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Aging can be conceptualized as the progressive disequilibrium between stochastic damage accumulation and resilience mechanisms that continuously repair that damage, which eventually cause the development of chronic disease, frailty, and death. The immune system is at the forefront of these resilience mechanisms. Indeed, aging is associated with persistent activation of the immune system, witnessed by a high circulating level of inflammatory markers and activation of immune cells in the circulation and in tissue, a condition called "inflammaging." Like aging, inflammaging is associated with increased risk of many age-related pathologies and disabilities, as well as frailty and death. Herein we discuss recent advances in the understanding of the mechanisms leading to inflammaging and the intrinsic dysregulation of the immune function that occurs with aging. We focus on the underlying mechanisms of chronic inflammation, in particular the role of NF-κB and recent studies targeting proinflammatory mediators. We further explore the dysregulation of the immune response with age and immunosenescence as an important mechanistic immune response to acute stressors. We examine the role of the gastrointestinal microbiome, age-related dysbiosis, and the integrated stress response in modulating the inflammatory "response" to damage accumulation and stress. We conclude by focusing on the seminal question of whether reducing inflammation is useful and the results of related clinical trials. In summary, we propose that inflammation may be viewed both as a clinical biomarker of the failure of resilience mechanisms and as a causal factor in the rising burden of disease and disabilities with aging. The fact that inflammation can be reduced through nonpharmacological interventions such as diet and exercise suggests that a life course approach based on education may be a successful strategy to increase the health span with few adverse consequences.
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Age-associated DNA methylation in blood cells convey information on health status. However, the mechanisms that drive these changes in circulating cells and their relationships to gene regulation are unknown. We identified age-associated DNA methylation sites in six purified blood-borne immune cell types (naive B, naive CD4+ and CD8+ T cells, granulocytes, monocytes, and NK cells) collected from healthy individuals interspersed over a wide age range. Of the thousands of age-associated sites, only 350 sites were differentially methylated in the same direction in all cell types and validated in an independent longitudinal cohort. Genes close to age-associated hypomethylated sites were enriched for collagen biosynthesis and complement cascade pathways, while genes close to hypermethylated sites mapped to neuronal pathways. In silico analyses showed that in most cell types, the age-associated hypo- and hypermethylated sites were enriched for ARNT (HIF1ß) and REST transcription factor (TF) motifs, respectively, which are both master regulators of hypoxia response. To conclude, despite spatial heterogeneity, there is a commonality in the putative regulatory role with respect to TF motifs and histone modifications at and around these sites. These features suggest that DNA methylation changes in healthy aging may be adaptive responses to fluctuations of oxygen availability.
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Envejecimiento , Linfocitos T CD8-positivos , Humanos , Envejecimiento/genética , Activación de Complemento , Metilación de ADN , Epigénesis GenéticaRESUMEN
DNA damage is a prominent biomarker for numerous diseases, including cancer, as well as for the aging process. Detection of DNA damage routinely relies on traditional microscopy or cytometric methods. However, these techniques are typically of limited throughput and are not ideally suited for large-scale longitudinal and population studies that require analysis of large sample sets. We have developed HiIDDD (High-throughput Immune cell DNA Damage Detection), a robust, quantitative and single-cell assay that measures DNA damage by high-throughput imaging using the two major DNA damage markers 53BP1 and [Formula: see text]-H2AX. We demonstrate sensitive detection with low inter-assay variability of DNA damage in various types of freshly isolated and cryopreserved primary human immune cells, including CD4 + and CD8 + T cells, B cells and monocytes. As proof of principle, we demonstrate parallel batch processing of several immune cell types from multiple donors. We find common patterns of DNA damage in multiple immune cell types of donors of varying ages, suggesting that immune cell properties are specific to individuals. These results establish a novel high-throughput assay for the evaluation of DNA damage in large-scale studies.
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Daño del ADN , Ensayos Analíticos de Alto Rendimiento , Bioensayo , Criopreservación , Diagnóstico por Imagen , Ensayos Analíticos de Alto Rendimiento/métodos , HumanosRESUMEN
Epigenetic reprogramming underlies specification of immune cell lineages, but patterns that uniquely define immune cell types and the mechanisms by which they are established remain unclear. Here, we identified lineage-specific DNA methylation signatures of six immune cell types from human peripheral blood and determined their relationship to other epigenetic and transcriptomic patterns. Sites of lineage-specific hypomethylation were associated with distinct combinations of transcription factors in each cell type. By contrast, sites of lineage-specific hypermethylation were restricted mostly to adaptive immune cells. PU.1 binding sites were associated with lineage-specific hypo- and hypermethylation in different cell types, suggesting that it regulates DNA methylation in a context-dependent manner. These observations indicate that innate and adaptive immune lineages are specified by distinct epigenetic mechanisms via combinatorial and context-dependent use of key transcription factors. The cell-specific epigenomics and transcriptional patterns identified serve as a foundation for future studies on immune dysregulation in diseases and aging.
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Metilación de ADN , Epigénesis Genética , Epigenómica , Regulación de la Expresión Génica , Inmunidad , Factores de Transcripción/metabolismo , Transcriptoma , Epigenómica/métodos , Humanos , Sistema Inmunológico/citología , Sistema Inmunológico/inmunología , Sistema Inmunológico/metabolismo , Factores de Transcripción/genéticaRESUMEN
A central clinical question as the world deals with the COVID-19 pandemic is what the long-term sequelae for the millions of individuals will be who recover from the hyperinflammatory state characterizing COVID-19 and in particular for the hundreds of thousands who are ill enough to need hospitalization and in particular ICU care. Even when the pandemic is finally controlled, will COVID-19 survivors face exaggerated internal inflammatory processes, worsening co-morbidities, and increased susceptibility to age-related diseases? Clues for what may happen in post-COVID-19 patients can be elicited from those who recovered from other conditions that lead to similar hyperinflammatory states such as Severe Acute Respiratory Syndrome (SARS), acute respiratory disease syndrome (ARDS), cytokine storm syndrome, and post-ICU syndrome. The short-and long-term sequalae following recovery from each of these conditions suggests that these syndromes lead to an accelerated state of chronic subclinical systemic inflammation often seen in aging (termed inflammaging) resulting in increased and worsening age-related conditions including frailty even in younger individuals.
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BACKGROUND: Because immune responses are sensitive to environmental changes that drive selection of genetic variants, we hypothesized that polymorphisms of some xenobiotic response and immune response genes may be associated with specific types of immune-mediated diseases (IMD), while others may be associated with IMD as a larger category regardless of specific phenotype or ethnicity. OBJECTIVE: To examine transethnic gene-IMD associations for single nucleotide polymorphism (SNP) frequencies of prototypic xenobiotic response genes-aryl hydrocarbon receptor (AHR), AHR nuclear translocator (ARNT), AHR repressor (AHRR) - and a prototypic immune response gene, protein tyrosine phosphatase, non-receptor type 22 (PTPN22), in subjects from the Environmental Polymorphisms Registry (EPR). METHODS: Subjects (nâ¯=â¯3731) were genotyped for 14 SNPs associated with functional variants of the AHR, ARNT, AHRR, and PTPN22 genes, and their frequencies were compared among African Americans (nâ¯=â¯1562), Caucasians (nâ¯=â¯1838), and Hispanics (nâ¯=â¯331) with previously reported data. Of those genotyped, 2015 EPR subjects completed a Health and Exposure survey. SNPs were assessed via PLINK for associations with IMD, which included those with autoimmune diseases, allergic disorders, asthma, or idiopathic pulmonary fibrosis. Transethnic meta-analyses were performed using METAL and MANTRA approaches. RESULTS: ARNT SNP rs11204735 was significantly associated with autoimmune disease by transethnic meta-analyses using METAL (odds ratio, OR [95% confidence interval]â¯=â¯1.29 [1.08-1.55]) and MANTRA (ORs ranged from 1.29 to 1.30), whereas ARNT SNP rs1889740 showed a significant association with autoimmune disease by METAL (ORâ¯=â¯1.25 [1.06-1.47]). For Caucasian females, PTPN22 SNP rs2476601 was significantly associated with autoimmune disease by allelic association tests (ORâ¯=â¯1.99, [1.30-3.04]). In Caucasians and Caucasian males, PTPN22 SNP rs3811021 was significantly associated with IMD (ORâ¯=â¯1.39 [1.12-1.72] and 1.50 [1.12-2.02], respectively) and allergic disease (ORâ¯=â¯1.39 [1.12-1.71], and 1.62 [1.19-2.20], respectively). In the transethnic meta-analysis, PTPN22 SNP rs3811021 was significantly implicated in IMD by METAL (ORâ¯=â¯1.31 [1.10-1.56]), and both METAL and MANTRA suggested that rs3811021 was associated with IMD and allergic disease in males across all three ethnic groups (IMD METAL ORâ¯=â¯1.50 [1.15-1.95]; IMD MANTRA ORs ranged from 1.47 to 1.50; allergic disease METAL ORâ¯=â¯1.58 [1.20-2.08]; allergic disease MANTRA ORs ranged from 1.55 to 1.59). CONCLUSIONS: Some xenobiotic and immune response gene polymorphisms were shown here, for the first time, to have associations across a broad spectrum of IMD and ethnicities. Our findings also suggest a role for ARNT in the development of autoimmune diseases, implicating environmental factors metabolized by this pathway in pathogenesis. Further studies are needed to confirm these data, assess the implications of these findings, define gene-environment interactions, and explore the mechanisms leading to these increasingly prevalent disorders.
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Translocador Nuclear del Receptor de Aril Hidrocarburo/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Inmunomodulación/genética , Polimorfismo de Nucleótido Simple , Proteína Tirosina Fosfatasa no Receptora Tipo 22/genética , Alelos , Enfermedades Autoinmunes/etiología , Enfermedades Autoinmunes/metabolismo , Enfermedades Autoinmunes/patología , Autoinmunidad , Genotipo , Humanos , Desequilibrio de Ligamiento , FenotipoRESUMEN
To gain understanding on the mechanisms that drive immunosenescence in humans, we examined CD4+ T cells obtained from younger (20-39 years-old) and older (70+ years-old) healthy participants of the Baltimore Longitudinal Study on Aging (BLSA). We found that mitochondrial proteins involved in the electron transport chain were overrepresented in cells from older participants, with prevalent dysregulation of oxidative phosphorylation and energy metabolism molecular pathways. Surprisingly, gene transcripts coding for mitochondrial proteins pertaining to oxidative phosphorylation and electron transport chain pathways were underrepresented in older individuals. Paralleling the observed decrease in gene expression, mitochondrial respiration was impaired in CD4+ T cells from older subjects. Though mitochondrial number in both naïve and memory cells visualized with electron microcopy was similar in older versus younger participants, there were a significantly higher number of autophagosomes, many of them containing undegraded mitochondria, in older individuals. The presence of mitochondria inside the accumulated autophagic compartments in CD4+ T cells from older individuals was confirmed by immunofluorescence. These findings suggest that older age is associated with persistence of dysfunctional mitochondria in CD4+ T lymphocytes caused by defective mitochondrial turnover by autophagy, which may trigger chronic inflammation and contribute to the impairment of immune defense in older persons.
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Linfocitos T CD4-Positivos/metabolismo , Inmunosenescencia , Mitocondrias/metabolismo , Mitofagia , Adulto , Anciano , Respiración de la Célula , Humanos , Estudios Longitudinales , Mitocondrias/ultraestructura , Adulto JovenRESUMEN
The aging process is driven by interrelated mechanisms that lead to the emergence of characteristic phenotypes that include changes in body composition, energy production and utilization imbalance, homeostatic dysregulation, and neurodegeneration and loss of neuroplasticity. Mainstream theories of aging all recognize that the aging phenotypes result from an imbalance between stressors and stress buffering mechanisms and a resultant loss of compensatory reserve leading to accumulation of unrepaired damage. This in turn results in increased disease susceptibility, reduced functional reserve, reduced healing capacity and stress resistance, unstable health and finally failure to thrive. The resultant physical and cognitive decline that culminates with the frailty syndrome is a tipping point of healthspan and implies a high risk of system decompensation and death. Preserving physical and cognitive function is the main focus of geriatric and gerontological research, but it is important to recognize that accomplishing this goal requires a profound understanding of the molecular, cellular and physiological mechanisms that ultimately determine functional changes. In this context, the proinflammatory state of aging plays a major role. Longitudinal studies have shown that with aging most individuals tend to develop a chronic low-grade proinflammatory state, and that such a state is a strong risk factor for multimorbidity, physical and cognitive disability, frailty and death. A number of environmental factors may play an important role in modifying the proinflammatory state. We explore processes and mechanisms of aging that affect human biology and the possible links of inflammation and the environment to aging, especially those related to metabolism. We point out that longitudinal studies with a life course approach are needed to gain further mechanistic insight on the processes that lead to functional decline with aging, and the role played in this process by inflammation and environmental challenges.
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Envejecimiento/fisiología , Ambiente , Anciano Frágil/psicología , Inflamación/fisiopatología , Anciano , Cognición , Humanos , Estudios Longitudinales , Factores de RiesgoRESUMEN
The aging process is driven by a finite number of inter-related mechanisms that ultimately lead to the emergence of characteristic phenotypes, including increased susceptibility to multiple chronic diseases, disability, and death. New assays and analytical tools have become available that start to unravel some of these mechanisms. A prevailing view is that aging leads to an imbalance between stressors and stress-buffering mechanisms that causes loss of compensatory reserve and accumulation of unrepaired damage. Central to this paradigm are changes in the immune system and the chronic low-grade proinflammatory state that affect many older individuals, even when they are apparently healthy and free of risk factors. Independent of chronological age, high circulating levels of proinflammatory markers are associated with a high risk of multiple adverse health outcomes in older persons. In this review, we discuss current theories about causes and consequences of the proinflammatory state of aging, with a focus on changes in T cell function. We examine the role of NF-κB activation and its dysregulation and how NF-κB activity differs among subgroups of T cells. We explore emerging hypotheses about immunosenescence and changes in T cell behavior with age, including consideration of the T cell antigen receptor and regulatory T cells (Tregs). We conclude by illustrating how research using advanced technology is uncovering clues at the core of inflammation and aging. Some of the preliminary work in this field is already improving our understanding of the complex mechanisms by which immunosenescence of T cells is intertwined during human aging.
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Envejecimiento/inmunología , Senescencia Celular/inmunología , Linfocitos T Reguladores/inmunología , Animales , Humanos , FN-kappa B/inmunologíaRESUMEN
Immune impairment and high circulating level of pro-inflammatory cytokines are landmarks of human aging. However, the molecular basis of immune dys-regulation and the source of inflammatory markers remain unclear. Here we demonstrate that in the absence of overt cell stimulation gene expression mediated by the transcription factor NF-κB is higher in purified and rested human CD4+ T lymphocytes from older compared to younger individuals. This increase of NF-κB -associated transcription includes transcripts for pro-inflammatory cytokines such as IL-1 and chemokines such as CCL2 and CXCL10. We demonstrate that NF-κB up-regulation is cell-intrinsic and mediated in part by phosphatidylinositol 3-kinase (PI3K) activity induced in response to metabolic activity, which can be moderated by rapamycin treatment. Our observations provide direct evidence that dys-regulated basal NF-κB activity may contribute to the mild pro-inflammatory state of aging.
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Envejecimiento/metabolismo , Linfocitos T CD4-Positivos/enzimología , FN-kappa B/metabolismo , Fosfatidilinositol 3-Quinasa/metabolismo , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Envejecimiento/genética , Envejecimiento/inmunología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Células Cultivadas , Citocinas/genética , Citocinas/inmunología , Citocinas/metabolismo , Femenino , Humanos , Mediadores de Inflamación/inmunología , Mediadores de Inflamación/metabolismo , Masculino , Persona de Mediana Edad , FN-kappa B/inmunología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/farmacología , Transducción de Señal , Sirolimus/farmacología , Transcripción GenéticaRESUMEN
Age associated immune dysregulation results in a pro-inflammatory state and increased susceptibility to infections and autoimmune diseases. Studies show that signaling initiated at the T cell antigen receptor (TCR) is impaired in CD4+ T cells from old compared to young mice. Here we examined TCR-inducible gene expression changes in CD4+ T cells during human aging. We reveal a dichotomy in gene expression mediated by the inducible transcription factor NF-κB. Most NF-κB target genes are not induced in a sustained manner in cells derived from older compared to younger individuals. However, a subset of NF-κB target genes including genes associated with chronic pro-inflammatory state in the elderly, such as interleukin 1 and 6, continue to be up-regulated even in the absence of NF-κB induction. In addition, we identify other widespread changes in gene expression between cells derived from older and younger individuals. Surprisingly, many of the most noteworthy age-associated changes in human CD4+ T cells differ from those seen in murine models. Our studies provide the first view of age-associated alteration of TCR-inducible gene expression in human CD4+ T cells.
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Envejecimiento/metabolismo , Linfocitos T CD4-Positivos/metabolismo , FN-kappa B/metabolismo , Transcripción Genética , Adulto , Anciano , Anciano de 80 o más Años , Envejecimiento/inmunología , Femenino , Regulación de la Expresión Génica , Humanos , Interleucina-6/metabolismo , Masculino , Persona de Mediana EdadRESUMEN
A defect in klotho gene expression in the mouse results in a syndrome that resembles human aging, with greatly shortened lifespan, arteriosclerosis, and defective hearing. In an effort to find functional murine variants of klotho, we sequenced the gene and examined renal expression of the secreted and membrane-bound Klotho isoforms from 16 laboratory-derived and 4 wild-derived inbred strains. Among the laboratory-derived strains, no sequence variation was found in any of the exons or intron-exon boundaries. Among the wild-derived strains, we found 45 sequence variants with six resulting in amino acid substitutions. One wild-derived strain, SPRET/Ei, had four amino acid substitutions and higher levels of the membrane form and total klotho mRNA. In addition, the membrane to secreted klotho expression ratio was elevated in three wild-derived strains with amino acid substitutions. Interestingly, SPRET/Ei mice have longer lifespans, decreased atherosclerosis risk factors, and better hearing than almost all other mouse strains.