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1.
Nature ; 596(7870): 43-53, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34349292

RESUMO

The genomes of virtually all organisms contain repetitive sequences that are generated by the activity of transposable elements (transposons). Transposons are mobile genetic elements that can move from one genomic location to another; in this process, they amplify and increase their presence in genomes, sometimes to very high copy numbers. In this Review we discuss new evidence and ideas that the activity of retrotransposons, a major subgroup of transposons overall, influences and even promotes the process of ageing and age-related diseases in complex metazoan organisms, including humans. Retrotransposons have been coevolving with their host genomes since the dawn of life. This relationship has been largely competitive, and transposons have earned epithets such as 'junk DNA' and 'molecular parasites'. Much of our knowledge of the evolution of retrotransposons reflects their activity in the germline and is evident from genome sequence data. Recent research has provided a wealth of information on the activity of retrotransposons in somatic tissues during an individual lifespan, the molecular mechanisms that underlie this activity, and the manner in which these processes intersect with our own physiology, health and well-being.


Assuntos
Envelhecimento/genética , Envelhecimento/patologia , Doença/genética , Retroelementos/genética , Animais , Dano ao DNA , Inativação Gênica , Genoma Humano/genética , Genômica , Humanos , Imunidade Inata
2.
Rev Assoc Med Bras (1992) ; 67(2): 173-177, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34406239

RESUMO

The aging process occurs due to the decline of vital physiological functions and adaptability of the body, being influenced by genetics and lifestyle. With advances in genetics, biological aging can be calculated by telomere length. Telomeres are regions at the ends of chromosomes that play a role in the maintenance and integrity of DNA. With biological aging, telomere shortening occurs, causing cellular senescence. Several studies show that shorter telomeres are associated with acute and chronic diseases, stress, addictions, and intoxications. Even in the current COVID-19 pandemic, telomere shortening is proposed as a marker of severity in individuals infected by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). On the other hand, healthy lifestyle habits increase telomere length and balance of various cellular functions, preventing diseases.


Assuntos
COVID-19 , Telômero , Envelhecimento/genética , Biomarcadores , Humanos , Pandemias , SARS-CoV-2 , Telômero/genética
3.
Adv Exp Med Biol ; 1319: 287-314, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34424521

RESUMO

The naked mole-rat (Heterocephalus glaber) is the longest-lived rodent, with a maximal reported lifespan of 37 years. In addition to its long lifespan - which is much greater than predicted based on its small body size (longevity quotient of ~4.2) - naked mole-rats are also remarkably healthy well into old age. This is reflected in a striking resistance to tumorigenesis and minimal declines in cardiovascular, neurological and reproductive function in older animals. Over the past two decades, researchers have been investigating the molecular mechanisms regulating the extended life- and health- span of this animal, and since the sequencing and assembly of the naked mole-rat genome in 2011, progress has been rapid. Here, we summarize findings from published studies exploring the unique molecular biology of the naked mole-rat, with a focus on mechanisms and pathways contributing to genome stability and maintenance of proteostasis during aging. We also present new data from our laboratory relevant to the topic and discuss our findings in the context of the published literature.


Assuntos
Ratos-Toupeira , Proteostase , Envelhecimento/genética , Animais , Instabilidade Genômica , Longevidade/genética , Ratos-Toupeira/genética
4.
Nat Commun ; 12(1): 4813, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34376664

RESUMO

Differences in immune responses to viruses and autoimmune diseases such as systemic lupus erythematosus (SLE) can show sexual dimorphism. Age-associated B cells (ABC) are a population of CD11c+T-bet+ B cells critical for antiviral responses and autoimmune disorders. Absence of DEF6 and SWAP-70, two homologous guanine exchange factors, in double-knock-out (DKO) mice leads to a lupus-like syndrome in females marked by accumulation of ABCs. Here we demonstrate that DKO ABCs show sex-specific differences in cell number, upregulation of an ISG signature, and further differentiation. DKO ABCs undergo oligoclonal expansion and differentiate into both CD11c+ and CD11c- effector B cell populations with pathogenic and pro-inflammatory function as demonstrated by BCR sequencing and fate-mapping experiments. Tlr7 duplication in DKO males overrides the sex-bias and further augments the dissemination and pathogenicity of ABCs, resulting in severe pulmonary inflammation and early mortality. Thus, sexual dimorphism shapes the expansion, function and differentiation of ABCs that accompanies TLR7-driven immunopathogenesis.


Assuntos
Envelhecimento/imunologia , Linfócitos B/imunologia , Diferenciação Celular/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Fatores Etários , Envelhecimento/genética , Animais , Linfócitos B/citologia , Linfócitos B/metabolismo , Antígeno CD11c/imunologia , Antígeno CD11c/metabolismo , Diferenciação Celular/genética , Células Cultivadas , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/imunologia , Proteínas de Ligação a DNA/metabolismo , Feminino , Fatores de Troca do Nucleotídeo Guanina/genética , Fatores de Troca do Nucleotídeo Guanina/imunologia , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Estimativa de Kaplan-Meier , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Antígenos de Histocompatibilidade Menor/genética , Antígenos de Histocompatibilidade Menor/imunologia , Antígenos de Histocompatibilidade Menor/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/imunologia , Proteínas Nucleares/metabolismo , Fatores Sexuais , Proteínas com Domínio T/imunologia , Proteínas com Domínio T/metabolismo
5.
FASEB J ; 35(9): e21752, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34369602

RESUMO

Aging, obesity, and insulin resistance are associated with low levels of PGC1α and PGC1ß coactivators and defective mitochondrial function. We studied mice deficient for PGC1α and PGC1ß [double heterozygous (DH)] to investigate their combined pathogenic contribution. Contrary to our hypothesis, DH mice were leaner, had increased energy dissipation, a pro-thermogenic profile in BAT and WAT, and improved carbohydrate metabolism compared to wild types. WAT showed upregulation of mitochondriogenesis/oxphos machinery upon allelic compensation of PGC1α4 from the remaining allele. However, DH mice had decreased mitochondrial OXPHOS and biogenesis transcriptomes in mitochondria-rich organs. Despite being metabolically healthy, mitochondrial defects in DH mice impaired muscle fiber remodeling and caused qualitative changes in the hepatic lipidome. Our data evidence first the existence of organ-specific compensatory allostatic mechanisms are robust enough to drive an unexpected phenotype. Second, optimization of adipose tissue bioenergetics is sufficient to maintain a healthy metabolic phenotype despite a broad severe mitochondrial dysfunction in other relevant metabolic organs. Third, the decrease in PGC1s in adipose tissue of obese and diabetic patients is in contrast with the robustness of the compensatory upregulation in the adipose of the DH mice.


Assuntos
Tecido Adiposo/metabolismo , Mitocôndrias/genética , Proteínas Nucleares/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Fatores de Transcrição/genética , Envelhecimento/genética , Animais , Modelos Animais de Doenças , Metabolismo Energético/genética , Heterozigoto , Resistência à Insulina/genética , Masculino , Camundongos , Obesidade/genética , Termogênese/genética , Transcriptoma/genética
6.
FASEB J ; 35(9): e21864, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34423880

RESUMO

Resistance training (RT) dynamically alters the skeletal muscle nuclear DNA methylome. However, no study has examined if RT affects the mitochondrial DNA (mtDNA) methylome. Herein, ten older, Caucasian untrained males (65 ± 7 y.o.) performed six weeks of full-body RT (twice weekly). Body composition and knee extensor torque were assessed prior to and 72 h following the last RT session. Vastus lateralis (VL) biopsies were also obtained. VL DNA was subjected to reduced representation bisulfite sequencing providing excellent coverage across the ~16-kilobase mtDNA methylome (254 CpG sites). Biochemical assays were also performed, and older male data were compared to younger trained males (22 ± 2 y.o., n = 7, n = 6 Caucasian & n = 1 African American). RT increased whole-body lean tissue mass (p = .017), VL thickness (p = .012), and knee extensor torque (p = .029) in older males. RT also affected the mtDNA methylome, as 63% (159/254) of the CpG sites demonstrated reduced methylation (p < .05). Several mtDNA sites presented a more "youthful" signature in older males after RT in comparison to younger males. The 1.12 kilobase mtDNA D-loop/control region, which regulates replication and transcription, possessed enriched hypomethylation in older males following RT. Enhanced expression of mitochondrial H- and L-strand genes and complex III/IV protein levels were also observed (p < .05). While limited to a shorter-term intervention, this is the first evidence showing that RT alters the mtDNA methylome in skeletal muscle. Observed methylome alterations may enhance mitochondrial transcription, and RT evokes mitochondrial methylome profiles to mimic younger men. The significance of these findings relative to broader RT-induced epigenetic changes needs to be elucidated.


Assuntos
Envelhecimento , Metilação de DNA , DNA Mitocondrial/metabolismo , Epigenoma , Regulação da Expressão Gênica , Genes Mitocondriais/genética , Músculo Esquelético/metabolismo , Treinamento de Força , Idoso , Envelhecimento/genética , Envelhecimento/metabolismo , DNA Mitocondrial/genética , Humanos , Masculino , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Músculo Esquelético/citologia , RNA Mensageiro/análise , RNA Mensageiro/genética , Adulto Jovem
7.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(8): 818-821, 2021 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-34365634

RESUMO

The progress of epigenetic research has led to the discovery and confirmation of age-related markers based on DNA methylation. These DNA methylation indices are called "epigenetic clock/age". The concept of "epigenetic clock/age" and the establishment of its evaluation system are helpful to solve some of the long-standing problems in the field of life and medicine. When facing the current global aging, it is of great significance to refer to the comprehensive health parameters to determine the biological age and life span of an individual, and thus to design a plan to slow down the process of life cycle. This paper has summarized the concept and development of "epigenetic clock/age" in recent years.


Assuntos
Metilação de DNA , Epigênese Genética , Envelhecimento/genética , Biomarcadores , Humanos
8.
Nat Commun ; 12(1): 4336, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34267196

RESUMO

Glutathione (GSH) is the most abundant cellular antioxidant. As reactive oxygen species (ROS) are widely believed to promote aging and age-related diseases, and antioxidants can neutralize ROS, it follows that GSH and its precursor, N-acetyl cysteine (NAC), are among the most popular dietary supplements. However, the long- term effects of GSH or NAC on healthy animals have not been thoroughly investigated. We employed C. elegans to demonstrate that chronic administration of GSH or NAC to young or aged animals perturbs global gene expression, inhibits skn-1-mediated transcription, and accelerates aging. In contrast, limiting the consumption of dietary thiols, including those naturally derived from the microbiota, extended lifespan. Pharmacological GSH restriction activates the unfolded protein response and increases proteotoxic stress resistance in worms and human cells. It is thus advantageous for healthy individuals to avoid excessive dietary antioxidants and, instead, rely on intrinsic GSH biosynthesis, which is fine-tuned to match the cellular redox status and to promote homeostatic ROS signaling.


Assuntos
Acetilcisteína/farmacologia , Envelhecimento/efeitos dos fármacos , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/fisiologia , Glutationa/farmacologia , Envelhecimento/genética , Envelhecimento/fisiologia , Animais , Animais Geneticamente Modificados , Proteínas de Caenorhabditis elegans/genética , Proteínas de Ligação a DNA/genética , Suplementos Nutricionais , Escherichia coli , Feminino , Fibroblastos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Glutationa/metabolismo , Humanos , Masculino , Paraquat/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Compostos de Sulfidrila/metabolismo , Fatores de Transcrição/genética , Resposta a Proteínas não Dobradas/fisiologia
9.
Ageing Res Rev ; 70: 101402, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34242808

RESUMO

Alzheimer's disease (AD) is a complex neurological disorder of uncertain aetiology, although substantial research has been conducted to explore important factors related to risk of onset and progression. Both lifestyle (e.g., complex mental stimulation, vascular health) and genetic factors (e.g., APOE, BDNF, PICALM, CLU, APP, PSEN1, PSEN2, and other genes) have been associated with AD risk. Despite more than thirty years of genetic research, much of the heritability of AD is not explained by measured loci. This suggests that the missing heritability of AD might be potentially related to rare variants, gene-environment and gene-gene interactions, and potentially epigenetic modulators. Moreover, while ageing is the most substantial factor risk for AD, there are limited longitudinal studies examining the association of genetic factors with decline in cognitive function due to ageing and the preclinical stages of this condition. This review summarises findings from currently available research on the genetic factors of ageing-related cognitive change and AD and suggests some future research directions.


Assuntos
Doença de Alzheimer , Envelhecimento/genética , Doença de Alzheimer/genética , Apolipoproteínas E , Cognição , Predisposição Genética para Doença , Humanos , Estudos Longitudinais
10.
Nat Commun ; 12(1): 4398, 2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34285226

RESUMO

Studies in rodents and captive primates suggest that the early-life social environment affects future phenotype, potentially through alterations to DNA methylation. Little is known of these associations in wild animals. In a wild population of spotted hyenas, we test the hypothesis that maternal care during the first year of life and social connectedness during two periods of early development leads to differences in DNA methylation and fecal glucocorticoid metabolites (fGCMs) later in life. Here we report that although maternal care and social connectedness during the den-dependent life stage are not associated with fGCMs, greater social connectedness during the subadult den-independent life stage is associated with lower adult fGCMs. Additionally, more maternal care and social connectedness after den independence correspond with higher global (%CCGG) DNA methylation. We also note differential DNA methylation near 5 genes involved in inflammation, immune response, and aging that may link maternal care with stress phenotype.


Assuntos
Epigênese Genética/fisiologia , Hyaenidae/psicologia , Comportamento Materno/fisiologia , Meio Social , Estresse Psicológico/diagnóstico , Envelhecimento/genética , Envelhecimento/psicologia , Animais , Metilação de DNA/fisiologia , Fezes/química , Feminino , Glucocorticoides/análise , Glucocorticoides/metabolismo , Hyaenidae/genética , Hyaenidae/crescimento & desenvolvimento , Masculino , Estresse Psicológico/genética , Estresse Psicológico/metabolismo , Estresse Psicológico/psicologia
12.
Int J Mol Sci ; 22(11)2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34204879

RESUMO

Aging is the most critical factor that influences the quality of post-ovulatory oocytes. Age-related molecular pathways remain poorly understood in fish oocytes. In this study, we examined the effect of oocyte aging on specific histone acetylation in common carp Cyprinus carpio. The capacity to progress to the larval stage in oocytes that were aged for 28 h in vivo and in vitro was evaluated. Global histone modifications and specific histone acetylation (H3K9ac, H3K14ac, H4K5ac, H4K8ac, H4K12ac, and H4K16ac) were investigated during oocyte aging. Furthermore, the activity of histone acetyltransferase (HAT) was assessed in fresh and aged oocytes. Global histone modifications did not exhibit significant alterations during 8 h of oocyte aging. Among the selected modifications, H4K12ac increased significantly at 28 h post-stripping (HPS). Although not significantly different, HAT activity exhibited an upward trend during oocyte aging. Results of our current study indicate that aging of common carp oocytes for 12 h results in complete loss of egg viability rates without any consequence in global and specific histone modifications. However, aging oocytes for 28 h led to increased H4K12ac. Thus, histone acetylation modification as a crucial epigenetic mediator may be associated with age-related defects, particularly in oocytes of a more advanced age.


Assuntos
Envelhecimento/genética , Carpas/genética , Histona Acetiltransferases/genética , Acetilação , Animais , Carpas/crescimento & desenvolvimento , Histonas/genética , Oócitos/crescimento & desenvolvimento , Oócitos/metabolismo , Processamento de Proteína Pós-Traducional/genética
13.
Int J Mol Sci ; 22(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199458

RESUMO

As we age, our bodies accrue damage in the form of DNA mutations. These mutations lead to the generation of sub-optimal proteins, resulting in inadequate cellular homeostasis and senescence. The build-up of senescent cells negatively affects the local cellular micro-environment and drives ageing associated disease, including neurodegeneration. Therefore, limiting the accumulation of DNA damage is essential for healthy neuronal populations. The naked mole rats (NMR) are from eastern Africa and can live for over three decades in chronically hypoxic environments. Despite their long lifespan, NMRs show little to no biological decline, neurodegeneration, or senescence. Here, we discuss molecular pathways and adaptations that NMRs employ to maintain genome integrity and combat the physiological and pathological decline in organismal function.


Assuntos
Adaptação Fisiológica/genética , Senescência Celular/genética , Dano ao DNA/genética , Estresse Oxidativo/genética , Envelhecimento/genética , Animais , DNA/genética , Homeostase , Ratos-Toupeira/genética , Estresse Oxidativo/fisiologia
14.
Int J Mol Sci ; 22(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199515

RESUMO

Leaf senescence is a developmental process induced by various molecular and environmental stimuli that may affect crop yield. The dark-induced leaf senescence-91 (DLS-91) plants displayed rapid leaf senescence, dramatically decreased chlorophyll contents, low photochemical efficiencies, and upregulation of the senescence-associated marker gene BrSAG12-1. To understand DLS molecular mechanism, we examined transcriptomic changes in DLS-91 and control line DLS-42 following 0, 1, and 4 days of dark treatment (DDT) stages. We identified 501, 446, and 456 DEGs, of which 16.7%, 17.2%, and 14.4% encoded TFs, in samples from the three stages. qRT-PCR validation of 16 genes, namely, 7 MADS, 6 NAC, and 3 WRKY, suggested that BrAGL8-1, BrAGL15-1, and BrWRKY70-1 contribute to the rapid leaf senescence of DLS-91 before (0 DDT) and after (1 and 4 DDT) dark treatment, whereas BrNAC046-2, BrNAC029-2/BrNAP, and BrNAC092-1/ORE1 TFs may regulate this process at a later stage (4 DDT). In-silico analysis of cis-acting regulatory elements of BrAGL8-1, BrAGL42-1, BrNAC029-2, BrNAC092-1, and BrWRKY70-3 of B. rapa provides insight into the regulation of these genes. Our study has uncovered several AGL-MADS, WRKY, and NAC TFs potentially worthy of further study to understand the underlying mechanism of rapid DLS in DLS-91.


Assuntos
Envelhecimento/genética , Brassica rapa/genética , Fatores de Transcrição/genética , Transcriptoma/genética , Brassica rapa/crescimento & desenvolvimento , Clorofila/genética , Regulação da Expressão Gênica de Plantas/genética , Proteínas de Domínio MADS/genética , Folhas de Planta/genética , Proteínas de Plantas/genética
15.
Int J Mol Sci ; 22(11)2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34200325

RESUMO

The SARS-CoV-2 infection determines the COVID-19 syndrome characterized, in the worst cases, by severe respiratory distress, pulmonary and cardiac fibrosis, inflammatory cytokine release, and immunosuppression. This condition has led to the death of about 2.15% of the total infected world population so far. Among survivors, the presence of the so-called persistent post-COVID-19 syndrome (PPCS) is a common finding. In COVID-19 survivors, PPCS presents one or more symptoms: fatigue, dyspnea, memory loss, sleep disorders, and difficulty concentrating. In this study, a cohort of 117 COVID-19 survivors (post-COVID-19) and 144 non-infected volunteers (COVID-19-free) was analyzed using pyrosequencing of defined CpG islands previously identified as suitable for biological age determination. The results show a consistent biological age increase in the post-COVID-19 population, determining a DeltaAge acceleration of 10.45 ± 7.29 years (+5.25 years above the range of normality) compared with 3.68 ± 8.17 years for the COVID-19-free population (p < 0.0001). A significant telomere shortening parallels this finding in the post-COVID-19 cohort compared with COVID-19-free subjects (p < 0.0001). Additionally, ACE2 expression was decreased in post-COVID-19 patients, compared with the COVID-19-free population, while DPP-4 did not change. In light of these observations, we hypothesize that some epigenetic alterations are associated with the post-COVID-19 condition, particularly in younger patients (< 60 years).


Assuntos
Envelhecimento/genética , COVID-19/genética , COVID-19/fisiopatologia , Ilhas de CpG , Encurtamento do Telômero , Telômero/metabolismo , Adulto , Idoso , Enzima de Conversão de Angiotensina 2/sangue , Biomarcadores , COVID-19/complicações , COVID-19/etiologia , Metilação de DNA , Dipeptidil Peptidase 4/sangue , Epigenômica , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Interações entre Hospedeiro e Microrganismos , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Sobreviventes
16.
Int J Mol Sci ; 22(13)2021 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-34281245

RESUMO

Hutchinson-Gilford progeria syndrome (HGPS), or progeria, is an extremely rare disorder that belongs to the class of laminopathies, diseases characterized by alterations in the genes that encode for the lamin proteins or for their associated interacting proteins. In particular, progeria is caused by a point mutation in the gene that codifies for the lamin A gene. This mutation ultimately leads to the biosynthesis of a mutated version of lamin A called progerin, which accumulates abnormally in the nuclear lamina. This accumulation elicits several alterations at the nuclear, cellular, and tissue levels that are phenotypically reflected in a systemic disorder with important alterations, mainly in the cardiovascular system, bones, skin, and overall growth, which results in premature death at an average age of 14.5 years. In 2020, lonafarnib became the first (and only) FDA approved drug for treating progeria. In this context, the present review focuses on the different therapeutic strategies currently under development, with special attention to the new small molecules described in recent years, which may represent the upcoming first-in-class drugs with new mechanisms of action endowed with effectiveness not only to treat but also to cure progeria.


Assuntos
Piperidinas/uso terapêutico , Progéria/terapia , Piridinas/uso terapêutico , Envelhecimento/genética , Senilidade Prematura/genética , Núcleo Celular/metabolismo , Senescência Celular/genética , Fibroblastos/metabolismo , Humanos , Lamina Tipo A/genética , Laminopatias/terapia , Mutação , Lâmina Nuclear/genética , Lâmina Nuclear/fisiologia , Fenótipo , Progéria/genética , Progéria/metabolismo , Pele/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia
17.
Yi Chuan ; 43(6): 545-570, 2021 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-34284987

RESUMO

With the increase of life expectancy, the world's population is aging rapidly. Previous work in the field of aging greatly increases our understanding of biological mechanisms underlying longevity. Researchers have unraveled a number of longevity pathways conserved from yeast to mammals. However, recent evidence shows that mechanisms regulating the life span and those regulating age-related behavioral decline could be dissociated. The regulatory mechanisms underlying behavioral and cognitive aging is largely unknown. Previous work has described a significant age-related decline in cognitive behaviors including episodic memory, working memory, processing speed, as well as motor function deterioration and circadian dysfunction. With the advance of neuroscience and technology, more and more studies have focused on the age-related changes in structure and function of the brain. In this review, we briefly describe the deterioration of cognitive function and other behaviors in the aging process, and survey the role of age-related changes in brain structure and network, neuron morphology and function, transcriptome in brain and some conserved biological pathways on age-related cognitive and behavioral decline. Further studies on the mechanisms underpinning age-related cognitive and behavioral decline may provide clues not only for improving the quality of life for the ageing population, but also for developing intervention approaches for neurodegenerative diseases.


Assuntos
Envelhecimento Cognitivo , Envelhecimento/genética , Animais , Cognição , Longevidade , Qualidade de Vida
18.
Aging (Albany NY) ; 13(13): 17428-17441, 2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34257163

RESUMO

Skeletal muscle is capable of repairing itself after injury to maintain the stability of its own tissue, but this ability declines with aging. Circular RNAs (circRNAs) are involved in cell aging. However, there is little research into their role and underlying mechanisms, especially in skeletal muscle stem cells (SkMSCs). In this study, we assessed circRNA FUT10 expression in aged and adult SkMSCs. We observed that circRNA FUT10 was upregulated in aged SkMSCs compared with that in adult SkMSCs. Furthermore, we identified putative miR-365-3p binding sites on circRNA FUT10, suggesting that this circRNA sponges miR-365a-3p. We also found that HOXA9 is a downstream target of miR-365a-3p and confirmed that miR-365a-3p can bind to circRNA FUT10 and the 3'-untranslated region of HOXA9 mRNA. This finding indicated that miR-365a-3p might serve as a "bridge" between circRNA FUT10 and HOXA9. Finally, we found that the circRNA FUT10/miR365a-3p/HOXA9 axis is involved in SkMSC aging. Collectively, our results show that the circRNA FUT10/miR365a-3p/HOXA9 axis is a promising therapeutic target and are expected to facilitate the development of therapeutic strategies to improve the prognosis of degenerative muscle disease.


Assuntos
Fucosiltransferases/genética , Proteínas de Homeodomínio/genética , Fibras Musculares Esqueléticas/fisiologia , RNA Circular/genética , Células-Tronco , Regiões 3' não Traduzidas , Envelhecimento/genética , Animais , Feminino , Marcação de Genes , Camundongos , Camundongos Endogâmicos BALB C , Doenças Musculares/genética , Doenças Musculares/patologia , Regulação para Cima/genética
19.
Int J Mol Sci ; 22(14)2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34298947

RESUMO

Hutchinson-Gilford progeria syndrome (HGPS) is a deadly childhood disorder, which is considered a very rare disease. It is caused by an autosomal dominant mutation on the LMNA gene, and it is characterized by accelerated aging. Human cell lines from HGPS patients and healthy parental controls were studied in parallel using next-generation sequencing (NGS) to unravel new non-previously altered molecular pathways. Nine hundred and eleven transcripts were differentially expressed when comparing healthy versus HGPS cell lines from a total of 21,872 transcripts; ITPR1, ITPR3, CACNA2D1, and CAMK2N1 stood out among them due to their links with calcium signaling, and these were validated by Western blot analysis. It was observed that the basal concentration of intracellular Ca2+ was statistically higher in HGPS cell lines compared to healthy ones. The relationship between genes involved in Ca2+ signaling and mitochondria-associated membranes (MAM) was demonstrated through cytosolic calcium handling by means of an automated fluorescent plate reading system (FlexStation 3, Molecular Devices), and apoptosis and mitochondrial ROS production were examined by means of flow cytometry analysis. Altogether, our data suggest that the Ca2+ signaling pathway is altered in HGPS at least in part due to the overproduction of reactive oxygen species (ROS). Our results unravel a new therapeutic window for the treatment of this rare disease and open new strategies to study pathologies involving both accelerated and healthy aging.


Assuntos
Sinalização do Cálcio/genética , Progéria/genética , Envelhecimento/genética , Apoptose/genética , Células Cultivadas , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Ensaios de Triagem em Larga Escala/métodos , Humanos , Lamina Tipo A/genética , Mitocôndrias/genética , Mutação/genética , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/genética
20.
Transl Psychiatry ; 11(1): 404, 2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34294682

RESUMO

The increasingly compelling data supporting the involvement of immunobiological mechanisms in Major Depressive Disorder (MDD) might provide some explanation forthe variance in this heterogeneous condition. Peripheral blood measures of cytokines and chemokines constitute the bulk of evidence, with consistent meta-analytic data implicating raised proinflammatory cytokines such as IL6, IL1ß and TNF. Among the potential mechanisms linking immunobiological changes to affective neurobiology is the accelerated biological ageing seen in MDD, particularly via the senescence associated secretory phenotype (SASP). However, the cellular source of immunobiological markers remains unclear. Pre-clinical evidence suggests a role for peripheral blood mononuclear cells (PBMC), thus here we aimed to explore the transcriptomic profile using RNA sequencing in PBMCs in a clinical sample of people with various levels of depression and treatment response comparing it with that in healthy controls (HCs). There were three groups with major depressive disorder (MDD): treatment-resistant (n = 94), treatment-responsive (n = 47) and untreated (n = 46). Healthy controls numbered 44. Using PBMCs gene expression analysis was conducted using RNAseq to a depth of 54.5 million reads. Differential gene expression analysis was performed using DESeq2. The data showed no robust signal differentiating MDD and HCs. There was, however, significant evidence of elevated biological ageing in MDD vs HC. Biological ageing was evident in these data as a transcriptional signature of 888 age-associated genes (adjusted p < 0.05, absolute log2fold > 0.6) that also correlated strongly with chronological age (spearman correlation coefficient of 0.72). Future work should expand clinical sample sizes and reduce clinical heterogeneity. Exploration of RNA-seq signatures in other leukocyte populations and single cell RNA sequencing may help uncover more subtle differences. However, currently the subtlety of any PBMC signature mitigates against its convincing use as a diagnostic or predictive biomarker.


Assuntos
Transtorno Depressivo Maior , Envelhecimento/genética , Biomarcadores , Transtorno Depressivo Maior/genética , Humanos , Leucócitos Mononucleares , Transcriptoma
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