The field of epigenetics has evolved greatly over the past several years, how is this new information affecting cliniciansâ ability to resolve chronic illness?
Dr. Hu: New epigenetics findings have changed cliniciansâ understanding of disease mechanisms. Researchers have made progress in discovering the meaning and functions behind epigenetic modifications, revealing the importance of epigenetic mechanisms in disease programming.1 Epidemiological and clinical studies have identified many DNA-methylation and histone-modification loci and microRNAs associated with risk and progression of chronic diseases. Many of these findings point to pathways relevant to disease pathologies.2-6 This new information has greatly advanced understanding of mechanisms underlying chronic-disease development, showing that chronic diseases are not only impacted by genetic and modifiable risk factors, but also regulated at an epigenetic level.
Such understanding of disease mechanisms may open new avenues for developing diagnostic and prognostic biomarkers and potential therapeutic strategies. For example, multiple clinical and epidemiological studies found that methylation levels at several tumor-related genes in blood, lymph nodes, or cancer tissues, are predictive for cancer risk and prognosis and may be useful in molecular subtype reclassification.4,7-9 These findings still need to be translated clinically and carefully tested through further studies and clinical trials, but may shed light on future targeted prevention and treatment.
New epigenetic findings have also changed cliniciansâ understanding of how modifiable risk factors impact our health. An increasing number of studies have shown that environmental exposures and smoking are associated with epigenetics alterations that may later put individuals at higher risk of diseases, while healthy dietary and lifestyle factorsâfor example, vitamin-B intake and physical activityâmay protect against some adverse methylation alterations.10-13 This evidence enhances our understanding of how diet and lifestyle may positively or negatively impact our health at a molecular level. Thus, healthy diet and lifestyle recommendations are particularly important for high-risk populations and chronic-disease patients.
How can it be used to help healthy people remain so?
Dr. Hu: New epigenetic findings emphasize the importance of adopting and maintaining a healthy diet and lifestyle throughout life. Methylation alterations associated with diet and lifestyle factors may persist long-term and impact health and disease risk in later life. For example, cigarette smoking has a broad, long-lasting impact on DNA methylation profilesâsome modifications may even persist for decades after cessation.14,15 Methylation alterations associated with smoking are mapped to genes linked to cancer and diabetes pathogenesis, and some methylation alterations may act as mediators for the adverse association between smoking and risk of cardiovascular outcomes and mortality.11, 16-17Â The DNA methylome plays an important role in early development and is sensitive to prenatal exposures. Studies have shown that exposure to maternal smoking in early development is associated with extensive methylation alterations in offspring, particularly for genes relevant to diseases that can be caused by maternal smoking, such as orofacial clefts and asthma in offspring, or smoking as an adult, such as certain cancers.18 Longitudinal data also suggest that some methylation patterns from prenatal smoking exposures could persist through the offspringâs teenage years.19 Such evidence indicates that unhealthy behavioral factors may have epigenetic effects which impact our health later in life, further emphasizing the importance of adopting and maintaining healthy behaviors throughout life.
These new findings also highlight the need for early detection. The association between modifiable risk factors and chronic diseases may have a latent period. Molecular changes, at epigenetic levels or other molecular levels, and subclinical pathologies such as increased glucose intolerance or insulin insensitivity for coronary heart disease, atherosclerosis, and type 2 diabetes may happen before the clinical appearance and diagnosis of diseases. For individuals who are free of chronic diseases but have risk factors, health examinations may help identify subclinical changes so that the disease can be prevented.
What role does whole food play in accessing epigenetics for health promotion?
Dr. Hu: Accumulating evidence suggests that diets rich in fruits, vegetables, and whole grains are beneficial for longevity and prevention of chronic diseases.20,21 Such diets contain nutrients that act as methyl donors, contributing to DNA methylation programming. B vitamins including folate found in fruits, vegetables, whole grains, beans, breakfast cereals, and fortified grains; vitamin B6 found in fortified cereals, beans, poultry, fish, and some vegetables and fruitsâ particularly dark leafy greens, papayas, oranges, and cantaloupe; and vitamin B12 found in fish, poultry, meat, eggs, fortified breakfast cereals, dairy, and enriched soy or rice milk play essential roles in one-carbon transfer and balancing DNA-methylation reactions.22 A recent study showed that DNA-methylation changes caused by fine particulate matter exposure can be reduced by B vitamins.12 Folate is also important in DNA-methylation reprogramming during the early embryonic period, and folate deficiency in early pregnancy has been associated with increased risk of neural tube defects and low birth weight.22 Maternal plasma folate levels were found to be associated with cord-bloodâ fetal bloodâmethylation levels at genes in the pathways relevant to birth defects and neurological functions, suggesting that aberrant DNA-methylation reprogramming could be a mechanism underlying the association between folate levels and some adverse birth outcomes.23 Vitamin C, an antioxidant present in many fruits and vegetables, is involved in DNA demethylation.24 In a small clinical trial, vitamin-C intake during pregnancy attenuated the offspringâs methylation alteration associated with maternal smoking.13 Taken together, some beneficial effects of diets rich in fruits, vegetables, and whole grains may be partially mediated by methyl-donor nutrients which contribute to the homeostasis of DNA-methylation reactions.
What other factors can be modified through coaching or therapy that will impact epigenetic expression of an individual?
Dr Hu: Besides dietary factors, smoking cessation and physical activity have been shown to have significant impacts on epigenetic profiles and can be incorporated into lifestyle therapies. Despite smokingâs extensive, long-lasting impact on the DNA methylome, a recent study suggested that some smoking-induced DNA-methylation changes can be slowly reversed after long-term smoking cessation.14,15 Several large, epigenetic epidemiological studies found that obesity-related, DNA-methylation genes were involved in metabolic pathways relevant to diabetes pathologies, and were associated with future type 2 diabetes risk.25 Interestingly, several clinical studies also observed that weight loss, resulting from increased physical activity in healthy people or gastric bypass surgery in severely obese people, was associated with changes in DNA methylation levels in adipose tissue at genes relevant to insulin and glucose regulation. These methylation changes were also associated with changes in insulin and glucose levels.26,27 This evidence suggests that emphasizing smoking cessation as well as weight loss through physical activity and reduced energy intake may help lower disease risk, partially through modulation of epigenetic expression.
What knowledge and tools will cliniciansâ need to harness the power of epigenetics?
Dr. Hu: To harness the power of epigenetics, clinicians need in-depth knowledge of the genes and epigenetic findings related to their areas of expertise. Clinicians can also contribute to the epigenetics field by conducting or assisting with clinical studies that validate current findings or translate them into clinical uses. Although the field of epigenetics has evolved greatly over the past several years, additional work is necessary to improve study design, as well as validate, interpret, and translate results into clinical uses. Through research, clinicians can help to fill in the current knowledge gaps. For example, multiple studies have found that methylation levels at tumor-related genes in blood, cancer tissue, or lymph nodes were predictive for cancer recurrence and survival. More well-designed studies are needed to validate these findings and realize potential clinical use of these methylation markers.
In what areas are the most promising research advances occurring?
Dr. Hu: Despite the large number of functional and experimental studies of epigenetics coding, the functions of the epigenome are still a mystery. Further insight into the epigenome may advance our understanding of current epigenetics findings and open opportunities for new epigenetics studies.
Epigenetics epidemiology, including disease epidemiology and nutritional epidemiology offer another avenue that will increase the data available to refine analysis. High-throughput technologies have enabled epidemiologists to incorporate epigenome-wide profiling in large-scale population studies to identify disease-related epigenetic loci. Although nutritional factors play critical roles in DNA-methylation reactions, studies linking diets and nutrients to epigenetic mechanisms are very limited. Furthermore, longitudinal studies are needed to examine whether epigenetic factors mediate the association of dietary and lifestyle factors on future disease risks.
As I previously mentioned, clinical studies are needed to validate and translate epidemiological findings into diagnostic/prognostic markers, or potential therapeutic targets.
As methylation plays a critical role in early development reprogramming, studies linking prenatal factors such as diet, lifestyle, and exposures to methylation mechanisms and fetal outcomesâat birth, in childhood and later in lifeâmay help us understand how epigenetics impacts health trajectories, and may provide prevention strategies and potential intervention and therapeutic targets.
Another promising area is the use of novel DNA-methylation aging markers. Several studies have suggested that DNA methylation markers can accurately and quantitatively estimate human aging rates, and these markers have been associated with multiple disease outcomes and mortality risk.28-30 More studies are needed to understand the underlying mechanisms of such aging markers and validate their value.
What two or three points would you like attendees to take away from your presentation?
Dr. Hu: First, epigenetic mechanisms integrate the effects of genetics and modifiable risk factors, and are related to biological functions, human aging, and development of many diseases.
Second, multiple dietary and lifestyle factors may change epigenetic actions, thereby modifying the expression of disease-related genes and influencing future disease risks; maternal diet and lifestyle in pregnancy may have an impact on offspring DNA-methylation patterns, influencing their heath trajectories. Therefore, it is critically important to adopt and maintain a healthy diet and lifestyle over the course of life.
Frank Hu, MD, PhD, is professor and chair of the Department of Nutrition in the Harvard T.H. Chan School of Public Health and professor of medicine at Harvard Medical School.
