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1.
Cell ; 186(2): 243-278, 2023 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-36599349

RESUMO

Aging is driven by hallmarks fulfilling the following three premises: (1) their age-associated manifestation, (2) the acceleration of aging by experimentally accentuating them, and (3) the opportunity to decelerate, stop, or reverse aging by therapeutic interventions on them. We propose the following twelve hallmarks of aging: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, disabled macroautophagy, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation, and dysbiosis. These hallmarks are interconnected among each other, as well as to the recently proposed hallmarks of health, which include organizational features of spatial compartmentalization, maintenance of homeostasis, and adequate responses to stress.


Assuntos
Envelhecimento , Senescência Celular , Epigênese Genética , Proteostase , Células-Tronco , Envelhecimento/genética , Envelhecimento/patologia
2.
Cell ; 186(2): 287-304.e26, 2023 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-36610399

RESUMO

Whether and how certain transposable elements with viral origins, such as endogenous retroviruses (ERVs) dormant in our genomes, can become awakened and contribute to the aging process is largely unknown. In human senescent cells, we found that HERVK (HML-2), the most recently integrated human ERVs, are unlocked to transcribe viral genes and produce retrovirus-like particles (RVLPs). These HERVK RVLPs constitute a transmissible message to elicit senescence phenotypes in young cells, which can be blocked by neutralizing antibodies. The activation of ERVs was also observed in organs of aged primates and mice as well as in human tissues and serum from the elderly. Their repression alleviates cellular senescence and tissue degeneration and, to some extent, organismal aging. These findings indicate that the resurrection of ERVs is a hallmark and driving force of cellular senescence and tissue aging.


Assuntos
Envelhecimento , Retrovirus Endógenos , Idoso , Animais , Humanos , Camundongos , Envelhecimento/genética , Envelhecimento/patologia , Senescência Celular , Retrovirus Endógenos/genética , Primatas
3.
Cell ; 186(2): 233-235, 2023 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-36669469

RESUMO

Reactivation of endogenous retroviruses (ERVs), the relics of ancient infections, has been implicated in a number of disease contexts. In this issue of Cell, Liu et al. show how reactivation of ERVs in old age can induce senescence. This awakening of ERVs is associated with their epigenetic derepression and contributes to age-associated chronic inflammation.


Assuntos
Envelhecimento , Retrovirus Endógenos , Retrovirus Endógenos/genética , Envelhecimento/genética , Envelhecimento/patologia , Inflamação
4.
Cell Death Dis ; 14(1): 35, 2023 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-36653345

RESUMO

The SIRT6 deacetylase has been implicated in DNA repair, telomere maintenance, glucose and lipid metabolism and, importantly, it has critical roles in the brain ranging from its development to neurodegeneration. Here, we combined transcriptomics and metabolomics approaches to characterize the functions of SIRT6 in mouse brains. Our analysis reveals that SIRT6 is a central regulator of mitochondrial activity in the brain. SIRT6 deficiency in the brain leads to mitochondrial deficiency with a global downregulation of mitochondria-related genes and pronounced changes in metabolite content. We suggest that SIRT6 affects mitochondrial functions through its interaction with the transcription factor YY1 that, together, regulate mitochondrial gene expression. Moreover, SIRT6 target genes include SIRT3 and SIRT4, which are significantly downregulated in SIRT6-deficient brains. Our results demonstrate that the lack of SIRT6 leads to decreased mitochondrial gene expression and metabolomic changes of TCA cycle byproducts, including increased ROS production, reduced mitochondrial number, and impaired membrane potential that can be partially rescued by restoring SIRT3 and SIRT4 levels. Importantly, the changes we observed in SIRT6-deficient brains are also occurring in aging human brains and particularly in patients with Alzheimer's, Parkinson's, Huntington's, and Amyotrophic lateral sclerosis disease. Overall, our results suggest that the reduced levels of SIRT6 in the aging brain and neurodegeneration initiate mitochondrial dysfunction by altering gene expression, ROS production, and mitochondrial decay.


Assuntos
Sirtuínas , Animais , Humanos , Camundongos , Encéfalo/metabolismo , DNA Mitocondrial/metabolismo , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Sirtuínas/genética , Sirtuínas/metabolismo , Envelhecimento/metabolismo , Envelhecimento/patologia
5.
Int J Mol Sci ; 24(2)2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36674977

RESUMO

It has been suggested that functional traits of the adult brain-all of which are established early in life-may affect the brain's susceptibility to Alzheimer's disease (AD). Results of our previous studies on senescence-accelerated OXYS rats, a model of sporadic AD, support this hypothesis. Here, to elucidate the molecular genetic nature of the aberrations revealed during brain maturation, we analyzed transcriptomes (RNA-seq data) of the prefrontal cortex (PFC) and hippocampus of OXYS rats and Wistar (control) rats in the period of brain maturation critical for OXYS rats (ages P3 and P10; P: postnatal day). We found more than 1000 differentially expressed genes in both brain structures; functional analysis indicated reduced efficiency of the formation of neuronal contacts, presumably explained mainly by deficits of mitochondrial functions. Next, we compared differentially expressed genes in the rat PFC and hippocampus from infancy to the progressive stage of AD-like pathology (five ages in total). Three genes (Thoc3, Exosc8, and Smpd4) showed overexpression in both brain regions of OXYS rats throughout the lifespan. Thus, reduced efficiency of the formation of neural networks in the brain of OXYS rats in infancy likely contributes to the development of their AD-like pathology.


Assuntos
Doença de Alzheimer , Ratos , Animais , Ratos Wistar , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Transcriptoma , Envelhecimento/genética , Envelhecimento/patologia , Encéfalo/patologia , Modelos Animais de Doenças
6.
Nat Immunol ; 24(1): 96-109, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36510022

RESUMO

Immune aging combines cellular defects in adaptive immunity with the activation of pathways causing a low-inflammatory state. Here we examined the influence of age on the kinetic changes in the epigenomic and transcriptional landscape induced by T cell receptor (TCR) stimulation in naive CD4+ T cells. Despite attenuated TCR signaling in older adults, TCR activation accelerated remodeling of the epigenome and induced transcription factor networks favoring effector cell differentiation. We identified increased phosphorylation of STAT5, at least in part due to aberrant IL-2 receptor and lower HELIOS expression, as upstream regulators. Human HELIOS-deficient, naive CD4+ T cells, when transferred into human-synovium-mouse chimeras, infiltrated tissues more efficiently. Inhibition of IL-2 or STAT5 activity in T cell responses of older adults restored the epigenetic response pattern to the one seen in young adults. In summary, reduced HELIOS expression in non-regulatory naive CD4+ T cells in older adults directs T cell fate decisions toward inflammatory effector cells that infiltrate tissue.


Assuntos
Envelhecimento , Linfócitos T CD4-Positivos , Fator de Transcrição Ikaros , Idoso , Animais , Humanos , Camundongos , Adulto Jovem , Envelhecimento/imunologia , Envelhecimento/patologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Montagem e Desmontagem da Cromatina , Ativação Linfocitária , Receptores de Antígenos de Linfócitos T , Fator de Transcrição STAT5 , Fator de Transcrição Ikaros/metabolismo
7.
J Alzheimers Dis ; 91(2): 683-695, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36502330

RESUMO

BACKGROUND: The strongest risk factor for the development of Alzheimer's disease (AD) is age. The progression of Braak stage and Thal phase with age has been demonstrated. However, prior studies did not include cognitive status. OBJECTIVE: We set out to define normative values for Alzheimer-type pathologic changes in individuals without cognitive decline, and then define levels that would qualify them to be resistant to or resilient against these changes. METHODS: Utilizing neuropathology data obtained from the National Alzheimer's Coordinating Center (NACC), we demonstrate the age-related progression of Alzheimer-type pathologic changes in cognitively normal individuals (CDR = 0, n = 542). With plots generated from these data, we establish standard lines that may be utilized to measure the extent to which an individual's Alzheimer-type pathology varies from the estimated normal range of pathology. RESULTS: Although Braak stage and Thal phase progressively increase with age in cognitively normal individuals, the Consortium to Establish a Registry for Alzheimer's Disease neuritic plaque score and Alzheimer's disease neuropathologic change remain at low levels. CONCLUSION: These findings suggest that an increasing burden of neuritic plaques is a strong predictor of cognitive decline, whereas, neurofibrillary degeneration and amyloid-ß (diffuse) plaque deposition, both to some degree, are normal pathologic changes of aging that occur in almost all individuals regardless of cognitive status. Furthermore, we have defined the amount of neuropathologic change in cognitively normal individuals that would qualify them to be "resilient" against the pathology (significantly above the normative values for age, but still cognitively normal) or "resistant" to the development of pathology (significantly below the normative values for age).


Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/patologia , Emaranhados Neurofibrilares/patologia , Peptídeos beta-Amiloides , Envelhecimento/patologia , Placa Amiloide/patologia
8.
Nature ; 613(7942): 120-129, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36517604

RESUMO

Myelin is required for the function of neuronal axons in the central nervous system, but the mechanisms that support myelin health are unclear. Although macrophages in the central nervous system have been implicated in myelin health1, it is unknown which macrophage populations are involved and which aspects they influence. Here we show that resident microglia are crucial for the maintenance of myelin health in adulthood in both mice and humans. We demonstrate that microglia are dispensable for developmental myelin ensheathment. However, they are required for subsequent regulation of myelin growth and associated cognitive function, and for preservation of myelin integrity by preventing its degeneration. We show that loss of myelin health due to the absence of microglia is associated with the appearance of a myelinating oligodendrocyte state with altered lipid metabolism. Moreover, this mechanism is regulated through disruption of the TGFß1-TGFßR1 axis. Our findings highlight microglia as promising therapeutic targets for conditions in which myelin growth and integrity are dysregulated, such as in ageing and neurodegenerative disease2,3.


Assuntos
Sistema Nervoso Central , Microglia , Bainha de Mielina , Adulto , Animais , Humanos , Camundongos , Axônios/metabolismo , Sistema Nervoso Central/citologia , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Microglia/citologia , Microglia/metabolismo , Microglia/patologia , Bainha de Mielina/metabolismo , Bainha de Mielina/patologia , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Cognição , Fator de Crescimento Transformador beta1/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Metabolismo dos Lipídeos , Envelhecimento/metabolismo , Envelhecimento/patologia
9.
Neurobiol Aging ; 122: 112-119, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36543016

RESUMO

White matter hyperintensities (WMHs) may be one of the earliest pathological changes in aging. Race differences in WMH burden has been conflicting. This study examined if race influences WMHs and whether these differences are influenced by vascular risk factors. Alzheimer's Disease Neuroimaging Initiative participants were included if they had a baseline MRI, diagnosis, and WMH measurements. Ninety-one Blacks and 1937 Whites were included. Using bootstrap re-sampling, 91 Whites were randomly sampled and matched to Blacks based on age, sex, education, and diagnosis 1000 times. Linear models examined the influence of race on baseline WMHs, and change of WMHs over time, with and without vascular factors. Vascular risk factors had higher prevalence in Blacks than Whites. When not including vascular factors, Blacks had greater frontal, parietal, deep, and total WMH burden compared to Whites. There were no race differences in longitudinal progression of WMH accumulation. After controlling for vascular factors, only overall longitudinal parietal WMH group differences remained significant, suggesting that vascular factors contribute to racial group differences observed in WMHs.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Substância Branca , Humanos , Idoso , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Fatores Raciais , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Envelhecimento/patologia , Imageamento por Ressonância Magnética/métodos , Disfunção Cognitiva/patologia
10.
J Dent ; 129: 104393, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36563839

RESUMO

OBJECTIVES: To investigate whether tooth loss was associated with regional grey matter volume (GMV) in a group of community dwelling older men and women from Ireland. METHODS: A group of 380 dementia-free men and women underwent a dental examination and had a Magnetic Resonance Imaging (MRI) scan as part of The Irish Longitudinal Study of Aging (TILDA). Cortical parcellation was conducted using Freesurfer utilities to produce volumetric measures of gyral based regions of interest. Analysis included multiple linear regression to investigate the association between tooth loss and regional GMVs with adjustment for various confounders. RESULTS: The mean age of participants was 68.1 years (SD 7.3) and 51.6% of the group were female. 50 (13.2%) of the participants were edentulous, 148 (38.9%) had 1-19 teeth, and 182 (47.9%) had ≥20 teeth. Multiple liner regression analysis with adjustment for a range of potential confounders showed associations between the number of teeth and GMVs in the paracentral lobule and the cuneus cortex. In the paracentral lobule, comparing participants with 1-19 teeth versus edentates there was an increase in GMV of ß=323.0mm3 (95% Confidence Interval [CI] 84.5, 561.6) and when comparing participants with ≥20 teeth to edentates there was an increase of ß=382.3mm3 (95% CI 126.9, 637.7). In the cuneus cortex, comparing participants with ≥20 teeth to edentates there was an increase in GMV of ß=380.5mm3 (95% CI 69.4, 691.5). CONCLUSIONS: In this group of older men and women from Ireland, the number of teeth was associated with GMVs in the paracentral lobule and the cuneus cortex independent of various known confounders. CLINICAL SIGNIFICANCE: Although not proof of causation, the finding that tooth loss was associated with regional reduced GMV in the brain may represent a potential explanatory link to the observed association between tooth loss and cognitive decline.


Assuntos
Substância Cinzenta , Perda de Dente , Masculino , Humanos , Feminino , Idoso , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/patologia , Perda de Dente/epidemiologia , Estudos Longitudinais , Encéfalo/patologia , Envelhecimento/patologia
11.
Mol Cells ; 45(12): 950-962, 2022 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-36572563

RESUMO

Aging is a major risk factor for common neurodegenerative diseases. Although multiple molecular, cellular, structural, and functional changes occur in the brain during aging, the involvement of caveolin-2 (Cav-2) in brain ageing remains unknown. We investigated Cav-2 expression in brains of aged mice and its effects on endothelial cells. The human umbilical vein endothelial cells (HUVECs) showed decreased THP-1 adhesion and infiltration when treated with Cav-2 siRNA compared to control siRNA. In contrast, Cav-2 overexpression increased THP-1 adhesion and infiltration in HUVECs. Increased expression of Cav-2 and iba-1 was observed in brains of old mice. Moreover, there were fewer iba-1-positive cells in the brains of aged Cav-2 knockout (KO) mice than of wild-type aged mice. The levels of several chemokines were higher in brains of aged wild-type mice than in young wild-type mice; moreover, chemokine levels were significantly lower in brains of young mice as well as aged Cav-2 KO mice than in their wild-type counterparts. Expression of PECAM1 and VE-cadherin proteins increased in brains of old wild-type mice but was barely detected in brains of young wild-type and Cav-2 KO mice. Collectively, our results suggest that Cav-2 expression increases in the endothelial cells of aged brain, and promotes leukocyte infiltration and age-associated neuroinflammation.


Assuntos
Envelhecimento , Caveolina 2 , Doenças Neuroinflamatórias , Animais , Humanos , Camundongos , Encéfalo/metabolismo , Caveolina 2/genética , Caveolina 2/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Camundongos Knockout , Doenças Neuroinflamatórias/genética , RNA Interferente Pequeno/metabolismo , Envelhecimento/patologia
12.
Nature ; 611(7935): 358-364, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36323784

RESUMO

The accumulation of senescent cells is a major cause of age-related inflammation and predisposes to a variety of age-related diseases1. However, little is known about the molecular basis underlying this accumulation and its potential as a target to ameliorate the ageing process. Here we show that senescent cells heterogeneously express the immune checkpoint protein programmed death-ligand 1 (PD-L1) and that PD-L1+ senescent cells accumulate with age in vivo. PD-L1- cells are sensitive to T cell surveillance, whereas PD-L1+ cells are resistant, even in the presence of senescence-associated secretory phenotypes (SASP). Single-cell analysis of p16+ cells in vivo revealed that PD-L1 expression correlated with higher levels of SASP. Consistent with this, administration of programmed cell death protein 1 (PD-1) antibody to naturally ageing mice or a mouse model with normal livers or induced nonalcoholic steatohepatitis reduces the total number of p16+ cells in vivo as well as the PD-L1+ population in an activated CD8+ T cell-dependent manner, ameliorating various ageing-related phenotypes. These results suggest that the heterogeneous expression of PD-L1 has an important role in the accumulation of senescent cells and inflammation associated with ageing, and the elimination of PD-L1+ senescent cells by immune checkpoint blockade may be a promising strategy for anti-ageing therapy.


Assuntos
Envelhecimento , Antígeno B7-H1 , Fenótipo , Receptor de Morte Celular Programada 1 , Animais , Camundongos , Envelhecimento/imunologia , Envelhecimento/metabolismo , Envelhecimento/patologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Inflamação/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo , Análise de Célula Única , Hepatopatia Gordurosa não Alcoólica , Fígado , Rejuvenescimento
13.
Int J Mol Sci ; 23(20)2022 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-36293430

RESUMO

The relationship between inflammation and age-related neurocognitive changes is significant, which may relate to the age-related immune dysfunctions characterized by the senescence of immune cells and elevated inflammatory markers in the peripheral circulation and the central nervous system. In this review, we discuss the potential mechanisms, including the development of vascular inflammation, neuroinflammation, organelle dysfunctions, abnormal cholesterol metabolism, and glymphatic dysfunctions as well as the role that the key molecules play in the immune-cognition interplay. We propose potential therapeutic pharmacological and behavioral strategies for ameliorating age-related neurocognitive changes associated with inflammation. Further research to decipher the multidimensional roles of chronic inflammation in normal and pathological aging processes will help unfold the pathophysiological mechanisms underpinning neurocognitive disorders. The insight gained will lay the path for developing cost-effective preventative measures and the buffering or delaying of age-related neurocognitive decline.


Assuntos
Inflamação , Transtornos Neurocognitivos , Humanos , Cognição/fisiologia , Envelhecimento/patologia , Sistema Nervoso Central
14.
Biochim Biophys Acta Rev Cancer ; 1877(6): 188826, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36273511

RESUMO

Cellular senescence is a state of growth arrest where nonproliferative cells accumulate over time in the aging microenvironment under multiple external factors. Senescent cells exert a double-edged sword effect in an autocrine or paracrine manner: physiologically, they contribute to tissue development, prevent the multiplication of damaged cells and contribute to tissue repair and tumor suppression while favoring the onset of age-related diseases, including tumors. The microbiota in human tissues is intricately linked to cellular senescence and is reportedly present in the tissues of various tumors (including pancreatic tumors), closely associated with tumorigenesis and progression. The microbiota can induce cells to undergo senescence, and their long-term effects can assist senescent cells in transforming and successfully escaping senescence, contributing to tumorigenesis and progression. Here, we focus on the correlation between the microbiota, cellular senescence, and pancreatic cancer to provide novel ideas for the study and therapy of pancreatic cancer.


Assuntos
Microbiota , Neoplasias Pancreáticas , Humanos , Envelhecimento/patologia , Envelhecimento/fisiologia , Senescência Celular/fisiologia , Transformação Celular Neoplásica , Microambiente Tumoral
15.
J Cell Mol Med ; 26(21): 5335-5359, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36251271

RESUMO

Cardiovascular disease (CVD) is highly prevalent in an ageing society. The increased incidence and mortality rates of CVD are global issues endangering human health. There is an urgent requirement for understanding the aetiology and pathogenesis of CVD and developing possible interventions for preventing CVD in ageing hearts. It is necessary to select appropriate models and treatment methods. The D-galactose-induced cardiac ageing model possesses the advantages of low mortality, short time and low cost and has been increasingly used in the study of cardiovascular diseases in recent years. Therefore, understanding the latest progress in D-galactose-induced cardiac ageing is valuable. This review highlights the recent progress and potential therapeutic interventions used in D-galactose-induced cardiac ageing in recent years by providing a comprehensive summary of D-galactose-induced cardiac ageing in vivo and in vitro. This review may serve as reference literature for future research on age-related heart diseases.


Assuntos
Doenças Cardiovasculares , Galactose , Humanos , Estresse Oxidativo , Envelhecimento/patologia , Coração
16.
J Vis Exp ; (187)2022 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-36282698

RESUMO

Deafness is the most common sensory impairment, affecting approximately 5% or 430 million people worldwide as per the World Health Organization1. Aging or presbycusis is a primary cause of sensorineural hearing loss and is characterized by damage to hair cells, spiral ganglion neurons (SGNs), and the stria vascularis. These structures reside within the cochlea, which has a complex, spiral-shaped anatomy of membranous tissues suspended in fluid and surrounded by bone. These properties make it technically difficult to investigate and quantify histopathological changes. To address this need, we developed a light-sheet microscope (TSLIM) that can image and digitize the whole cochlea to facilitate the study of structure-function relationships in the inner ear. Well-aligned serial sections of the whole cochlea result in a stack of images for three-dimensional (3D) volume rendering and segmentation of individual structures for 3D visualization and quantitative analysis (i.e., length, width, surface, volume, and number). Cochleae require minimal processing steps (fixation, decalcification, dehydration, staining, and optical clearing), all of which are compatible with subsequent high-resolution imaging by scanning and transmission electron microscopy. Since all the tissues are present in the stacks, each structure can be assessed individually or relative to other structures. In addition, since imaging uses fluorescent probes, immunohistochemistry and ligand binding can be used to identify specific structures and their 3D volume or distribution within the cochlea. Here we used TSLIM to examine cochleae from aged mice to quantify the loss of hair cells and spiral ganglion neurons. In addition, advanced analyses (e.g., cluster analysis) were used to visualize local reductions of spiral ganglion neurons in Rosenthal's canal along its 3D volume. These approaches demonstrate TSLIM microscopy's ability to quantify structure-function relationships within and between cochleae.


Assuntos
Cóclea , Corantes Fluorescentes , Camundongos , Animais , Ligantes , Cóclea/diagnóstico por imagem , Gânglio Espiral da Cóclea/diagnóstico por imagem , Gânglio Espiral da Cóclea/patologia , Microscopia de Fluorescência , Envelhecimento/patologia
17.
Int J Mol Sci ; 23(19)2022 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-36233146

RESUMO

Cellular senescence is characterized by irreversible cell cycle arrest in response to different triggers and an inflammatory secretome. Although originally described in fibroblasts and cell types of solid organs, cellular senescence affects most tissues with advancing age, including the lymphoid tissue, causing chronic inflammation and dysregulation of both innate and adaptive immune functions. Besides its normal occurrence, persistent microbial challenge or pathogenic microorganisms might also accelerate the activation of cellular aging, inducing the premature senescence of immune cells. Therapeutic strategies counteracting the detrimental effects of cellular senescence are being developed. Their application to target immune cells might have the potential to improve immune dysfunctions during aging and reduce the age-dependent susceptibility to infections. In this review, we discuss how immune senescence influences the host's ability to resolve more common infections in the elderly and detail the different markers proposed to identify such senescent cells; the mechanisms by which infectious agents increase the extent of immune senescence are also reviewed. Finally, available senescence therapeutics are discussed in the context of their effects on immunity and against infections.


Assuntos
Envelhecimento , Senescência Celular , Idoso , Envelhecimento/patologia , Humanos , Inflamação
18.
Neurobiol Dis ; 174: 105887, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36209950

RESUMO

We have previously reported that the single transmembrane protein Dipeptidyl Peptidase Like 6 (DPP6) impacts neuronal and synaptic development. DPP6-KO mice are impaired in hippocampal-dependent learning and memory and exhibit smaller brain size. Recently, we have described novel structures in hippocampal area CA1 in aging mice, apparently derived from degenerating presynaptic terminals, that are significantly more prevalent in DPP6-KO mice compared to WT mice of the same age and that these structures were observed earlier in development in DPP6-KO mice. These novel structures appear as clusters of large puncta that colocalize NeuN, synaptophysin, and chromogranin A, and also partially label for MAP2, amyloid ß, APP, α-synuclein, and phosphorylated tau, with synapsin-1 and VGluT1 labeling on their periphery. In this current study, using immunofluorescence and electron microscopy, we confirm that both APP and amyloid ß are prevalent in these structures; and we show with immunofluorescence the presence of similar structures in humans with Alzheimer's disease. Here we also found evidence that aging DPP6-KO mutants show additional changes related to Alzheimer's disease. We used in vivo MRI to show reduced size of the DPP6-KO brain and hippocampus. Aging DPP6-KO hippocampi contained fewer total neurons and greater neuron death and had diagnostic biomarkers of Alzheimer's disease present including accumulation of amyloid ß and APP and increase in expression of hyper-phosphorylated tau. The amyloid ß and phosphorylated tau pathologies were associated with neuroinflammation characterized by increases in microglia and astrocytes. And levels of proinflammatory or anti-inflammatory cytokines increased in aging DPP6-KO mice. We finally show that aging DPP6-KO mice display circadian dysfunction, a common symptom of Alzheimer's disease. Together these results indicate that aging DPP6-KO mice show symptoms of enhanced neurodegeneration reminiscent of dementia associated with a novel structure resulting from synapse loss and neuronal death. This study continues our laboratory's work in discerning the function of DPP6 and here provides compelling evidence of a direct role of DPP6 in Alzheimer's disease.


Assuntos
Doença de Alzheimer , Humanos , Camundongos , Animais , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Envelhecimento/patologia , Hipocampo/metabolismo , Sinapses/metabolismo , Camundongos Transgênicos , Proteínas tau/genética , Proteínas tau/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Dipeptidil Peptidases e Tripeptidil Peptidases/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Canais de Potássio/metabolismo
19.
Oxid Med Cell Longev ; 2022: 1534470, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36225176

RESUMO

Vascular aging is a specific type of organic aging that plays a central role in the morbidity and mortality of cardiovascular and cerebrovascular diseases among the elderly. It is essential to develop novel interventions to prevent/delay age-related vascular pathologies by targeting fundamental cellular and molecular aging processes. Endogenous vasoactive peptides are compounds formed by a group of amino acids connected by peptide chains that exert regulatory roles in intercellular interactions involved in a variety of biological and pathological processes. Emerging evidence suggests that a variety of vasoactive peptides play important roles in the occurrence and development of vascular aging and related diseases such as atherosclerosis, hypertension, vascular calcification, abdominal aortic aneurysms, and stroke. This review will summarize the cumulative roles and mechanisms of several important endogenous vasoactive peptides in vascular aging and vascular aging-related diseases. In addition, we also aim to explore the promising diagnostic function as biomarkers and the potential therapeutic application of endogenous vasoactive peptides in vascular aging-related diseases.


Assuntos
Aterosclerose , Doenças Vasculares , Idoso , Envelhecimento/patologia , Aminoácidos , Biomarcadores/metabolismo , Humanos , Peptídeos
20.
Biochem Biophys Res Commun ; 632: 62-68, 2022 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-36201882

RESUMO

Age-related macular degeneration (AMD) is a chronic and progressive disease characterized by degeneration of the retinal pigment epithelium (RPE) and retina that ultimately leads to loss of vision. The pathological mechanisms of AMD are not fully known. Cellular senescence, which is a state of cell cycle arrest induced by DNA-damage or aging, is hypothesized to critically affect the pathogenesis of AMD. In this study, we examined the relationship between cellular senescence and RPE/retinal degeneration in mouse models of natural aging and accelerated aging. We performed a bulk RNA sequencing of the RPE cells from adult (8 months old) and naturally-aged old (24 months old) mice and found that common signatures of senescence and AMD pathology - inflammation, apoptosis, and blood vessel formation - are upregulated in the RPE of old mice. Next, we investigated markers of senescence and the degree of RPE/retinal degeneration in Zmpste24-deficient (Zmpste24-/-) mice, which is a model for progeria and accelerated aging. We found that Zmpste24-/- mice display markedly greater level of senescence-related markers in RPE and significant RPE/retinal degeneration compared to wild-type mice, in a manner consistent with natural aging. Overall, these results provide support for the association between cellular senescence of RPE and the pathogenesis of AMD, and suggest the use of Zmpste24-/- mice as a novel senescent RPE model of AMD.


Assuntos
Degeneração Macular , Degeneração Retiniana , Epitélio Pigmentado da Retina , Animais , Camundongos , Envelhecimento/patologia , DNA/metabolismo , Degeneração Macular/genética , Degeneração Macular/patologia , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Metaloendopeptidases/genética , Metaloendopeptidases/metabolismo , Fenótipo , Degeneração Retiniana/genética , Degeneração Retiniana/patologia , Epitélio Pigmentado da Retina/metabolismo
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