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1.
Nat Commun ; 13(1): 5187, 2022 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-36057685

RESUMO

Specific functions of the immune system are essential to protect us from infections caused by pathogens such as viruses and bacteria. However, as we age, the immune system shows a functional decline that can be attributed in large part to age-associated defects in hematopoietic stem cells (HSCs)-the cells at the apex of the immune cell hierarchy. Here, we find that the Hippo pathway coactivator TAZ is potently induced in old HSCs and protects these cells from functional decline. We identify Clca3a1 as a TAZ-induced gene that allows us to trace TAZ activity in vivo. Using CLCA3A1 as a marker, we can isolate "young-like" HSCs from old mice. Mechanistically, Taz acts as coactivator of PU.1 and to some extent counteracts the gradual loss of PU.1 expression during HSC aging. Our work thus uncovers an essential role for Taz in a previously undescribed fail-safe mechanism in aging HSCs.


Assuntos
Envelhecimento , Células-Tronco Hematopoéticas , Envelhecimento/fisiologia , Animais , Células-Tronco Hematopoéticas/metabolismo , Camundongos
2.
Int J Mol Sci ; 23(17)2022 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-36077021

RESUMO

Tissue regeneration substantially relies on the functionality of tissue-resident endogenous adult stem cell populations. However, during aging, a progressive decline in organ function and regenerative capacities impedes endogenous repair processes. Especially the adult human heart is considered as an organ with generally low regenerative capacities. Interestingly, beneficial effects of systemic factors carried by young blood have been described in diverse organs including the heart, brain and skeletal muscle of the murine system. Thus, the interest in young blood or blood components as potential therapeutic agents to target age-associated malignancies led to a wide range of preclinical and clinical research. However, the translation of promising results from the murine to the human system remains difficult. Likewise, the establishment of adequate cellular models could help to study the effects of human blood plasma on the regeneration of human tissues and particularly the heart. Facing this challenge, this review describes the current knowledge of blood plasma-mediated protection and regeneration of aging tissues. The current status of preclinical and clinical research examining blood borne factors that act in stem cell-based tissue maintenance and regeneration is summarized. Further, examples of cellular model systems for a more detailed examination of selected regulatory pathways are presented.


Assuntos
Células-Tronco Adultas , Células-Tronco , Idoso , Envelhecimento/fisiologia , Animais , Humanos , Camundongos , Músculo Esquelético/fisiologia , Células-Tronco/fisiologia , Cicatrização
3.
PLoS One ; 17(9): e0273304, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36070253

RESUMO

Factors affecting successful listening in older adults and the corresponding electrophysiological signatures are not well understood. The present study investigated age-related differences in attention and temporal processing, as well as differences in the neural activity related to signal degradation during a number comparison task. Participants listened to digits presented in background babble and were tested at two levels of signal clarity, clear and degraded. Behavioral and electrophysiological measures were examined in 30 older and 20 younger neurologically-healthy adults. Relationships between performance on the number comparison task, behavioral measures, and neural activity were used to determine correlates of listening deficits associated with aging. While older participants showed poorer performance overall on all behavioral measures, their scores on the number comparison task were largely predicted (based on regression analyses) by their sensitivity to temporal fine structure cues. Compared to younger participants, older participants required higher signal-to-noise ratios (SNRs) to achieve equivalent performance on the number comparison task. With increasing listening demands, age-related changes were observed in neural processing represented by the early-N1 and later-P3 time windows. Source localization analyses revealed age differences in source activity for the degraded listening condition that was located in the left prefrontal cortex. In addition, this source activity negatively correlated with task performance in the older group. Together, these results suggest that older adults exhibit reallocation of processing resources to complete a demanding listening task. However, this effect was evident only for poorer performing older adults who showed greater posterior to anterior shift in P3 response amplitudes than older adults who were good performers and younger adults. These findings might reflect less efficient recruitment of neural resources that is associated with aging during effortful listening performance.


Assuntos
Envelhecimento , Percepção da Fala , Idoso , Envelhecimento/fisiologia , Atenção/fisiologia , Percepção Auditiva , Humanos , Percepção da Fala/fisiologia , Análise e Desempenho de Tarefas
4.
PLoS Comput Biol ; 18(9): e1010431, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36054198

RESUMO

The human brain generates a rich repertoire of spatio-temporal activity patterns, which support a wide variety of motor and cognitive functions. These patterns of activity change with age in a multi-factorial manner. One of these factors is the variations in the brain's connectomics that occurs along the lifespan. However, the precise relationship between high-order functional interactions and connnectomics, as well as their variations with age are largely unknown, in part due to the absence of mechanistic models that can efficiently map brain connnectomics to functional connectivity in aging. To investigate this issue, we have built a neurobiologically-realistic whole-brain computational model using both anatomical and functional MRI data from 161 participants ranging from 10 to 80 years old. We show that the differences in high-order functional interactions between age groups can be largely explained by variations in the connectome. Based on this finding, we propose a simple neurodegeneration model that is representative of normal physiological aging. As such, when applied to connectomes of young participant it reproduces the age-variations that occur in the high-order structure of the functional data. Overall, these results begin to disentangle the mechanisms by which structural changes in the connectome lead to functional differences in the ageing brain. Our model can also serve as a starting point for modeling more complex forms of pathological ageing or cognitive deficits.


Assuntos
Conectoma , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/fisiologia , Encéfalo/diagnóstico por imagem , Encéfalo/fisiologia , Criança , Cognição , Conectoma/métodos , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/fisiologia , Adulto Jovem
5.
Auton Neurosci ; 242: 103023, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36087362

RESUMO

BACKGROUND: Neuroplasticity and cardiovascular health behavior are critically important factors for optimal brain health. OBJECTIVE: To assess the association between the efficacy of the mechanisms of neuroplasticity and metrics of cardiovascular heath in sedentary aging adults. METHODS: We included thirty sedentary individuals (age = 60.6 ± 3.8 y; 63 % female). All underwent assessments of neuroplasticity, measured by the change in amplitude of motor evoked potentials elicited by single-pulse Transcranial Magnetic Stimulation (TMS) at baseline and following intermittent Theta-Burst (iTBS) at regular intervals. Cardiovascular health measures were derived from the Incremental Shuttle Walking Test and included Heart Rate Recovery (HRR) at 1-min/2-min after test cessation. We also collected plasma levels of brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), and c-reactive protein. RESULTS: We revealed moderate but significant relationships between TMS-iTBS neuroplasticity, and the predictors of cardiovascular health (|r| = 0.38 to 0.53, p < .05). HRR1 was the best predictor of neuroplasticity (ß = 0.019, p = .002). The best fit model (Likelihood ratio = 5.83, p = .016) of the association between neuroplasticity and HRR1 (ß = 0.043, p = .002) was selected when controlling for demographics and health status. VEGF and BDNF plasma levels augmented the association between neuroplasticity and HRR1. CONCLUSIONS: Our findings build on existing data demonstrating that TMS may provide insight into neuroplasticity and the role cardiovascular health have on its mechanisms. These implications serve as theoretical framework for future longitudinal and interventional studies aiming to improve cardiovascular and brain health. HRR1 is a potential prognostic measure of cardiovascular health and a surrogate marker of brain health in aging adults.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Córtex Motor , Adulto , Envelhecimento/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Córtex Motor/fisiologia , Plasticidade Neuronal/fisiologia , Análise de Regressão , Fator A de Crescimento do Endotélio Vascular
6.
Artigo em Inglês | MEDLINE | ID: mdl-36078725

RESUMO

Handgrip strength (GS) is used as an indicator of overall muscle strength and health outcomes for aging adults. GS has also been evaluated as a potential link with sport performances. We quantified the age-associated decline in grip strength for males and females engaged in weekly vigorous physical activity, differentiated by body mass, and investigated whether there was an acceleration of decline at any age. The Survey of Health, Ageing and Retirement in Europe is a multinational complex panel data survey with a target population of individuals aged 50 years or older. Data from 48,070 individuals from 20 European countries, collected from 2004 to 2015, were used in multivariable regression models to study the association of age and body weight with grip strength for individuals engaged in vigorous physical activity at least once a week. The annual rate of change in GS differed for males and females; it was constant from ages 50 to 55 years and then accelerated for females, possibly due to the menopausal transition. In contrast, the decline in GS accelerates with each year of increase in age for males. Higher body mass was associated with an increase in GS, but the increase was less pronounced for older males. The increase in GS diminished with a body mass above the median even with engagement in weekly vigorous physical activities. GS reference values for individuals engaged in vigorous physical activity add to existing reference values for general populations.


Assuntos
Força da Mão , Caracteres Sexuais , Adulto , Envelhecimento/fisiologia , Exercício Físico , Feminino , Força da Mão/fisiologia , Humanos , Masculino , Força Muscular/fisiologia
7.
Comput Intell Neurosci ; 2022: 1748162, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36017459

RESUMO

In this paper, we have investigated the frailty's prevalence and the association with aging-related health conditions in Chinese community dwelling elderly aged ≥60 years in Lianyungang City of China. In this regard, participants were 1,072 adults aged ≥60 years from Houhe Community of Lianyungang City of China. All the enrolled participants were tested for following parameters: (1) the related risk factors of frailty: including economic status, personal health, understanding and communication skills, and mental and psychological status; (2) aging-related health conditions related to frailty: Charlson's comorbidity index (CCI), Mini Nutritional Assessment Short Form (MNA-SF), Patient Health Questionnaire-9 (PHQ-9), and Generalized Anxiety Disorder 7-item (GAD-7); (3) body composition, physical strength, and function testing: appendicular skeletal muscle mass index (ASMI), grip strength, five-repetition sit-to-stand test, 6 m walking speed, and strength assistance rise-climb-fall (SARC-F); (4) assessment of the degree and severity of frailty: physical frailty phenotype (PFP), Morse fall scale (MFS), and activities of daily living (ADL). The frailty's prevalence among the elderly aged ≥60 years in the community of Lianyungang City was 13.8%, 55.4% were prefrail, and 30.8% were robust. The independent risk factors of frailty were age, appendicular skeletal muscle mass index, sarcopenia, education, nutrition, and strength assistance rise-climb-fall (P < 0.05). Aging-related health conditions were associated with frailty, including sarcopenia, nutrition, and falls. However, mental and psychological statuses were not significantly associated with frailty.


Assuntos
Fragilidade , Sarcopenia , Atividades Cotidianas , Idoso , Envelhecimento/fisiologia , Estudos Transversais , Fragilidade/epidemiologia , Avaliação Geriátrica , Humanos , Vida Independente , Prevalência , Sarcopenia/epidemiologia
8.
Cells ; 11(16)2022 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-36010618

RESUMO

Skin aging is induced and sustained by chronological aging and photoaging. Aging skin pigmentation such as mottled pigmentation (senile lentigo) and melasma are typical signs of photoaging. The skin, like other human organs, undergoes cellular senescence, and senescent cells in the skin increase with age. The crosstalk between melanocytes as pigmentary cells and other adjacent types of aged skin cells such as senescent fibroblasts play a role in skin-aging pigmentation. In this review, we provide an overview of cellular senescence during the skin-aging process. The discussion also includes cellular senescence related to skin-aging pigmentation and the therapeutic potential of regulating the senescence process.


Assuntos
Envelhecimento da Pele , Pigmentação da Pele , Idoso , Envelhecimento/fisiologia , Senescência Celular/fisiologia , Humanos , Melanócitos
9.
Stem Cell Res Ther ; 13(1): 405, 2022 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-35932084

RESUMO

BACKGROUND: During aging, perturbation of muscle progenitor cell (MPC) constituents leads to progressive loss of muscle mass and accumulation of adipose and fibrotic tissue. Mesenchymal stem cells (MSCs) give rise to adipocytes and fibroblasts that accumulate in injured and pathological skeletal muscle through constitutive activation of platelet-derived growth factor receptors (PDGFRs). Although the role of the PDGFRα has been widely explored, there is a paucity of evidence demonstrating the role of PDGFRß in aged skeletal muscle. METHODS: In this study, we investigated the role of PDGFRß lineage cells in skeletal muscle during aging by using Cre/loxP lineage tracing technology. The PDGFR-Cre mice were crossed with global double-fluorescent Cre reporter mice (mTmG) that indelibly marks PDGFRß lineage cells. Those cells were analyzed and compared at different ages in the skeletal muscle of the mice. RESULTS: Our results demonstrated that PDGFRß lineage cells isolated from the muscles of young mice are MPC-like cells that exhibited satellite cell morphology, expressed Pax7, and undergo myogenic differentiation producing myosin heavy chain expressing myotubes. Conversely, the PDGFRß lineage cells isolated from muscles of old mice displayed MSC morphology with a reduced myogenic differentiation potential while expressing adipogenic and fibrotic differentiation markers. PDGFRß lineage cells also gave rise to newly regenerated muscle fibers in young mice after muscle injury, but their muscle regenerative process is reduced in old mice. CONCLUSIONS: Our data suggest that PDGFRß lineage cells function as MPCs in young mice, while the same PDGFRß lineage cells from old mice undergo a fate switch participating in adipose and fibrotic tissue infiltration in aged muscle. The inhibition of fate-switching in PDGFRß lineage cells may represent a potential approach to prevent fibrosis and fatty infiltration in skeletal muscle during the aging process.


Assuntos
Músculo Esquelético , Células Satélites de Músculo Esquelético , Adipogenia/genética , Envelhecimento/fisiologia , Animais , Diferenciação Celular , Fibrose , Camundongos , Desenvolvimento Muscular
10.
Neurobiol Aging ; 118: 108-116, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35914473

RESUMO

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


Assuntos
Restrição Calórica , Longevidade , Envelhecimento/fisiologia , Animais , Restrição Calórica/psicologia , Cognição , Jejum , Humanos , Longevidade/fisiologia , Camundongos
11.
Nat Med ; 28(8): 1556-1568, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35953721

RESUMO

Interlinked and fundamental aging processes appear to be a root-cause contributor to many disorders and diseases. One such process is cellular senescence, which entails a state of cell cycle arrest in response to damaging stimuli. Senescent cells can arise throughout the lifespan and, if persistent, can have deleterious effects on tissue function due to the many proteins they secrete. In preclinical models, interventions targeting those senescent cells that are persistent and cause tissue damage have been shown to delay, prevent or alleviate multiple disorders. In line with this, the discovery of small-molecule senolytic drugs that selectively clear senescent cells has led to promising strategies for preventing or treating multiple diseases and age-related conditions in humans. In this Review, we outline the rationale for senescent cells as a therapeutic target for disorders across the lifespan and discuss the most promising strategies-including recent and ongoing clinical trials-for translating small-molecule senolytics and other senescence-targeting interventions into clinical use.


Assuntos
Envelhecimento , Senoterapia , Envelhecimento/fisiologia , Pontos de Checagem do Ciclo Celular , Senescência Celular , Humanos
12.
eNeuro ; 9(3)2022.
Artigo em Inglês | MEDLINE | ID: mdl-35998297

RESUMO

Fear-based disorders such as post-traumatic stress disorder (PTSD) steepen age-related cognitive decline and double the risk for developing Alzheimer's disease (AD). Because of the seemingly hyperactive properties of fear memories, PTSD symptoms can worsen with age. Perturbations in the synaptic circuitry supporting fear memory extinction are key neural substrates of PTSD. The basolateral amygdala (BLA) is a medial temporal lobe structure that is critical in the encoding, consolidation, and retrieval of fear memories. As little is known about fear extinction memory and BLA synaptic dysfunction within the context of aging and AD, the goal of this study was to investigate how fear extinction memory deficits and basal amygdaloid nucleus (BA) synaptic dysfunction differentially associate in nonpathologic aging and AD in the TgF344AD (TgAD) rat model of AD. Young, middle-aged, and older-aged WT and TgAD rats were trained on a delay fear conditioning and extinction procedure before ex vivo extracellular field potential recording experiments in the BA. Relative to young WT rats, long-term extinction memory was impaired, and in general, was associated with a hyperexcitable BA and impaired LTP in TgAD rats at all ages. In contrast, long-term extinction memory was impaired in aged WT rats and was associated with impaired LTP but not BA hyperexcitability. Interestingly, the middle-aged TgAD rats showed intact short-term extinction and BA LTP, which is suggestive of a compensatory mechanism, whereas differential neural recruitment in older-aged WT rats may have facilitated short-term extinction. As such, associations between fear extinction memory and amygdala deficits in nonpathologic aging and AD are dissociable.


Assuntos
Envelhecimento/fisiologia , Doença de Alzheimer/psicologia , Complexo Nuclear Basolateral da Amígdala/fisiologia , Extinção Psicológica/fisiologia , Medo/psicologia , Envelhecimento/psicologia , Doença de Alzheimer/etiologia , Tonsila do Cerebelo/fisiopatologia , Animais , Modelos Animais de Doenças , Ratos , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Transtornos de Estresse Pós-Traumáticos/psicologia
13.
PLoS One ; 17(8): e0263457, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35976884

RESUMO

There has been an increasing awareness of sarcopenia, which is characterized by a concomitant decrease in skeletal muscle mass and quality due to aging. Resistance exercise is considered more effective than aerobic exercise in terms of therapeutic exercise. To confirm the effect of long-term aerobic exercise in preventing sarcopenia, we evaluated the skeletal muscle mass, quality, and angiogenic capacity of super-aged mice that had undergone lifelong spontaneous exercise (LSE) through various experiments. Our findings show that LSE could maintain skeletal muscle mass, quality, and fitness levels in super-aged mice. In addition, ex vivo experiments showed that the angiogenic capacity was maintained at a high level. However, these results were not consistent with the related changes in the expression of genes and/or proteins involved in protein synthesis or angiogenesis. Based on the results of previous studies, it seems certain that the expression at the molecular level does not represent the phenotypes of skeletal muscle and angiogenesis. This is because aging and long-term exercise are variables that can affect both protein synthesis and the expression patterns of angiogenesis-related genes and proteins. Therefore, in aging and exercise-related research, various physical fitness and angiogenesis variables and phenotypes should be analyzed. In conclusion, LSE appears to maintain the potential of angiogenesis and slow the aging process to maintain skeletal muscle mass and quality. Aerobic exercise may thus be effective for the prevention of sarcopenia.


Assuntos
Condicionamento Físico Animal , Sarcopenia , Envelhecimento/fisiologia , Animais , Fenômenos Fisiológicos Cardiovasculares , Camundongos , Músculo Esquelético/fisiologia , Condicionamento Físico Animal/fisiologia , Sarcopenia/patologia
14.
Neuroimage ; 262: 119547, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-35940423

RESUMO

Age-related declines in cognitive control, an ability critical in most daily tasks, threaten individual independence. We previously showed in both older and younger adults that transcranial alternating current stimulation (tACS) can improve cognitive control, with effects observed across neural regions distant from the stimulated site and frequencies outside the stimulated range. Here, we assess network-level changes in neural activity that extend beyond the stimulated site and evaluate anatomical pathways that subserve these effects. We investigated the potential to rescue cognitive control in aging using prefrontal (F3-F4) theta (6 Hz) or control (1 Hz) tACS while older adults engaged in a cognitive control video game intervention on three consecutive days. Functional connectivity was assessed with EEG by measuring daily changes in frontal-posterior phase-locking values (PLV) from the tACS-free baseline. Structural connectivity was measured using MRI diffusion tractography data collected at baseline. Theta tACS improved multitasking performance, and individual gains reflected a dissociation in daily PLV changes, where theta tACS strengthened PLV and control tACS reduced PLV. Strengthened alpha-beta PLV in the theta tACS group correlated positively with inferior longitudinal fasciculus and corpus callosum body integrity, and further explained multitasking gains. These results demonstrate that theta tACS can improve cognitive control in aging by strengthening functional connectivity, particularly in higher frequency bands. However, the extent of functional connectivity gains is limited by the integrity of structural white matter tracts. Given that advanced age is associated with decreased white matter integrity, results suggest that the deployment of tACS as a therapeutic is best prior to advanced age.


Assuntos
Estimulação Transcraniana por Corrente Contínua , Idoso , Envelhecimento/fisiologia , Cognição , Humanos , Rede Nervosa/diagnóstico por imagem , Estimulação Transcraniana por Corrente Contínua/métodos
15.
Aging (Albany NY) ; 14(15): 6028-6046, 2022 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-35951355

RESUMO

Aging affects salivary gland function and alters saliva production and excretion. This study aimed to investigate whether ascorbic acid can be used to treat salivary gland dysfunction in an extensive aging mouse model of SAMP1/Klotho-/- mice. In our previous study, we found that ascorbic acid biosynthesis was disrupted in the salivary glands of SAMP1/Klotho (-/-) mice subjected to metabolomic profiling analysis. In SAMP1/Klotho -/- mice, daily supplementation with ascorbic acid (100 mg/kg for 18 days) significantly increased saliva secretion compared with the control. The expression of salivary gland functional markers (α-amylase, ZO-1, and Aqua5) is upregulated. Additionally, acetylcholine and/or beta-adrenergic receptors (M1AchR, M3AchR, and Adrb1) were increased by ascorbic acid in the salivary glands of aging mice, and treatment with ascorbic acid upregulated the expression of acetylcholine receptors through the DNA demethylation protein TET2. These results suggest that ascorbic acid could overcome the lack caused by dysfunction of ascorbic acid biosynthesis and induce the recovery of salivary gland function.


Assuntos
Acetilcolina , Dioxigenases , Envelhecimento/fisiologia , Animais , Ácido Ascórbico/metabolismo , Ácido Ascórbico/farmacologia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Dioxigenases/metabolismo , Proteínas Klotho/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Proteínas Nucleares/metabolismo , Receptores Colinérgicos/metabolismo , Glândulas Salivares/fisiologia
16.
Prog Brain Res ; 273(1): 257-273, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35940719

RESUMO

Optical and neural changes in the aging human visual system are reviewed in terms of factors that can influence the study of light-mediated effects on circadian physiology. All aspects of early stage visual mechanisms change continuously from the first days of life, and these changes must be understood when investigating both conscious and unconscious visual responses to light throughout the life span.


Assuntos
Envelhecimento , Envelhecimento/fisiologia , Humanos
17.
JACC Clin Electrophysiol ; 8(8): 997-1009, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35981805

RESUMO

BACKGROUND: Cardioinhibition may diminish with age, but the changing balance of cardioinhibition and vasodepression with age has not been quantified, leaving the mechanism of vasovagal syncope (VVS) in old age unclear. OBJECTIVES: This study sought to quantify age-related changes of vasodepression and cardioinhibition in tilt-induced VVS. METHODS: We studied 163 cases of tilt-induced VVS, evoked using the Italian protocol with blood pressure, heart rate, and video-electroencephalographic monitoring. Presyncope was excluded. Cardioinhibition was defined as the heart rate decrease before syncope; asystolic pauses (≥3 seconds) were divided into early and late asystole, ie, beginning early enough to or too late to be the major cause of loss of consciousness. The log-ratio method was used to quantify contributions of cardioinhibition and vasodepression, assessed in 2 10-second periods before the onset of cardioinhibition and before syncope. RESULTS: With increasing age, cardioinhibition decreased, ie, heart rate decreased less and more slowly near syncope (P < 0.0001), while vasodepression increased. Asystolic pauses were less frequent in the older one-half of the group than the younger one-half (26% vs 57%; P < 0.00001), but when it did, late asystole occurred more often (58% vs 15%; P < 0.001). CONCLUSIONS: The shift toward less cardioinhibition and more vasodepression with increased age probably reflects a physiological shift in circulatory control. The weakening of cardioinhibition with age may detract from the efficacy of pacing in older patients with VVS. Cardioinhibition-vasodepression balance should be considered in pacing decisions in older subjects with VVS.


Assuntos
Envelhecimento/fisiologia , Parada Cardíaca , Síncope Vasovagal/etiologia , Idoso , Pressão Sanguínea , Eletroencefalografia/métodos , Frequência Cardíaca , Humanos , Teste da Mesa Inclinada/métodos
18.
Aging (Albany NY) ; 14(16): 6829-6839, 2022 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-36040386

RESUMO

Genomic instability, telomere attrition, epigenetic alterations, mitochondrial dysfunction, loss of proteostasis, deregulated nutrient-sensing, cellular senescence, stem cell exhaustion, and altered intercellular communication were the original nine hallmarks of ageing proposed by López-Otín and colleagues in 2013. The proposal of these hallmarks of ageing has been instrumental in guiding and pushing forward research on the biology of ageing. In the nearly past 10 years, our in-depth exploration on ageing research has enabled us to formulate new hallmarks of ageing which are compromised autophagy, microbiome disturbance, altered mechanical properties, splicing dysregulation, and inflammation, among other emerging ones. Amalgamation of the 'old' and 'new' hallmarks of ageing may provide a more comprehensive explanation of ageing and age-related diseases, shedding light on interventional and therapeutic studies to achieve healthy, happy, and productive lives in the elderly.


Assuntos
Envelhecimento , Epigênese Genética , Idoso , Envelhecimento/fisiologia , Senescência Celular/fisiologia , Instabilidade Genômica , Humanos , Telômero
19.
Biogerontology ; 23(5): 571-585, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35969289

RESUMO

Glutamate and -aminobutyric acid (GABA) are the most abundant amino acids in the retina. An imbalance of the glutamate/GABA system is involved in the pathogenesis of various neurodegenerative disorders. Here we for the first time analyzed alterations of expression of glutamate- and GABA-synthesizing enzymes, transporters, and relevant receptors in the retina with age in Wistar rats and in senescence-accelerated OXYS rats who develop AMD-like retinopathy. We noted consistent age-dependent expression changes of GABAergic-system proteins (GAD67, GABA-T, and GAT1) in OXYS and Wistar rats: upregulation by age 3 months and downregulation at age 18 months. At a late stage of AMD-like retinopathy in OXYS rats (18 months), there was significant upregulation of glutaminase and downregulation of glutamine synthetase, possibly indicating an increasing level of glutamate in the retina. AMD-like-retinopathy development in the OXYS strain was accompanied by underexpression of glutamate transporter GLAST. Prolonged supplementation with both melatonin and SkQ1 (separately) suppressed the progression of the AMD-like pathology in OXYS rats without affecting the glutamate/GABA system but worsened the condition of the Wistar rat's retina during normal aging. We observed decreasing protein levels of glutamine synthetase, GLAST, and GABAAR1 and an increasing level of glutaminase in Wistar rats. In summary, both melatonin and mitochondrial antioxidant SkQ1 had different effect on the retinal glutamate / GABA in healthy Wistar and senescence-accelerated OXYS rats.


Assuntos
Degeneração Macular , Melatonina , Envelhecimento/fisiologia , Aminobutiratos/metabolismo , Aminobutiratos/farmacologia , Animais , Antioxidantes/farmacologia , Suplementos Nutricionais , Modelos Animais de Doenças , Glutamato-Amônia Ligase/metabolismo , Glutamato-Amônia Ligase/farmacologia , Ácido Glutâmico/metabolismo , Ácido Glutâmico/farmacologia , Glutaminase/metabolismo , Glutaminase/farmacologia , Degeneração Macular/metabolismo , Masculino , Melatonina/farmacologia , Ratos , Ratos Wistar , Retina/metabolismo , Ácido gama-Aminobutírico/metabolismo , Ácido gama-Aminobutírico/farmacologia
20.
Brain Behav ; 12(9): e2736, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35971662

RESUMO

INTRODUCTION: Increasing age is the number one risk factor for developing cognitive decline and neurodegenerative disease. Aged humans and mice exhibit numerous molecular changes that contribute to a decline in cognitive function and increased risk of developing age-associated diseases. Here, we characterize multiple age-associated changes in male C57BL/6J mice to understand the translational utility of mouse aging. METHODS: Male C57BL/6J mice from various ages between 2 and 24 months of age were used to assess behavioral, as well as, histological and molecular changes across three modalities: neuronal, microgliosis/neuroinflammation, and the neurovascular unit (NVU). Additionally, a cohort of 4- and 22-month-old mice was used to assess blood-brain barrier (BBB) breakdown. Mice in this cohort were treated with a high, acute dose of lipopolysaccharide (LPS, 10 mg/kg) or saline control 6 h prior to sacrifice followed by tail vein injection of 0.4 kDa sodium fluorescein (100 mg/kg) 2 h later. RESULTS: Aged mice showed a decline in cognitive and motor abilities alongside decreased neurogenesis, proliferation, and synapse density. Further, neuroinflammation and circulating proinflammatory cytokines were increased in aged mice. Additionally, we found changes at the BBB, including increased T cell infiltration in multiple brain regions and an exacerbation in BBB leakiness following chemical insult with age. There were also a number of readouts that were unchanged with age and have limited utility as markers of aging in male C57BL/6J mice. CONCLUSIONS: Here we propose that these changes may be used as molecular and histological readouts that correspond to aging-related behavioral decline. These comprehensive findings, in the context of the published literature, are an important resource toward deepening our understanding of normal aging and provide an important tool for studying aging in mice.


Assuntos
Disfunção Cognitiva , Doenças Neurodegenerativas , Idoso , Envelhecimento/fisiologia , Animais , Pré-Escolar , Disfunção Cognitiva/patologia , Citocinas/metabolismo , Fluoresceína/metabolismo , Hipocampo/metabolismo , Humanos , Lactente , Lipopolissacarídeos , Masculino , Camundongos , Camundongos Endogâmicos C57BL
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