and worse measures of corneal nerve morphology compared to those without DKD. Renal hemodynamic parameters did not associate with autonomic nerve function. CONCLUSIONS: Although neurological dysfunction in the presence of diabetes may contribute to impaired renal blood flow resulting in ischemic injury in patients with T1D, early autonomic dysfunction does not appear to be associated with kidney function changes.


Assuntos
Diabetes Mellitus Tipo 1 , Nefropatias Diabéticas , Adulto , Humanos , Longevidade/fisiologia , Canadá/epidemiologia , Hemodinâmica/fisiologia , Taxa de Filtração Glomerular , Albuminas
4.
Aging (Albany NY) ; 14(20): 8270-8291, 2022 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-36287172

RESUMO

Why biological age is a major risk factor for many of the most important human diseases remains mysterious. We know that as organisms age, stem cell pools are exhausted while senescent cells progressively accumulate. Independently, induction of pluripotency via expression of Yamanaka factors (Oct4, Klf4, Sox2, c-Myc; OKSM) and clearance of senescent cells have each been shown to ameliorate cellular and physiological aspects of aging, suggesting that both processes are drivers of organismal aging. But stem cell exhaustion and cellular senescence likely interact in the etiology and progression of age-dependent diseases because both undermine tissue and organ homeostasis in different if not complementary ways. Here, we combine transient cellular reprogramming (stem cell rejuvenation) with targeted removal of senescent cells to test the hypothesis that simultaneously targeting both cell-fate based aging mechanisms will maximize life and health span benefits. We find that OKSM extends lifespan and show that both interventions protect the intestinal stem cell pool, lower inflammation, activate pro-stem cell signaling pathways, and synergistically improve health and lifespan. Our findings suggest that a combination therapy, simultaneously replacing lost stem cells and removing senescent cells, shows synergistic potential for anti-aging treatments. Our finding that transient expression of both is the most effective suggests that drug-based treatments in non-genetically tractable organisms will likely be the most translatable.


Assuntos
Longevidade , Rejuvenescimento , Humanos , Longevidade/fisiologia , Rejuvenescimento/fisiologia , Senescência Celular/fisiologia , Envelhecimento/fisiologia , Células-Tronco
5.
Nutrients ; 14(19)2022 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-36235629

RESUMO

Queen bee larva (QBL) is one kind of important edible insect that is harvested during royal jelly production process. QBL has many physiological functions; however, limited information is available regarding its antiaging effects. In this study, the antiaging function of freeze-dried QBL powder (QBLP) was investigated by combining the Caenorhabditis elegans (C. elegans) model and transcriptomics. The administration of QBLP to C. elegans was shown to improve lifespan parameters. Additionally, QBLP improved the mobility of nematodes. Transcriptome analysis showed the differentially expressed genes (DEGs) were significantly enriched in Gene Ontology (GO) terms that were almost all related to the biological functions of cell metabolism and stress, which are associated with lifespan. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis suggested that the lifespan of C. elegans was related to the longevity regulating pathway-worm. The expression levels of the key genes sod-3, gst-6, hsp-12.6, lips-7, ins-8, and lips-17 were upregulated. sod-3, hsp-12.6, lips-7, and lips-17 are downstream targets of DAF-16, which is an important transcription factor related to lifespan extension. CF1038 (daf-16(mu86)) supplemented with QBLP did not show a life-prolonging. This indicates that the antiaging function of QBLP is closely related to daf-16. Thus, QBLP is a component that could potentially be used as a functional material to ameliorate aging and aging-related symptoms.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Abelhas , Caenorhabditis elegans/fisiologia , Proteínas de Caenorhabditis elegans/metabolismo , Suplementos Nutricionais , Fatores de Transcrição Forkhead/metabolismo , Larva , Longevidade/fisiologia , Estresse Oxidativo , Pós
6.
Commun Biol ; 5(1): 1139, 2022 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-36302976

RESUMO

Probiotics have been characterized as useful for maintaining the balance of host gut flora and conferring health effects, but few studies have focused on their potential for delaying aging in the host. Here we show that Lacticaseibacillus rhamnosus Probio-M9 (Probio-M9), a healthy breast milk probiotic, enhances the locomotor ability and slows the decline in muscle function of the model organism Caenorhabditis elegans. Live Probio-M9 significantly extends the lifespan of C. elegans in a dietary restriction-independent manner. By screening various aging-related mutants of C. elegans, we find that Probio-M9 extends lifespan via p38 cascade and daf-2 signaling pathways, independent on daf-16 but dependent on skn-1. Probio-M9 protects and repairs damaged mitochondria by activating mitochondrial unfolded protein response. The significant increase of amino acids, sphingolipid, galactose and fatty acids in bacterial metabolites might be involved in extending the lifespan of C. elegans. We reveal that Probio-M9 as a dietary supplementation had the potential to delay aging in C. elegans and also provide new methods and insights for further analyzing probiotics in improving host health and delaying the occurrence of age-related chronic diseases.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Humanos , Caenorhabditis elegans/metabolismo , Longevidade/fisiologia , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Resposta a Proteínas não Dobradas , Mitocôndrias/metabolismo
7.
Mech Ageing Dev ; 208: 111741, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36167215

RESUMO

Dietary restriction (DR) represents one of the most robust interventions for extending lifespan. It is not known how DR increases lifespan. The prevailing evolutionary hypothesis suggests the DR response redirects metabolic resources towards somatic maintenance at the expense of investment in reproduction. Consequently, DR acts as a proximate mechanism which promotes a pro-longevity phenotype. This idea is known as resource reallocation. However, growing findings suggest this paradigm could be incomplete. It has been argued that during DR it is not always possible to identify a trade-off between reproduction and lifespan. It is also suggested the relationship between reproduction and somatic maintenance can be uncoupled by the removal or inclusion of specific nutrients. These findings have created an imperative to re-explore the nexus between DR and evolutionary theory. In this review I will address this evolutionary conundrum. My overarching objectives are fourfold: (1) to outline some of the evidence for and against resource reallocation; (2) to examine recent findings which have necessitated a theoretical re-evaluation of the link between life history theory and DR; (3) to present alternatives to the resource reallocation model; (4) to present emerging variables which potentially influence how DR effects evolutionary trade-offs.


Assuntos
Restrição Calórica , Longevidade , Longevidade/fisiologia , Evolução Biológica , Reprodução
8.
PLoS One ; 17(9): e0273098, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36107951

RESUMO

Naked mole-rats are a long-lived rodent species (current lifespan >37 years) and an increasingly popular biomedical model. Naked mole-rats exhibit neuroplasticity across their long lifespan. Previous studies have begun to investigate their neurogenic patterns. Here, we test the hypothesis that neuronal maturation is extended in this long-lived rodent. We characterize cell proliferation and neuronal maturation in established rodent neurogenic regions over 12 months following seven days of consecutive BrdU injection. Given that naked mole-rats are eusocial (high reproductive skew where only a few socially-dominant individuals reproduce), we also looked at proliferation in brain regions relevant to the social-decision making network. Finally, we measured co-expression of EdU (newly-born cells), DCX (immature neuron marker), and NeuN (mature neuron marker) to assess the timeline of neuronal maturation in adult naked mole-rats. This work reaffirms the subventricular zone as the main source of adult cell proliferation and suggests conservation of the rostral migratory stream in this species. Our profiling of socially-relevant brain regions suggests that future work which manipulates environmental context can unveil how newly-born cells integrate into circuitry and facilitate adult neuroplasticity. We also find naked mole-rat neuronal maturation sits at the intersection of rodents and long-lived, non-rodent species: while neurons can mature by 3 weeks (rodent-like), most neurons mature at 5 months and hippocampal neurogenic levels are low (like long-lived species). These data establish a timeline for future investigations of longevity- and socially-related manipulations of naked mole-rat adult neurogenesis.


Assuntos
Ratos-Toupeira , Neurogênese , Animais , Bromodesoxiuridina , Longevidade/fisiologia , Ratos-Toupeira/fisiologia , Neurônios/fisiologia
9.
PLoS One ; 17(9): e0270436, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36137094

RESUMO

Nutrition and growth are strongly linked, but not much is known about how nutrition leads to growth. To understand the connection between nutrition through the diet, growth, and proliferation, we need to study the phenotypes resulting from the activation and inhibition of central metabolic pathways. One of the most highly conserved metabolic pathways across eukaryotes is the Target of Rapamycin (TOR) pathway, whose primary role is to detect the availability of nutrients and to either induce or halt cellular growth. Here we used the model organism Drosophila melanogaster (D. mel.) and three non-model Drosophila species with different dietary needs, Drosophila guttifera (D. gut.), Drosophila deflecta (D. def.), and Drosophila tripunctata (D. tri.), to study the effects of dietary amino acid availability on fecundity and longevity. In addition, we inhibited the Target of Rapamycin (TOR) pathway, using rapamycin, to test how the inhibition interplays with the nutritional stimuli in these four fruit fly species. We hypothesized that the inhibition of the TOR pathway would reverse the phenotypes observed under conditions of overfeeding. Our results show that female fecundity increased with higher yeast availability in all four species but decreased in response to TOR inhibition. The longevity data were more varied: most species experienced an increase in median lifespan in both genders with an increase in yeast availability, while the lifespan of D. mel. females decreased. When exposed to the TOR inhibitor rapamycin, the life spans of most species decreased, except for D. tri, while we observed a major reduction in fecundity across all species. The obtained data can benefit future studies on the evolution of metabolism by showing the potential of using non-model species to track changes in metabolism. Particularly, our data show the possibility to use relatively closely related Drosophila species to gain insight on the evolution of TOR signaling.


Assuntos
Proteínas de Drosophila , Drosophila , Aminoácidos , Animais , Drosophila/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Feminino , Longevidade/fisiologia , Saccharomyces cerevisiae/metabolismo , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
10.
Aging (Albany NY) ; 14(18): 7223-7239, 2022 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-35980264

RESUMO

Aging is associated with changes in heart rate (HR), heart rate variability (HRV), and 24-h rhythms in HR. Longevity has been linked to lower resting HR, while a higher resting HR and a decreased HRV were linked to cardiovascular events and increased mortality risk. HR and HRV are often investigated during a short electrocardiogram (ECG) measurement at a hospital. In this study, we aim to investigate the relationship between HR parameters with familial longevity and chronological age derived from continuous ambulatory ECG measurements collected over a period of 24 to 90 hours. We included 73 middle-aged participants (mean (SD) age: 67.0 (6.16) years), comprising 37 offspring of long-lived families, 36 of their partners, and 35 young participants (22.8 (3.96) years). We found no association with familial longevity, but middle-aged participants had lower 24-h HR (average and maximum HR, not minimum HR), lower amplitudes, and earlier trough and peak times than young participants. Associations in HR with chronological age could be caused by the aging process or by differences in environmental factors. Interestingly, middle-aged participants had a less optimal HRV during long-term recordings in both the sleep and awake periods, which might indicate that their heart is less adaptable than that of young participants. This could be a first indication of deteriorated cardiovascular health in middle-aged individuals.


Assuntos
Eletrocardiografia Ambulatorial , Longevidade , Idoso , Envelhecimento/fisiologia , Eletrocardiografia , Frequência Cardíaca/fisiologia , Humanos , Longevidade/fisiologia , Pessoa de Meia-Idade
11.
Neurobiol Aging ; 118: 108-116, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35914473

RESUMO

Several studies report that caloric restriction (CR) or intermittent fasting (IF) can improve cognition, while others report limited or no cognitive benefits. Here, we compare the effects of 20% CR, 40% CR, 1-day IF, and 2-day IF feeding paradigms to ad libitum controls on Y-maze working memory (WM) and contextual fear memory (CFM) in a large population of Diversity Outbred mice that model the genetic diversity of humans. While CR and IF interventions improve lifespan, we observed no enhancement of working memory or CFM in mice on these feeding paradigms, and report 40% CR to be damaging to recall of CFM. Using Quantitative Trait Loci mapping, we identified the gene Slc16a7 to be associated with CFM outcomes in aged mice on lifespan promoting feeding paradigms. Limited utility of dieting and fasting on memory in mice that recapitulate genetic diversity in the human population highlights the need for anti-aging therapeutics that promote cognitive function, with the neuronal monocarboxylate transporter MCT2 encoded by Slc16a7 highlighted as novel target.


Assuntos
Restrição Calórica , Longevidade , Envelhecimento/fisiologia , Animais , Restrição Calórica/psicologia , Cognição , Jejum , Humanos , Longevidade/fisiologia , Camundongos
12.
Aging Cell ; 21(9): e13693, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35977034

RESUMO

Aging is a complex and highly regulated process of interwoven signaling mechanisms. As an ancient transcriptional regulator of thermal adaptation and protein homeostasis, the Heat Shock Factor, HSF-1, has evolved functions within the nervous system to control age progression; however, the molecular details and signaling dynamics by which HSF-1 modulates age across tissues remain unclear. Herein, we report a nonautonomous mode of age regulation by HSF-1 in the Caenorhabditis elegans nervous system that works through the bone morphogenic protein, BMP, signaling pathway to modulate membrane trafficking in peripheral tissues. In particular, HSF-1 represses the expression of the neuron-specific BMP ligand, DBL-1, and initiates a complementary negative feedback loop within the intestine. By reducing receipt of DBL-1 in the periphery, the SMAD transcriptional coactivator, SMA-3, represses the expression of critical membrane trafficking regulators including Rab GTPases involved in early (RAB-5), late (RAB-7), and recycling (RAB-11.1) endosomal dynamics and the BMP receptor binding protein, SMA-10. This reduces cell surface residency and steady-state levels of the type I BMP receptor, SMA-6, in the intestine and further dampens signal transmission to the periphery. Thus, the ability of HSF-1 to coordinate BMP signaling along the gut-brain axis is an important determinate in age progression.


Assuntos
Proteínas de Caenorhabditis elegans , Longevidade , Animais , Receptores de Proteínas Morfogenéticas Ósseas/metabolismo , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Resposta ao Choque Térmico , Longevidade/fisiologia , Neurônios/metabolismo , Transdução de Sinais , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
13.
Mech Ageing Dev ; 207: 111723, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35988813

RESUMO

Microplastic pollution has attracted growing attention due to its prevalent and persistent exposure to general population through the food chain, but few reports have focused on the toxicological prevention of polystyrene (PS). Using the wild-type and mutant strains, this study explored the impacts of PS and cyanidin-3-O-glucoside (C3G) on stress tolerance and lifespan of Caenorhabditis elegans (C. elegans). In N2 nematodes, PS exposure initiated the oxidative stress and subsequent lifespan reduction, while these adverse impacts could be positively improved by C3G treatment. Considering the pivotal role of DAF-16 pathway in stress tolerance and lifespan regulation, the expression of the daf-16 gene and its downstream antioxidant genes (clt-2, hsp-16.1, sod-3, sod-5) were examined, and found to be significantly enhanced by C3G. Since the sod-3 gene was up-regulated the most fold by C3G, the activity of SOD enzyme that encoded by the sod-3 was examined, and could be obviously enhanced upon C3G treatment. This explained the improved oxidative stress and delayed oxidation-associated aging after C3G intervention. Nevertheless, these positive effects of C3G were weakened in daf-16(-) mutant strain (with deleted DAF-16 gene), for which the beneficial effects of C3G in promoting stress resistance and lifespan extension were inhibited. These findings suggested that the DAF-16 gene and its downstream antioxidant genes, have participated in C3G's regulations on redox balance and lifespan that impacted by nano-polystyrene particles. This study highlighted the link between dietary components and environmentally driven disturbance.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Antocianinas , Antioxidantes/metabolismo , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Fatores de Transcrição Forkhead/farmacologia , Glucosídeos/farmacologia , Humanos , Longevidade/fisiologia , Microplásticos , Estresse Oxidativo , Plásticos/metabolismo , Plásticos/farmacologia , Poliestirenos/metabolismo , Poliestirenos/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo
14.
Eur J Nutr ; 61(8): 4179-4190, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35864340

RESUMO

PURPOSE: Agaro-oligosaccharides (AGO), hydrolysis products of agarose, is known to have antioxidant and anti-inflammatory properties. Speculating that AGO is effective for preventing aging, we investigated the longevity-supporting effects of AGO and their mechanisms using Caenorhabditis elegans. METHODS: Caenorhabditis elegans were fed AGO from young adulthood. The lifespan, locomotory activity, lipofuscin accumulation, and heat stress resistance of the worms were examined. To elucidate mechanisms of AGO-mediated longevity, we conducted comprehensive expression analysis using microarrays. Moreover, we used quantitative real-time PCR (qRT-PCR) to verify the genes showing differential expression levels. Furthermore, we measured the lifespan of loss-of-function mutants to determine the genes related to AGO-mediated longevity. RESULTS: AGO extended the lifespan of C. elegans, reduced lipofuscin accumulation, and maintained vigorous locomotion. The microarray analysis revealed that the endoplasmic reticulum-unfolded protein response (ER-UPR) and insulin/insulin-like growth factor-1-mediated signaling (IIS) pathway were activated in AGO-fed worms. The qRT-PCR analysis showed that AGO treatment suppressed sir-2.1 expression, which is a negative regulator of ER-UPR. In loss-of-function mutant of sir-2.1, AGO-induced longevity and heat stress resistance were decreased or cancelled completely. Furthermore, the pro-longevity effect of AGO was decreased in loss-of-function mutants of abnormal Dauer formation (daf) -2 and daf-16, which are IIS pathway-related genes. CONCLUSION: AGO delays the C. elegans aging process and extends their lifespan through the activations of ER-UPR and the IIS pathway.


Assuntos
Proteínas de Caenorhabditis elegans , Insulinas , Sirtuínas , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Longevidade/fisiologia , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Ágar/metabolismo , Ágar/farmacologia , Antioxidantes/farmacologia , Sefarose/metabolismo , Sefarose/farmacologia , Lipofuscina/metabolismo , Lipofuscina/farmacologia , Resposta a Proteínas não Dobradas , Oligossacarídeos/farmacologia , Oligossacarídeos/metabolismo , Insulinas/genética , Insulinas/metabolismo , Insulinas/farmacologia , Fatores de Transcrição Forkhead/genética , Sirtuínas/genética , Sirtuínas/metabolismo
15.
Cells ; 11(13)2022 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-35805145

RESUMO

Reducing the oxidative stress in neurons extends lifespan in Drosophila melanogaster, highlighting the crucial role of neuronal oxidative damage in lifespan determination. However, the source of the reactive oxygen species (ROS) that provoke oxidative stress in neurons is not clearly defined. Here, we identify dual oxidase (duox), a calcium-activated ROS-producing enzyme, as a lifespan determinant. Due to the lethality of duox homozygous mutants, we employed a duox heterozygote that exhibited normal appearance and movement. We found that duox heterozygous male flies, which were isogenized with control flies, demonstrated extended lifespan. Neuronal knockdown experiments further suggested that duox is crucial to oxidative stress in neurons. Our findings suggest duox to be a source of neuronal oxidative stress associated with animal lifespan.


Assuntos
Drosophila melanogaster , Longevidade , Animais , Drosophila melanogaster/metabolismo , Oxidases Duais/metabolismo , Hidrogênio , Peróxido de Hidrogênio , Longevidade/fisiologia , Masculino , Neurônios/metabolismo , Estresse Oxidativo , Espécies Reativas de Oxigênio
16.
JAMA Netw Open ; 5(7): e2223285, 2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-35895062

RESUMO

Importance: Accelerated biological aging is associated with decreased physical capability and cognitive functioning, which are associated with increased risk of morbidity and mortality. Objective: We investigated associations between epigenetic age acceleration (EAA), a biomarker associated with aging, and healthy longevity among older women. Design, Setting, and Participants: This cohort study was a secondary analysis of participants in the Women's Health Initiative (WHI) who were eligible to survive to age 90 years by September 30, 2020. Participants were located in multiple centers. This study was restricted to women with genome-wide DNA methylation data, generated from baseline blood samples within 3 WHI ancillary studies. Median (IQR) follow-up times from baseline were 21.6 (19.6-22.9) years and 21.4 (19.8-22.7) years for women who survived to age 90 years with and without intact mobility, respectively, and 13.2 (8.8-16.7) for women who did not survive to age 90 years. Data were analyzed from December 2020 to July 2021. Exposures: EAA was estimated using 4 established "clocks": Horvath pantissue, Hannum, Pheno, and Grim. Main Outcomes and Measures: Using multinomial logistic regression, odds ratios (ORs) and 95% CIs were estimated for 3 healthy longevity outcomes for each clock: survival to age 90 years with intact mobility, survival to age 90 years without intact mobility, and no survival to age 90 years. Results: Among 1813 women, there were 464 women (mean [SD] age at baseline, 71.6 [3.5] years) who survived to age 90 years with intact mobility and cognitive functioning, 420 women (mean [SD] age at baseline, 71.3 [3.2] years) who survived to age 90 years without intact mobility and cognitive functioning, and 929 women (mean [SD] age at baseline, 70.2 [3.4] years) who did not survive to age 90 years. Women who survived to age 90 years with intact mobility and cognitive function were healthier at baseline compared with women who survived without those outcomes or who did not survive to age 90 years (eg, 143 women [30.8%] vs 101 women [24.0%] and 202 women [21.7%] with 0 chronic conditions). The odds of surviving to age 90 years with intact mobility were lower for every 1 SD increase in EAA compared with those who did not survive to age 90 years as measured by AgeAccelHorvath (OR, 0.82; 95% CI, 0.69-0.96; P = .01), AgeAccelHannum (OR, 0.67; 95% CI, 0.56-0.80; P < .001), AgeAccelPheno (OR, 0.60; 95% CI, 0.51-0.72; P < .001), and AgeAccelGrim (OR, 0.68; 95% CI, 0.55-0.84; P < .001). ORs were similar for women who survived to age 90 years with intact mobility and cognitive function (eg, AgeAccelHorvath: OR per 1 SD increase in EAA, 0.83; 95% CI, 0.71-0.98; P = .03) compared with women who did not survive to age 90 years. Conclusions and Relevance: These findings suggest that EAA may be a valid biomarker associated with healthy longevity among older women and may be used for risk stratification and risk estimation of future functional and cognitive aging. Outcomes suggest that future studies may focus on the potential for public health interventions to counteract EAA and its association with poor health outcomes to lower disease burden while increasing longevity.


Assuntos
Envelhecimento , Epigênese Genética , Longevidade , Idoso de 80 Anos ou mais , Envelhecimento/genética , Envelhecimento/fisiologia , Estudos de Coortes , Epigênese Genética/fisiologia , Feminino , Humanos , Longevidade/genética , Longevidade/fisiologia , Estados Unidos
17.
EMBO Rep ; 23(9): e55299, 2022 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-35796299

RESUMO

Lifespan is determined by complex and tangled mechanisms that are largely unknown. The early postnatal stage has been proposed to play a role in lifespan, but its contribution is still controversial. Here, we show that a short rapamycin treatment during early life can prolong lifespan in Mus musculus and Drosophila melanogaster. Notably, the same treatment at later time points has no effect on lifespan, suggesting that a specific time window is involved in lifespan regulation. We also find that sulfotransferases are upregulated during early rapamycin treatment both in newborn mice and in Drosophila larvae, and transient dST1 overexpression in Drosophila larvae extends lifespan. Our findings unveil a novel link between early-life treatments and long-term effects on lifespan.


Assuntos
Proteínas de Drosophila , Longevidade , Envelhecimento/fisiologia , Animais , Drosophila/fisiologia , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Longevidade/fisiologia , Camundongos , Sirolimo/farmacologia
18.
Aging Cell ; 21(8): e13656, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35770332

RESUMO

Hypothalamic integrity increasingly is being recognized as a marker of healthy longevity in rodent models. Insight into hypothalamic function in humans with exceptional longevity can be gained via investigation of the hypothalamic-pituitary-testicular (HPT) axis in men with exceptional longevity. This study aimed to characterize the HPT axis function, defined by levels of testosterone (T) and luteinizing hormone (LH), in 84 Ashkenazi Jewish men aged 90-106 years. We found that 94% of men exhibited preserved hypothalamic-pituitary function, as evidenced by either normal testosterone and LH levels (25%) or an appropriate rise in LH in response to aging-related primary testicular dysfunction (69%), a hormone pattern mirroring female menopause. Total T level was not associated with metabolic parameters or survival. These results demonstrate a high prevalence of testicular dysfunction with preserved hypothalamic-pituitary function in men with exceptional longevity. Thus, the role of hypothalamic integrity and HPT axis in healthy aging warrants further investigation.


Assuntos
Hipotálamo , Longevidade , Hipófise , Testículo , Envelhecimento/sangue , Envelhecimento/metabolismo , Hormônio Foliculoestimulante/metabolismo , Humanos , Hipotálamo/metabolismo , Longevidade/fisiologia , Hormônio Luteinizante/sangue , Hormônio Luteinizante/metabolismo , Masculino , Hipófise/metabolismo , Doenças Testiculares/sangue , Doenças Testiculares/metabolismo , Testículo/metabolismo , Testosterona/sangue , Testosterona/metabolismo
19.
Biochem Biophys Res Commun ; 614: 107-113, 2022 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-35576681

RESUMO

SKN-1, the ortholog of mammalian Nrf2 proteins, is a transcription factor that plays an important role in oxidative stress resistance and longevity. Similar to other defense systems, the Nrf2-mediated stress response is compromised in aging and neurodegenerative diseases. Our previous studies demonstrated that tetramethylpyrazine nitrone (TBN), a derivative of tetramethylpyrazine armed with a potent free radical-scavenging nitrone moiety, exerted multifunctional neuroprotection in neurological and other diseases. However, the ability of TBN to extend a healthy lifespan and its underlying mechanisms of action are not yet clear. C. elegans have become a popular animal model in aging research. Herein, we demonstrate that TBN can extend the lifespan, promote age-associated health indicators, and restore mitochondrial function in C. elegans. TBN also significantly reduced ROS levels and superoxide accumulation in C. elegans. We show that TBN-mediated lifespan extension is SKN-1dependent. The present study provides valuable insights into the mechanisms by which TBN inhibits aging via the Nrf2/SKN-1 pathway in C. elegans.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Fator de Transcrição de Proteínas de Ligação GA/metabolismo , Longevidade/fisiologia , Mamíferos/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Pirazinas , Transdução de Sinais , Fatores de Transcrição/metabolismo
20.
Redox Biol ; 53: 102335, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35598379

RESUMO

Mild impairment of mitochondrial function has been shown to increase lifespan in genetic model organisms including worms, flies and mice. To better understand the mechanisms involved, we analyzed RNA sequencing data and found that genes involved in the mitochondrial thioredoxin system, trx-2 and trxr-2, are specifically upregulated in long-lived mitochondrial mutants but not other non-mitochondrial, long-lived mutants. Upregulation of trx-2 and trxr-2 is mediated by activation of the mitochondrial unfolded protein response (mitoUPR). While we decided to focus on the genes of the mitochondrial thioredoxin system for this paper, we identified multiple other antioxidant genes that are upregulated by the mitoUPR in the long-lived mitochondrial mutants including sod-3, prdx-3, gpx-6, gpx-7, gpx-8 and glrx-5. In exploring the role of the mitochondrial thioredoxin system in the long-lived mitochondrial mutants, nuo-6 and isp-1, we found that disruption of either trx-2 or trxr-2 significantly decreases their long lifespan, but has no effect on wild-type lifespan, indicating that the mitochondrial thioredoxin system is specifically required for their longevity. In contrast, disruption of the cytoplasmic thioredoxin gene trx-1 decreases lifespan in nuo-6, isp-1 and wild-type worms, indicating a non-specific detrimental effect on longevity. Disruption of trx-2 or trxr-2 also decreases the enhanced resistance to stress in nuo-6 and isp-1 worms, indicating a role for the mitochondrial thioredoxin system in protecting against exogenous stressors. Overall, this work demonstrates an important role for the mitochondrial thioredoxin system in both stress resistance and lifespan resulting from mild impairment of mitochondrial function.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Longevidade , Mitocôndrias , Estresse Oxidativo , Tiorredoxinas , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Glutarredoxinas/metabolismo , Longevidade/genética , Longevidade/fisiologia , Mitocôndrias/genética , Mitocôndrias/metabolismo , Estresse Oxidativo/genética , Estresse Oxidativo/fisiologia , Tiorredoxina Dissulfeto Redutase/metabolismo , Tiorredoxinas/genética , Tiorredoxinas/metabolismo
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