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Aging Nov 2021The search continues for possible interventions that delay and/or reverse biological aging, resulting in extended healthspan and lifespan. Interventions delaying aging...
Rejuvant®, a potential life-extending compound formulation with alpha-ketoglutarate and vitamins, conferred an average 8 year reduction in biological aging, after an average of 7 months of use, in the TruAge DNA methylation test.
The search continues for possible interventions that delay and/or reverse biological aging, resulting in extended healthspan and lifespan. Interventions delaying aging in animal models are well established; however, most lack validation in humans. The length of human lifespan makes it impractical to perform survival analysis. Instead, aging biomarkers, such as DNA methylation (DNAm) clocks, have been developed to monitor biological age. Herein we report a retrospective analysis of DNA methylation age in 42 individuals taking Rejuvant®, an alpha-ketoglutarate based formulation, for an average period of 7 months. DNAm testing was performed at baseline and by the end of treatment with Rejuvant® supplementation. Remarkably, individuals showed an average decrease in biological aging of 8 years (p-value=6.538x10). Furthermore, the supplementation with Rejuvant® is robust to individual differences, as indicated by the fact that a large majority of participants decreased their biological age. Moreover, we found that Rejuvant® is of additional benefit to chronologically and biologically older individuals. While continued testing, particularly in a placebo-controlled design, is required, the nearly 8-year reversal in the biological age of individuals taking Rejuvant® for 4 to 10 months is noteworthy, making the natural product cocktail an intriguing candidate to affect human aging.
Topics: Adult; Aged; Aging; DNA Methylation; Dietary Supplements; Female; Geroscience; Humans; Ketoglutaric Acids; Male; Middle Aged; Vitamins
PubMed: 34847066
DOI: 10.18632/aging.203736 -
Trends in Endocrinology and Metabolism:... Sep 2019Epigenetics can be defined as 'the structural adaptation of chromosomal regions so as to register, signal, or perpetuate altered activity states.' Increased... (Review)
Review
Epigenetics can be defined as 'the structural adaptation of chromosomal regions so as to register, signal, or perpetuate altered activity states.' Increased transcription of key regulatory, metabolic, and myogenic genes is an early response to exercise and is important in mediating subsequent adaptations in skeletal muscle. DNA hypomethylation and histone hyperacetylation are emerging as important crucial events for increased transcription. The complex interactions between multiple epigenetic modifications and their regulation by metabolic changes and signaling events during exercise, with implications for enhanced understanding of the acute and chronic adaptations to exercise, are questions for further investigation.
Topics: DNA Methylation; Epigenesis, Genetic; Exercise; Histones; Humans; Muscle, Skeletal
PubMed: 31279665
DOI: 10.1016/j.tem.2019.06.002 -
Genetics in Medicine : Official Journal... Aug 2023HNRNPU haploinsufficiency is associated with developmental and epileptic encephalopathy 54. This neurodevelopmental disorder is characterized by developmental delay,...
PURPOSE
HNRNPU haploinsufficiency is associated with developmental and epileptic encephalopathy 54. This neurodevelopmental disorder is characterized by developmental delay, intellectual disability, speech impairment, and early-onset epilepsy. We performed genome-wide DNA methylation (DNAm) analysis in a cohort of individuals to develop a diagnostic biomarker and gain functional insights into the molecular pathophysiology of HNRNPU-related disorder.
METHODS
DNAm profiles of individuals carrying pathogenic HNRNPU variants, identified through an international multicenter collaboration, were assessed using Infinium Methylation EPIC arrays. Statistical and functional correlation analyses were performed comparing the HNRNPU cohort with 56 previously reported DNAm episignatures.
RESULTS
A robust and reproducible DNAm episignature and global DNAm profile were identified. Correlation analysis identified partial overlap and similarity of the global HNRNPU DNAm profile to several other rare disorders.
CONCLUSION
This study demonstrates new evidence of a specific and sensitive DNAm episignature associated with pathogenic heterozygous HNRNPU variants, establishing its utility as a clinical biomarker for the expansion of the EpiSign diagnostic test.
Topics: Humans; DNA Methylation; Epigenomics; Phenotype; Neurodevelopmental Disorders; Biomarkers
PubMed: 37120726
DOI: 10.1016/j.gim.2023.100871 -
Nature Aging Dec 2021DNA methylation dynamics emerged as a promising biomarker of mammalian aging, with multivariate machine learning models ('epigenetic clocks') enabling measurement of...
DNA methylation dynamics emerged as a promising biomarker of mammalian aging, with multivariate machine learning models ('epigenetic clocks') enabling measurement of biological age in bulk tissue samples. However, intrinsically sparse and binarized methylation profiles of individual cells have so far precluded the assessment of aging in single-cell data. Here, we introduce , a statistical framework for epigenetic age profiling at single-cell resolution, and validate our approach in mice. Our method recapitulates the chronological age of tissues, while uncovering heterogeneity among cells. We show accurate tracking of the aging process in hepatocytes, demonstrate attenuated epigenetic aging in muscle stem cells, and track age dynamics in embryonic stem cells. We also use to reveal, at the single-cell level, a natural and stratified rejuvenation event occurring during early embryogenesis. We provide our framework as a resource to enable exploration of epigenetic aging trajectories at single-cell resolution.
Topics: Animals; Mice; Epigenesis, Genetic; Aging; DNA Methylation; Biomarkers; Hepatocytes; Mammals
PubMed: 36211119
DOI: 10.1038/s43587-021-00134-3 -
Nature Biotechnology Aug 2022
Topics: DNA Methylation; Epigenomics
PubMed: 35945440
DOI: 10.1038/s41587-022-01433-9 -
Handbook of Clinical Neurology 2021Animal and humans exposed to stress early in life are more likely to suffer from long-term behavioral, mental health, metabolic, immune, and cardiovascular health... (Review)
Review
Animal and humans exposed to stress early in life are more likely to suffer from long-term behavioral, mental health, metabolic, immune, and cardiovascular health consequences. The hypothalamus plays a nodal role in programming, controlling, and regulating stress responses throughout the life course. Epigenetic reprogramming in the hippocampus and the hypothalamus play an important role in adapting genome function to experiences and exposures during the perinatal and early life periods and setting up stable phenotypic outcomes. Epigenetic programming during development enables one genome to express multiple cell type identities. The most proximal epigenetic mark to DNA is a covalent modification of the DNA itself by enzymatic addition of methyl moieties. Cell-type-specific DNA methylation profiles are generated during gestational development and define cell and tissue specific phenotypes. Programming of neuronal phenotypes and sex differences in the hypothalamus is achieved by developmentally timed rearrangement of DNA methylation profiles. Similarly, other stations in the life trajectory such as puberty and aging involve predictable and scheduled reorganization of DNA methylation profiles. DNA methylation and other epigenetic marks are critical for maintaining cell-type identity in the brain, across the body, and throughout life. Data that have emerged in the last 15 years suggest that like its role in defining cell-specific phenotype during development, DNA methylation might be involved in defining experiential identities, programming similar genes to perform differently in response to diverse experiential histories. Early life stress impact on lifelong phenotypes is proposed to be mediated by DNA methylation and other epigenetic marks. Epigenetic marks, as opposed to genetic mutations, are reversible by either pharmacological or behavioral strategies and therefore offer the potential for reversing or preventing disease including behavioral and mental health disorders. This chapter discusses data testing the hypothesis that DNA methylation modulations of the HPA axis mediate the impact of early life stress on lifelong behavioral and physical phenotypes.
Topics: Animals; DNA Methylation; Epigenesis, Genetic; Female; Humans; Hypothalamo-Hypophyseal System; Male; Phenotype; Pituitary-Adrenal System; Pregnancy; Stress, Psychological
PubMed: 34225925
DOI: 10.1016/B978-0-12-820107-7.00008-2 -
Current Stem Cell Research & Therapy 2022Emerging evidence suggests that ascorbic acid (vitamin C) enhances the reprogramming process by multiple mechanisms primarily due to its cofactor role in Fe(II) and... (Review)
Review
Emerging evidence suggests that ascorbic acid (vitamin C) enhances the reprogramming process by multiple mechanisms primarily due to its cofactor role in Fe(II) and 2-oxoglutarate-dependent dioxygenases, including the DNA demethylases Ten Eleven Translocase (TET) and histone demethylases. Epigenetic variations have been shown to play a critical role in somatic cell reprogramming. DNA methylation and histone methylation are extensively recognized as barriers to somatic cell reprogramming. N6-methyladenosine (m6A), known as RNA methylation, is an epigenetic modification of mRNAs and has also been shown to play a role in regulating cellular reprogramming. Multiple cofactors are reported to promote the activity of these demethylases, including vitamin C. Therefore, this review focuses and examines the evidence and mechanism of vitamin C in DNA and histone demethylation and highlights its potential involvement in the regulation of m6A demethylation. It also shows the significant contribution of vitamin C in epigenetic regulation, and the affiliation of demethylases with vitamin C-facilitated epigenetic reprogramming.
Topics: Antioxidants; Ascorbic Acid; Cellular Reprogramming; DNA Methylation; Epigenesis, Genetic
PubMed: 34264189
DOI: 10.2174/1574888X16666210714152730 -
Theranostics 2023DNA methylation is the most stable epigenetic modification. In mammals, it usually occurs at the cytosine of CpG dinucleotides. DNA methylation is essential for many... (Review)
Review
DNA methylation is the most stable epigenetic modification. In mammals, it usually occurs at the cytosine of CpG dinucleotides. DNA methylation is essential for many physiological and pathological processes. Aberrant DNA methylation has been observed in human diseases, particularly cancer. Notably, conventional DNA methylation profiling technologies require a large amount of DNA, often from a heterogeneous cell population, and provide an average methylation level of many cells. It is often not realistic to collect sufficient numbers of cells, such as rare cells and circulating tumor cells in peripheral blood, for bulk sequencing assays. It is therefore essential to develop sequencing technologies that can accurately profile DNA methylation using small numbers of cells or even single cells. Excitingly, many single-cell DNA methylation sequencing and single-cell omics sequencing technologies have been developed, and applications of these methods have greatly expanded our understanding of the molecular mechanism of DNA methylation. Here, we summaries single-cell DNA methylation and multi-omics sequencing methods, delineate their applications in biomedical sciences, discuss technical challenges, and present our perspective on future research directions.
Topics: Animals; Humans; DNA Methylation; CpG Islands; Epigenesis, Genetic; DNA; Sequence Analysis, DNA; Mammals
PubMed: 37215576
DOI: 10.7150/thno.82582 -
Nature Communications Dec 2022The interplay between histone modifications and DNA methylation drives the establishment and maintenance of the cellular epigenomic landscape, but it remains challenging...
The interplay between histone modifications and DNA methylation drives the establishment and maintenance of the cellular epigenomic landscape, but it remains challenging to investigate the complex relationship between these epigenetic marks across the genome. Here we describe a nanopore-sequencing-based-method, nanoHiMe-seq, for interrogating the genome-wide localization of histone modifications and DNA methylation from single DNA molecules. nanoHiMe-seq leverages a nonspecific methyltransferase to exogenously label adenine bases proximal to antibody-targeted modified nucleosomes in situ. The labelled adenines and the endogenous methylated CpG sites are simultaneously detected on individual nanopore reads using a hidden Markov model, which is implemented in the nanoHiMe software package. We demonstrate the utility, robustness and sensitivity of nanoHiMe-seq by jointly profiling DNA methylation and histone modifications at low coverage depths, concurrently determining phased patterns of DNA methylation and histone modifications, and probing the intrinsic connectivity between these epigenetic marks across the genome.
Topics: DNA Methylation; Histone Code; Nanopore Sequencing; Sequence Analysis, DNA; DNA; Epigenesis, Genetic
PubMed: 36566265
DOI: 10.1038/s41467-022-35650-2 -
Journal of Integrative Plant Biology Dec 2022DNA methylation plays essential homeostatic functions in eukaryotic genomes. In animals, DNA methylation is also developmentally regulated and, in turn, regulates... (Review)
Review
DNA methylation plays essential homeostatic functions in eukaryotic genomes. In animals, DNA methylation is also developmentally regulated and, in turn, regulates development. In the past two decades, huge research effort has endorsed the understanding that DNA methylation plays a similar role in plant development, especially during sexual reproduction. The power of whole-genome sequencing and cell isolation techniques, as well as bioinformatics tools, have enabled recent studies to reveal dynamic changes in DNA methylation during germline development. Furthermore, the combination of these technological advances with genetics, developmental biology and cell biology tools has revealed functional methylation reprogramming events that control gene and transposon activities in flowering plant germlines. In this review, we discuss the major advances in our knowledge of DNA methylation dynamics during male and female germline development in flowering plants.
Topics: Animals; DNA Methylation; Epigenesis, Genetic; Germ Cells; Reproduction
PubMed: 36478632
DOI: 10.1111/jipb.13422