epigenetics

Epigenetics Revolution: How Modern Biology Is Rewriting Our Understanding of Genetics, Disease and Inheritance

by Nessa Carey  · 31 Aug 2011  · 357pp  · 98,854 words

-term psychological damage as a result of childhood abuse. But these stories are linked at a very fundamental biological level. They are all examples of epigenetics. Epigenetics is the new discipline that is revolutionising biology. Whenever two genetically identical individuals are non-identical in some way we can measure, this is called

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repression. The other interpretation was that the CpG island became methylated, and it was this methylation that switched the gene off. In this model the epigenetic modification actually causes the change in gene expression. Although there is still the occasional argument about this between competing labs, the vast majority of scientists

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have overlaps in their presentation. Both lead to cleft palate and mental retardation. Both of these symptoms are classically considered as reflecting problems during development. Epigenetic pathways are important throughout life, but seem to be particularly significant during development. In addition to these histone writers and erasers there are over 100

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have different epigenomes. Interestingly, though, they also found that even the MZ twins differed in their DNA methylation patterns, suggesting identical twins begin to diverge epigenetically during development in the uterus. Combining the information from the two papers, and from additional studies, we can conclude that even genetically identical individuals are

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five generations of genetically identical individuals. Needless to say, this isn’t feasible for humans. This is why experimental animals have been so useful in epigenetics. They allow scientists to address really complex questions, whilst controlling the environment as much as possible. The data that are generated in these animal studies

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biology this way. Various comparative studies have shown that many systems have stayed broadly the same in different organisms over almost inconceivably long periods. The epigenetic machinery of yeast and humans, for example, share more similarities than differences and yet the common ancestor for the two species lies about one billion

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more variability in the body weights within the group. Further experiments published in the same paper assessed the effects of the decreased expression of these epigenetic proteins. Their decreased expression was linked to changes in expression levels of selected genes involved in metabolism6, and increased variability in that expression. In other

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proteins, and the precise effects that they have at specific chromosomal regions. A little bit more DNA methylation here, a little bit less there. The epigenetic machinery reinforces and then maintains particular patterns of modifications, thus creating the levels of gene expression. Consequently, these initial small fluctuations in histone and DNA

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a gradually increasing functional impairment. Clinically, we don’t recognise this until it passes some invisible threshold and the patient begins to show symptoms. The epigenetic variation that occurs in developmental programming is at heart a predominantly random process, normally referred to as ‘stochastic’. This stochastic process may account for a

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identical twins become phenotypically different, sometimes in the most dramatic of ways. Such a random process, caused by individually minor fluctuations in the expression of epigenetic genes during early development also provides a very good model for understanding how genetically identical Avy/a mice can end up with different coat colours

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pronounced. A major metabolic disturbance during early pregnancy, such as the dramatically decreased availability of food during the Dutch Hunger Winter, would significantly alter the epigenetic processes occurring in the foetal cells. The cells would change metabolically, in an attempt to keep the foetus growing as healthily as possible despite the

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keep everything a little clearer, we’ll use the phrase ‘transgenerational inheritance’ to describe the phenomenon of transmission of an acquired characteristic and only use ‘epigenetics’ to describe molecular events. Some of the strongest evidence for transgenerational inheritance in humans comes from the survivors of the Dutch Hunger Winter. Because the

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of malnutrition during early development. This seems like a good example of transgenerational (Lamarckian) inheritance, but has it has been caused by an epigenetic mechanism? Did an epigenetic change (altered DNA methylation and/or variations in histone modifications) that had occurred in Basje as a result of malnutrition during her first twelve

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cytoplasm could stimulate an unusual growth pattern in the foetus. This again would result in transgenerational inheritance but not through the direct transmission of an epigenetic modification. So we can see that there are various mechanisms that could explain the inheritance patterns seen through the maternal line in the Dutch Hunger

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we see transgenerational inheritance from father to child, it isn’t likely to be caused by intra-uterine or cytoplasmic effects. Under these circumstances, an epigenetic mechanism would be an attractive candidate for explaining transgenerational inheritance of an acquired characteristic. Greedy fellows in Sweden Some data suggesting that male transgenerational inheritance

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, for the reasons outlined earlier. Therefore, it seems reasonable to hypothesise that the transgenerational consequences of food availability in the grandparental generation were mediated via epigenetics. These data are particularly striking when you consider that the original nutritional effect happened when the boys were pre-pubescent and so had not even

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whom the agouti gene is expressed continuously, due to low levels of DNA methylation of the regulatory retrotransposon, never give birth to dark pups. The epigenetically – rather than genetically – determined characteristics of the mother influence her offspring. Because Emma Whitelaw was working on inbred mice, she was able to perform this

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model systems have been really useful in demonstrating that transgenerational inheritance of a non-genetic phenotype does actually occur, and that this takes place via epigenetic modifications. This is truly revolutionary. It confirms that for some very specific situations Lamarckian inheritance is taking place, and we have a handle on the

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least four generations, so this is another example of Lamarckian inheritance. Given the male transmission pattern, it is likely this is another example of an epigenetic inheritance mechanism. A follow-on publication from the same research group has identified regions of the genome where vinclozolin treatment leads to unusual DNA methylation

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the gene expression patterns of the zygote and the subsequent developmental stages. But this reprogramming also has another effect. Cells can accumulate inappropriate or abnormal epigenetic modifications at various genes. These disrupt normal gene expression and can even contribute to disease, as we shall see later in this book. The reprogramming

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, and mechanisms have evolved in our cells to control the activity of these types of retrotransposons. One of the major mechanisms that cells use is epigenetic. The retrotransposon DNA gets methylated by the cell, turning off retrotransposon RNA expression. This prevents the RNA disrupting expression of neighbouring genes. One particular class

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this. The reprogramming machinery has evolved to skip these rogue elements and leave the DNA methylation marks on them. This keeps the retrotransposons in an epigenetically repressed state. This has probably evolved as a mechanism to reduce the risk that potentially dangerous IAP retrotransposons will get accidentally re-activated. This is

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of nutrition on subsequent generations, and the transgenerational effects of environmental pollutants such as vinclozolin. Researchers are exploring the hypothesis that these environmental stimuli create epigenetic changes in the chromatin of the gametes. These alterations are probably in regions that are protected from reprogramming during early development after the egg and

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can become temporarily more pluripotent, lose their imprinting marks and transfer across into the germ cell lineage. Once the primordial germ cells have been diverted, epigenetic modifications again get attached to the genome. This is partly because pluripotent cells are potentially extremely dangerous as a multi-cellular organism develops. It might

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on their retrotransposon, which is why transmission of the phenotype only occurs through the maternal line30. This is a slightly more indirect method of transmitting epigenetic information. Instead of direct carry-over of DNA methylation, an intermediate surrogate (a repressive histone modification) is used instead. This is probably why the maternal

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controlled manner, in response to developmental cues or environmental signals. Women really are more complicated than men One interesting consequence of X inactivation is that (epigenetically) females are more complicated than males. Males only have one X chromosome in their cells, so they don’t carry out X inactivation. But females

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be very comforting to think that science generally proceeds in a logical and ordered fashion. Here’s one way we could imagine such progress in epigenetics … Epigenetic modifications control cell fate – it’s these processes by which liver cells, for example, stay as liver cells and don’t turn into other cell

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remove acetyl groups from histone proteins. Superficially, these seem like very different processes. Maybe it’s just coincidence that both 5-azacytidine and SAHA inhibit epigenetic enzymes? Epigeneticists believe that it is far from being a coincidence. DNA methyltransferase enzymes add a methyl group to the cytidine base. High concentrations of

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, two patients whose cancers appear very similar may be ill because of very different molecular processes. Their cancers may have rather different combinations of mutations, epigenetic modifications and other factors driving the growth and aggressiveness of the tumour. This means that different patients are likely to require different types and combinations

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prognosis for the patient. So, histone modifications and DNA methylation pathways interact. This may explain, at least in part, one of the mysteries of existing epigenetic therapies. Why are compounds like 5-azacytidine and SAHA only controllers of cancer cells, rather than complete destroyers? In our model, treatment with 5-azacytidine

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tumour suppressors without needing to worry about DNA methylation. An uneasy truce Is there something special about the tumour suppressor genes that get silenced using epigenetic modifications? There are two contrasting theories about this. The first is that there’s nothing special about these genes and the process is completely random

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mature, and for tissue regeneration following injury. The fates and identities of these tissue-specific stem cells are controlled by the precise patterns of epigenetic modifications. By using epigenetic modifications to control gene expression, the cells keep some flexibility. They have the potential to change into more specialised cells, for example. Perhaps

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teenager during the Dutch Hunger Winter. Imprinted genes get switched off at certain stages in development, and stay off throughout the rest of life. Indeed, epigenetic modifications are the only known mechanism for maintaining cells in a particular state for exceptionally long periods of time. The hypothesis that epigeneticists are testing

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is that early childhood trauma causes an alteration in gene expression in the brain, which is generated or maintained (or both) by epigenetic mechanisms. These epigenetically mediated abnormalities in gene expression predispose adults to increased risk of mental illnesses. In recent years, scientists have begun to generate data suggesting that

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repressive marks to that region of the genome. When the phosphorylated MeCP2 falls off the arginine vasopressin gene, it can no longer recruit these different epigenetic proteins. Because of this, the chromatin loses it repressive marks. Activating modifications get put on instead, such as high levels of histone acetylation. Ultimately, even

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argue that just because the changes are present, it doesn’t mean they’re necessarily having a functional effect. They worry that the alterations in epigenetic modifications are simply correlative, not causative. The scientists who have been investigating the behavioural responses in the different rodent systems counter this by arguing that

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that neurons contain higher levels of this chemical than any other cell type21. Remember, remember Despite these controversies, research is continuing into the importance of epigenetic modifications in brain function. One area that is attracting a lot of attention is the field of memory. Memory is an incredibly complex phenomenon. Both

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which over-expressed Hdac2 formed far fewer connections than normal, whereas the opposite was true for the neurons lacking Hdac2. This supports our model of epigenetically-driven changes in gene expression ultimately altering complex networks in the brain. SAHA improves memory in the mice that over-express Hdac2, presumably by dampening

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. Addressing this question is hugely challenging, and particularly difficult to assess in human populations. Guilt by more than association Having said that, there are some epigenetic modifications that are definitely involved in disease initiation or progression. The case for these is strongest in cancer, as we saw in Chapter 11. The

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shorter than usual. In 2009, Professor Shelley Berger, an incredibly dynamic scientist at the University of Pennsylvania whose group has been very influential in molecular epigenetics, published the results of a really elegant set of genetic and molecular experiments in yeast. Her research showed that the Sir2 protein influences ageing by

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inherited neurodegenerative disorder5. The greatest excitement, for both cancer and non-oncology conditions, is currently centred around the development of drugs that inhibit more focused epigenetic enzymes. These include enzymes that change just one modification at one specific amino acid position on histone proteins. Hundreds of millions of dollars are being

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molecules which are identical to the original. DNMT DNA methyltransferase. An enzyme that can add methyl groups to cytosine bases in DNA. Epigenome All the epigenetic modifications on the DNA genome and its associated histone proteins. ES Cells Embryonic stem cells. Pluripotent cells experimentally derived from the Inner Cell Mass. Exon

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Histone deacetylase. An enzyme that can remove acetyl groups from histone proteins. Histones Globular proteins that are closely associated with DNA, and which can be epigenetically modified. Imprinting Phenomenon in which expression of certain genes depends on whether they were inherited from the mother or the father. Inner Cell Mass (ICM

Epigenetics: How Environment Shapes Our Genes

by Richard C. Francis  · 14 May 2012

, it affected them equally. The same goes for whatever stress she experienced during pregnancy. More typical siblings, however, can experience quite different fetal environments. The epigenetic alterations that result will make one or the other more susceptible to obesity, diabetes, heart disease, and atherosclerosis, as well as depression, anxiety, and schizophrenia

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the cell, not the genes themselves. That is, gene regulation is a cellular activity. This is true for both garden-variety gene regulation and epigenetic gene regulation. Epigenetics is one form of cellular control over gene activity on this view. Genes and Traits Genes influence our traits through the proteins constructed from

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. Some individuals or ethnic groups are predisposed toward obesity because of their biological inheritance. In this chapter we will explore a different sort of predisposition: epigenetic. These epigenetic predispositions generally develop in the womb or in infancy. Thrifty Genes? Obesity per se is not a public health problem; it’s the bad

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come from diets formulated specifically for those either susceptible to or experiencing these ailments—from childhood on. Both the prophylactic and therapeutic potential of nutritional epigenetics extends to many other ailments as well, such as cancer, which I will discuss later in the book. What Predisposed Paradorn? We have explored

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A. thalinia is mediated by a number of resistance (R) genes. There is one particular cluster, located on chromosome 4, that is subject to epigenetic regulation. An epigenetic variant called bal causes one gene in this cluster to be chronically active. The gene behaves like the plant is under attack even when

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highly speculative. Diagram by the author. The transition from pluripotent embryonic stem cells to multipotent somatic stem cells, such as neural stem cells, is an epigenetic process during which an increasing number of genes are permanently inactivated (while other genes are newly activated). Differentiation continues past the multipotent somatic stem cell

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state—through further progressive epigenetic inactivation—until terminal differentiation into one of the two hundred plus cell types, such as cone cells or heart muscle cells. Cone cells and heart

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transcription, messenger RNA (mRNA) is constructed from the DNA template. During the second stage, called translation, a protoprotein is constructed from the RNA template. Most epigenetic gene regulation occurs at the first stage, usually by inhibiting transcription. MicroRNAs, in contrast, exert their influence during the second stage, translation. Though transcription is

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of its neighbor cells with which it (chemically) interacts. These intercellular interactions influence the environment within the cell, which in turn influences which genes are epigenetically activated or inactivated. Hence, if you move cells around, especially during early stages of embryonic development, their fates change, just as in Driesch’s sea

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differentiation, undermines preformationism as genetic program, most fundamentally, by challenging the view that genes are software that instructs the cellular machinery, viewed as hardware. Modern epigenetics makes sense only if genes are viewed as hardware, like other cellular constituents—as much instructed as instructor, as much directed as director, as much

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the disruption of normal interactions between cells. The disruption of cellular interactions alters the internal environment of the cells, which results in hypomethylation and other epigenetic changes. A carcinogen, on this view, is carcinogenic by virtue of disrupting normal cellular interactions within a tissue. Cancer development can potentially be detected much

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with great fidelity in the offspring. Much more indirect are the transgenerational effects observed in the maternal behavior and stress response of rats. Here, the epigenetic alterations that influence these behaviors are recreated through the social interactions that they both influence and are influenced by. This transgenerational effect is a positive

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) discusses dedifferentiation in kidney repair. 20. Stocum (2002). Interestingly, biochemicals obtained from amphibians can boost regeneration in mammals, an indication that the mammalian genome can epigenetically respond in an ordered way to environmental influences to which it is never normally exposed. 21. Fibroblast cells were used in these experiments (see Takahashi

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al. (1992). “Motherless mothers revisited: Rhesus maternal behavior and rearing history.” Primates 33: 251–255. Chang, H. S., M. D. Anway, et al. (2006). “Transgenerational epigenetic imprinting of the male germline by endocrine disruptor exposure during gonadal sex determination.” Endocrinology 147(12): 5524–5541. Chen, C., J. Visootsak, et al. (2007

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(17[.beta]-estradiol): Support for the demasculinization/feminization hypothesis.” Environ Health Perspect 114(Suppl 1): 134–141. Henderson, I. R., and S. E. Jacobsen (2007). “Epigenetic inheritance in plants.” Nature 447(7143): 418–424. Hendriks-Jansen, H. (1996). Catching ourselves in the act: Situated activity, integrative emergence, evolution, and human thought

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genome by nuclear transplantation.” Genes Dev 18(15): 1875–1885. Holliday, R. (1996). “Endless quest.” BioEssays 18(1): 3–5. Holliday, R. (2006). “Epigenetics: A historical overview.” Epigenetics 1(2): 76–80. Horvitz, H. R., and J. E. Sulston (1980). “Isolation and genetic characterization of cell-lineage mutants of the nematode Caenorhabditis

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(2010). “Reprogramming with defined factors: From induced pluripotency to induced transdifferentiation.” Mol Hum Reprod 16(11): 856–868. Mastroeni, D., A. McKee, et al. (2009). “Epigenetic differences in cortical neurons from a pair of monozygotic twins discordant for Alzheimer’s disease.” PLoS One 4(8): e6617. Mattick, J. (2003). “Challenging the

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(2005). “Developmental origins of the metabolic syndrome: Prediction, plasticity, and programming.” Physiol Rev 85(2): 571–633. Meaney, M. J., M. Szyf, et al. (2007). “Epigenetic mechanisms of perinatal programming of hypothalamic-pituitary-adrenal function and health.” Trends Mol Med 13(7): 269–277. Meder, A. (1993). “The effect of familiarity

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N Y Acad Sci 1179: 167–178. Rheinberger, H.-J. (2008). “Gene.” Stanford encyclopedia of philosophy. Stanford, CA: Stanford University. Richards, E. J. (2006). “Inherited epigenetic variation—revisiting soft inheritance.” Nat Rev Genet 7(5): 395–401. Riggs, A. D. (2002). “X chromosome inactivation, differentiation, and DNA methylation revisited, with a

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257. Zeisel, S. H. (2009). “Importance of methyl donors during reproduction.” Am J Clin Nutr 89(2): 673S–677S. Zilberman, D., and S. Henikoff (2005). “Epigenetic inheritance in Arabidopsis: Selective silence.” Curr Opin Genet Dev 15(5): 557–562. Index abuse, childhood acetylation activation, of genes, see gene expression adenine adipose

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: Dutch famine and gene expression correlated with life expectancy and neonatal health and obesity and bisphenol A Bissell, Mary blastocysts blastula as pluripotent blood cells, epigenetic changes in blood stem cells brain androgen receptors in gene expression in glucocorticoid receptors in hippocampus in hypothalamus in stress biasing and breast cancer gene

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and aneuploid theory of cellular dedifferentiation and cellular stability of dedifferentiation theory of demethylation in in dogs embryonic stem cells and endocrine disruptors and epigenetic alterations in epigenetic inheritance and gene regulation and immune system and metastasis of microenvironmental view of mutation and normalization and somatic mutation theory (SMT) of spontaneous remission

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treatment of see also specific cancers cancers, embryonic canine transmissible venereal tumor (CTVT) canonical gene Canseco, José carbohydrates carcinogens cardiovascular disease: in Dutch famine cohort epigenetic inheritance and genomic imprinting and metabolic syndrome and stress biasing and Caroms (game) Castle, William Catholic Church cavies Cc (cat) cell division cells, cellular environment

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Famine Birth Cohort Study birth weight in cardiovascular disease in diabetes in obesity in psychiatric disorders in timing of exposure as factor in egg cells, epigenetic attachments removed in production of egg fertilization embryonic cancers embryonic skin cells embryonic stem cells cancer and cellular interactions and controversy surrounding as pluripotent endocrine

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disruptor mimicking of evolutionary biology executive function: as residing in cells as residing in genes as residing in genome exons extracellular matrix eye color famine: epigenetic inheritance and see also Dutch famine; Dutch Famine Birth Cohort Study fast-food chains fat cells (adipose tissue): gene expression in melanin production in Faulkner

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gene regulation gene regulation cancer and as cell type-specific executive function in, see executive function garden-variety (short-term) social interactions and gene regulation, epigenetic in development Driesch and as long-term methylation and, see methylation/demethylation microRNA and in plants as reversible stress biasing and war and Xist RNA

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-origin effect in paternal origin and transgenerational effects of imprinting control regions (ICRs) Indian Ocean tsunami (2004) induced pluripotent stem cells (iPSCs) inheritance: epigenetic processes in see also epigenetic inheritance; imprinting, genomic; social inheritance injury repair, cellular dedifferentiation in intracisternal A particle (IAP) introns Inuits Janus metaphor Juiced (Canseco) Just, Ernest Everett

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in, see agouti locus Axin gene in gene methylation in imprinting disruption in stress biasing in microenvironment, of cancer cells microRNA monozygotic twins: discordances in epigenetic alterations in Kallmann syndrome in stress responses in Morgan, Thomas Hunt mortality, male vs. female risk of mothering: affectionless control in in gorillas hormonal changes

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factor A) NGF gene normalization, of cancer cells nutrition, maternal, fetal development and obesity: agouti alleles and birth weight and childhood in Dutch famine cohort epigenetic explanations of as family trait fetal environment and gene mutation and genetic explanations of genomic imprinting and GR expression and Western lifestyle and obsessive-compulsive

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disorder, maternal style and Ohno, Susumu olfaction, epigenetic inheritance and olfaction, Kallmann syndrome and, ix–x olfactory placode oligopotent cells oncogenes see also cancer “one gene – one protein” rule opsin genes organicism organ

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parent-of-origin effect see also imprinting, genomic paternal care pathogen defense, growth vs. Petchburi Province, Thailand phenotypes thrifty pheromones pituitary placenta, imprinting in plants, epigenetic inheritance in pleiotropy pluripotent cells polychlorinated biphenyls (PCBs) population genetics postnatal environment, mismatch between fetal environment and posttranslational processing posttraumatic stress disorder (PTSD) Holocaust and

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species processed foods proopiomelanocortin (POMC) gene prostate cancer protein, dietary protein synthesis protoprotein psychiatric disorders, Dutch famine and Rainbow (cat) randomness: in biochemical processes in epigenetic inheritance Wright’s emphasis on in X inactivation rats, see mice and rats reciprocal causation (feedback) regeneration: in amphibians in mammals resistance (R) genes retrotransposon

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rhesus monkeys rheumatoid arthritis RNA: editing of in epigenetic inheritance messenger (mRNA) micro- pre–messenger RNA small interfering (siRNAs) Xist RNA interference rodents see also specific species Rosenberg, K. M. Roux, Wilhelm sainthood, criteria

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somatic mutation theory (SMT) of cancer somatic stem cells cancer and, see somatic mutation theory (SMT) of cancer spatial cognition sperm cells: in egg fertilization epigenetic attachments removed in production of sperm development spina bifida stamping, genetic stature, genomic imprinting and stem cells blood induced pluripotent neural see also embryonic stem

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cells; somatic stem cells stress, maternal stress axis hyperresponsiveness in, see stress biasing stress biasing epigenetic gene regulation and maternal style and in mice and rat studies in primates stress response to chronic stressors fight or flight hyperactivity of, see stress

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thymine tigons tissue-based theory of cancer Toguchi, Audrey Toronto zoo totipotent cells traits: genes as linked to sex-linked transcription transcription factors transdifferentiation transgenerational epigenetic processes translation translocation tumor suppressor genes Turner neurocognitive phenotype Turner syndrome unipotent cells viable yellow (Avy) agouti allele Vietnam Veterans Memorial Vietnam War vinclozolin Vindicated

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(Canseco) violence, steroid use and vision, color, see color vision vitalism vitamin B12 Waddington, Conrad war, epigenetic changes induced by Washington, George Watson, James Wayne, John weed killers Weismann, August Western lifestyle: obesity and stress in Wilhelmina Gasthuis Hospital Wilms’ tumor Wolf

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World War II: battle fatigue in Dutch famine in, see Dutch famine Wright, Sewall X chromosome opsins on see also sex-linked traits X inactivation epigenetic processes in histones in in marsupials methylation in randomness in X-inactivation center (Xic) X-inactive-specific transcript (Xist) XO females “X-women,” Y

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Courier Westford Book design by Lovedog Studio Production manager: Anna Oler Library of Congress has cataloged the hardcover edition as follows: Francis, Richard C., 1953– Epigenetics : the ultimate mystery of inheritance / Richard C. Francis. — 1st ed. p. cm. Includes bibliographical references and index. ISBN 978-0-393-07005-7 (hardcover) 1

Beyond Inheritance: Our Ever-Mutating Cells and a New Understanding of Health

by Roxanne Khamsi;  · 21 Apr 2026  · 335pp  · 91,958 words

caught on widely among the public. When many folks contemplate DNA alterations that happen in an individual over time, they often think about shifts in epigenetic marks. These are chemical tags that sit on top of our genetic material (epi means “over” or “upon” in Greek

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). Epigenetic marks help to switch genes on or keep them suppressed. And they aren’t static: They can disappear or appear over the course of a

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lifetime. Cigarette smoking, weight changes, and stress have all been linked to epigenetic changes. Those findings have garnered big headlines and captured the public imagination. But less attention has been paid to the fact that, beyond the changes

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to this noise might be alterations to the chemical groups that sit upon our DNA, known as epigenetic marks, which can be influenced by our environment and behavior. Interestingly, researchers have found patterns of epigenetic change associated with aging. (These changes have garnered so much interest as predictors of age that some

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scientists refer to them as “epigenetic clocks.”) Moreover, in one analysis of data from more than nine thousand people, the

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hot spots of mutation within the genome corresponded to the areas with epigenetic marks linked to aging. It’s unclear whether changes to the genome

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precipitate epigenetic changes or vice versa, or whether these are both downstream effects of an earlier event. Whatever the source

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DNA repair and gene editing there are even more ideas about how to reverse the genetic changes associated with aging. Scientists now talk about “cellular epigenetic rejuvenation.” This refers to a theoretical approach in which the chemical markers on the genome are restored to a pattern found in cells of more

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youthful individuals. Potential downsides to this theoretical treatment exist. Epigenetic marks help guide the function of cells, so an indiscriminate reformatting of such marks might cause cells to lose their cellular identity and become malignant

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/​j.exger.2017.02.073. GO TO NOTE REFERENCE IN TEXT hot spots of mutation: Zane Koch et al., “Somatic Mutation as an Explanation for Epigenetic Aging,” Nature Aging 5, no. 4 (2025): 709–19, doi.org/​10.1038/​s43587-024-00794-x. GO TO NOTE REFERENCE IN TEXT 3,200

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Stability and Interaction with Lamin A,” EMBO Journal 41, no. 21 (2022), doi.org/​10.15252/​embj.2021110393. GO TO NOTE REFERENCE IN TEXT “cellular epigenetic rejuvenation”: Jan Vijg et al., “Mitigating Age-Related Somatic Mutation Burden,” Trends in Molecular Medicine 29, no. 7 (2023): 530–40, doi.org/​10.1016

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fruit flies, 38–40 Roux and Der Kampf, 32–38, 42, 46–49, 60, 227–28 CellRaft AIR System, 223–24 “cellular democracy,” 31 “cellular epigenetic rejuvenation,” 217 centenarians, xix, 210, 216 Centre for Genomic Regulation, 168–69 CFTR gene, 113 CH103 antibody, 71–73 chemotherapy, 4, 10, 19, 21, 22

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–42 Roux’s research, 36–38, 42–43, 46, 48 Zlotnikov’s research, 107–8 endometriosis, 119–20 epidermolysis bullosa, 138, 151–52 epigenetics, xvii–xviii epigenetic clocks, 202 epigenetic marks, xvii, 202, 217 epilepsy, 109, 111, 112, 221 error catastrophe theory of aging, 201–2 Escherichia (E. coli), 59 esophageal cancer, 4

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–48, 117, 208 multifactorial phenomenon, 197 multiple-hit theory, 20 muscle cells, 33, 42–43, 134, 204 muscle pain, 15 mutation. See also specific topics epigenetics, xvii–xviii origin of term, xii overview of, ix–xix mutational “signatures,” 224–25 mutation-driven microglial clonal expansion (MiCE), 207 Mycobacterium tuberculosis, 179 N

We Are as Gods: A Survival Guide for the Age of Abundance

by Peter H. Diamandis and Steven Kotler  · 13 Apr 2026  · 225pp  · 76,418 words

ecosystems. Healing Miracles Gene therapy and CRISPR cure disease at a genetic level. Stem cell therapy and tissue engineering repair what disease and injury destroy. Epigenetic reprogramming can reverse ocular degeneration in animals, and soon will be able to do the same in humans. Telemedicine enables the remote diagnosis and treatment

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. Every bit of data we encounter stirs neurons, excites nerve tissue, and fires electrochemical signals. Action potentials race along axons. Neurotransmitters flood synapses. Genes mutate. Epigenetic cascades unfold. And all this neural noise produces feelings. Emotion is the body’s readout of information. There’s nothing abstract about it. Information changes

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piling up: CRISPR lets us edit the genome; Yamanaka factors, a set of four transcription genes, roll back the biological age of cells; cellular reprogramming, epigenetic editing, mitochondrial enhancement. Each of these technologies adds more possibility, and all of them are being accelerated by AI. “What we do now [using AI

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years,” Sinclair explained on Peter’s Moonshots podcast. AI lets Sinclair simulate trillions of molecules, screening for the rare combinations that reverse aging at the epigenetic level. His team has identified four key enzyme pathways. If you inhibit three and activate one, you can reset a cell’s biological clock. It

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’s called epigenetic reprogramming, a technique that suggests we can reverse aging altogether. Just five years ago, age reversal was a crazy idea. “In 2017, it was just

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of the world’s tech-forward billionaires are funding start-ups in the area. OpenAI’s Sam Altman is backing Joe Betts-Lacroix in an epigenetic reprogramming company called Retro Biosciences; while Brian Armstrong, cofounder and CEO of Coinbase, has teamed with investor Blake Byers to build another reprogramming company called

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: “I think someday we can cure all disease with the help of AI. I think that’s within reach within the next decade.” Genetic engineering, epigenetic reprogramming, longevity pharmacology, bioinformatics, AI everything—and again, the same question: Where does it lead? We’re nearing what Ray Kurzweil called longevity escape velocity

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Abundance: Demonstrate the ability to regrow a backup heart, liver, lung, or kidney using your own genetic material. Double Human Healthspan: Use AI-driven biotech—epigenetic reprogramming, senolytics, cellular regeneration—to extend the human healthspan to one hundred fifty–plus years with the aesthetics and functionality of a thirty-year-old

Ageless: The New Science of Getting Older Without Getting Old

by Andrew Steele  · 24 Dec 2020  · 399pp  · 118,576 words

of sugary and other modifications lead to problems with proteins that are responsible for many of the issues we experience as we age. 4. Epigenetic alterations Epigenetics is the collective term for a biochemical zoo of molecular decorations sprinkled on the DNA inside cells. It is a chemical code of its own

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which sits above (hence ‘epi’) our genetics. Epigenetics unravels a seeming paradox in our biology: the cells of our body are almost ridiculously diverse, and yet almost all of them contain exactly the

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is an instruction manual to build you, it’s a particularly well-thumbed one, covered in bookmarks, placeholders and notes scrawled in the margin. These epigenetic annotations tell the cell what to do with the DNA they’re attached to – whether, for example, to read a particular gene to be used

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at that time, or whether to ignore a whole section because it’s never going to be needed. There are dozens of different types of epigenetic marks, but we’ll concentrate on one of the best-studied in the context of ageing: DNA methylation, meaning ‘methyl groups’ made of a

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methylation at tens or hundreds of thousands of locations across the genome that methylation could be understood in more detail. It turned out that our epigenetics knows how old we are even better than we do. Steve Horvath, a mathematician-turned-biologist at the University of California, Los Angeles, was

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fascinated to know if patterns of DNA methylation could be used to glean any insight into ageing. Unfortunately, very few people were specifically interested in epigenetics and ageing at the time, but Horvath had an ace up his sleeve: the long-standing culture in genomics of making data freely accessible. Thanks

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to methylation chips being cheap and readily available, there were thousands of epigenetic datasets available from studies looking at other things entirely. Horvath combed through these, grabbing those which fulfilled one simple criterion: that the experimenters had made

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which, together, were sufficient to predict someone’s age. With this comparative handful of locations, the predictions were unnervingly accurate. The correlation between the predicted ‘epigenetic age’ and the actual age was 0.96 – where 0 would mean that they were totally unrelated, and 1 is perfect. This is off-the

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-charts performance: using telomere length to predict age, for example, scores less than 0.5. If you were to have your epigenetic age measured by Horvath’s methylation clock, it would probably differ from your chronological age by less than four years. This level of performance was

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possible to be biologically younger than your calendar age, too, and thereby healthier and at less risk of death. The morbid precision of epigenetic clocks either suggests that epigenetic changes are a cause of ageing, or at least that they are a window through which to understand how our bodies get biologically

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spectrum of species from those still living at home. In spite of this complexity, we have managed to build ‘microbial clocks’ which, rather like the epigenetic clock we met recently, can determine someone’s age to within four years or so based on the relative proportions of different bugs in their

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less effective at replenishing our blood cells. This is down to a number of the hallmarks we’ve already discussed, including DNA damage and mutations, epigenetic changes, problems with autophagy and changes to signalling from cells in their environment. The irony is that all of these changes actually increase the number

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‘senomorphics’. Secondly, we could try to coax senescent cells back into the fold and turn them into normal cells again. This could be achieved by epigenetic reprogramming, which we’ll discuss in a lot more detail in Chapter 8. Eventually, the ideal outcome would be a visit to a gleaming clinic

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thymus, as you’d hope – but they also saw improvements in kidney function and, most excitingly, a reduction in their epigenetic age, as measured by the morbidly accurate epigenetic clocks we met a couple of chapters ago. This suggests that rejuvenating the thymus can go on to rejuvenate the body more

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examine the radical effect of just four genes which have the power to reverse ageing in cells … and maybe whole bodies, too. Turning back the epigenetic clock Throughout this book we’ve learned that the process of ageing is surprisingly malleable. Whether it’s dietary restriction, genetic changes or sewing a

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and thus this idea is known as rejuvenation by reprogramming. The first line of evidence for this rejuvenation is the epigenetic clock, the freakishly accurate predictor of biological age based on epigenetic marks on your DNA we met in Chapter 4. Steve Horvath actually found this in the 2013 paper where he

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established that it worked over many different types of tissue, he made one final test of its predictive power: he used it to calculate the epigenetic age of both embryonic stem cells – ‘naturally’ young cells isolated from a human embryo just a few days after sperm met egg – and iPSCs,

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since have doubled down on this finding: fully functional iPSCs have been successfully derived from people as old as 114, and the cells have an epigenetic age of zero whether the donor was a young adult or a centenarian. Even better, differentiating these iPSCs into specific cell types leaves their

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epigenetic youthfulness intact. This means that you can take a 90-year-old’s skin cells, make iPSCs and differentiate them back into skin cells again

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or whatever we produced from them would be young again, ready for another few decades of use and abuse. Even better, it appears that the epigenetic reset doesn’t occur in isolation but is accompanied by other rejuvenative effects. The iPSCs also have better-looking mitochondria, and lower levels of mitochondrial

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deep-cleaning process analogous to that which undoes the ravages of time in the germline. There are some caveats: for example, there’s a faint epigenetic shadow which allows iPSCs made from young and old donors to be distinguished, though it seems to fade if you let the iPSCs divide a

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an across-the-board turning back of their biological clocks but, crucially, without losing their cellular identities. The process knocked a few years off their epigenetic clocks, pepped up their mitochondria, increased levels of autophagy … the only thing that wasn’t changed was telomere length, which is probably actually a

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what order. Experiments on cells in a dish show that it’s a multi-step process: the first stage seems to be scrubbing off the epigenetic signs of old age, and it’s only after that has been largely completed that the cell begins its dedifferentiation journey proper, from adult cell

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to stem cell. It needn’t be this way – the process of epigenetic clock reversal could easily be simultaneous with that of dedifferentiation, or it might be that a cell has to get all the way to being

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of trying to emulate reprogramming. The fact that the first part of reprogramming seems to be the reversal of age-related epigenetic changes adds weight to the idea that epigenetics is a causal mechanism behind the ageing process, rather than simply a clock face giving us a readout of our age

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we’d be better off steering clear of the black magic of the Yamanaka factors and focusing on reprogramming our epigenetics directly. There are now modified versions of CRISPR that can alter epigenetic marks at multiple locations in our DNA simultaneously – and scientists are working on technologies to edit hundreds, or

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replicate what OKSM does by brute force. However, the black magic approach retains a certain appeal – if we can let nature’s own tools restore epigenetic order in our cells, we might be able to avoid the troublesome process of working out what exactly needs changing in order to do it

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ourselves. Exactly how we’ll disentangle the different kinds of epigenetic and other changes which occur during the wide-ranging process of induced pluripotency and transdifferentiation is yet to be seen. There are undoubtedly years of

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genes. The fact that it works is inspiration to go out in search of genes or drugs specifically for their powers to turn back the epigenetic clock, revitalise mitochondria, extend telomeres and so on, which the Yamanaka factors have shown us how to do as a side effect. Therapies based

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and could eventually result in stem cell exhaustion. We might be able to compensate by adding more stem cells, or using telomerase, altered signals or epigenetic reprogramming to encourage existing ones to divide a few more times, which might put our mitochondria out of kilter, or do something weird to our

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better at determining how long you might live, how long until you get cancer or heart disease, and so on. A new version of the epigenetic clock was developed in 2018 which is a much more accurate predictor of death than the original. It also predicts cancer, Alzheimer’s and, more

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abstractly, how many diseases someone is likely to simultaneously suffer from in future. Unlike the original epigenetic clock, it also detects if a patient has smoked, or does so currently – a further smoking gun, if you will, suggesting that tobacco accelerates ageing

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we mentioned in Chapter 6 that used a hormonal treatment to rejuvenate the thymus was accompanied by a reduction in subjects’ epigenetic age. In mice, the ticking of their rodent epigenetic clocks is slowed by dietary restriction, treatment with rapamycin, and in mice with genes which increase lifespan. A 22-month-

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old mouse on DR, for example, has a biological age of just 13 months, an epigenetic manifestation of the slowing of ageing expected from DR. A similar result in rhesus monkeys showed that those on DR had an

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to work out which biomarkers perform best under what circumstances, but results like these are a promising start. If a biomarker as accurate as current epigenetic clocks was meaningfully turned back by anti-ageing treatments, a study equivalent in accuracy to the TAME trial – which needs 3,000 patients, five

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findings which could impact on both cancer and the wider ageing process. Similar quantitative investigation is needed for all the hallmarks of ageing – changes in epigenetics, levels and modifications of proteins, numbers of cells, mitochondria, levels of signals, and so on. In the short term, this will inform our first

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1038/nrm3810 ageless.link/qbo7fa The Maillard reaction is behind the crust … Andy Extance, ‘The marvellous Maillard reaction’, Chemistry World (2018) ageless.link/pygx4v 4. Epigenetic alterations … hundreds of different types of cells … ‘Cell types’ are hotly contested in biology, and assigning a precise number doesn’t really make sense. Cells

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7, e42677 (2012). DOI: 10.1371/journal.pone.0042677 ageless.link/rdzawt … a small human trial … Intervene Immune Gregory M. Fahy et al., ‘Reversal of epigenetic aging and immunosenescent trends in humans’, Aging Cell 18, e13028 (2019). DOI: 10.1111/acel.13028 ageless.link/ebi7qv … FOXN1 … driving thymic regeneration … ‘Engage reverse

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DNA without double-stranded DNA cleavage’, Nature 533, 420–24 (2016). DOI: 10.1038/nature17946 ageless.link/xmk79n Turning back the epigenetic clock This article explores the topic of epigenetic reprogramming by profiling one of the scientists at the cutting edge of the technique: Usha Lee McFarling, ‘The creator of the pig

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’, Biochem. Biophys. Res. Commun. (in press, 2020). DOI: 10.1016/j.bbrc.2020.02.092 ageless.link/rpwt3z … epigenetic age of zero … or a centenarian Francesco Ravaioli et al., ‘Age-related epigenetic derangement upon reprogramming and differentiation of cells from the elderly’, Genes 9, 39 (2018). DOI: 10.3390/genes9010039 ageless

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.link/3i4jtt … the epigenetic reset … rejuvenative effects Burcu Yener Ilce, Umut Cagin and Acelya Yilmazer, ‘Cellular reprogramming: a new way to understand aging mechanisms’, Wiley Interdiscip. Rev. Dev. Biol

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ageless.link/96ac3p … reprogramming … eye injuries in middle-aged mice Yuancheng Lu et al., ‘Reversal of ageing- and injury-induced vision loss by Tet-dependent epigenetic reprogramming’, bioRxiv (2019). DOI: 10.1101/710210 ageless.link/7zv3rh … [inducing pluripotency is] a multi-step process … Nelly Olova et al., ‘Partial reprogramming induces

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a steady decline in epigenetic age before loss of somatic identity’, Aging Cell 18, e12877 (2019). DOI: 10.1111/acel.12877 ageless.link/yo3wwk … a different cocktail of genes turns

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TAME in the last part of this talk: Barzilai, 2017 ageless.link/awkcqw … quickly tot up a patient’s epigenetic age … Steve Horvath and Kenneth Raj, ‘DNA methylation-based biomarkers and the epigenetic clock theory of ageing’, Nat. Rev. Genet. 19. 371–84 (2018). DOI: 10.1038/s41576-018-0004-3

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and longevity’, Trends Pharmacol. Sci. 40, 546–9 (2019). DOI: 10.1016/j.tips.2019.05.004 ageless.link/uvip6c … epigenetic clocks … slowed by dietary restriction … Tina Wang et al., ‘Epigenetic aging signatures in mice livers are slowed by dwarfism, calorie restriction and rapamycin treatment’, Genome Biol. 18, 57 (2017). DOI:

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soma theory, here, here, here, here, here, here DNA, here, here, here, here, here, here, here, here and babies, here and cloning, here, here and epigenetics, here ‘junk DNA’, here and longevity, here methylation, here mitochondrial, here, here, here, here artificial, here see also telomeres DNA damage and mutations, here, here

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, here dopamine, here dyskeratosis congenita (DC), here E. coli, here, here Easter Island see Rapa Nui elastin, here, here, here elephants, here, here Epicurus, here epigenetics, here, here, here, here, here, here and reprogramming, here erectile dysfunction, here eugenics, here eunuchs, here, here European Medicines Agency, here evolution, here, here,

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here, here, here, here Socrates, here Solomon, Beka, here spermidine, here, here Stargardt disease, here stem cells, here, here, here, here, here, here, here and epigenetic age, here in practical roles, here therapies, here, here, here and thymus rejuvenation, here see also haematopoietic stem cells (HSCs) sterilisation, here Strategies for Engineered

Lifespan: Why We Age—and Why We Don't Have To

by David A. Sinclair and Matthew D. Laplante  · 9 Sep 2019

Today, analog information is more commonly referred to as the epigenome, meaning traits that are heritable that aren’t transmitted by genetic means. The term epigenetics was first coined in 1942 by Conrad H. Waddington, a British developmental biologist, while working at Cambridge University. In the past decade, the meaning of

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the word epigenetics has expanded into other areas of biology that have less to do with heredity—including embryonic development, gene switch networks, and chemical modifications of DNA

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much to the chagrin of orthodox geneticists in my department at Harvard Medical School. In the same way that genetic information is stored as DNA, epigenetic information is stored in a structure called chromatin. DNA in the cell isn’t flailing around disorganized, it is wrapped around tiny balls of protein

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tags from histones and other proteins and, by doing so, change the packaging of the DNA, turning genes off and on when needed. These critical epigenetic regulators sit at the very top of cellular control systems, controlling our reproduction and our DNA repair. After a few billion years of advancement since

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to handle. Even if the cell is able to repair the breaks in the short term without leaving mutations, there is information loss at the epigenetic level. Here’s the important point: there are plenty of stressors that will activate longevity genes without damaging the cell, including certain types of exercise

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epigenome, causing the cells to lose their identity and become sterile while they fixed the damage. Those were the analog scratches on the digital DVDs. Epigenetic changes cause aging. There was, I imagined, a singular process that controlled them all. Not a countless number of separate cellular changes or diseases.

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environmental influences on the epigenome, such as folic acid, vitamin B12, genistein from soy, or the toxin bisphenol A.15 Similarly, among monozygotic human twins, epigenetic forces can drive two people with the same genome in vastly different directions. It can even cause them to age differently. You can see this

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SIR2 gene, we gave the yeast cells what evolution failed to provide. If the information theory is correct—that aging is caused by overworked epigenetic signalers responding to cellular insult and damage—it doesn’t so much matter where the damage occurs. What matters is that it is being damaged

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of damage, such as broken strands of DNA, cannot be avoided. They overwork the survival circuit and change cellular identity. We’re all subject to epigenetic noise that should, under the Information Theory of Aging, cause aging. Yet different organisms age at very different rates. And sometimes, it appears, they

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could possibly produce different programs. There had to be something more than genetics at play: a program that controlled the code. Waddington conceived of an “epigenetic landscape,” a three-dimensional relief map that represents the dynamic world in which our genes exist. More than half a century later, Waddington’s landscape

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the ICE mice, when you disrupt the epigenome by forcing it to deal with DNA breaks, you introduce noise, leading to an erosion of the epigenetic landscape. The mice’s bodies turned into chimeras of misguided, malfunctioning cells. THE CHANGING LANDSCAPE OF OUR LIVES. The Waddington landscape is a metaphor for

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do what they have been doing since primordial times: boost cellular defenses, keep organisms alive during times of adversity, ward off disease and deterioration, minimize epigenetic change, and slow down aging. But this has, for obvious reasons, proven a challenge to test on humans in a controlled scientific setting. Sadly,

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to aging, “normal” is bad enough. When our sirtuins have to respond to many disasters—especially those that cause double-strand DNA breaks—these epigenetic signalers are forced to leave their posts and head to other places on the genome where DNA breaks have occurred. Sometimes they make their way

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ve known for a long time that greater parental age is a risk factor for disease in the next generation. That’s the power of epigenetics. But mice treated with rapamycin buck this trend. When researchers from the German Center for Neurodegenerative Diseases inhibited mTOR in mice born to older

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it prevents spikes of freely floating sugar from essentially caramelizing proteins in the body. Recent results indicate high blood sugar can also speed up the epigenetic clock. Thanks to an increasingly sedentary lifestyle and the abundance of sugars and carbohydrates on every supermarket shelf around the globe, high blood sugar is

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and turns on sirtuins and other defenses against aging as a whole—engaging the survival circuit upstream of these conditions, ostensibly slowing the loss of epigenetic information and keeping metabolism in check, so all organs stay younger and healthier. Most of us assume that the effects of a pill like metformin

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now working to create and analyze natural and synthetic molecules that have the potential to be even better at suppressing epigenomic noise and resetting our epigenetic landscape. There are hundreds of compounds that have already shown potential in this area and hundreds of thousands more that are waiting to be researched

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youthful information. DNA stores information digitally, a robust format, whereas the epigenome stores it in analog format, and is therefore prone to the introduction of epigenetic “noise.” An apt metaphor is a DVD player from the 1990s. The information is digital; the reader that moves around is analog. Aging is similar

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• The “transmitter” is the epigenome, transmitting analog information through space and time. • The “receiver” is your body in the future. When an egg is fertilized, epigenetic information—biological “radio signals”—is sent out. It travels between dividing cells and across time. If all goes well, the egg develops into a healthy

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include the blood-thinning drugs Coumadin and Plavix, the chemotherapy drugs Erbitux and Vecitibix, and the depression drug Celexa. In the future, a patient’s epigenetic age will also be determined and used to predict drug responses, a new field called pharmacoepigenetics. It’s a rapidly advancing technology but some pharmacogenetic

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hundred twenty is our known potential and one that many people could reach—again, in good health if technologies in development come to fruition. If epigenetic reprogramming reaches its potential or someone comes up with another way to convince cells to be young again, 150 might even be possible for someone

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guru, having established Florida State University’s Center for Genomics. I’ll never forget the day he showed me the whole-genome analysis of the epigenetic changes in the ICE mice that helped reinforce the Information Theory of Aging. Down the hall, past framed copies of research papers we’ve

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that allow us to regenerate optic nerves. Perhaps these creatures have access to the biological equivalent of Shannon’s observer, the one who stores youthful epigenetic information. Abhirup Das, who spearheaded the old mouse marathon project, was studying the impact of precursors such as hydrogen sulfide and NMN on wound healing

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proliferate continuously. STEVE HORVATH (October 25, 1967–): Austrian-born American professor at the University of California at Los Angeles known for his pioneering work on epigenetics and aging and for codeveloping algorithms that predict the age of organisms based on DNA methylation patterns, known as the Horvath aging clock. SHIN-ICHIRO

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of a human cell. CONRAD H. WADDINGTON (November 8, 1905–September 26, 1975): British geneticist and philosopher who laid the foundations of systems biology and epigenetics. His Waddington Landscape was proposed to help understand how a cell can divide to become the hundreds of different cell types in the body. ROY

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that would normally take much longer or otherwise never happen. Sirtuins, for example, are enzymes that use NAD to remove acetyl chemical groups from histones. EPIGENETIC: Refers to changes to a cell’s gene expression that do not involve altering its DNA code. Instead the DNA and the histones that the

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DNA is wrapped around are “tagged” with removable chemical signals (see Demethylation and deacetylation). Epigenetic marks tell other proteins where and when to read the DNA, comparable to sticking a note that says “Skip” onto a page of a book

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. A reader will ignore the page, but the book itself has not been changed. EPIGENETIC DRIFT AND EPIGENETIC NOISE: Alterations to the epigenome that take place with age due to changes in methylation, often related to an individual’s exposure to environmental

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with diluted herbicide and afterward grew faster. INFORMATION THEORY OF AGING: The idea that aging is due to the loss of information over time, primarily epigenetic information, much of which can be recovered. METFORMIN: A molecule derived from the French hellebore used to treat type 2 (age-associated) diabetes that

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of T cells and B cells by reducing their sensitivity to the signaling molecule interleukin-2. Extends lifespan by inhibiting mTOR. REDIFFERENTIATION: The reversal of epigenetic changes that occur during aging. RIBOSOMAL DNA (rDNA): A key component of the manufacture of new proteins within cells; the source of the genetic code

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27, no. 9 (September 27, 2017): 685–96, https://www.ncbi.nlm.nih.gov/pubmed/28528987. 15. D. C. Dolinoy, “The Agouti Mouse Model: An Epigenetic Biosensor for Nutritional and Environmental Alterations on the Fetal Epigenome,” Nutrition Reviews 66, suppl. 1 (August 2008): S7–11, https://www.ncbi.nlm.nih.gov

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in protecting against the instability of rDNA, also guards against the death of human cells. S. Paredes, M. Angulo-Ibanez, L. Tasselli, et al., “The Epigenetic Regulator SIRT7 Guards Against Mammalian Cellular Senescence Induced by Ribosomal DNA Instability,” Journal of Biological Chemistry 293 (July 13, 2018): 11242–50, http://www.jbc

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Newcastle 85+ Cohort Study,” British Medical Journal, December 23, 2009, https://www.bmj.com/content/339/bmj.b4904. 19. The possibility that both genetic and epigenetic aging are needed for a tumor to develop we’ve termed “geroncogenesis,” and it explains why tumors don’t occur in young people even after

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Mice,” Nature 460 (July 8, 2009): 392–95, https://www.nature.com/articles/nature08221. 10. K. Xie, D. P. Ryan, B. L. Pearson, et al., “Epigenetic Alterations in Longevity Regulators, Reduced Life Span, and Exacerbated Aging-Related Pathology in Old Father Offspring Mice,” Proceedings of the National Academy of Sciences of

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, M. Ustinova, et al., “Significantly Altered Peripheral Blood Cell DNA Methylation Profile as a Result of Immediate Effect of Metformin Use in Healthy Individuals,” Clinical Epigenetics 10, no. 1 (2018), https://doi.org/10.1186/s13148-018-0593-x. 27. B. K. Kennedy, M. Gotta, D. A. Sinclair, et al., “

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nlm.nih.gov/pmc/articles/PMC2853975/. 7. M. De Cecco, S. W. Criscione, E. J. Peckham, et al., “Genomes of Replicatively Senescent Cells Undergo Global Epigenetic Changes Leading to Gene Silencing and Activation of Transposable Elements,” Aging Cell 12, no. 2 (April 2013): 247–56, https://www.ncbi.nlm.nih.gov

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144–45, 148–49, 264, 296 amputations, 75, 124 analog information, 20–21, 22–23, 35, 60, 62, 127, 160, 161, 162 See also epigenome/epigenetics Anderson, Rozalyn, 95 “antagonistic pleiotropy” (Medawar), 11, 152 antioxidants, 14–15, 130 antiretrovirals, 155 apes: senescence in, 152–53 apples, 285 arginine, 101 Aristotle, 10

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consumption and, 287 cutting of, 48, 49, 51, 287 and diagnosing disease, 201 and diet, 91 as digital information, 20 and economic divisions, 232 and epigenetic landscape, 58 and epigenome, 36 and evolution of aging, 4, 7 and funding for aging research, 271 helicases, 33 “junk,” 27–28, 154, 295 and

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model of life and death, 41 Waddington research on, 21 and why we age, 17, 26 and yeast studies, 34, 35 See also analog information; epigenetic landscape; epigenetic noise; Waddington, Conrad H. Erbitux, 183 ERCs (extrachromosomal ribosomal DNA circles), 40–41, 42, 43, 44, 47, 91 “Error Catastrophe Hypothesis” (Orgel), 14

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, 199–201, 258 tour of Sinclair, 294–98 See also specific laboratory or researcher Lamming, Dudley, 100 landscape Waddington, 58–59, 61, 138 See also epigenetic landscape larotrectinib, 184 Lassa fever, 204 Law of Human Mortality, 69–70, 76, 246 Lawan Kuhn, 176, 177, 178, 180, 182 Lecomte du Nouy,

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23 and yeast studies, 33, 34 N-nitroso compounds, 114 NAD (nicotinamide adenine dinucleotide) and attempts to explain life, 118, 119 discovery of, 134 and epigenetic landscape, 137 exercise and, 103 and expansion of lifespan, 145, 264 fertility and, 138–39 functions of, 24, 129, 134, 137, 140 Imai research about

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11, 12, 152, 243 Navratilova, Martina, 73 nerves/nervous system, 137, 150, 167, 168, 171, 200, 296–97 neurons degeneration of, 132, 136, 190 and epigenetics, 22 ongoing research about, 297 Newton, Isaac, 239 niacin, 134, 305 nicotinamide, 305 nicotinamide mononucleotide. See NMN Nicoya, Costa Rica: as centenarian-heavy place, 88

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, 164 and temperature, 108 See also mice Ravussin, Eric, 93 rDNA. See ribosomal DNA Rebelo, Bernard, 110 Reich, David, 294 religion, 294–95 reproduction and epigenetic landscape, 59 and evolution of aging, 5, 6, 7, 8 sirtuins and, 24, 45, 46 survival circuit and, 24, 45, 46, 47 and why

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11–12 and yeast studies, 30, 34 See also fertility; infertility; sterility reprogramming and chromosomes, 159 and DNA, 159, 162, 169, 170, 171, 174 and epigenetics, 158, 161, 162, 164, 166, 169, 170 ethics of, 173–75 and expansion of lifespan, 264 and genome, 172 histones and, 171 immune system and

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See also income; poverty; wealth Stanford University: cancer research at, 155–56 statins, 78 stem cells access to, 231 and cause of aging, 51 and epigenetic landscape, 58–59 fertility and, 140 and ICE mice research, 51 ongoing research about, 298 and printing living tissue, 207 reprogramming and, 163–64 and

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Sterne, Jean, 124 Streisand, Barbra, 161 Streptococcus pneumoniae, 202 Streptomyces hygroscopicus, 120–21, 145 stress and biosensors/trackers, 188, 190 diet and, 113–14 and epigenetic landscape, 137 and evolution of aging, 26 examples of, 26 exercise and, 103, 104 and longevity genes, 111, 112 NAD and, 137 pharmaceuticals for, 26

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Sundrop Farms (Australia), 289 supplements, 286, 303, 304–5, 307 See also specific supplement survival and “carrying capacity” of planet, 242–43 and consumption, 288 epigenetics importance to, 21–22 and evolution of humans, 220 and longevity pathways, 129 pharmaceuticals and, 146 sirtuins and, 24 See also survival circuit survival circuit

Brain Energy: A Revolutionary Breakthrough in Understanding Mental Health--And Improving Treatment for Anxiety, Depression, OCD, PTSD, and More

by Christopher M. Palmer Md  · 15 Nov 2022  · 402pp  · 107,908 words

8A Brain Energy Imbalance PART III: CAUSES AND SOLUTIONS CHAPTER 9What’s Causing the Problem and What Can We Do? CHAPTER 10Contributing Cause: Genetics and Epigenetics CHAPTER 11Contributing Cause: Chemical Imbalances, Neurotransmitters, and Medications CHAPTER 12Contributing Cause: Hormones and Metabolic Regulators CHAPTER 13Contributing Cause: Inflammation CHAPTER 14Contributing Cause: Sleep, Light, and

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list includes biological, psychological, and social factors, ranging from things like diet and exercise, smoking, drug and alcohol use, and sleep . . . to hormones, inflammation, genetics, epigenetics, and the gut microbiome. The list also extends to relationships, love, having meaning and purpose in life, and stress levels. You can isolate any one

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not always about the genes themselves, but more about what causes certain genes to turn on or off. This is the field of epigenetics. Mitochondria are primary regulators of epigenetics. They send signals to the nuclear DNA in several different ways. This is sometimes referred to as the retrograde response. It has

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to directly control the expression of genes in the nucleus. In 2002, it was discovered that mitochondria are required for the transport of an important epigenetic factor, nuclear protein histone H1.26 This protein helps regulate gene expression and is transported from the cytoplasm to the nucleus, a process that requires

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. Without mitochondria, this transfer doesn’t happen. In 2013, it was discovered that mitochondrial ROS directly inactivate an enzyme called histone demethylase Rph1p, which regulates epigenetic gene expression in the cell nucleus.27 This process was found to play a role in extending lifespan in yeast and is thought to possibly

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Picard and colleagues experimentally manipulated the number of mitochondria with mutations in cells and found that as they increased the number of dysfunctional mitochondria, more epigenetic problems and changes occurred.30 The impact was on almost all of the genes expressed in the cells. Ultimately, in situations in which almost all

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much more than that. Metabolism affects the structure and function of all cells in the human body. Regulators of metabolism include many things, such as epigenetics, hormones, neurotransmitters, and inflammation. Mitochondria are the master regulators of metabolism, and they play a role in controlling the factors just listed. When mitochondria aren

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mental health using metabolic interventions. Their names have been changed to protect their privacy, but their stories are true. Chapter 10 CONTRIBUTING CAUSE Genetics and Epigenetics Mental disorders run in families. This has been known for centuries and established now as fact based on tremendous amounts of research. This observation has

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problem does not lie in the genes themselves. If genes don’t fully explain why mental disorders run in families, then what could it be? Epigenetics Epigenetics, which we covered briefly in Part Two, is the field dedicated to understanding what causes genes to turn on or off. Most of us have

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. However, what is clearly different is the expression of all these genes. Skin cells, brain cells, and liver cells all have the same DNA. However, epigenetics is responsible for making the different cells in the human body different from each other. These different cells express different genes. Throughout the day, genes

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all have similar underlying genes. There are specific patterns of gene expression that have been associated with different traits, both physical and mental. These longstanding epigenetic changes are a way for the body to come up with a metabolic strategy and then stick with it

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. Epigenetics provides a memory of what the body has been through. There are many ways that the body controls gene expression. One way is to modify

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. They, too, influence which genes get turned on or off. In addition to methylation and histones, there are many other factors that are involved in epigenetics. More and more are being discovered every year. They include factors like micro-RNAs, hormones, neuropeptides, and others. This field quickly becomes confusing and overwhelming

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, as there are so many factors that are involved in the epigenetic control of our DNA. However, if you take a step back and look at the field from a broader perspective, things become less confusing. What

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triggers all these different factors to change gene expression? Almost all of them revolve around metabolism and mitochondria. Factors thought to influence epigenetics include diet, exercise, drug and alcohol use, hormones, light exposure, and sleep—all related to metabolism and mitochondria (as you will soon learn). As a

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nonsmokers.11 However, if they stop smoking, this change in methylation is reversible. In the end, it’s important to think about epigenetics as metabolic blueprints for cells. Epigenetics simply reflect the gene patterns that allow cells to do their best to survive and cope with their environments. However, if they get

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stuck in a maladaptive pattern or if the appropriate signals aren’t being sent, that can become problematic. Recall that mitochondria are regulators of epigenetics. They influence gene expression through levels of ROS, levels of glucose and amino acids, and levels of ATP. Also recall that mitochondria appear to control

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that found that as the number of defective mitochondria in a cell increases, the number of gene expression abnormalities also increases. It turns out that epigenetic factors are heritable. This occurs in different ways. I’ll discuss a few of them. Womb Environment As a fetus is growing inside the womb

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role. However, the mother’s hormones, neuropeptides, use of alcohol, drugs, prescription medications, and so many other factors are also playing roles. One example of epigenetics playing a clear role in the transmission of both metabolic and mental disorders is the famous Dutch winter famine, which took place between 1944 and

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the psychiatric and neurological disorders but have failed to see the metabolic connection among all of them. Early Life Some of the factors that regulate epigenetics, metabolism, and mitochondria get transferred to the baby after birth through behaviors and early life experiences. Many studies have looked at caregiver behaviors toward infants

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the ACEs studies that I already described. Caregiver neglect and deprivation have profound effects on children for life. They include both metabolic and mental disorders. Epigenetic mechanisms play a role in all of this. A concrete example down to the molecular level is the passing of a metabolic factor from mothers

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. It is essential to mitochondria for energy production but also plays a role in the maintenance of DNA and epigenetics. Low levels of this enzyme are known to impair mitochondrial function and cause epigenetic changes, and have been associated with aging and many diseases.13 One group of researchers looked at mice

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will naturally have different levels of this coenzyme that they transfer to their babies. Intergenerational Transmission of Trauma The most widely studied phenomenon of how epigenetics relate to mental health is the intergenerational transmission of trauma. Dr. Rachel Yehuda, a leading authority in this field, outlined decades of research in a

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comprehensive review article: “Intergenerational Transmission of Trauma Effects: Putative Role of Epigenetic Mechanisms.”15 This field dates back to 1966, when an astute psychiatrist, Dr. Vivian Rakoff, noticed that children of Holocaust survivors appeared to sometimes have

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of cortisol in utero appear to “program” children, resulting in higher risk for developing mental and metabolic disorders later in life. With the genetic and epigenetic revolution came the discovery that many of these people have differences in methylation patterns of the glucocorticoid receptor and other DNA regions (promoter regions) associated

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with the stress response system. Most recently, it has been discovered that even fathers might be passing on their traumatic experiences through epigenetic mechanisms in sperm, such as micro-RNA (miRNA) molecules, which are known to modify gene expression. Studies have now shown that sperm in both mice

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directly to mitochondria, given that mitochondria initiate production of cortisol. This line of research continues to this day, but what it clearly demonstrates is that epigenetics appears to be playing a significant role in the transmission of mental disorders from parents to children, and even grandchildren. What Genetics and

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Epigenetics Can Tell Us About Causes—and Treatment Although some have been disappointed with our inability to find specific genes related to mental disorders, at the

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illness. It’s much more likely that the transmission of mental illness from parents to children takes place through epigenetic mechanisms. The hopeful aspect of this insight is that most of these epigenetic mechanisms are known to be reversible! The effects of in utero stress, micro-RNA levels, and levels of NAD

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cell and then travel through the body to impact other cells. The human body produces numerous hormones. All of them affect mitochondrial function and cause epigenetic changes in their target cells. Hormones change the metabolism of cells. In turn, they can play a role in both mental and metabolic disorders. As

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and numerous mental symptoms, including anxiety, fear, depression, mania, psychosis, and cognitive impairment. High levels in utero affect fetal development and play a role in epigenetics, which can lead to the later development of both metabolic and mental disorders. Cortisol always begins in mitochondria, which have the enzyme that initiates its

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light to the scalp and even inside the nose. This treatment is called brain photobiomodulation. These lights increase ATP production, change calcium levels, and stimulate epigenetic signals through direct actions on mitochondria. They are thought to enhance the metabolic capacity of neurons, have anti-inflammatory effects, and stimulate neuroplasticity.14 The

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another role for these magnificent organelles. Ketones are an alternate source of energy to cells. They also serve as important metabolic signaling molecules, resulting in epigenetic changes. Ketones can be a rescue energy source to insulin-resistant brain cells. While glucose might have trouble getting into these cells, ketones can get

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you are following a perfectly healthy diet, your metabolism and mitochondria can become impaired. This can be due to non-dietary factors such as genetics, epigenetics, inflammation, stress, sleep problems, hormones, medications, toxins, etc. Even in cases like these, dietary interventions can still play a role in treatment. For example, IF

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stress response. They influence all aspects of the stress response, including the production and regulation of key hormones and neurotransmitters, nervous system responses, inflammation, and epigenetic changes. When mitochondria are not functioning properly, all of these can be affected. One research study demonstrated a direct relationship between everyday stress and changes

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, exercise, stress, light, sleep, hormones, inflammation, relationships, love, and meaning and purpose in life, to name just a few. Yes, some people may have inherited epigenetic factors, such as micro-RNAs, and these might be a contributing cause to their mental illness, but these can be changed, too. Metabolism is malleable

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Catalyzed Phosphotransfer.” Proc Natl Acad Sci USA 99(15) (2002): 10156. doi: 10.1073/pnas.152259999. 27E.A. Schroeder, N. Raimundo, and G. S. Shadel. “Epigenetic Silencing Mediates Mitochondria Stress-Induced Longevity.” Cell Metab 17(6) (2013): 954–964. doi: 10.1016/j.cmet.2013.04.003. 28M. D. Cardamone, B

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.1016/j.cell.2012.09.004. PMID: 23063123; PMCID: PMC4175720. 11Centers for Disease Control and Prevention. “What Is Epigenetics?” CDC, US Department of Health and Human Services. https://www.cdc.gov/genomics/disease/epigenetics.htm. Retrieved 10/30/21. 12T. J. Roseboom. “Epidemiological Evidence for the Developmental Origins of Health and Disease

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.” J Endocrinol 242(1) (July 1, 2019): T135–T144. doi: 10.1530/JOE-18-0683. 13J. P. Etchegaray and R. Mostoslavsky. “Interplay Between Metabolism and Epigenetics: A Nuclear Adaptation to Environmental Changes.” Mol Cell 62(5) (2016): 695–711. doi: 10.1016/j.molcel.2016.05.029. 14P. H. Ear, A

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) (2019): 969–983.e4. doi: 10.1016/j.celrep.2019.01.007. 15R. Yehuda and A. Lehrner. “Intergenerational Transmission of Trauma Effects: Putative Role of Epigenetic Mechanisms.” World Psychiatry 17(3) (2018): 243–257. doi: 10.1002/wps.20568. 16D. A. Dickson, J. K. Paulus, V. Mensah, et al. “Reduced Levels

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root cause comorbidity connections contributing causes of mental illness. see also individual causes chemical imbalance depression drugs and alcohol food, fasting, and gut genetics and epigenetics hormones importance of identifying inflammation and metabolic disorders physical activity psychological and social factors sleep, light, and circadian rhythms successful treatments of (see also metabolic

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in the brain (see brain energy theory) and mental or medical disorders metabolic disorders as (see also metabolic disorders) Engel, George environmental toxins epidemiology studies epigenetics epilepsy contributing causes of ketogenic diet for mental symptoms related to and other disorders treatments for estrogen eukaryotic cells evolution exercise. see physical activity/exercise

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circadian rhythms quality of Frankl, Viktor free radical theory of aging Freud, Sigmund functional brain connectivity studies G GABA genes evolution of expression of (see epigenetics) in human DNA mitochondrial and risk for broad range of disorders that cause disorders genetics and “biological” disorders and depression and risk for metabolic disorders

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response, brain functions and traumatic brain injury treatments for mental disorders. see also individual disorders diet as estrogen as exercise/physical activity as genetics and epigenetics related to ineffective insulin in medical disorders related to metabolic treatment plan metabolism affected by psychological and social factors addressed in role of inflammation in

Human Diversity: The Biology of Gender, Race, and Class

by Charles Murray  · 28 Jan 2020  · 741pp  · 199,502 words

changing self-concept.” “The second premise is wrong because some aspects of the nonshared environment can be affected by outside interventions.” “But you’re ignoring epigenetics!” “The First Premise Is Wrong for Some Important Outcomes” In the Polderman meta-analysis discussed in chapter 11, there were exceptions to the generalization that

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possible that aspects of the nonshared environment can be affected by outside interventions? The prospects are, to borrow a word, gloomy. “But You’re Ignoring Epigenetics!” Raise the topic of genes’ role in affecting human behavior, and chances are good that someone is going to tell you that you’re hopelessly

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behind the times. Epigenetics has proved that alterations in the environment can change our genes, and therefore traditional beliefs about inborn characteristics are outdated and irrelevant. It’s no

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been reporting it for years. Time magazine explained “Why Your DNA Isn’t Your Destiny” back in 2010, with the subtitle “The new field of epigenetics is showing how your environment and your choices can influence your genetic code—and that of your kids.”57 In 2013, Discover magazine told us

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too. Here’s Tara Swart, holder of a PhD in neuropharmacology from King’s College London, writing in Forbes: The new and evolving science [of epigenetics] tells us that our gene expression is malleable, influenced by external stressors and lifestyle choices, from running outside to who you have your coffee break

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with. Rather than having a set genetic blueprint, epigenetics demonstrates that although our genes themselves are fixed, our genetic expression, much of which is heritable, is also interconnected with a wide range of environmental

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factors.60 With rare exceptions, the mainstream media’s reporting on the science behind epigenetics bears little resemblance to what’s actually been discovered. The Basics Your personal double helix of DNA resides in the nucleus of a cell. The

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involve a class of chemical modifications to DNA or to components of the “packaging” of DNA (chromatin) that has led to what is now called epigenetics. The word epigenesis was first used in 1651 by William Harvey to describe the developmental process that allows the homogeneous fertilized egg to become a

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Waddington’s definition. Nanney described two types of cellular control systems. One consisted of “genetics systems” that are involved in transcription. The other consisted of “epigenetic systems” that were auxiliary mechanisms for determining whether expression occurred, and if so, its intensity.62 Nanney’s article also drew attention to what would

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become a major aspect of epigenetics: “persistent homeostasis,” referring to cellular memory that survives cell division.63 What caused “persistent homeostasis”? Collapsing decades of research into a few sentences and simplifying

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, the answer turned out to be epigenetic marks of two kinds: those caused by DNA methylation and those caused by histone modifications. I will concentrate on DNA methylation, which has been more

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this short description. THE DNA DOESN’T CHANGE No one claims that the DNA code is modified by environmental events. All the scientific claims involving epigenetics, correct and incorrect, are about changes in gene expression, not changes in DNA. For DNA methylation, the genetic mark can be thought of as a

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your respiratory system. That the environment interacts with genes to change the phenotype temporarily is not news. It happens all the time. The distinctiveness of epigenetic change lies in the cellular memory of methylation that survives cell duplication. Suppose that a negative environmental event early in childhood not only caused temporary

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of capabilities and outcomes across groups. As these potential extensions of findings about gene expression sank in during the 2000s, the use of the term epigenetics expanded to include all forms of transmission of the phenotype by mechanisms that did not involve changes in the DNA sequence—in other words, to

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Nanney’s emphasis on cellular memory and instead treat the larger realm of transmission of the phenotype through RNA and transcription factors as part of epigenetics.66 For John Greally, director of the Center for Epigenomics at the Albert Einstein College of Medicine, this is too broad a definition, conflating changes

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reasons because a change in DNA methylation can be an effect instead of a cause.67 But for better or worse, the broad interpretation of epigenetics has taken hold and a correspondingly broad research agenda based on it has been pursued for two decades. What has been found? The Claims of

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the Advocates The first significant claims for epigenetic change were tailor-made to feed into both the optimism and the media excitement: They dealt with the effects of maternal love in infancy. The

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article “Epigenetic Programming by Maternal Behavior,” published in 2004 (first author was Ian Weaver), reported that rat pups who received high levels of arched-back nursing plus

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are consistent with the hypothesis that the associations between exposure to an adverse environment during early development and health outcomes in adulthood are mediated by epigenetic factors. The specific causal mechanism awaits elucidation.71 In other words, what happened to the children in utero probably affected DNA methylation in ways similar

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of their adult offspring, the authors (first author was Rachel Yehuda) reported, “This is the first demonstration of an association of preconception parental trauma with epigenetic alterations that is evident in both exposed parent and offspring, providing potential insight into how severe psychophysiological trauma can have intergenerational effects.”72 The key

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of scientists, and finally wins acceptance as the geezers die off (“Science advances one funeral at a time”).75 But that’s not how the epigenetics debate is being conducted within the profession. Epigeneticists who are still young themselves and doing cutting-edge work see their discipline as the victim of

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a hijacking. In their view, too many epigenetics enthusiasts are reaching conclusions and publishing them without understanding the science that already exists. For John Greally, the Yehuda study of Holocaust survivors “is pretty

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typical of all epigenetics studies today for being uninterpretable.”76 Geneticist Graham Coop had a Twitter response to the New York Review of Books article that began, “Utter nonsense

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generation—the week that the New York Review of Books article came out, evolutionary biologist Jerry Coyne’s blog began with “Another lousy article on epigenetics.” For those who want to pursue the debate, I can point you to an exchange that gives you an overview of the issues and references

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sources. The protagonists are neuroscientist Kevin Mitchell and Jill Escher, a well-known advocate for autistic children. Mitchell’s case against the popularized version of epigenetics began with two long scholarly appraisals of the data posted on his blog, Wiring the Brain, in January 2013.77 In May 2018 he returned

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, Germline Exposures, with a list of 49 references documenting her allegation that Mitchell cherry-picked studies to make his case and ignored abundant evidence of epigenetic inheritance in mammals. She was as blunt as Mitchell: Sloppy overstatement and dogmatism from the Ivory Tower, such as Mitchell’s blog post, can breed

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outspoken academicians to distort the state of the science, unchallenged.79 Four days later, Mitchell responded to Escher with another detailed methodological critique of the epigenetics literature.80 If you’re wondering how an outsider is to form an opinion, I sympathize. Of the many complex topics in this book, I

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the Institut für Humangenetik at the University of Duisburg-Essen, has expressed the problems at greater length by putting together a “roadmap to proving transgenerational epigenetic inheritance.” I’ve consigned it to a note because it is long and technical—but that’s my point.[86] The accounts of the transgenerational

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in the reviews of the literature at face value, their applications are far down the road. My point with regard to Proposition #10 is limited. Epigenetics properly understood is a vibrant field with findings that have important medical implications. But as far as I can tell, no serious epigeneticist is prepared

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underpinnings. The gloomy prospect for systematically affecting the nonshared environment seems vindicated. Nothing in the pipeline shows promise of overturning the negative results to date. Epigenetics as portrayed in the media has no relevance to Proposition #10 for the foreseeable future. The widespread popular belief that environmental pressures routinely and permanently

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found multiple reports of associations between the quality of childhood experience and the methylation status of the [relevant receptors].” “Recent evidence supports the hypothesis that epigenetic plasticity is sustained in the brain throughout adulthood, potentially as a mechanism to cope with the evolving demands of the environment; yet, there are clear

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constitutes humans’ stress response system] occurs at multiple levels of the HPA axis in addition to effects on hippocampal GR expression.” “The initial reports of epigenetic regulation of hippocampal GR expression are now accompanied by reports of environmentally regulated alterations in the methylation status of multiple genes directly implicated in HPA

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author is the director of the Institut für Humangenetik at the University of Duisburg-Essen. Here is his account of “the roadmap to proving transgenerational epigenetic inheritance” on pages 2 and 3 of 3: 1. Rule out genetic, ecological and cultural inheritance. For studies in mice and rats, inbred strains and

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investigation. Unfortunately, if you don’t find anything, you still cannot be 100% sure that a genetic variant does not exist. 2. Identify the responsible epigenetic factor in the germ cells. Admittedly, this is easier said than done, especially in female germ cells, which are scarce or unavailable. Be aware that

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molecular testing, for example by methylation analysis of imprinted genes, which are fully methylated or fully unmethylated only in germ cells. 3. Demonstrate that the epigenetic factor in the germ cells is responsible for the phenotypic effect in the next generation. If possible, remove the factor from the affected germ cells

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is gained.… In light of [the problems of doing such experiments in humans], this might currently be too much to ask for to prove transgenerational epigenetic inheritance in humans, but should, nevertheless, be kept in mind and discussed. Despite some unfamiliar technical language, enough of Horsthemke’s description of the roadmap

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pronouncement about the state of knowledge, here is Horsthemke’s closing paragraph: In conclusion, in my opinion, even if the molecular mechanisms exist to transmit epigenetic information across generations in humans, it is very likely that the transgenerational transmission of culture by communication, imitation, teaching and learning surpasses the effects of

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our ability to detect this phenomenon. Cultural inheritance has certainly had an adaptive role in the evolution of our species, but the evidence for transgenerational epigenetic inheritance, as laid out above, is not (yet) conclusive. For now, I remain skeptical. 87. I am referring to the phenomenon known as regression to

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and the Politics of Knowledge: Moral Foundations Theory and Disciplinary Controversies.” American Sociologist 49 (4): 459–95. Horsthemke, Bernhard. 2018. “A Critical View on Transgenerational Epigenetic Inheritance in Humans.” Nature Communications 9 (1): 2973. Huerta-Sanchez, Emilia, Xin Jin, Asan et al. 2014. “Altitude Adaptation in Tibetans Caused by Introgression of

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, Hajnalka Kompagne, Hajnalka Orvos et al. 2007. “Gender-Related Differences in Neonatal Imitation.” Infant and Child Development 16 (3): 267–76. Nanney, D. L. 1958. “Epigenetic Control Systems.” Proceedings of the National Academy of Sciences 44 (7): 712. Narasimhan, Vagheesh M., Raheleh Rahbari, Aylwyn Scally et al. 2017. “Estimating the Human

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She Has Her Mother's Laugh

by Carl Zimmer  · 29 May 2018

high cravat. New Scientist covered the study in the same spirit, describing it in an editorial entitled “Mouse Memory Inheritance May Revitalise Lamarckism.” Transgenerational epigenetic inheritance, as this new flavor of Lamarckism came to be known, inspired giddiness far beyond scientific journals. It implied that our health and even our

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Kevin Mitchell, a neurogeneticist at Trinity College, Dublin, took to Twitter to express his skepticism. He delivered a rant worthy of August Weismann. “For transgeneration epigenetic transmission of behaviour to occur in mammals,” he wrote, “here’s what would have to happen: Experience—>Brain state—>Altered gene expression in some specific

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same circuits to the behaviour of the animal itself (which supposedly kicked off the whole cascade in the first place) For scientists like Mitchell, an epigenetic form of heredity suffers from more than just biological gaps. It demands rewriting entire fields of science that researchers already understand very well. * * * — In

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a plant’s growth. Scientists are searching for such changes and trying to propagate the plants so that the new generations inherit the same epigenetic profile. Transgenerational epigenetic inheritance is a real phenomenon in plants, but many scientists are skeptical that it matters very much in nature. It’s wrong to call

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has to be transmitted from mother to offspring. Enzyme: A protein that catalyzes a chemical reaction in the cell, such as breaking down nutrients. Epigenetic: Related to molecules such as transcription factors and methylation that affect the expression of genes by altering their DNA sequence. Epigenome: The physical factors that

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Institute. how much skepticism there is in scientific circles: See Heard and Martienssen 2014; Whitelaw 2015. the causes may have nothing to do with inherited epigenetic marks: Greally 2015. the most potent attacks: Francis 2014. primordial germ cells: See Guo et al. 2015; Tang et al. 2016. methylation suffers radical

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amnesia: Chen, Yan, and Duan 2016. Kevin Mitchell, a neurogeneticist: Mitchell 2016. “Transgenerational Epigenetic Inheritance: Myths and Mechanisms”: Heard and Martienssen 2014. Azim Surani: Tang et al. 2015. Tracy Bale: Rodgers et al. 2015. the effect of stress that

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and Possible Accelerated Growth and Visceral Affections. European Journal of Pediatrics 140:5–12. Wilde, Jonathan J., Juliette R. Petersen, and Lee Niswander. 2014. “Genetic, Epigenetic, and Environmental Contributions to Neural Tube Closure.” Annual Review of Genetics 48:583–611. Wilkins, Adam S., and Robin Holliday. 2009. “The Evolution of Meiosis

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512 Boubakar, Leila, 343–44 Boveri, Marcella, 353, 392–93 Boveri, Theodor, 352–54 Boyle, Robert, 137 brain physiology and cultural heredity, 469–70 and epigenetics, 432–34 and inheritance of behavioral traits, 429–30 and intelligence research, 295–96 and mitochondrial replacement therapy, 520–21 and mosaicism, 368–69 and

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CRISPR mechanism, 143, 494, 523, 525, 552–54, 558, 573 and discovery of genes, 123–24 and Drosophila research, 98 and embryonic development, 328 and epigenetic inheritance, 472 and eukaryotes, 144 and fertilization process, 341, 542 and gene drives, 155, 473 and genetic testing and counseling, 3, 5, 505 and horizontal

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and paleogenetics, 239, 242–43 and spread of genetic variations, 205, 207 and tracing lineages, 176, 178–79, 186–87, 190–92, 223 and transgenerational epigenetic inheritance, 441 chronic myelogenous leukemia, 354 Church, George, 528, 529–30, 560 clams, 397–400, 408, 412 Claypoole, James, 165 Clerget-Darpoux, Françoise, 280

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genetic inheritance, 471–80 Cushing, Harvey, 274 cystic fibrosis, 503, 535 Danbury, Lewis, 104 Dar-Nimrod, Ilan, 317–18 Darnovsky, Marcy, 528 Darwin, Charles and epigenetics, 435, 442 and Galton’s plant breeding experiments, 260 and modern concept of heredity, 6, 43–56, 58–62, 426 and recessive traits, 473 research

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and diagnosis of hereditary diseases, 133 and discovery of genes, 123–26 and effects of meiosis on heredity, 150–52 and embryonic development, 333 and epigenetics, 430–31, 433, 436–41 and ethical issues of scientific advances, 542 and family genealogies, 160 fingerprinting, 381 and gene drives, 155, 572–73

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Waldo, 166 The End of Sex and the Future of Human Reproduction (Greely), 547 endosymbiosis, 410–17, 419 Enlightenment, 256–57, 427 Enterococcus faecium, 141 epigenetics and epigenesis and animal biology, 440–42 and cell lineages, 344 and CRISPR research, 566 and embryonic development, 325, 332 and environmental influences, 430–34

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445, 461, 463 of DNA-based life, 138–39 and endosymbiosis, 410 and environmental impact of humans, 570 and environmental influences, 466, 468–69 and epigenetics, 442 and eugenics ideology, 235–37 of eukaryotes, 144 and gene drives, 154–55, 572 and genetic engineering, 508, 546 and genome sequencing, 2 and

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276–77 Merrick, Joseph (the Elephant Man), 351–52, 356 Mesoudi, Alex, 464 Metamorphoses (Ovid), 484 methyl groups and methylation and CRISPR system, 489 and epigenetics, 430–31, 433–34, 436–41, 566 and genetic vs. nongenetic heredity, 479 and lyonization, 338 and the Peloria plant, 425 and pluripotent cells, 342

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factors, 208 Risch, Neil, 276–77 RNA (ribonucleic acid) and bacterial restriction enzymes, 488 and CRISPR system, 489–91 and DNA replication, 125 and epigenetics, 439–42 and evolution of DNA-based life, 138–39 and gene drives, 155 and genetic vs. nongenetic heredity, 475 and lyonization, 338–39 and

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limpets, 329–30 Smith, David, 479 Society of Friends, 287–88 somatic cells and CRISPR technology, 524 and engineering of embryonic cells, 544, 546 and epigenetics, 439, 442 and genetic engineering, 511 and human germ line engineering, 526–27 and microbiomes, 409 and preimplantation genetic diagnosis, 532 somatic mutation, 354, 360

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80 Tishkoff, Sarah, 229–31 toadflax, 423–25, 439, 443, 475 tomatoes, 492–93 totipotency, 341–42, 382, 407, 436, 546 transcription factors, 242 transgenerational epigenetic inheritance, 435–36, 438–41, 443, 566 transplantation, 375–76, 543 Treatise on Cattle (Mills), 370 Treatise on Natural Inheritance (Lucas), 45–46 Treves, Frederick

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Richard, 111–12 water fleas, 475–76 Watson, James, 124–25 Weismann, August and chimerism, 394 and embryonic development research, 328–29, 332–33 and epigenetics, 437 and ethical issues of scientific advances, 543 and genetic vs. nongenetic heredity, 472–73, 478–79 and germ line/soma distinction, 56–60, 143

Deep Nutrition: Why Your Genes Need Traditional Food

by Catherine Shanahan M. D.  · 2 Jan 2017  · 659pp  · 190,874 words

sculpted, in part, by the foods our parents and grandparents ate (or didn’t eat) generations ago. The body of evidence compiled by thousands of epigenetic researchers working all over the world suggests that the majority of people’s medical problems do not come from inherited mutations, as previously thought, but

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. Their songs and prayers reflected the belief that in consuming food, each of us comes in contact with the great, interconnected web of life. Epigenetics proves that intuitive idea to be essentially true. Our genes make their day-to-day decisions based on chemical information they receive from the food

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engineer and enrolled in every course I could to study genetics. I went to graduate school at Cornell, where I learned about gene regulation and epigenetics from Nobel Prize–winning researchers, then straight to Robert Wood Johnson Medical School in New Jersey, in hopes of putting my knowledge of the fundamentals

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traditional cuisine, I changed everything about the way I eat. For me, eating in closer accordance with historical human nutrition corrected some of my damaged epigenetic programming. I got fewer colds, less heartburn, improved my moods, lost my belly fat, had fewer headaches, and increased my mental energy. And eventually

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leaves curl and its color fade knows that proper care and feeding can have dramatic, restorative effects. The same applies to our genes—and our epigenetic programming. Not only will you personally benefit from this during your lifetime with improved health, normalization of fat distribution, remission of chronic disease, and

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why this built-in ability makes me certain that many of us have untapped genetic potential waiting to be released. CHAPTER 2 The Intelligent Gene Epigenetics and the Language of DNA “Good genes” make us healthy, strong, and beautiful and represent a kind of family fortune we call genetic wealth.

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the last two decades, scientists have discovered that this material has some amazing abilities. This line of discovery emerges from a branch of genetics called epigenetics. Epigenetic researchers investigate how genes get turned on or off. This is how the body modulates genes in response to the environment, and it is how

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two twins with identical DNA can develop different traits. Epigenetic researchers exploring this expansive genetic territory are finding a hidden world of ornate complexity. Unlike genes, which function as a relatively static repository of encoded

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be that the same mechanisms facilitating cell maturation also function over generations, enabling species to evolve? According to Arturas Petronis, head of the Krembil Family Epigenetics Laboratory at the Centre for Addiction and Mental Health in Toronto, “We really need some radical revision of key principles of the traditional genetic research

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our misapprehension of evolution in perspective: mutation- and selection-driven evolutionary change is just the tip of the iceberg. “The bottom of the iceberg is epigenetics.”22 The more we study this mysterious 98 percent, the more we find it seems to function as a massively complicated regulatory system that serves

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in analog terms rather than digital, enabling our DNA to store and compute far more information than previously imagined. One of the positive functions of epigenetics is to come up with novel and creative solutions to less-t genes to make intelligent compromises. Take the development of the eye, for

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from two sets of identical twins, one set aged three and the other aged fifty. Using fluorescent green and red molecules that bind, respectively, to epigenetically modified and unmodified segments of DNA, they examined the two sets of genes. The children’s genes looked very similar, indicating that, as one

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far, the processes identified include bookmarking, imprinting, gene silencing, X chromosome inactivation, position effect, reprogramming, transvection, maternal effects, histone modification, and paramutation. Many of these epigenetic regulatory processes involve tagging sections of DNA with markers that govern how often a gene uncoils and unzips. Once exposed, a gene is receptive to

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what the various nutrients it contacts are good for. Through mechanisms not fully understood, DNA has been programmed at some point in the past by epigenetic markers that can turn certain DNA portions on or off in response to certain nutrients. The entire programming system is designed for change; these

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levels of certain nutrients could promote these reproduction errors. Folic acid, B12, and a number of essential amino acids are used for a type of epigenetic bookmarking called methylation; a lack of any one of these vital nutrients would result in undermethylation and critical bookmarks may be omitted. Their research showed

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in utero nutrition may be a major contributor to the current cycle of obesity.”33 The article shows that children born to overweight mothers are epigenetically programmed to build adipose tissue in unhealthy amounts. This suggests that millions of malnourished moms are, unbeknownst to them, programming their children for a

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vitamin C. After generations of nonuse (due to abundance of vitamin C in our food), the gene would have grown very “sleepy.” Eventually, when epigenetic “test marketing” had demonstrated that we could live without being able to make our own vitamin C, a mutation within the gene permanently deactivated it

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. How, exactly, might this test marketing work? Certain markers increase the error rate during reproduction, and thus a temporary epigenetic change can set up the gene to be permanently altered by a base pair mutation.41 Genes are like tiny protein-producing machines that create

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different products. If a factory worker (think epigenetic tagging) shuts off one machine and everything in the cell continues to run smoothly over the ensuing generations, then that particular machine (gene) can

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be refashioned to produce something else, or turned off altogether. The more we learn about epigenetics, the more it seems that genetic change—both the development of disease and even evolution itself—is as tightly controlled and subject to feedback as

…

which programming codes work best for what, or how the many environmental inputs—minerals, vitamins, toxins, and so on—might be translated into a new epigenetic strategy, but some intriguing research offers support to the idea that DNA can indeed take notes. In 1994, mathematicians observed that junk DNA contained patterns

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fed vitamin A, the next litters developed normal eyeballs, suggesting that eyeball growth was not switched off due to (permanent) mutation, but to a temporary epigenetic modification. Vitamin A is derived from retinoids, which come from plants, which in turn depend on sunlight. So in responding to the absence of vitamin

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that makes them beautiful. BEAUTY EMERGES FROM MATH Every line of Marquardt’s Mask is geometrically plotted according to the dynamic symmetry of phi. When epigenetic conditions provide for optimal growth, facial features “crystalize” in a pattern that conforms to the mask. This is the female mask. According to Marquardt,

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of successful survival in the wild was squandered as poverty or plague denied genes the nutrients they needed. During each period of nutritional deprivation valuable epigenetic programming was lost. As time has passed, we have required more and more safety nets and invented correctives like glasses, braces, and thousands of

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proper timing of gene expression requires specific nutrients in specific concentrations, if a second sibling gestates in a lessor nutritional environment than the first, their epigenetic expression will be suboptimal, and growth and development will be impaired. We know, for example, that low birth weight, often due to mom’s

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pressure (both associated with poor nutrition), puts children at risk for low bone mass and relative obesity for the rest of their lives.131 Abnormal epigenetic responses due to nutrient deficiency may explain why children of subsequent births are at higher risk for disease, from cancer132 to diabetes133 to low IQ

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of prescriptions, and expand our definition of normal childhood health to encompass all manner of medical intervention. This latest generation of children has accumulated the epigenetic damage of at least the three previous generations due to lack of adequate nutrition along with the overconsumption of sugar and new artificial fats found

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, brain, and other organ growth. Many physicians have noted an apparent increase in young couples complaining of problems with fertility which, given the implications of epigenetic science, should come as no surprise. Children born today, I’m afraid, may be so genomically compromised that, for many, reproduction will not be

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operating under moderate duress for a spell is effectively rehabilitated. SKELETAL RESPONSES TO DIET CHANGE Short stature may be a kind of biologic “choice,” an epigenetic adaptation to inadequate bone-building material in a previous generation’s diet. Rather than build weak, breakable bones, the genome makes bone of the same

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women with higher levels.306 Even when carried to term, babies of mothers with low cholesterol are often born smaller, with abnormally small brains. Remember, epigenetic alterations can accumulate over generations. So when these small-brained babies have babies of their own while on low-cholesterol diets themselves, it’s anybody

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lose our personalities, and our connections to the world. 6. Gene replication. Vegetable oils impair brain development through direct mutagenic effects on DNA and altered epigenetic expression. If you’ve read Grain Brain, Cereal Killer, Sugar Crush, Sweet Poison, The Sugar Blues, Fat Chance, Sugar Nation, The Starch Solution, or

…

Chapter 2, I touched upon the idea that an optimal nutritional environment is required to ensure the accurate transcription of genetic material and communication of epigenetic bookmarking, and how a pro-oxidative, pro-inflammatory diet can sabotage this delicate operation in ways that can lead to mutation and alter normal growth

…

gene expression.” In other words, the study rats had been programmed to consume substances that stimulate their opiate receptors.448 Sugar acts as a powerful epigenetic instructor, telling your child’s genes to construct a brain with a built-in hankering for drugs. As Michael Pollan points out in The

…

s a common misperception that milk drinking is a relatively new practice, one limited to Europeans. The reality is that our cultural—and now, our epigenetic—dependence on milk most likely originated somewhere in Africa. It is highly likely that milk consumption gave those who practiced animal husbandry such an advantage

…

irritating lactose sugars are gone. A child living in a warmer climate would, after weaning, have such infrequent need for the lactase enzyme that the epigenetic librarian would simply switch the gene off. In cooler European climates, fresh milk stays fresh for hours or days, and was presumably consumed that

…

way often enough to keep the lactase enzyme epigenetically activated throughout a person’s life. If you have true lactose intolerance, as opposed to a protein allergy, you should be able to tolerate plain

…

and a half months in utero is a minor miracle requiring a wholesome, rich environment. No physiologic event is as dramatic as the transcription of epigenetic data from gametes to zygote. And therefore none is as dependent on good nutrients, or more vulnerable to the interference of toxins. Nutrition’s

…

and behavior—from assigning cellular identity to cell growth and maturation—is a process that continues throughout our entire lives. What scientists have learned about epigenetics and the protean nature of cells tells us that, just like a baby developing inside the womb, our bodies continue to be a work

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, at http://www.Alzheimers.net/resources/Alzheimers-statistics/ Chapter 1 8. Dr. Michael Dexter, Wellcome Trust. 9. Transposable elements: targets for early nutritional effects on epigenetic gene regulation, Waterland RA, Molecular and Cellular Biology, August 2003, vol. 23, no. 15, pp. 5293–5300. 10. Nutrition and Physical Degeneration, Price W,

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pregnancy and childhood bone mass at age nine years: a longitudinal study, Javaid MK, Obstetrical and Gynecological Survey, 61(5):305-307, May 2006. 15. Epigenetic epidemiology of the developmental origins hypothesis, Waterland RA, Annual Review of Nutrition, vol. 27, August 2007, pp. 363-388. 16. See Chapter 11. 17.

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. 20. Pluripotency of mesenchymal stem cells derived from adult marrow, Jiang Y, Nature, July 2002, 4;418(6893):41-9, epub Jun 20, 2002. 21. Epigenetics, the science of change, Environ Health Perspect, March 2006, 114(3): A160–A167. 22. Environmental Health Perspectives, vol. 114, no. 3, March 2006. 23.

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Pflueger C, Cairns BR, Carrell DT, 2014, PLoS Genet, 10(7). 31. Effects of an increased paternal age on sperm quality, reproductive outcome and associated epigenetic risk to offspring, Rakesh Sharma et al, Reproductive Biology and Endocrinology, 2015, 13:35. 32. Age-associated sperm DNA methylation alterations: possible implications in offspring

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p. 224. 521. Dietary fat requirements in health and development, Thomas H Applewhite, American Oil Chemists Society, 1988, p. 30. Chapter 11 522. Jaenisch, R, Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals, Nature Genetics, 33, 245-254 (2003). 523. Orexins in the brain-gut axis

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dog food, compared to cereal dynamic symmetry E E. coli as pathogen eczema eggs Egyptians, nutrition among ancient elastin Enig, Mary endorphins endothelial function enzymes epigenetics See also genes; genetics erectile dysfunction (ED) Essylstein, Rip estrogen Etcoff, Nancy eugenics evolution exercise aerobic anaerobic benefits of successful habits for and sugar eyes

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and autism beauty and damage to and diet and exercise and heart disease importance of, to good health and pregnancy programming of See also DNA; epigenetics genetic momentum genetic potential genetic wealth economics of loss of maximizing and restoring gastro-esophageal reflux disease (GERD) germination Ghandi, Mahatma ginseng glucose gluten,

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Notice Dedication Author’s Note Introduction Part One: The Wisdom of Tradition 1 Reclaiming Your Health The Origins of Deep Nutrition 2 The Intelligent Gene Epigenetics and the Language of DNA 3 The Greatest Gift The Creation and Preservation of Genetic Wealth 4 Dynamic Symmetry The Beauty-Health Connection 5 Letting

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