- 1 Section A
- 2 Introduction
- 3 The Epigenome
- 4 check other mech & Hak
- 5 DNA Methylation
- 6 Epigenetic Clock
- 7 Section B
- 8 Mechanisms of Action
- 9 The Epigenetic Drift
- 10 Epigenetic Drift Is a Determinant of Mammalian Lifespan and therefore an important Hallmark to Aging
- 11 Complementary Mechanisms check this %
- 12 Holistic Solutions with regard to extending Lifespan via the taming of the Epigenetic Drift
- 13 Concluding remarks
- 14 Reference and Precisions Notes
The expression of genes and the mitigating of the epigenetic drift via external stimuli have become one of the key mechanisms that governs health and longevity. In this Page, I will first define what Epigenetics is (Section A) and thereafter, delved into a few of its mechanisms (Section B).
Epigenetics is a relatively new science that deals with the epigenome, meaning “that which is above” the genome. An epigenome consists of a record of the chemical changes to the DNA and histone proteins of an organism. These changes can be passed down to an organism’s offspring via transgenerational epigenetic inheritance. The French scientist Lamark noted this, but Darwin wasn’t interested. Changes to the epigenome can result in changes to the structure of chromatin and changes to the function of the genome. (1)
The epigenome is also involved in regulating gene expression, human development, tissue differentiation and the suppression of transposable elements. Unlike the underlying genome which is largely static within an individual, (ie, made from 23,000 genes) the epigenome can be dynamically altered by environmental conditions. (2)
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check other mech & Hak
One of Epigenetics’ central modus operendi is via the DNA methylation pathway. This is a process by which methyl groups are added to the DNA molecule. Methylation can change the activity of a DNA segment without changing the sequence. When located in a gene promoter, DNA methylation typically acts to repress gene transcription. DNA methylation is essential for normal development and is associated with a number of key processes including genomic imprinting, X-chromosome inactivation, repression of transposable elements, aging and carcinogenesis. (3
Two of DNA’s four bases, cytosine and adenine, can be methylated. Cytosine methylation is widespread in both eukaryotes and prokaryotes, even though the rate of cytosine DNA methylation can differ greatly between species. (4)
Evans, JH, Evans, TE (1970). “Methylation of the deoxyribonucleic acid of Physarum polycephalum at various periods during the mitotic cycle”. Journal of Biological Chemistry. 245: 6436–6441. PMID 5530731
This is great news for Holistic scientists because it confirms the millennia intuition that the micro-environment or what Claude Bernard called the bio-terrain determines biological configuration. The example of the Queen Bee is a good one, to understand. Born just like all of the other worker bees in terms of genetic composition and the preliminary conditions associated with Hive birth, once fed with the royal nectar, the Queen bee epigenetically expresses dormant genes turning her into a massive big bee gifted with multiple talents, including but not limited to the laying of thousands and thousands of eggs. Similarly for human longevity, rather than being genetically predetermined, our life span appears to be largely epigenetically determined. Just like with the Queen Bee, Diet and other environmental influences impact our lifespan by changing the epigenetic information via enzymes and what is called the methylation drift.
Mechanisms of Action
Over the years, epigenetic scientists have been perfecting the epigenome model, thanks to which a number of key mechanisms have been identified, including the DNA methylation Drift
The Epigenetic Drift
The epigenetic drift is characterized by gains and losses in DNA methylation in the genome over time, this occurs more rapidly in mice than in monkeys and more rapidly in monkeys than in humans. This is one reason why certain animals live for shorter or longer periods of time. (3) On the other hand, DNA methylation is the epigenetic mechanism characterized by suppressing gene expression as a result of adding methyl groups onto DNA. This “tag” serves as a molecular bookmark in order to control mammalian genes, indicating when they should be used. (4)
Methylation patterns drift steadily throughout life, with methylation increasing in some areas of the genome, and decreasing in others. These epigenetic changes have previously been linked to age, but their connection to lifespan was uncertain.
In order to ascertain this connection, scientists recently examined DNA methylation patterns in blood from three different species: mouse, human, and monkey. The samples were from animals at different ages. The mice ranged from a couple months to nearly three years old, the monkeys ranged from under one year to 30 years old, and the humans ranged from 0 to 86 years old. The researchers used cord blood to measure epigenetic patterns at age zero.
Variations in DNA methylation related to age were analyzed by deep sequencing technology. The results revealed unique patterns, specifically showing that there were increases in methylation in older individuals at certain sites compared to unmethylated sites in young individuals at the same genomic sites, and vice versa. The scientists conclusion was that the Epigenetic drift is conserved across species and the rate of drift correlates with lifespan when comparing mice, rhesus monkeys, and humans.
Furthermore, in genomic areas that had increased methylation as the animals got older, there were dramatic losses in gene expression. Conversely, certain genes with reduced methylation showed increases in gene expression. Further analysis of a subset of genes impacted by age-related adjustments in methylation levels demonstrated an inverse relationship between longevity and methylation drift. (5) (Source) In conclusion, what appears to be clear is the observation according to which the more epigenetic change there has been, and the faster it occurred, the shorter the animals’ lifespan.
Epigenetic Drift Is a Determinant of Mammalian Lifespan and therefore an important Hallmark to Aging
In somatic animal cells, the epigenome, which controls cell identity and function, can be subjected to dysfunctions in the maintenance of the epigenome thereby leading to epigenetic drift. Looking at the scientific litterature, we find numerous studies that have described DNA methylation clocks that correlate epigenetic drift with increasing age. The question of how significant a role epigenetic drift plays in creating the phenotypes (6) associated with aging remains open. In this perspective, new clues have been identified while new longevity stratagems are pondered upon.
A recent study describes a new DNA methylation clock that can be slowed by caloric restriction (CR) in a way that correlates with the degree of lifespan and healthspan extension conferred by CR, suggesting that epigenetic drift itself is a determinant of mammalian lifespan. Genetic transplantation using genomic editing of DNA methylation homeostatic genes from long-lived to short-lived species is one way to potentially demonstrate a causative role for DNA methylation. Whether the DNA methylation clock be reset to youthful state, eliminating the effects of epigenetic drift without requiring a pluripotent cell intermediate is a critical question with profound implications for the development of aging therapeutics. Methods that transiently erase the DNA methylation pattern of somatic cells may be developed that reset this aging hallmark with potentially profound effects on lifespan, if DNA methylation-based epigenetic drift really plays a primary role in aging. (Source) (7)
In humans and other mammals, DNA methylation levels can be used to accurately estimate the age of tissues and cell types, forming an accurate epigenetic clock.
A longitudinal study of twin children showed that, between the ages of 5 and 10, there was divergence of methylation patterns due to environmental rather than genetic influences. There is a global loss of DNA methylation during aging.
In a study that analyzed the complete DNA methylomes of CD4+ T cells in a newborn, a 26 years old individual and a 103 years old individual was observed that the loss of methylation is proportional to age. Hypomethylated CpGs observed in the centenarian DNAs compared with the neonates covered all genomic compartments (promoters, intergenic, intronic and exonic regions). However, some genes become hypermethylated with age, including genes for the estrogen receptor, p16, and insulin-like growth factor 2.
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^ Lund, G.L.; Andersson, L.; Lauria, M.; Lindholm, M.; Fraga, M.F.; Villar-Garea, A.; Ballestar, E.; Esteller, M.; Zaina, S. (2004). “DNA methylation polymorphisms precede any histological sign of atherosclerosis in mice lacking Apolipoprotein E”. J Biol Chem. 279 (28): 29147–29154. doi:10.1074/jbc.m403618200. PMID 15131116.
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^ Castro, R.; Rivera, I.; Struys, E.A.; Jansen, E.E.; Ravasco, P.; Camilo, M.E.; Blom, H.J.; Jakobs, C.; Tavares; de Almeida, T. (2003). “Increased homocysteine concentrations and S-adenosylhomocysteine concentrations and DNA hypomethylation in vascular disease”. Clin Chem. 49 (8): 1292–1296. doi:10.1373/49.8.1292.
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^ Huang, Y.S.; Zhi, Y.F.; Wang, S.R. (2009). “Hypermethylation of estrogen receptor-α gene in atheromatosis patients and its correlation with homocysteine”. Pathophysiology. 16 (4): 259–265. doi:10.1016/j.pathophys.2009.02.010.
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^ Dong, C.D.; Yoon, W.; Goldschmidt-Clermont, P.J. (2002). “DNA methylation and atherosclerosis”. J Nutr. 132 (8): 2406S–2409S.
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^ Ying, A.K.; Hassanain, H.H.; Roos, C.M.; Smiraglia, D.J.; Issa, J.J.; Michler, R.E.; Caligiuri, M.; Plass, C.; Goldschmidt-Clermont, P.J. (2000). “Methylation of the estrogen receptor- α gene promoter is selectively increased in proliferating human aortic smooth muscle cells”. Cardiovas Res. 46 (1): 172–179. doi:10.1016/s0008-6363(00)00004-3.
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^ Zhu, S.; Goldschmidt-Clermont, P.J.; Dong, C. (2005). “Inactivation of Monocarboxylate Transporter MCT3 by DNA methylation in atherosclerosis”. Circulation. 112 (9): 1353–1361. doi:10.1161/circulationaha.104.519025. PMID 16116050.
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^ Wong CC1, Caspi A, Williams B, Craig IW, Houts R, Ambler A, Moffitt TE, Mill J (2010). “A longitudinal study of epigenetic variation in twins”. Epigenetics. 5 (6): 516–526. doi:10.4161/epi.5.6.12226. PMC 3322496 . PMID 20505345.
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^ Heyn, Holger; Li, Ning; Ferreira, Humberto J.; Moran, Sebastian; Pisano, David G.; Gomez, Antonio; Diez, Javier; Sanchez-Mut, Jose V.; Setien, Fernando (2012-06-26). “Distinct DNA methylomes of newborns and centenarians”. Proceedings of the National Academy of Sciences. 109 (26): 10522–10527. doi:10.1073/pnas.1120658109. ISSN 0027-8424. PMC 3387108 . PMID 22689993.
In mammals however, DNA methylation is almost exclusively found in CpG dinucleotides, with the cytosines on both strands being usually methylated. Non-CpG methylation can however be observed in embryonic stem cells, and has also been indicated in neural development. Furthermore, non-CpG methylation has also been observed in hematopoietic progenitor cells, and it occurred mainly in a CpApC sequence context.
Repression of CpG-dense promoters
DNA methylation was probably present at some extent in very early eukaryote ancestors. In virtually every organism analyzed, methylation in promoter regions correlates negatively with gene expression. CpG-dense promoters of actively transcribed genes are never methylated, but reciprocally transcriptionally silent genes do not necessarily carry a methylated promoter. In mouse and human, around 60–70% of genes have a CpG island in their promoter region and most of these CpG islands remain unmethylated independently of the transcriptional activity of the gene, in both differentiated and undifferentiated cell types. Of note, whereas DNA methylation of CpG islands is unambiguously linked with transcriptional repression, the function of DNA methylation in CG-poor promoters remains unclear; albeit there is little evidence that it could be functionally relevant.
DNA methylation may affect the transcription of genes in two ways. First, the methylation of DNA itself may physically impede the binding of transcriptional proteins to the gene, and second, and likely more important, methylated DNA may be bound by proteins known as methyl-CpG-binding domain proteins (MBDs). MBD proteins then recruit additional proteins to the locus, such as histone deacetylases and other chromatin remodeling proteins that can modify histones, thereby forming compact, inactive chromatin, termed heterochromatin. This link between DNA methylation and chromatin structure is very important. In particular, loss of methyl-CpG-binding protein 2 (MeCP2) has been implicated in Rett syndrome; and methyl-CpG-binding domain protein 2 (MBD2) mediates the transcriptional silencing of hypermethylated genes in cancer.
Complementary Mechanisms check this %
Epigenetics is also related to other mechanisms than mythelation, including, but not limited to histone modification, Non-coding RNA, Telomere shortening, Histone acetylation, chromatin and more. One of the more interesting mechanisms is hinged on the role of stressful experience in the biology of aging and diseases. Below, a corroborating excerpt.
“…. Exciting studies in the fields of neuroscience, psychology, and psychiatry have provided new insights into the epigenetic factors (e.g. DNA methylation) that are responsive to environmental input and serve as biological pathways in behavioral development. Here we highlight the experimental evidence, mainly from animal models, that factors such as psychosocial stress and environmental adversity can become encoded within epigenetic factors with functional consequences for brain plasticity and behavior. We also highlight evidence that epigenetic marking of genes in one generation can have consequences for future generations (i.e. inherited), and work with humans linking epigenetics, cognitive dysfunction, and psychiatric disorder. Though epigenetics has offered more of a beginning than an answer to the centuries-old nature-nurture debate, continued research is certain to yield substantial information regarding biological determinants of CNS changes and behavior with relevance for the study of developmental psychopathology.” (8)
Since the birth of behavioral epigenetics research, we have gained insight into the link between regulation of chromatin structure and plasticity. Studies have revealed that environmental adversity, for example in the form of social stress or traumatic experiences, can become encoded within epigenetic factors that control gene activity. Together, it has become clear that epigenetic mechanisms are poised to facilitate gene-environment communication throughout our lifespan. Epigenetic effects may also have implications for the stress susceptibility and well-being of future generations, providing a molecular mechanism to explain the transgenerational continuity of the effects of, for example, abuse and trauma. We still lack a complete understanding of the cause-and-effect role of epigenetic mechanisms in brain development, function, and plasticity, but continued exploration of the regulatory role of epigenetic processes in aspects of normal and abnormal brain and behavior development will continue to be an informative approach for understanding the biology of risk and resilience for cognitive dysfunction and psychiatric disorders.
Holistic Solutions with regard to extending Lifespan via the taming of the Epigenetic Drift
The impacts of calorie restriction on lifespan have been known for millennia, but thanks to modern quantitative techniques, scientists have been able to show for the first time a causative correlation between the slowing down of epigenetic drift and the increase of a healthy lifespan.
Even though we need to better understanding DNA methylation drift and how it determines lifespan in mammals, we already know enough in terms of what to do and what not do to favorably modulate the DNA methylation drift with Holistic savoir-faire.
Whether genetic editing or synthetic drugs will be able to catch up to evolutionary finesse remains to be proven. Meanwhile, the focus should be the taming of this epigenetic drift with the holistic tools we have at hand including, but not limited to stress control, caloric restriction and selective nutrient uptake. In addition to Life extension, with the slowing down of Epigenetic Drift, the likelihood of contracting chronic diseases like cancer is also significantly lessened. We are thus in a win-win type of situation.
“It is well-established that the DNA methylation landscape of normal cells undergoes a gradual modification with age, termed as ‘epigenetic drift’. Here, we review the current state of knowledge of epigenetic drift and its potential role in cancer etiology. We propose a new terminology to help distinguish the different components of epigenetic drift, with the aim of clarifying the role of the epigenetic clock, mitotic clocks and active changes, which accumulate in response to environmental disease risk factors. We further highlight the growing evidence that epigenetic changes associated with cancer risk factors may play an important causal role in cancer development, and that monitoring these molecular changes in normal cells may offer novel risk prediction and disease prevention strategies”. (9) (Source)
Likewise with cardiovascular issues. In this case below, we have DNA methylation drift of the atherosclerotic aorta that is shown to increase with lesion progression. So by targeting DNA methylation-epigenetic drift with holistic tooks, we can help to mitigate if not reverse aortas’ atheroscherosis.
“Atherosclerosis severity-independent alterations in DNA methylation, a reversible and highly regulated DNA modification, have been detected in aortic atheromas, thus supporting the hypothesis that epigenetic mechanisms participate in the pathogenesis of atherosclerosis….” (Source) (10)
In many disease processes, such as cancer, gene promoter CpG islands acquire abnormal hypermethylation, which results in transcriptional silencing that can be inherited by daughter cells following cell division. Alterations of DNA methylation have been recognized as an important component of cancer development. Hypomethylation, in general, arises earlier and is linked to chromosomal instability and loss of imprinting, whereas hypermethylation is associated with promoters and can arise secondary to gene (oncogene suppressor) silencing, but might be a target for epigenetic therapy.
Global hypomethylation has also been implicated in the development and progression of cancer through different mechanisms. Typically, there is hypermethylation of tumor suppressor genes and hypomethylation of oncogenes.
Generally, in progression to cancer, hundreds of genes are silenced or activated. Although silencing of some genes in cancers occurs by mutation, a large proportion of carcinogenic gene silencing is a result of altered DNA methylation (see DNA methylation in cancer). DNA methylation causing silencing in cancer typically occurs at multiple CpG sites in the CpG islands that are present in the promoters of protein coding genes.
Altered expressions of microRNAs also silence or activate many genes in progression to cancer (see microRNAs in cancer). Altered microRNA expression occurs through hyper/hypo-methylation of CpG sites in CpG islands in promoters controlling transcription of the microRNAs.
Silencing of DNA repair genes through methylation of CpG islands in their promoters appears to be especially important in progression to cancer (see methylation of DNA repair genes in cancer).
Epigenetic modifications such as DNA methylation have been implicated in cardiovascular disease, including atherosclerosis. In animal models of atherosclerosis, vascular tissue as well as blood cells such as mononuclear blood cells exhibit global hypomethylation with gene-specific areas of hypermethylation. DNA methylation polymorphisms may be used as an early biomarker of atherosclerosis since they are present before lesions are observed, which may provide an early tool for detection and risk prevention.
Two of the cell types targeted for DNA methylation polymorphisms are monocytes and lymphocytes, which experience an overall hypomethylation. One proposed mechanism behind this global hypomethylation is elevated homocysteine levels causing hyperhomocysteinemia, a known risk factor for cardiovascular disease.
Holistically, one of the keys to mitigating the epigenetic drift is to reduce calories while also maintaining a healthy intake of essential nutrients. In this perspective, the Tollefsbol Lab tried caloric restriction on mice and monkeys and saw great results. In young mice, the researchers cut calorie intake by 40 percent. For middle-aged monkeys, they cut calorie intake by 30 percent. Significant decreases in epigenetic drift were observed in both species. Age-related changes in DNA methylation in older, calorie-restricted animals were comparable to those of young animals. (11 )
For millennia, in Holistic milieus, we have known that isolating and processing any food can have toxic effects that outweigh benefits. This is the case of cocaine, hard alcohol, heroin, vegetable oils, refined breads and sugar. That glucose restriction leads to extension of the lifespan of human cells and kills precancerous cells should therefore be all the more a wake up call for mainstreman conventional medicine experts that Science can now identify the epigenetic mechanisms whereby sugar leads to accelerated aging. So the Solution is in reality a piece of cake. Stop the sugar. In the United States, over 150 lb of sugar is consumed per year and per American. Unless the Government imposes a hefty tax like the Mexico government dit on surgary sodas and the like, the epidemics of obesity, diabetes, metabolic syndrome and other chronic diseases will continue unabated.
DNA methylation plays a role in both gene silencing and gene expression. Research is honing in on the epigenetic control of telomerase, which is key for better holistic tools to optimize longevity and prevent chronic diseases. By knowing how to avoid epigenetic short-circuiting, we can therefore have a control over accelerated aging and chronic diseases. Aging has been connected to profound epigenetic changes that lead to alterations in gene expression. Unravelling this process and harnessing its plasticity can help us to reach our evolutionary designed 120 years in relative good shape. Epigenetics and therefore holistic lifestyle determine healthy lifespans way more than genes.
Christian Joubert (HM Institute Director)
DNA methylation is a powerful transcriptional repressor, at least in CpG dense contexts. Transcriptional repression of protein-coding genes appears essentially limited to very specific classes of genes that need to be silent permanently and in almost all tissues. While DNA methylation does not have the flexibility required for the fine-tuning of gene regulation, its stability is perfect to ensure the permanent silencing of transposable elements.
Transposon control is one the most ancient function of DNA methylation that is shared by animals, plants and multiple protists. It is even suggested that DNA methylation evolved precisely for this purpose.
Reference and Precisions Notes
(1) Bernstein, Bradley E.; Meissner, Alexander; Lander,Eric S. (February 2007). “The Mammalian Epigenome”. Cell. 128 (4): 669–681. doi:10.1016/j.cell.2007.01.033. PMID 17320505. Retrieved 19 December 2011.
(2). Conley, A.B., King Jordan, I. (2012). Endogenous Retroviruses and the Epigenome. In: Witzany, G. (ed). Viruses: Essential Agents of Life, Springer, Dordrecht, pp. 309-323.
(3). For instance, on average, mice live for two to three years, whereas rhesus monkeys live for 25 years and humans live to around 70-80 years.
(4) https://www.epigentek.com/catalog/dna-methylation-c-75_21.html. The addition of a methyl group to cytosine nucleotides (the C of ATCG). Methylcytosine behaves much like normal cytosine; it can bond with guanine and be transcribed into RNA. However for reasons that are not fully understood, heavily methylated regions of DNA are transcribed less often, leading to fewer copies of the proteins those genes code for. Amount of methylation can provide something of a calibration knob to let cells control how much of a particular protein they produce.
(5). Maegawa, S. et al. (2017). Caloric restriction delays age-related methylation drift. Nature Communications, 8(1). Temple Health. Temple Researchers Uncover Mechanism Behind Calorie Restriction and Lengthened Lifespan. Temple Health News & Announcements. 14 Sep 2017. Web.
(6). A phenotype (from Greek phainein, meaning ‘to show’, and typos, meaning ‘type’) is the composite of an organism’s observable characteristics or traits, such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior (such as a bird’s nest). A phenotype results from the expression of an organism’s genetic code, its genotype, as well as the influence of environmental factors and the interactions between the two. When two or more clearly different phenotypes exist in the same population of a species, the species is called polymorphic. A well-documented polymorphism is Labrador Retriever coloring; while the coat color depends on many genes, it is clearly seen in the environment as yellow, black and brown. On the other hand, a genotype is the part of the genetic makeup of a cell, and therefore of an organism or individual, which determines one of its characteristics (phenotype). Genotype is one of three factors that determine phenotype, along with inherited epigenetic factors and non-inherited environmental factors. Not all organisms with the same genotype look or act the same way because appearance and behavior are modified by environmental and growing conditions. Likewise, not all organisms that look alike necessarily have the same genotype.
(7). Rejuvenation Res. 2017 Oct;20(5):430-436. doi: 10.1089/rej.2017.2024.
(8) Dev Psychopathol. 2015 May; 27(2): 637–648, “Epigenetic pathways through which experiences become linked with biology”. Experiences, particularly those occurring during sensitive periods of development, are well-recognized for their ability to canalize neurobiological trajectories and yield significant consequences for life-long health and mental well-being. For some time now it has also been recognized that proper brain development and life-long function rely on the coordination of an extraordinarily complex set of neurodevelopmental events that involve genetic and environmental interactions. The past decade of behavioral epigenetics research has begun to shed light on mechanisms through which our experiences can interact with and become linked with our biology, providing a new framework to understand the brain’s ability to change as a result of experience (i.e. plasticity) and thus how behavior can arise
(9) Epigenomics. 2016 May;8(5):705-19. doi: 10.2217/epi-2015-0017. Epub 2016 Apr 22.
(10). BMC Med Genomics. 2015; 8: 7.
(11) The Tollefsbol Lab at University of Alabama at Birmingham (UAB) has revealed fascinating epigenetic insights into aging and cancer. Trygve Tollefsbol, Ph.D., D.O., is a professor of Biology and a Senior Scientist at the UAB Comprehensive Cancer Center, the Comprehensive Center for Healthy Aging, the Nutrition Obesity Research Center, and the Comprehensive Diabetes Center. He is also the Director of the Cell Senescence Culture Facility at UAB and the editor of a new book on applied epigenetics called Medical Epigenetics, which focuses on epigenetics diseases, their impact on the human body, and avenues for treatment. Tollefsbol and his team have published over 40 peer-reviewed articles in the past 5 years. Initially designated solely to epigenetics, his lab has since branched out into nutrition and cancer prevention epigenetics..