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1.
Biomed J ; 47(2): 100654, 2023 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-37604250

RESUMO

Comparative oncology is an understudied field of science. We are far from understanding the key mechanisms behind Peto's paradox, i.e., understanding how long-lived and large animals are not subject to a higher cancer burden despite the longer exposure time to mutations and the larger number of cells exposed. In this work, we investigated the scientific evidence on such mechanisms through a systematic mini-review of the literature about the relation of longevity and/or large body mass with physiological, genetic, or environmental traits among mammalian species. More than forty thousand articles were retrieved from three repositories, and 383 of them were screened using an active-learning-based tool. Of those, 36 articles on longevity and 37 on body mass were selected for the review. Such articles were examined focusing on: number and type of species considered, statistical methods used, traits investigated, and observed relationship with longevity and/or body mass. Where applicable, the traits investigated were matched with one or more hallmarks of cancer. We obtained a list of potential candidate traits to explain Peto's paradox related to replicative immortality, cell senescence, genome instability and mutations, proliferative signaling, growth suppression evasion, and cell resistance to death. Our investigation suggests that different strategies have been followed to prevent cancer in large and long-lived species. The large number of papers retrieved emphasizes that more studies can be launched in the future, using more efficient analytical approaches to comprehensively evaluate the convergent biological mechanisms essential for acquiring longevity and large body mass without increasing cancer risk.

2.
Front Psychol ; 14: 1152150, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37151325

RESUMO

Personality functioning and psychodynamic conflicts are central constructs in psychoanalytic theories of psychopathology as well as in many psychodynamic treatment models. Although there has been a longstanding conceptual discussion on how they relate to each other, empirical evidence on this question is still scarce. In this study, we explore the associations between psychodynamic conflicts and levels of structural integration (which can be used synonymously with personality functioning) by means of a partial correlation network analysis in a sample of N = 220 outpatients interviewed and rated according to Operationalized Psychodynamic Diagnosis (OPD-2). We examined network centrality, bridge centrality, clustering, and network stability. The network analysis resulted in separate clusters for levels of structural integration and conflicts, supporting the assumption of distinct psychodynamic constructs. The greatest association between the two clusters was found between the individuation vs. dependency conflict (C1) and the structural capacity to attach to internal objects. In general, C1 showed significantly greater connections with structural dimensions compared to the other five OPD conflicts included. C1 was also more central in the network compared to most other conflicts, whereas the structural dimensions did not differ in centrality. All structural dimensions were found to be strongly interconnected. C1 showed exclusively negative edges to the other conflicts, suggesting that a profound C1 decreases the probability of other psychodynamic conflicts. We discuss clinical as well as conceptual implications of our findings for psychodynamic diagnosis and treatment.

3.
Z Psychosom Med Psychother ; 69(2): 108-122, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37249378

RESUMO

Objective: The study aims to assess interrater reliability of the revised Operationalized Psychodynamic Diagnosis 3 (OPD-3) system. Three OPD axes were included in the reliability analysis: the Levels of Structural Integration Axis (OPD-LSIA), the Conflict Axis (OPD-CA), and the Interpersonal Relations Axis (OPD-IRA). Methods: A heterogeneous sample of n = 80 patients was diagnostically assessed with SCID-I and SCID-II as well as with an OPD interview. Two raters of a group of five independently rated each patient's OPD interview according to OPD-3. Results: Interrater reliability was good to excellent for OPD-LSIA [ICC1,1 = .874 - .920], and moderate to good forOPD-CA [ICC1,1 = .547 - .764] as well as forOPD-IRA at the aggregated level of Agency and Communion [ICC1,1 = .575 - .793], except for raters' self-perceived tendencies to act towards the patient. Conclusion: The revised OPD-3 can be used as a reliable instrument for a psychodynamic diagnosis of conflicts, levels of structural integration, and dysfunctional relationship patterns.


Assuntos
Terapia Psicanalítica , Humanos , Reprodutibilidade dos Testes , Relações Interpessoais
4.
Biomed J ; 46(3): 100596, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37149260

RESUMO

BACKGROUND: The Peto's paradox consists in the observation that individuals from long-lived and large animal species do not experience a higher cancer incidence, despite being exposed for longer time to the possibility of accumulating mutations and having more target cells exposed to the phenomenon. The existence of this paradox has been recently confirmed (Vincze et al., 2022). Concurrently, robust evidence has been published that longevity involves a convergent evolution of cellular mechanisms that prevent the accumulation of mutations (Cagan et al., 2022). It remains unclear which cellular mechanisms are critical to allow the evolution of a large body mass while keeping cancer at bay. METHODS: Adding to existing data linking cellular replicative potential and species body mass (Lorenzini et al., 2005), we have grown a total of 84 skin fibroblast cell strains from 40 donors of 17 mammalian species and analyzed their Hayflick's limit, i.e., their senescent plateau, and eventual spontaneous immortalization escape. The correlation of immortalization and replicative capacity of the species with their longevity, body mass and metabolism has been assessed through phylogenetic multiple linear regression (MLR). RESULTS: The immortalization probability is negatively related to species body mass. The new evaluation and additional data about replicative potential strengthen our previous observation, confirming that stable and extended proliferation is strongly correlated with the evolution of a large body mass rather than lifespan. CONCLUSION: The relation between immortalization and body mass suggests a need to evolve stringent mechanisms that control genetic stability during the evolution of a large body mass.


Assuntos
Longevidade , Neoplasias , Animais , Filogenia , Técnicas de Cultura de Células , Probabilidade , Mamíferos
5.
Mol Biol Cell ; 33(5): ar36, 2022 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-35196069

RESUMO

Cellular senescence is a terminal cell fate characterized by growth arrest and a metabolically active state characterized by high glycolytic activity. Human fibroblasts were placed in a unique metabolic state using a combination of methionine restriction (MetR) and rapamycin (Rapa). This combination induced a metabolic reprogramming that prevented the glycolytic shift associated with senescence. Surprisingly, cells treated in this manner did not undergo senescence but continued to divide at a slow rate even at high passage, in contrast with either Rapa treatment or MetR, both of which extended life span but eventually resulted in growth arrest. Transcriptome-wide analysis revealed a coordinated regulation of metabolic enzymes related to one-carbon metabolism including three methyltransferase enzymes (KMT2D, SETD1B, and ASH1L), key enzymes for both carnitine synthesis and histone modification. These enzymes appear to be involved in both the metabolic phenotype of senescent cells and the chromatin changes required for establishing the senescence arrest. Targeting one of these enzymes, ASH1L, produced both a glycolytic shift and senescence, providing proof of concept. These findings reveal a mechanistic link between a major metabolic hallmark of senescence and nuclear events required for senescence.


Assuntos
Senescência Celular , Epigênese Genética , Senescência Celular/genética , Fibroblastos/metabolismo , Glicólise , Metionina/metabolismo , Sirolimo/farmacologia
6.
Geroscience ; 44(2): 683-698, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34550526

RESUMO

Persistent DNA damage (genotoxic stress) triggers signaling cascades that drive cells into apoptosis or senescence to avoid replicating a damaged genome. Sp1 has been found to play a role in double strand break (DSB) repair, and a link between Sp1 and aging has also been established, where Sp1 protein, but not RNA, levels decrease with age. Interestingly, inhibition ATM reverses the age-related degradation of Sp1, suggesting that DNA damage signaling is involved in senescence-related degradation of Sp1. Proteasomal degradation of Sp1 in senescent cells is mediated via sumoylation, where sumoylation of Sp1 on lysine 16 is increased in senescent cells. Taking into consideration our previous findings that Sp1 is phosphorylated by ATM in response to DNA damage and that proteasomal degradation of Sp1 at DSBs is also mediated by its sumoylation and subsequent interaction with RNF4, we investigated the potential contribution of Sp1's role as a DSB repair factor in mediating cellular senescence. We report here that Sp1 expression is decreased with a concomitant increase in senescence markers in response to DNA damage. Mutation of Sp1 at serine 101 to create an ATM phospho-null mutant, or mutation of lysine 16 to create a sumo-null mutant, prevents the sumoylation and subsequent proteasomal degradation of Sp1 and results in a decrease in senescence. Conversely, depletion of Sp1 or mutation of Sp1 to create an ATM phosphomimetic results in premature degradation of Sp1 and an increase in senescence markers. These data link a loss of genomic stability with senescence through the action of a DNA damage repair factor.


Assuntos
Dano ao DNA , Lisina , Senescência Celular , Reparo do DNA , Sumoilação
8.
Cell Cycle ; 20(3): 247-255, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33475456

RESUMO

A key to longevity assurance is the nutrient-sensing mTOR pathway. Inhibition of mTOR extends lifespan in a variety of organisms. However, the downstream effectors of the mTOR pathway for lifespan regulation are elusive. In a recent report, we described the role of Maf1 as a critical lifespan regulator downstream of the mTOR pathway in fission yeast. Maf1 is the master negative regulator of RNA polymerase III-directed transcription (e.g. tRNAs and 5S rRNAs) and is regulated by mTOR-mediated phosphorylation. We demonstrated that Maf1 is required for lifespan extension under calorie restriction or when mTOR is inhibited. We also showed that Maf1 prevents DNA damage at tRNA genes, which appears to contribute to lifespan maintenance by Maf1. Here we highlight these observations and present additional results to discuss the role of the mTOR-Maf1-Pol III axis in promoting genomic integrity in the face of DNA replication-transcription conflicts in order to maintain normal lifespan.


Assuntos
Dano ao DNA/fisiologia , Longevidade/fisiologia , RNA Polimerase III/genética , Proteínas Repressoras/genética , Proteínas de Schizosaccharomyces pombe/genética , Serina-Treonina Quinases TOR/genética , Transcrição Gênica/fisiologia , Restrição Calórica/métodos , RNA Polimerase III/metabolismo , Proteínas Repressoras/metabolismo , Schizosaccharomyces , Proteínas de Schizosaccharomyces pombe/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo
9.
Res Psychother ; 24(3): 577, 2021 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-35047430

RESUMO

Guided imagery psychotherapy (GIP) is an established therapeutic method using creative mental imagery within a psychodynamic frame of reference. Although there is evidence for the method's general effectiveness, it is yet unclear under which conditions and for which patients it should be used. The aim of this study was therefore to empirically identify indication criteria for the use of guided affective imagery (GAI) as part of psychodynamic therapies. We conducted semi-structured interviews with N=15 psychodynamic therapists also qualified as GAI training therapists. We asked them to recollect cases in which they had decided either for or against the use of imagery. The therapists described a complex interplay of different factors. Using grounded theory coding supplemented by elements of Consensual Qualitative Research we reconstructed from their accounts a sequential model of their indicative decisions. First, there is a consideration of clear contraindications related to reality testing and destructiveness. Second, there are aspects requiring a modified application of GAI such as emotional instability and post-traumatic stress disorder symptoms. In a final step, there are a number of characteristics of the patient, the therapist, the therapeutic relationship, the patients' initial imagery and different therapeutic goals and foci which are weighed relatively to each other in order for therapists to reach an indication decision. We end by discussing ways in which the indicative decision model may be used to improve GAI training as well as the method's differential efficacy and effectiveness.

10.
Curr Biol ; 30(21): 4307-4315.e13, 2020 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-32888485

RESUMO

Lactase persistence (LP), the continued expression of lactase into adulthood, is the most strongly selected single gene trait over the last 10,000 years in multiple human populations. It has been posited that the primary allele causing LP among Eurasians, rs4988235-A [1], only rose to appreciable frequencies during the Bronze and Iron Ages [2, 3], long after humans started consuming milk from domesticated animals. This rapid rise has been attributed to an influx of people from the Pontic-Caspian steppe that began around 5,000 years ago [4, 5]. We investigate the spatiotemporal spread of LP through an analysis of 14 warriors from the Tollense Bronze Age battlefield in northern Germany (∼3,200 before present, BP), the oldest large-scale conflict site north of the Alps. Genetic data indicate that these individuals represent a single unstructured Central/Northern European population. We complemented these data with genotypes of 18 individuals from the Bronze Age site Mokrin in Serbia (∼4,100 to ∼3,700 BP) and 37 individuals from Eastern Europe and the Pontic-Caspian Steppe region, predating both Bronze Age sites (∼5,980 to ∼3,980 BP). We infer low LP in all three regions, i.e., in northern Germany and South-eastern and Eastern Europe, suggesting that the surge of rs4988235 in Central and Northern Europe was unlikely caused by Steppe expansions. We estimate a selection coefficient of 0.06 and conclude that the selection was ongoing in various parts of Europe over the last 3,000 years.


Assuntos
DNA Antigo , Lactase/genética , Seleção Genética , População Branca/genética , Adulto , Restos Mortais , DNA Mitocondrial/genética , Europa (Continente) , Feminino , Frequência do Gene , Humanos , Masculino , Adulto Jovem
11.
Geroscience ; 42(2): 813-815, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32227278

RESUMO

A response is provided to a commentary on a recent study examining the impact of low-dose topical application of rapamycin on markers of aging in the skin. The barriers to clinical implementation of therapies targeting the fundamental aging process are discussed, and the topical study is placed in context with the broader effort to develop new therapeutics for age-related disorders.


Assuntos
Sirolimo , Envelhecimento da Pele , Envelhecimento , Humanos , Imunossupressores , Estudos Prospectivos
12.
Gerontology ; 66(3): 223-230, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32036369

RESUMO

Across species, development and longevity are tightly linked. We discuss the relevant literature and suggest that the root for this stringent relationship is the rate of development. The basis for the relationship between rate of development and longevity lies in adaptations that have occurred through evolution at multiple levels of biological complexity: organism, organ, cellular, and molecular. Thus, the analysis of the relationship is of interest for multiple fields of biology.


Assuntos
Envelhecimento/fisiologia , Longevidade/fisiologia , Animais , Senescência Celular/fisiologia , Humanos , Telômero/fisiologia
13.
Geroscience ; 42(3): 867-879, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31098949

RESUMO

Cellular senescence is a fundamental process that may play positive or detrimental roles for the organism. It is involved in tissue development and in tumor prevention although during aging is becoming a detrimental process contributing to the decline of tissue functions. In previous investigations, we have uncovered a better capacity to detect DNA damage in cells from long-lived mammals. Here, we report that cultured cells derived from long-lived species have a higher propensity to undergo senescence when challenged with DNA damage than cells derived from short-lived species. Using a panel of cells derived from six mammals, which range in lifespan from 3-4 years up to 120 years, we examined cell cycle response, induction of apoptosis and of cellular senescence. All species exhibited a cell cycle arrest while induction of apoptosis was variable. However, a significant positive correlation was found between the relative percent of cells, within a population which entered senescence following damage, and the lifespan of the species. We suggest that cellular senescence may have a positive role during development allowing it to contribute to the evolution of longevity.


Assuntos
Senescência Celular , Longevidade , Envelhecimento , Animais , Dano ao DNA , beta-Galactosidase
14.
Int J Legal Med ; 134(1): 185-198, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31745634

RESUMO

We present results from an inter-laboratory massively parallel sequencing (MPS) study in the framework of the SeqForSTRs project to evaluate forensically relevant parameters, such as performance, concordance, and sensitivity, using a standardized sequencing library including reference material, mixtures, and ancient DNA samples. The standardized library was prepared using the ForenSeq DNA Signature Prep Kit (primer mix A). The library was shared between eight European laboratories located in Austria, France, Germany, The Netherlands, and Sweden to perform MPS on their particular MiSeq FGx sequencers. Despite variation in performance between sequencing runs, all laboratories obtained quality metrics that fell within the manufacturer's recommended ranges. Furthermore, differences in locus coverage did not inevitably adversely affect heterozygous balance. Inter-laboratory concordance showed 100% concordant genotypes for the included autosomal and Y-STRs, and still, X-STR concordance exceeded 83%. The exclusive reasons for X-STR discordances were drop-outs at DXS10103. Sensitivity experiments demonstrated that correct allele calling varied between sequencing instruments in particular for lower DNA amounts (≤ 125 pg). The analysis of compromised DNA samples showed the drop-out of one sample (FA10013B01A) while for the remaining three degraded DNA samples MPS was able to successfully type ≥ 87% of all aSTRs, ≥ 78% of all Y-STRs, ≥ 68% of all X-STRs, and ≥ 92% of all iSNPs demonstrating that MPS is a promising tool for human identity testing, which in return, has to undergo rigorous in-house validation before it can be implemented into forensic routine casework.


Assuntos
Impressões Digitais de DNA/métodos , Biblioteca Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Repetições de Microssatélites , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA , Alelos , Áustria , Eletroforese Capilar , Feminino , França , Alemanha , Humanos , Laboratórios , Masculino , Países Baixos , Reação em Cadeia da Polimerase , Sensibilidade e Especificidade , Suécia
15.
Aging Cell ; 19(2): e13068, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31833215

RESUMO

Maf1 is the master repressor of RNA polymerase III responsible for transcription of tRNAs and 5S rRNAs. Maf1 is negatively regulated via phosphorylation by the mTOR pathway, which governs protein synthesis, growth control, and lifespan regulation in response to nutrient availability. Inhibiting the mTOR pathway extends lifespan in various organisms. However, the downstream effectors for the regulation of cell homeostasis that are critical to lifespan extension remain elusive. Here we show that fission yeast Maf1 is required for lifespan extension. Maf1's function in tRNA repression is inhibited by mTOR-dependent phosphorylation, whereas Maf1 is activated via dephosphorylation by protein phosphatase complexes, PP4 and PP2A. Mutational analysis reveals that Maf1 phosphorylation status influences lifespan, which is correlated with elevated tRNA and protein synthesis levels in maf1∆ cells. However, mTOR downregulation, which negates protein synthesis, fails to rescue the short lifespan of maf1∆ cells, suggesting that elevated protein synthesis is not a cause of lifespan shortening in maf1∆ cells. Interestingly, maf1∆ cells accumulate DNA damage represented by formation of Rad52 DNA damage foci and Rad52 recruitment at tRNA genes. Loss of the Rad52 DNA repair protein further exacerbates the shortened lifespan of maf1∆ cells. Strikingly, PP4 deletion alleviates DNA damage and rescues the short lifespan of maf1∆ cells even though tRNA synthesis is increased in this condition, suggesting that elevated DNA damage is the major cause of lifespan shortening in maf1∆ cells. We propose that Maf1-dependent inhibition of tRNA synthesis controls fission yeast lifespan by preventing genomic instability that arises at tRNA genes.


Assuntos
Regulação Fúngica da Expressão Gênica , Instabilidade Genômica/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , RNA de Transferência/genética , Proteínas Repressoras/metabolismo , Proteínas de Schizosaccharomyces pombe/metabolismo , Schizosaccharomyces/genética , Imunoprecipitação da Cromatina , Dano ao DNA/genética , Glucose/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Fosfoproteínas Fosfatases/genética , Fosfoproteínas Fosfatases/metabolismo , Fosforilação , Biossíntese de Proteínas/genética , Biossíntese de Proteínas/fisiologia , Proteína Fosfatase 2/genética , Proteína Fosfatase 2/metabolismo , RNA de Transferência/biossíntese , RNA de Transferência/metabolismo , Proteína Rad52 de Recombinação e Reparo de DNA/genética , Proteína Rad52 de Recombinação e Reparo de DNA/metabolismo , Proteínas Repressoras/genética , Schizosaccharomyces/metabolismo , Schizosaccharomyces/fisiologia , Proteínas de Schizosaccharomyces pombe/genética
16.
Geroscience ; 41(6): 861-869, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31761958

RESUMO

Aging is a major risk factor for the majority of human diseases, and the development of interventions to reduce the intrinsic rate of aging is expected to reduce the risk for age-related diseases including cardiovascular disease, cancer, and dementia. In the skin, aging manifests itself in photodamage and dermal atrophy, with underlying tissue reduction and impaired barrier function. To determine whether rapamycin, an FDA-approved drug targeting the mechanistic target of rapamycin (mTOR) complex, can reduce senescence and markers of aging in human skin, an exploratory, placebo-controlled, interventional trial was conducted in a clinical dermatology setting. Participants were greater than 40 years of age with evidence of age-related photoaging and dermal volume loss and no major morbidities. Thirty-six participants were enrolled in the study, and nineteen discontinued or were lost to follow-up. A significant (P = 0.008) reduction in p16INK4A protein levels and an increase in collagen VII protein levels (P = 0.0077) were observed among participants at the end of the study. Clinical improvement in skin appearance was noted in multiple participants, and immunohistochemical analysis revealed improvement in histological appearance of skin tissue. Topical rapamycin reduced the expression of the p16INK4A protein consistent with a reduction in cellular senescence. This change was accompanied by relative improvement in clinical appearance of the skin and histological markers of aging and by an increase in collagen VII, which is critical to the integrity of the basement membrane. These results indicate that rapamycin treatment is a potential anti-aging therapy with efficacy in humans.Trial registration ClinicalTrials.gov Identifier: NCT03103893.


Assuntos
Sirolimo/administração & dosagem , Envelhecimento da Pele/efeitos dos fármacos , Dermatopatias/tratamento farmacológico , Pele/efeitos dos fármacos , Administração Tópica , Adulto , Biópsia , Senescência Celular/efeitos dos fármacos , Colágeno Tipo VII/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Imunossupressores/administração & dosagem , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Pele/metabolismo , Pele/patologia , Dermatopatias/metabolismo , Dermatopatias/patologia
17.
Bull Menninger Clin ; 83(4): 353-375, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31180236

RESUMO

The study aimed to test whether countertransference reactions contain valid information about the patient. The authors examined whether a significant part of the variance in emotional, cognitive, and motivational responses to recorded therapy sessions is attributable to the patient. Six student raters listened to 605 audiotaped sessions of 81 patients with major depression treated by 19 therapists and indicated their reactions using a modified version of the Countertransference Questionnaire. The relative amount of variance in countertransference reactions due to differences between patients, ranging from 2% to 16%, was significant for most of the countertransference dimensions. Reactions were influenced by type of treatment and severity of depression but not by comorbid personality disorder or interpersonal problems. The relative amount of variance due to differences between raters was large, averaging at 23%. The authors conclude that-albeit having a relatively low "signal-to-noise ratio"in raters without psychotherapy training-countertransference reactions contain valid clinical information.


Assuntos
Terapia Cognitivo-Comportamental , Contratransferência , Transtorno Depressivo Maior/terapia , Emoções/fisiologia , Pesquisa sobre Serviços de Saúde , Terapia Psicanalítica , Psicoterapia Psicodinâmica , Adulto , Terapia Cognitivo-Comportamental/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Psicanalítica/métodos , Psicometria , Psicoterapia Psicodinâmica/métodos , Pesquisa Qualitativa , Índice de Gravidade de Doença , Gravação em Vídeo , Adulto Jovem
18.
Artigo em Inglês | MEDLINE | ID: mdl-31130916

RESUMO

Lines of evidence from several studies have shown that increases in life expectancy are now accompanied by increased disability rate. The expanded lifespan of the aging population imposes a challenge on the continuous increase of chronic disease. The prevalence of overweight and obesity is increasing at an alarming rate in many parts of the world. Further to increasing the onset of metabolic imbalances, obesity leads to reduced life span and affects cellular and molecular processes in a fashion resembling aging. Nine key hallmarks of the aging process have been proposed. In this review, we will review these hallmarks and discuss pathophysiological changes that occur with obesity, that are similar to or contribute to those that occur during aging. We present and discuss the idea that obesity, in addition to having disease-specific effects, may accelerate the rate of aging affecting all aspects of physiology and thus shortening life span and health span.

19.
Geroscience ; 2018 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-29931650

RESUMO

Inhibition of mTOR signaling using rapamycin has been shown to increase lifespan and healthspan in multiple model organisms; however, the precise mechanisms for the beneficial effects of rapamycin remain uncertain. We have previously reported that rapamycin delays senescence in human cells and that enhanced mitochondrial biogenesis and protection from mitochondrial stress is one component of the benefit provided by rapamycin treatment. Here, using two models of senescence, replicative senescence and senescence induced by the presence of the Hutchinson-Gilford progeria lamin A mutation, we report that senescence is accompanied by elevated glycolysis and increased oxidative phosphorylation, which are both reduced by rapamycin. Measurements of mitochondrial function indicate that direct mitochondria targets of rapamycin are succinate dehydrogenase and matrix alanine aminotransferase. Elevated activity of these enzymes could be part of complex mechanisms that enable mitochondria to resume their optimal oxidative phosphorylation and resist senescence. This interpretation is supported by the fact that rapamycin-treated cultures do not undergo a premature senescence in response to the replacement of glucose with galactose in the culture medium, which forces a greater reliance on oxidative phosphorylation. Additionally, long-term treatment with rapamycin increases expression of the mitochondrial carrier protein UCP2, which facilitates the movement of metabolic intermediates across the mitochondrial membrane. The results suggest that rapamycin impacts mitochondrial function both through direct interaction with the mitochondria and through altered gene expression of mitochondrial carrier proteins.

20.
Mater Sci Eng C Mater Biol Appl ; 90: 189-197, 2018 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-29853082

RESUMO

The aim of this study was to encapsulate an antihypertensive drug (valsartan) within polyester microparticles, namely constituted of poly (lactic acid) (PLA) and poly (ε-caprolactone) (PCL), by using the emulsion solvent evaporation method. In order to optimize the parameters of valsartan encapsulation, design of experiments was applied. Thus, a Box-Behnken matrix was carried out with three independent variables: the PLA amount (X1), the aqueous phase volume (X2) and the surfactant concentration (X3). The analysis of the variance (ANOVA) showed a significant quadratic regression model with the high coefficients of determination values. The optimum conditions were found to be: X1 = 200 mg, X2 = 40 mL and X3 = 0.2%, respectively. Under these conditions, the experimental results showed that the valsartan encapsulation efficiency was equal to 60.05 ±â€¯1.806% with PLA, while it was equal to 69.82 ±â€¯0.645% with PCL. The SEM analysis showed that the shape of the particles was spherical for all formulations and that their size varied between 2 µm and 44 µm. The study of the in-vitro drug release performed in phosphate-buffered saline at pH = 6.8, showed that the valsartan release was more gradual with PCL than with PLA.


Assuntos
Materiais Biocompatíveis/química , Poliésteres/química , Valsartana/química , Análise de Variância , Emulsões/química , Tensoativos/química
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