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1.
NPJ Parkinsons Dis ; 7(1): 78, 2021 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-34493736

RESUMO

A prodromal phase of Parkinson's disease (PD) may precede motor manifestations by decades. PD patients' siblings are at higher risk for PD, but the prevalence and distribution of prodromal symptoms are unknown. The study objectives were (1) to assess motor and non-motor features estimating prodromal PD probability in PD siblings recruited within the European PROPAG-AGEING project; (2) to compare motor and non-motor symptoms to the well-established DeNoPa cohort. 340 PD siblings from three sites (Bologna, Seville, Kassel/Goettingen) underwent clinical and neurological evaluations of PD markers. The German part of the cohort was compared with German de novo PD patients (dnPDs) and healthy controls (CTRs) from DeNoPa. Fifteen (4.4%) siblings presented with subtle signs of motor impairment, with MDS-UPDRS-III scores not clinically different from CTRs. Symptoms of orthostatic hypotension were present in 47 siblings (13.8%), no different to CTRs (p = 0.072). No differences were found for olfaction and overall cognition; German-siblings performed worse than CTRs in visuospatial-executive and language tasks. 3/147 siblings had video-polysomnography-confirmed REM sleep behavior disorder (RBD), none was positive on the RBD Screening Questionnaire. 173/300 siblings had <1% probability of having prodromal PD; 100 between 1 and 10%, 26 siblings between 10 and 80%, one fulfilled the criteria for prodromal PD. According to the current analysis, we cannot confirm the increased risk of PD siblings for prodromal PD. Siblings showed a heterogeneous distribution of prodromal PD markers and probability. Additional parameters, including strong disease markers, should be investigated to verify if these results depend on validity and sensitivity of prodromal PD criteria, or if siblings' risk is not elevated.

3.
Aging Cell ; 20(7): e13409, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34160893

RESUMO

Blood circulating microRNAs (c-miRs) are potential biomarkers to trace aging and longevity trajectories to identify molecular targets for anti-aging therapies. Based on a cross-sectional study, a discovery phase was performed on 12 donors divided into four groups: young, old, healthy, and unhealthy centenarians. The identification of healthy and unhealthy phenotype was based on cognitive performance and capabilities to perform daily activities. Small RNA sequencing identified 79 differentially expressed c-miRs when comparing young, old, healthy centenarians, and unhealthy centenarians. Two miRs, that is, miR-19a-3p and miR-19b-3p, were found increased at old age but decreased at extreme age, as confirmed by RT-qPCR in 49 donors of validation phase. The significant decrease of those miR levels in healthy compared to unhealthy centenarians appears to be due to the presence of isomiRs, not detectable with RT-qPCR, but only with a high-resolution technique such as deep sequencing. Bioinformatically, three main common targets of miR-19a/b-3p were identified, that is, SMAD4, PTEN, and BCL2L11, converging into the FoxO signaling pathway, known to have a significant role in aging mechanisms. For the first time, this study shows the age-related increase of plasma miR-19a/b-3p in old subjects but a decrease in centenarians. This decrease is more pronounced in healthy centenarians and was confirmed by the modified pattern of isomiRs comparing healthy and unhealthy centenarians. Thus, our study paves the way for functional studies using c-miRs and isomiRs as additional parameter to track the onset of aging and age-related diseases using new potential biomarkers.

4.
Mech Ageing Dev ; 197: 111514, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34098514

RESUMO

Centenarians experience successful ageing, although they still present high heterogeneity in their health status. The frailty index is a biomarker of biological age, able to capture such heterogeneity, even at extreme old age. At the same time, other biomarkers (e.g., epigenetic clocks) may be informative the biological age of the individual and potentially describe the ageing status in centenarians. In this article, we explore the relationship between epigenetic clocks and frailty index in a cohort of Italian centenarians. No association was reported, suggesting that these two approaches may describe different aspects of the same ageing process.

5.
Clin Epigenetics ; 13(1): 114, 2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-34001206

RESUMO

BACKGROUND: Epigenetic modifications, such as DNA methylation, can influence the genetic susceptibility to type 2 diabetes mellitus (T2DM) and the progression of the disease. Our previous studies demonstrated that the regulation of the DNA methylation pattern involves the poly(ADP-ribosyl)ation (PARylation) process, a post-translational modification of proteins catalysed by the poly(ADP-ribose) polymerase (PARP) enzymes. Experimental data showed that the hyperactivation of PARylation is associated with impaired glucose metabolism and the development of T2DM. Aims of this case-control study were to investigate the association between PARylation and global and site-specific DNA methylation in T2DM and to evaluate metabolic correlates. RESULTS: Data were collected from 61 subjects affected by T2DM and 48 healthy individuals, recruited as controls. Global levels of poly(ADP-ribose) (PAR, a surrogate of PARP activity), cytosine methylation (5-methylcytosine, 5mC) and de-methylation intermediates 5-hydroxymethylcytosine (5hmC) and 5-formylcytosine (5fC) were determined in peripheral blood cells by ELISA-based methodologies. Site-specific DNA methylation profiling of SOCS3, SREBF1 and TXNIP candidate genes was performed by mass spectrometry-based bisulfite sequencing, methyl-sensitive endonucleases digestion and by DNA immuno-precipitation. T2DM subjects presented higher PAR levels than controls. In T2DM individuals, increased PAR levels were significantly associated with higher HbA1c levels and the accumulation of the de-methylation intermediates 5hmC and 5fC in the genome. In addition, T2DM patients with higher PAR levels showed reduced methylation with increased 5hmC and 5fC levels in specific SOCS3 sites, up-regulated SOCS3 expression compared to both T2DM subjects with low PAR levels and controls. CONCLUSIONS: This study demonstrates the activation of PARylation processes in patients with T2DM, particularly in those with poor glycaemic control. PARylation is linked to dysregulation of DNA methylation pattern via activation of the DNA de-methylation cascade and may be at the basis of the differential gene expression observed in presence of diabetes.

6.
Elife ; 102021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-33941312

RESUMO

Extreme longevity is the paradigm of healthy aging as individuals who reached the extreme decades of human life avoided or largely postponed all major age-related diseases. In this study, we sequenced at high coverage (90X) the whole genome of 81 semi-supercentenarians and supercentenarians [105+/110+] (mean age: 106.6 ± 1.6) and of 36 healthy unrelated geographically matched controls (mean age 68.0 ± 5.9) recruited in Italy. The results showed that 105+/110+ are characterized by a peculiar genetic background associated with efficient DNA repair mechanisms, as evidenced by both germline data (common and rare variants) and somatic mutations patterns (lower mutation load if compared to younger healthy controls). Results were replicated in a second independent cohort of 333 Italian centenarians and 358 geographically matched controls. The genetics of 105+/110+ identified DNA repair and clonal haematopoiesis as crucial players for healthy aging and for the protection from cardiovascular events.


Assuntos
Hematopoiese Clonal/genética , Reparo do DNA , Longevidade/genética , Sequenciamento Completo do Genoma/estatística & dados numéricos , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Patrimônio Genético , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Mutação , Sequenciamento Completo do Genoma/métodos
7.
Geroscience ; 43(3): 1283-1302, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33870444

RESUMO

Ageing leaves characteristic traces in the DNA methylation make-up of the genome. However, the importance of DNA methylation in ageing remains unclear. The study of subtelomeric regions could give promising insights into this issue. Previously reported associations between susceptibility to age-related diseases and epigenetic instability at subtelomeres suggest that the DNA methylation profile of subtelomeres undergoes remodelling during ageing. In the present work, this hypothesis has been tested in the context of the European large-scale project MARK-AGE. In this cross-sectional study, we profiled the DNA methylation of chromosomes 5 and 21 subtelomeres, in more than 2000 age-stratified women and men recruited in eight European countries. The study included individuals from the general population as well as the offspring of nonagenarians and Down syndrome subjects, who served as putative models of delayed and accelerated ageing, respectively. Significant linear changes of subtelomeric DNA methylation with increasing age were detected in the general population, indicating that subtelomeric DNA methylation changes are typical signs of ageing. Data also show that, compared to the general population, the dynamics of age-related DNA methylation changes are attenuated in the offspring of centenarian, while they accelerate in Down syndrome individuals. This result suggests that subtelomeric DNA methylation changes reflect the rate of ageing progression. We next attempted to trace the age-related changes of subtelomeric methylation back to the influence of diverse variables associated with methylation variations in the population, including demographics, dietary/health habits and clinical parameters. Results indicate that the effects of age on subtelomeric DNA methylation are mostly independent of all other variables evaluated.


Assuntos
Envelhecimento , Metilação de DNA , Idoso de 80 Anos ou mais , Envelhecimento/genética , Células Sanguíneas , Estudos Transversais , Europa (Continente) , Feminino , Humanos , Masculino
8.
Front Aging Neurosci ; 13: 639428, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33790779

RESUMO

Alzheimer's disease (AD) is characterized by specific alterations of brain DNA methylation (DNAm) patterns. Age and sex, two major risk factors for AD, are also known to largely affect the epigenetic profiles in brain, but their contribution to AD-associated DNAm changes has been poorly investigated. In this study we considered publicly available DNAm datasets of four brain regions (temporal, frontal, entorhinal cortex, and cerebellum) from healthy adult subjects and AD patients, and performed a meta-analysis to identify sex-, age-, and AD-associated epigenetic profiles. In one of these datasets it was also possible to distinguish 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) profiles. We showed that DNAm differences between males and females tend to be shared between the four brain regions, while aging differently affects cortical regions compared to cerebellum. We found that the proportion of sex-dependent probes whose methylation is modified also during aging is higher than expected, but that differences between males and females tend to be maintained, with only a few probes showing age-by-sex interaction. We did not find significant overlaps between AD- and sex-associated probes, nor disease-by-sex interaction effects. On the contrary, we found that AD-related epigenetic modifications are significantly enriched in probes whose DNAm varies with age and that there is a high concordance between the direction of changes (hyper or hypo-methylation) in aging and AD, supporting accelerated epigenetic aging in the disease. In summary, our results suggest that age-associated DNAm patterns concur to the epigenetic deregulation observed in AD, providing new insights on how advanced age enables neurodegeneration.

9.
Aging (Albany NY) ; 12(23): 24057-24080, 2020 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-33276343

RESUMO

The existence of a sex gap in human health and longevity has been widely documented. Autosomal DNA methylation differences between males and females have been reported, but so far few studies have investigated if DNA methylation is differently affected by aging in males and females. We performed a meta-analysis of 4 large whole blood datasets, comparing 4 aspects of epigenetic age-dependent remodeling between the two sexes: differential methylation, variability, epimutations and entropy. We reported that a large fraction (43%) of sex-associated probes undergoes age-associated DNA methylation changes, and that a limited number of probes show age-by-sex interaction. We experimentally validated 2 regions mapping in FIGN and PRR4 genes and showed sex-specific deviations of their methylation patterns in models of decelerated (centenarians) and accelerated (Down syndrome) aging. While we did not find sex differences in the age-associated increase in epimutations and entropy, we showed that the number of probes having an age-related increase in methylation variability is 15 times higher in males compared to females. Our results can offer new epigenetic tools to study the interaction between aging and sex and can pave the way to the identification of molecular triggers of sex differences in longevity and age-related diseases prevalence.


Assuntos
Envelhecimento/genética , Metilação de DNA , Epigênese Genética , ATPases Associadas a Diversas Atividades Celulares/genética , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Ilhas de CpG , Bases de Dados Genéticas , Síndrome de Down/diagnóstico , Síndrome de Down/genética , Feminino , Humanos , Longevidade/genética , Masculino , Proteínas Associadas aos Microtúbulos/genética , Pessoa de Meia-Idade , Domínios Proteicos Ricos em Prolina , Fatores Sexuais , Adulto Jovem
10.
Sci Rep ; 10(1): 19829, 2020 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-33199729

RESUMO

Gastrointestinal stromal tumours that are wild type for KIT and PDGFRA are referred to as WT GISTs. Of these tumours, SDH-deficient (characterized by the loss of SDHB) and quadruple WT GIST (KIT/PDGFRA/SDH/RAS-P WT) subgroups were reported to display a marked overexpression of FGF4, identifying a putative common therapeutic target for the first time. In SDH-deficient GISTs, methylation of an FGF insulator region was found to be responsible for the induction of FGF4 expression. In quadruple WT, recurrent focal duplication of FGF3/FGF4 was reported; however, how it induced FGF4 expression was not investigated. To assess whether overexpression of FGF4 in quadruple WT could be driven by similar epigenetic mechanisms as in SDH-deficient GISTs, we performed global and locus-specific (on FGF4 and FGF insulator) methylation analyses. However, no epigenetic alterations were detected. Conversely, we demonstrated that in quadruple WT GISTs, FGF4 expression and the structure of the duplication were intimately connected, with the copy of FGF4 closer to the ANO1 super-enhancer being preferentially expressed. In conclusion, we demonstrated that in quadruple WT GISTs, FGF4 overexpression is not due to an epigenetic mechanism but rather to the specific genomic structure of the duplication. Even if FGF4 overexpression is driven by different molecular mechanisms, these findings support an increasing biologic relevance of the FGFR pathway in WT GISTs, both in SDH-deficient and quadruple WT GISTs, suggesting that it may be a common therapeutic target.


Assuntos
Fator 4 de Crescimento de Fibroblastos/genética , Neoplasias Gastrointestinais/genética , Tumores do Estroma Gastrointestinal/genética , Duplicação Gênica , Regulação para Cima , Idoso , Anoctamina-1/genética , Metilação de DNA , Elementos Facilitadores Genéticos , Epigênese Genética , Feminino , Neoplasias Gastrointestinais/metabolismo , Tumores do Estroma Gastrointestinal/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Proteínas Proto-Oncogênicas c-kit/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Transdução de Sinais , Succinato Desidrogenase/genética , Proteínas ras/genética
11.
Semin Immunopathol ; 42(5): 635-645, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32705346

RESUMO

Down syndrome is the most common chromosomal disorder, associated with moderate to severe intellectual disability. While life expectancy of Down syndrome population has greatly increased over the last decades, mortality rates are still high and subjects are facing prematurely a phenomenon of atypical and accelerated aging. The presence of an immune impairment in Down syndrome subjects is suggested for a long time by the existence of an increased incidence of infections, the incomplete efficacy of vaccinations, and a high prevalence of autoimmunity. Immunologic abnormalities have been described since many years in this population, both from a numerical and a functional points of view, and these abnormalities can mirror the ones observed during normal aging. In this review, we summarize our knowledge on immunologic disturbances commonly observed in subjects with Down syndrome, and in innate and adaptive immunity, as well as regarding chronic inflammation. We then discuss the role of accelerated aging in these observed abnormalities and finally review the potential age-associated molecular and cellular mechanisms involved.


Assuntos
Síndrome de Down , Imunossenescência , Envelhecimento , Humanos , Imunidade Inata , Inflamação
12.
Front Aging Neurosci ; 12: 136, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32523526

RESUMO

Biological aging is a complex process involving multiple biological processes. These can be understood theoretically though considering them as individual networks-e.g., epigenetic networks, cell-cell networks (such as astroglial networks), and population genetics. Mathematical modeling allows the combination of such networks so that they may be studied in unison, to better understand how the so-called "seven pillars of aging" combine and to generate hypothesis for treating aging as a condition at relatively early biological ages. In this review, we consider how recent progression in mathematical modeling can be utilized to investigate aging, particularly in, but not exclusive to, the context of degenerative neuronal disease. We also consider how the latest techniques for generating biomarker models for disease prediction, such as longitudinal analysis and parenclitic analysis can be applied to as both biomarker platforms for aging, as well as to better understand the inescapable condition. This review is written by a highly diverse and multi-disciplinary team of scientists from across the globe and calls for greater collaboration between diverse fields of research.

13.
Front Public Health ; 8: 172, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32582603

RESUMO

Chronic pain prevalence is high worldwide and increases at older ages. Signs of premature aging have been associated with chronic pain, but few studies have investigated aging biomarkers in pain-related conditions. A set of DNA methylation (DNAm)-based estimates of age, called "epigenetic clocks," has been proposed as biological measures of age-related adverse processes, morbidity, and mortality. The aim of this study is to assess if different pain-related phenotypes show alterations in DNAm age. In our analysis, we considered three cohorts for which whole-blood DNAm data were available: heat pain sensitivity (HPS), including 20 monozygotic twin pairs discordant for heat pain temperature threshold; fibromyalgia (FM), including 24 cases and 20 controls; and headache, including 22 chronic migraine and medication overuse headache patients (MOH), 18 episodic migraineurs (EM), and 13 healthy subjects. We used the Horvath's epigenetic age calculator to obtain DNAm-based estimates of epigenetic age, telomere length, levels of 7 proteins in plasma, number of smoked packs of cigarettes per year, and blood cell counts. We did not find differences in epigenetic age acceleration, calculated using five different epigenetic clocks, between subjects discordant for pain-related phenotypes. Twins with high HPS had increased CD8+ T cell counts (nominal p = 0.028). HPS thresholds were negatively associated with estimated levels of GDF15 (nominal p = 0.008). FM patients showed decreased naive CD4+ T cell counts compared with controls (nominal p = 0.015). The severity of FM manifestations expressed through various evaluation tests was associated with decreased levels of leptin, shorter length of telomeres, and reduced CD8+ T and natural killer cell counts (nominal p < 0.05), while the duration of painful symptoms was positively associated with telomere length (nominal p = 0.034). No differences in DNAm-based estimates were detected for MOH or EM compared with controls. In summary, our study suggests that HPS, FM, and MOH/EM do not show signs of epigenetic age acceleration in whole blood, while HPS and FM are associated with DNAm-based estimates of immunological parameters, plasma proteins, and telomere length. Future studies should extend these observations in larger cohorts.


Assuntos
Epigênese Genética , Epigenômica , Idoso , Envelhecimento , Metilação de DNA/genética , Humanos , Pessoa de Meia-Idade , Dor
14.
Ageing Res Rev ; 62: 101073, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32446955

RESUMO

Lamin A, a main constituent of the nuclear lamina, is the major splicing product of the LMNA gene, which also encodes lamin C, lamin A delta 10 and lamin C2. Involvement of lamin A in the ageing process became clear after the discovery that a group of progeroid syndromes, currently referred to as progeroid laminopathies, are caused by mutations in LMNA gene. Progeroid laminopathies include Hutchinson-Gilford Progeria, Mandibuloacral Dysplasia, Atypical Progeria and atypical-Werner syndrome, disabling and life-threatening diseases with accelerated ageing, bone resorption, lipodystrophy, skin abnormalities and cardiovascular disorders. Defects in lamin A post-translational maturation occur in progeroid syndromes and accumulated prelamin A affects ageing-related processes, such as mTOR signaling, epigenetic modifications, stress response, inflammation, microRNA activation and mechanosignaling. In this review, we briefly describe the role of these pathways in physiological ageing and go in deep into lamin A-dependent mechanisms that accelerate the ageing process. Finally, we propose that lamin A acts as a sensor of cell intrinsic and environmental stress through transient prelamin A accumulation, which triggers stress response mechanisms. Exacerbation of lamin A sensor activity due to stably elevated prelamin A levels contributes to the onset of a permanent stress response condition, which triggers accelerated ageing.


Assuntos
Envelhecimento , Envelhecimento/genética , Humanos , Lamina Tipo A/genética , MicroRNAs , Mutação , Proteínas Nucleares , Progéria/genética , Precursores de Proteínas/genética
15.
J Extracell Vesicles ; 9(1): 1725285, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32158519

RESUMO

The role of epigenetics in endothelial cell senescence is a cutting-edge topic in ageing research. However, little is known of the relative contribution to pro-senescence signal propagation provided by microRNAs shuttled by extracellular vesicles (EVs) released from senescent cells. Analysis of microRNA and DNA methylation profiles in non-senescent (control) and senescent (SEN) human umbilical vein endothelial cells (HUVECs), and microRNA profiling of their cognate small EVs (sEVs) and large EVs demonstrated that SEN cells released a significantly greater sEV number than control cells. sEVs were enriched in miR-21-5p and miR-217, which target DNMT1 and SIRT1. Treatment of control cells with SEN sEVs induced a miR-21/miR-217-related impairment of DNMT1-SIRT1 expression, the reduction of proliferation markers, the acquisition of a senescent phenotype and a partial demethylation of the locus encoding for miR-21. MicroRNA profiling of sEVs from plasma of healthy subjects aged 40-100 years showed an inverse U-shaped age-related trend for miR-21-5p, consistent with senescence-associated biomarker profiles. Our findings suggest that miR-21-5p/miR-217 carried by SEN sEVs spread pro-senescence signals, affecting DNA methylation and cell replication.

16.
Ageing Res Rev ; 58: 101018, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31926964

RESUMO

Across eukaryotes, ribosomal DNA (rDNA) loci are characterized by intrinsic genomic instability due to their repetitive nature and their base composition that facilitate DNA double strand breaks and RNA:DNA hybrids formation. In the yeast, ribosomal DNA instability affects lifespan via the formation of extrachromosomal rDNA circles (ERC) that accrue into aged cells. In humans, rDNA instability has long been reported in a variety of progeric syndromes caused by the dysfunction of DNA helicases, but its role in physiological aging and longevity still needs to be clarified. Here we propose that rDNA instability leads to the activation of innate immunity and inflammation via the interaction with the cytoplasmic DNA sensing machinery. Owing to the recent clarified role of cytoplasmic DNA in the pro-inflammatory phenotype of senescent cells, we hypothesize that the accrual of rDNA derived molecules (i.e. ERC and RNA:DNA hybrids) may have a role in aging by contributing to inflammaging i.e. the systemic pro-inflammatory drift that associates with the onset of geriatric syndromes and age related dysfunctions in humans.


Assuntos
Evolução Biológica , DNA Ribossômico , Instabilidade Genômica , Saccharomyces cerevisiae , Idoso , Replicação do DNA , Humanos , Saccharomyces cerevisiae/genética
17.
Geroscience ; 42(2): 687-701, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31981007

RESUMO

Mediterranean diet has been proposed to promote healthy aging, but its effects on aging biomarkers have been poorly investigated. We evaluated the impact of a 1-year Mediterranean-like diet in a pilot study including 120 elderly healthy subjects from the NU-AGE study (60 Italians, 60 Poles) by measuring the changes in their epigenetic age, assessed by Horvath's clock. We observed a trend towards epigenetic rejuvenation of participants after nutritional intervention. The effect was statistically significant in the group of Polish females and in subjects who were epigenetically older at baseline. A genome-wide association study of epigenetic age changes after the intervention did not return significant (adjusted p value < 0.05) loci. However, we identified small-effect alleles (nominal p value < 10-4), mapping in genes enriched in pathways related to energy metabolism, regulation of cell cycle, and of immune functions. Together, these findings suggest that Mediterranean diet can promote epigenetic rejuvenation but with country-, sex-, and individual-specific effects, thus highlighting the need for a personalized approach to nutritional interventions.


Assuntos
Dieta Mediterrânea , Epigênese Genética , Rejuvenescimento , Idoso , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Projetos Piloto , Fatores Sexuais
18.
Nutrients ; 12(2)2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31973116

RESUMO

A growing amount of evidence suggests that the downregulation of protein synthesis is an adaptive response during physiological aging, which positively contributes to longevity and can be modulated by nutritional interventions like caloric restriction (CR). The expression of ribosomal RNA (rRNA) is one of the main determinants of translational rate, and epigenetic modifications finely contribute to its regulation. Previous reports suggest that hypermethylation of ribosomal DNA (rDNA) locus occurs with aging, although with some species- and tissue- specificity. In the present study, we experimentally measured DNA methylation of three regions (the promoter, the 5' of the 18S and the 5' of 28S sequences) in the rDNA locus in liver tissues from rats at two, four, 10, and 18 months. We confirm previous findings, showing age-related hypermethylation, and describe, for the first time, that this gain in methylation also occurs in human hepatocytes. Furthermore, we show that age-related hypermethylation is enhanced in livers of rat upon CR at two and 10 months, and that at two months a trend towards the reduction of rRNA expression occurs. Collectively, our results suggest that CR modulates age-related regulation of methylation at the rDNA locus, thus providing an epigenetic readout of the pro-longevity effects of CR.


Assuntos
Envelhecimento/metabolismo , Restrição Calórica , Metilação de DNA/fisiologia , Loci Gênicos/fisiologia , RNA Ribossômico/metabolismo , Animais , DNA Ribossômico/metabolismo , Epigênese Genética , Humanos , Fígado/metabolismo , Longevidade/fisiologia , Masculino , Regiões Promotoras Genéticas/fisiologia , Ratos
19.
Front Physiol ; 10: 996, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31427991

RESUMO

Human aging is accompanied by a decline in muscle mass and muscle function, which is commonly referred to as sarcopenia. Sarcopenia is associated with detrimental clinical outcomes, such as a reduced quality of life, frailty, an increased risk of falls, fractures, hospitalization, and mortality. The exact underlying mechanisms of sarcopenia are poorly delineated and the molecular mechanisms driving the development and progression of this disorder remain to be uncovered. Previous studies have described age-related differences in gene expression, with one study identifying an age-specific expression signature of sarcopenia, but little is known about the influence of epigenetics, and specially of DNA methylation, in its pathogenesis. In this review, we will focus on the available knowledge in literature on the characterization of DNA methylation profiles during skeletal muscle aging and the possible impact of physical activity and nutrition. We will consider the possible use of the recently developed DNA methylation-based biomarkers of aging called epigenetic clocks in the assessment of physical performance in older individuals. Finally, we will discuss limitations and future directions of this field.

20.
J Transl Med ; 17(1): 250, 2019 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-31383037

RESUMO

BACKGROUND: Here, we isolated, expanded and functionally characterized regulatory T cells (Tregs) from patients with end stage kidney and liver disease, waiting for kidney/liver transplantation (KT/LT), with the aim to establish a suitable method to obtain large numbers of immunomodulatory cells for adoptive immunotherapy post-transplantation. METHODS: We first established a preclinical protocol for expansion/isolation of Tregs from peripheral blood of LT/KT patients. We then scaled up and optimized such protocol according to good manufacturing practice (GMP) to obtain high numbers of purified Tregs which were phenotypically and functionally characterized in vitro and in vivo in a xenogeneic acute graft-versus-host disease (aGVHD) mouse model. Specifically, immunodepressed mice (NOD-SCID-gamma KO mice) received human effector T cells with or without GMP-produced Tregs to prevent the onset of xenogeneic GVHD. RESULTS: Our small scale Treg isolation/expansion protocol generated functional Tregs. Interestingly, cryopreservation/thawing did not impair phenotype/function and DNA methylation pattern of FOXP3 gene of the expanded Tregs. Fully functional Tregs were also isolated/expanded from KT and LT patients according to GMP. In the mouse model, GMP Tregs from LT or KT patient proved to be safe and show a trend toward reduced lethality of acute GVHD. CONCLUSIONS: These data demonstrate that expanded/thawed GMP-Tregs from patients with end-stage organ disease are fully functional in vitro. Moreover, their infusion is safe and results in a trend toward reduced lethality of acute GVHD in vivo, further supporting Tregs-based adoptive immunotherapy in solid organ transplantation.


Assuntos
Criopreservação/métodos , Falência Renal Crônica/imunologia , Hepatopatias/imunologia , Linfócitos T Reguladores/citologia , Adulto , Idoso , Animais , Transplante de Células , Metilação de DNA , Feminino , Fatores de Transcrição Forkhead/genética , Doença Enxerto-Hospedeiro , Humanos , Imunoterapia , Falência Renal Crônica/cirurgia , Hepatopatias/cirurgia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Pessoa de Meia-Idade , Fenótipo
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