The role of epigenetics in aging and age-related diseases

Calvanese, Vincenzo; Lara, Ester; Kahn, Arnold J.; Fraga, Mario F.

doi:10.1016/j.arr.2009.03.004

Cited by 295 publications

(193 citation statements)

References 108 publications

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“…Epigenetic changes during aging have also been reported (Calvanese et al 2009;Fraga et al 2005). We hypothesized that aged-related degeneration of epigenetic patterns must be functionally associated with age-associated dysfunction of macrophages.…”

Section: Tsa Suppresses Cox-2 Protein Expression By Upregulation Of Mmentioning

confidence: 89%

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Dysregulated expression of miR-101b and miR-26b lead to age-associated increase in LPS-induced COX-2 expression in murine macrophage

Liú

Wang

et al. 2015

AGE

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Aging is the natural process of decline in physiological structure and function of various molecules, cells, tissues, and organs. Growing evidence indicates that increased immune genetic diversity and dysfunction of immune system cause aging-related pathophysiological process with the growth of age. In the present study, we observed that LPS-induced higher activation of cyclooxygenase (COX)-2 promoter is associated with the upregulated binding activity of nuclear factor kappa B (NF-κB) in peritoneal macrophages of aged mice than young ones. Additionally, COX-2 is a direct target of miR-101b and miR-26b in the macrophages. Significant upregulation of miR-101b and miR26b effectively prevented LPS-induced excessive expression of COX-2 in the young mice. Because these negative regulatory factors were unresponsive to LPS stimulation, the levels of COX-2 were markedly higher in the macrophages of aged mice. Further study showed that NF-κB activation contributed to the increase in the expression of miR-101b and miR-26b in the LPSstimulated macrophages of young mice, but not aged ones. Moreover, histone deacetylase (HDAC) inhibitor trichostatin A (TSA) upregulated expression of miR101b and miR-26b in the aged mouse macrophages only, but not the young cells. This demonstrated that HDAC suppressed the expression of miR-101b and miR-26b in the LPS-treated macrophages of aged mice and contributed to the aging process. TSA-induced increased expression of miR-101b and miR-26b could further suppress COX-2 expression. These findings provide novel evidence on the regulation of immune senescence and miR-101b and miR-26b, which might be promising targets in treating aged-related inflammatory diseases. Epigenetic regulation of the microRNAs (miRNAs) provides an important evidence for the treatment of innate inflammatory disease with HDAC inhibitors in elderly.

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Section: Tsa Suppresses Cox-2 Protein Expression By Upregulation Of Mmentioning

confidence: 89%

“…Epigenetic modification has been demonstrated to be important in aging and age-related immune dysfunction (Calvanese et al 2009;Grolleau-Julius et al 2010;Issa 2003). There is growing evidence of epigenetic regulation on miRNA expression (Sato et al 2011).…”

Section: Tsa Suppresses Cox-2 Protein Expression By Upregulation Of Mmentioning

confidence: 99%

Dysregulated expression of miR-101b and miR-26b lead to age-associated increase in LPS-induced COX-2 expression in murine macrophage

Liú

Wang

et al. 2015

AGE

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“…Among epigenetic modifications, the most intensively studied is the methylation of cytosine residues at the carbon 5 position-5 m C (7). Reported age-related changes to DNA methylation have typically included a general loss of methylation, or hypomethylation, across the genome (6,8,9), accompanied by site-specific hypermethylation at several gene promoters (10,11).…”

Section: Introductionmentioning

confidence: 99%

A methylome-wide study of aging using massively parallel sequencing of the methyl-CpG-enriched genomic fraction from blood in over 700 subjects

McClay¹,

Åberg²,

Clark³

et al. 2013

Human Molecular Genetics

149

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The central importance of epigenetics to the aging process is increasingly being recognized. Here we perform a methylome-wide association study (MWAS) of aging in whole blood DNA from 718 individuals, aged 25 -92 years (mean 5 55). We sequenced the methyl-CpG-enriched genomic DNA fraction, averaging 67.3 million reads per subject, to obtain methylation measurements for the ∼27 million autosomal CpGs in the human genome. Following extensive quality control, we adaptively combined methylation measures for neighboring, highly-correlated CpGs into 4 344 016 CpG blocks with which we performed association testing. Eleven age-associated differentially methylated regions (DMRs) passed Bonferroni correction (P-value < 1.15 3 10 28 ). Top findings replicated in an independent sample set of 558 subjects using pyrosequencing of bisulfite-converted DNA (min P-value < 10 230 ). To examine biological themes, we selected 70 DMRs with false discovery rate of <0.1. Of these, 42 showed hypomethylation and 28 showed hypermethylation with age. Hypermethylated DMRs were more likely to overlap with CpG islands and shores. Hypomethylated DMRs were more likely to be in regions associated with polycomb/regulatory proteins (e.g. EZH2) or histone modifications H3K27ac, H3K4m1, H3K4m2, H3K4m3 and H3K9ac. Among genes implicated by the top DMRs were protocadherins, homeobox genes, MAPKs and ryanodine receptors. Several of our DMRs are at genes with potential relevance for age-related disease. This study successfully demonstrates the application of next-generation sequencing to MWAS, by interrogating a large proportion of the methylome and returning potentially novel age DMRs, in addition to replicating several loci implicated in previous studies using microarrays.

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“…Epigenetic apparatus control the differential expression of genes in certain cells, and are responsive to environmental stressors, providing a possible link between frailty, ageing and environmental factors (19). The combination of these genetic and molecular factors above are transmitted to cellular level as cell senescence of mitotic cells, and distinct but similar consequences for post-mitotic cells (e.g.…”

Section: Pathophysiological Mechanisms Of Frailtymentioning

confidence: 99%

Frailty Assessment in Acute Care

2015

The Gerontologist

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IntroductionFor some people, ageing is associated with the experience of increased co-morbidity, functional impairment, poor resilience and heightened vulnerability to external stressors, resulting in reduced lifespan as well as health-span. This frailty phenomenon poses challenges to health care systems in the form of increased patient complexity and resource utilisation. The acute care setting, characterised by time-pressure and high patient turn-over, is under strain and struggles to recognise and subsequently reliably intervene, to prevent, reverse or halt the decline of this vulnerable cohort. MethodsThis mixed-methods study probes existing evidence and 'real-world' processes with a systematic review of frailty assessments developed or validated in the acute care setting and a survey of contemporaneous clinical practice in London Acute Medical Units. Content validation and understanding of contextual factors for ideal frailty assessment in acute care is explored using Delphi consensus and Focus Group methodology respectively. The resultant model is developed on existing retrospective national Hospital Episode Statistics data, and prospectively tested on observational data in a local Acute Medical Unit setting. ResultsExisting frailty scores are preponderantly biophysical in nature, and have poor predictive power for adverse outcomes in the acute care setting. In clinical practice, single-dimension assessment tools predominate. Frailty syndromes and previous high resource utilisation in the form of a simple, clinically relevant tool useful to the multidisciplinary team gain consensus as optimal assessment for the setting. Retrospective testing of the frailty model displays moderate predictive powers for adverse events (inpatient mortality, emergency readmission and institutionalisation) and prospective testing provides concurrent (Frailty Index, Age, Co-Morbidity) and comparative predictive validity (Frailty Index, Co-Morbidity, 2 admission National Early Warning Score) with existing risk stratification models in this setting. ConclusionsA risk prediction model based on frailty syndromes and previous high resource utilisation is a valid, feasible and useful for the acute care setting.

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The role of epigenetics in aging and age-related diseases

Cited by 295 publications

References 108 publications

Dysregulated expression of miR-101b and miR-26b lead to age-associated increase in LPS-induced COX-2 expression in murine macrophage

Dysregulated expression of miR-101b and miR-26b lead to age-associated increase in LPS-induced COX-2 expression in murine macrophage

A methylome-wide study of aging using massively parallel sequencing of the methyl-CpG-enriched genomic fraction from blood in over 700 subjects

Frailty Assessment in Acute Care

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