#169: Lucia Aronica, PhD- How Low Carb, Ketogenic Diets Change Genetic Expression, Epigenetics

 

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About Lucia Aronica, PhD

Lucia is a researcher and instructor at Stanford University and San Jose State University. She is working with Prof Christopher Gardner on the largest study ever undertaken to compare low-carb vs. low fat with the goal of understanding how diet affects gene activity through epigenetic modifications. For this project Dr. Aronica has recently been awarded a Marie-Curie Fellowship, Europe’s most competitive research grant, scoring #1 among the applicants in the entire Life Sciences panel. Previously, she received a Hertha Firnberg award from the Austrian Science Funds, and became project leader at the Vienna-Biocenter in Austria. She has also received science communication awards from Europe PubMed Central and FameLab International. Dr. Aronica has research experience from the University of Oxford, University Federico II of Naples, University of Vienna, University of Southern California, and Stanford University. She has published research papers in top-ranked peer reviewed journals such as Cell, Genes and Development, the EMBO Journal and Nucleic Acid Research.

Connect

www.linkedin.com/in/luciaaronica

 

med.stanford.edu/profiles/lucia-aronica

Interview Show Notes

02:05 A to Z Study: Dr. Aronica is a researcher and instructor at Stanford. Her area of interest is personalized medicine, medicine that is tailored to our personal characteristics: genes, gene expression and lifestyle. The goal of the A to Z study is to understand the crosstalk between the three. She works with Professor Christopher Gardner on the largest study ever undertaken to understand low carb and low fat diets in terms of weight loss and risk of cardiovascular disease, as well as the microbiome, blood lipids, inflammation and epigenetics. It is the follow up to the A to Z (Atkins to Zone) study. More than 300 women were randomized to one of 4 diets from low carb Atkins to low fat Ornish. The study showed that no diet was better than Atkins in any category.

04:24 A to Z Follow Up: This follow up consists of 609 obese/overweight men and women. For one year participants follow either Atkins/low carb or low fat diet. Her role in the study is determining how diet influences gene expression. We think that good genes make us healthy and thin, and bad genes make us fat and sick. What if we could switch off the bad genes and turn on the good ones by making lifestyle choices?

06:11 Switching Genes On and Off: There are gene switches on the top of our DNA. The switches are influenced by lifestyle and environment: diet, stress, sleep, age, toxins and exercise. Epigenetic changes also play a role in our physiology. We have the same DNA in every cell of our body, but the cells look different. Despite having the same genes, they have different epigenetic modifications. DNA is the hardware and epigenetics is the software that enables variety.

07:54 Epigenetic Influence of Diet: Diet plays an important role in gene express. We are what we eat and perhaps what our grandmother ate. It is debated as to whether epigenetic modifications are transgenerational. Diet is what makes the difference between the queen bee in a hive and the workers. They are genetically identical, but the queen eats royal jelly. There are lots of examples of this in human and animal studies. In 1945 a famine in the Netherlands. Children that were exposed to the famine in the first 10 weeks after conception had lower methylation of the EGF gene (Epidermal Growth Factor) and they had an increased disposition to diabetes. Perhaps the genes of these children learned to cope with the famine with upregulated storage mechanisms. Sperm cells of obese men have distinct epigenetic marks compared to lean men. After weight loss from gastric surgery, their epigenetic marks became more similar to the lean men.

12:31 Heritable Epigenetics: Everything that is heritable are in the sperm or in the egg cells. We have a different epigenome for each cell in our body.

13:20 Reversible Epigenetics: Changes in epigenetics are reversible. There are two kinds of epigenetic markers: those that are permanent and those that are reversible. Permanent markers are usually established during embryonic development before birth.

15:20 Dr. Aronica’s Research Niche: She investigates how a low carb or low fat diet can change gene expression through epigenetic modifications and how the epigenetic modifications can be used to design a personalized weight loss program.

16:03 Genetic Variants and Epigenetic Modifications: Ninety-five genetic variants that are associated with the predisposition to become obese have been identified. The variants can only explain 2 percent of the predisposition. Gene expression and lifestyle make up the rest. There are 3 main kinds of epigenetic modifications: Non-coding RNA, DNA methylation and histone modifications.  Coding RNAs are messengers bringing the message of the gene to the protein. Non-coding RNAs regulate gene expression. Histones are a protein that organize the DNA within our cells. Our DNA is compactly roped around histones. The genes tightly packed are turned off. To turn them on, you need to open the chromatin using methyl and acetyl groups. In general, acetyl groups open the chromatin and methyl groups close it. Six feet of DNA is within one cell.

19:33 Ketones and Genetic Expression: Selective genetic expression differentiates cells and is controlled by expansion or contraction of histones. The main ketone body, beta hydroxybutyrate, helps with the relaxation or constriction of chromatins via inhibiting histone deacetylase. Histone deacetylases are chromatin remodelers, removing acetyl groups, therefore silencing genes. Food compounds with similar activity are curcumin, resveratrol and sulforaphane.

23:52 Royal Jelly: We humans have our own versions of royal jelly. Methyl donors, like vitamin B12, vitamin B9/folate, and methionine are found in a variety of plant and animal foods like green leafy vegetables, nuts, meat and eggs.

24:55 Weight Loss Reshapes Epigenetic Modifications: Dr. Aronica is studying DNA methylation, the addition of a methyl group on cytosines in our DNA. The cytosine receives a methyl group which will generally silence genes. Dr. Aronica measures DNA methylation in study participants before and after the study period. She also measures DNA methylation between high responders versus low responders to diet. Some people receive the benefit of a ketogenic diet on a medium carbohydrate diet and others need to far lower than that 20 grams per day.

28:40 Innovative Approach to Determining Diet’s Influence upon Gene Expression: Diet can change the expression of genes that play a role in obesity and inflammation.  A gene candidate approach is the exploration of a gene that played a role in leptin or TNF alpha. Then it was tested to see if diet changed that gene’s expression. Dr. Aronica and her team are using a discovery approach, looking genome wide at all of the genes in your non-coding regions of your DNA. This approach is much more expensive, but may lead to great discoveries in gene expression.

31:42 Research Status: Not all study participants were included in this exploration. They did genome wide methylation analysis. The data has been gathered and is being validated using pyrosequencing. This is to demonstrate that the data is reproducible using another approach. So far, Dr. Aronica sees many genes changing, some are huge changes in methylation.

34:28 Global DNA Methylation Versus Genome Wide: Global DNA methylation is not genome wide. It is a measurement within the DNA of the 30 million cytosines, the percentage of these which are methylated and which are not methylated. Genome wide can be site specific, but yet genome wide. It is a single base resolution. We see through global DNA methylation that there is a decrease in hypomethylation in cancer. Studies of weight loss and global demethylation say that there is hypomethylation and others say that there is hypermethylation. Neither are not reproducible. Study results can vary dramatically due to the study’s design, the participant subset and what questions are being asked.

39:20 Dr. Aronica Goes Low Carb: Dr. Aronica went on a successful low carb diet and read a book by Gary Taubes. She discovered his NuSI, Nutritional Science Initiative, promoting research studies to discover more about the role of fats in our diets. This lead her to her current position at Stanford. As an Italian, she had been eating a pasta-based diet, but discovered that she was gluten intolerant. She read about and went on a ketogenic diet. In less than a year, her blood was transformed. After the diet, her triglycerides dropped from 80 to 30. Her HDL (good cholesterol) went from 65 to 135. Consuming fat does not correlate to fat in our blood. Triglycerides come from carbohydrates. We can have a maximum of 1 teaspoon of sugar in our blood. When we go over this, our body transforms the sugar, including fructose, into fat via de novo lipogenesis.

46:02 Dr. Aronica’s Diet: A ketogenic diet is not only butter and meat. In general, people who limit carbohydrates eat more greens and other vegetables than vegetarians. Her diet is 50 to 60 % fat. She eats lots of low carb vegetables. She eats high carb vegetables and fruit as an occasional treat. She also eats protein: nuts, meat, fish and eggs. You need to experiment to find the diet for you. Read food labels for hidden ingredients, inflammatory foods and sugar. Dr. Aronica eats many small meals, though many people in ketosis do intermittent fasting. If you eat too much at once, even protein, you will fatigue your liver. Too much fat at once can cause its own set of issues. She finds that if she eats only 3 times per day, she over eats at one. Overeating entrains your relationship with food in negative way. Snacking is not a bad habit if you are eating good food.

53:06 Intermittent Fasting: It is useful for people who want to lose weight. It activates a lot of pathways associated with rejuvenation and long life. Fasting is not for everyone.

55:04 Gratitude: In Italy, small things are appreciated. They live in the moment. Dr. Aronica finds herself forgetting to live in the moment and appreciate small things. Diet, exercise, relationships, sharing and living in the moment and being thankful are all important.