Summary: Epigenetics is a field of study that investigates how our habits and environment might influence the way our genes function. DNA is the molecule that makes up genes. Epigenetic alterations are important for optimal biological function and can influence natural cellular death, renewal, and senescence cycles. Diet, sleep, exercise, smoking, and alcohol use can all change the content and placement of the chemical groups that link to our DNA. Environmental variables like chronic inflammation, stress and trauma may have a role. Epigenetics sheds light on how and why humans age at various speeds. While this subject is rapidly advancing, many of the technologies are still being tested in animal models and have yet to be authorized for human use.
While it’s exciting to think about how epigenetics could one day be used to repair or restore, the best advice for good aging remains the same: eat well, exercise regularly, get enough sleep, avoid harmful behaviors, and maintain social connections.
1. What is an epigenome and how does it regulate our gene expression?
Description
Epigenome is a collection of “chemical tags” on the surface of our genome. Those “chemical tags” switch on or off particular genes and thus regulate their functioning and phenotypic expression. Our epigenome is composed of epigenetic modifications happening to our genome. Epigenetic modifications control the expression of certain genes without affecting the DNA sequence, but only modifying the chromatin structure either in open or condensed state. Posttranslational histone modifications and DNA methylation are the key epigenetic modifications which regulate gene expression. These mechanisms are essential for the organism’s correct development and differentiation of diverse cell lineages. Mechanisms can be influenced by external factors, and as a result, they can contribute to or be the outcome of phenotypic or pathophenotypic changes.
Source: Epigenetic Modifications: Basic Mechanisms and Role in Cardiovascular Disease – PMC (nih.gov)
2. How posttranslational histone modifications affect chromatin state and gene expression?
Description
Eukaryotic genome is composed of chromosomes with its basic unit – chromatin which in turn consists of nucleosomes. Each nucleosome is composed of four histones that are wrapped around our DNA. H2A, H2B, H3, and H4 are the four main histones that make up each nucleosome. These core histones’ amino-terminal tails are exposed on the surface of nucleosomes and can undergo a variety of posttranslational changes. Modifications of histones include several reactions such as acetylation of lysine residues, methylation of lysine and arginine residues, phosphorylation of serine and threonine, ubiquitination of lysine , sumoylation, ADP ribosylation and more are still being discovered. Histone modifications have two fundamental effects on transcriptional activity: they change the structure and conformation of chromatin, and they signal specific enzymes to recruit transcriptional activators or suppressors.
Source: Frontiers | Epigenetics across the human lifespan (frontiersin.org)
3. What is the role of transcription factors and how their functioning is affected with age?
Description
Posttranslational modifications result in the recruitment of transcription factors which are sequence specific gene regulators. However, during aging the dysregulation of transcriptional and chromatin networks happen and it has been found that some transcription factors can initiate remodeling of a genetic locus by binding to closed chromatin and mediating nucleosome remodeling and changes in histone marks.
4. What age-associated changes happen to gene transcription regulation?
Description
Transcription activation happens in a sequential manner, beginning with the binding of a sequence-specific DNA-binding protein known as a pioneer transcription factor. Transcription factor then recruits nucleosome remodeling complexes and further they displace or relocate nucleosomes and open chromatin. This enhances DNA accessibility, allowing more transcription factors to bind, chromatin modifiers to remove repressive marks (red hexagons) and replace them with activating marks (green stars), and lastly, gene transcription. At every step of this process, age-related alterations have been seen, and changes in one phase (for example, the activity of the pioneer transcription factor) can have downstream effects on gene regulation.
5. Epigenetic modulation of human telomerase as cancer protective intervention and dietary substances to regulate the enzyme
Description
Telomeres are essential for cell growth and shield the chromosomes from deterioration and damage. Telomerase is an enzyme responsible for the maintenance of telomeres. Expression of a particular subunit, telomerase reverse transcriptase, controls the activity of the telomerase. Selective targeting of telomerase is a promising approach for cancer prevention and treatment because almost 90% of cancers have an aberrantly expressed telomerase. Several dietary compounds target this subunit to regulate enzyme activity, hence increasing protection of telomeres and chromosomes. They include compounds such as tea polyphenols, genistein – a phytoestrogen found in soybeans, fava beans, kudzu, lupin, and psoralea, resveratrol – a polyphenol derived from grapes, berries, peanuts, and other plant sources or from red wine, sulforaphane which is abundant in cruciferous vegetables including broccoli, cauliflower, cabbage, kale and finally, curcumin – all these can influence telomerase by increasing or decreasing the activities of enzymes that add or remove methyl groups from DNA and histone-modifying enzymes.
6. Epigenetic markers influenced by our dietary choices can affect more than just ourselves
Description
Our epigenetic marks influence our offspring. Studies suggest that epigenetic patterns are heritable and can stay the same unless the environment or lifestyle changes. More specifically, it has been found that our diet-induced epigenetic markers are similarly observed in the next generation. Offspring of males fed a low-protein diet exhibited elevated hepatic expression of many genes involved in lipid and cholesterol biosynthesis and decreased levels of cholesterol esters, relative to the offspring of males fed a control diet.
7. Mitochondrial well-being is important in gene regulation
Description
There are transcription factors that are sensitive to reactive oxygen species (ROS). ROS that are generated by mitochondria during mitochondrial dysfunction can affect gene transcription regulation. For example, in yeast, ROS signals from mitochondria can influence chromatin-mediated gene silencing. Furthermore, mitochondrial failure causes increased histone 3 methylation and chromatin compaction in C. elegans.
Source: Mitochondrial Stress Induces Chromatin Reorganization to Promote Longevity and UPRmt – ScienceDirect
8. How does the lifestyle alter our epigenetic processes?
Description
Nutrition, behavior, stress, physical exercise, working habits, smoking, and alcohol intake are all part of the ‘lifestyle’ notion. Environmental and lifestyle variables may alter epigenetic processes such as DNA methylation, histone acetylation, and miRNA expression, according to growing data. Several lifestyle variables have been identified as potentially altering epigenetic patterns, including food, obesity, physical activity, cigarette smoking, alcohol intake, environmental contaminants, psychological stress, and working night shifts. The majority of previous research has focused on DNA methylation, with just a few studies looking at lifestyle variables in connection to histone modifications and miRNAs. The existing research suggests that lifestyle variables may have an impact on human health via other epigenetic pathways as well.
9. Dietary interventions to regulate gene transcription and the reason why DNA repair is important to our epigenome
Description
There is a theory that aberrant gene transcription, which causes loss of capacity for homeostasis in aging, can be caused by unrepaired damage to the genome. Several nutritional modulating factors have been investigated to enhance the DNA repair and modify the rate of phenotypic aging. Among those are antioxidant dietary constituents such as trace metals including zinc and selenium, vitamins including A, C and E and non-nutrients such as lycopene and polyphenols which are not only effective against free radicals but also have specific roles in enhancing DNA repair. Another popular nutritional epigenetic modulator is calorie restriction. In the mouse brain, CR reduced the age-related activation of genes that code for inflammatory and stress responses. Even short periods of CR (2–8 weeks) resulted in a rapid and progressive alteration in gene expression in the liver, similar to that seen in animals exposed to long-term CR. However, changing from long-term CR to a control diet for as little as 2 months, on the other hand, corrected 90% of the gene expression changes in the rats subjected to long-term CR.
Source: Nutritional modulation of ageing: Genomic and epigenetic approaches – ScienceDirect
10. Calorie restriction and dietary compounds such as acetyl-CoA, nicotinamide mononucleotide (NMN) increases stem cell pool and have profound effects on epigenetic rejuvenation.
Description
Epigenetic strategies for rejuvenation include the maintenance of mitochondrial homeostasis, the repression of retrotransposable elements and the amelioration of inflammation. These strategies together with geroprotective compounds hold great promise for treating age-related conditions and for delaying aging. Metformin, rapamycin, acetyl-CoA, nicotinamide mononucleotide and aspirin are among such compounds. Another compound is ascorbate, which resets gene expression patterns, restores heterochromatin structure, and alleviates aging effects in an epigenetic-dependent pathway. Ascorbate acts as a cofactor for Jumonji C domain-containing demethylases, boosting histone demethylation and erasing epigenetic memory at the start of reprogramming. Furthermore, in humans and mice, ascorbate maintains unusually high quantities of hematopoietic stem cells.
Source: The ageing epigenome and its rejuvenation | Nature Reviews Molecular Cell Biology
11. Extrinsic factors such as tobacco smoke, metal ions, bisphenol A, benzene, alcohol and many other toxicants induce epigenetic alterations.
Description
Environmental toxicants have been proven to have an impact on epigenetic controls and their execution on development, health, and disease risk in a range of epidemiological and experimental research using animal, human, and in vitro models. These epigenetic changes were shown to be tissue-type specific and strongly correlated with exposure dose and duration. Though being small, toxicant-induced epigenetic changes may accumulate and have lasting impacts on human health or even future generations. Several studies have been published that show a relationship between ambient metals such as cadmium, nickel, arsenic, chromium, methyl mercury and DNA methylation. Low-level benzene exposure has been demonstrated to cause global hypomethylation in the peripheral blood of petrol station employees and traffic cops, as well as being a risk factor for acute myelogenous leukemia. More chemicals and more specific roles are yet to be discovered and more studies are necessary in this direction