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Surprising Findings about Your Ancestors, Obesity and Diabetes

New research shows that your health is related not only to what you eat but to what your grandparents ate, what your parents ate, and what you ate in the earliest days of your life—with more discreet differences based on your gender plus your genetic profile and your particular array of gut microbes. The story of these surprising findings began in The Netherlands during World War II.

THE DUTCH HUNGER WINTER
After Germany occupied Holland in 1940, in an attempt to hinder German military initiatives the exiled Dutch government ordered a national railway strike. As retaliation, in October 1944 German authorities blocked all food supplies to the occupied West of Holland. Until that blockade, nutrition among the Dutch had generally been adequate. But from October 1944 food was scarce, and by November 26, 1944, official rations were limited to bread and potatoes, offering less than 1,000kcal per day. By April 1945, rations had dwindled and kcal per day was just 5001.

In the 1970s Zena Stein and Mervyn Susser, epidem-iologists2, read about that period of nutritional deprivation and wondered whether the children of famished pregnant mothers had different health outcomes from those whose mothers were not undernourished during pregnancy. The authors drew on Dutch Second World War birth and death records and in 1975, with colleagues, they published Famine and Human Development: the Dutch Hunger Winter3

The findings were exciting. Where a mother had suffered famine only during the first weeks of her baby’s gestation, the baby’s birth weight was normal but in later life that same child had greater tendency to obesity than either a child born before the war or a child whose mother had started going hungry well into pregnancy. That study called into question the presumption that your lifestyle choices, including to a large extent what you eat, are the principle influence on your health outcomes. And, early findings presaged what scientists later confirmed: organs and cells respond to nutrition by marking the genome, and some of those responses are stored in the genome as epigenetic memory4,5.

YOU ARE WHAT YOUR GRANDPARENTS ATE
Geneticists Marcus E Pembrey at University College London and Lars Olov Bygren at Umeå University, Umeå, Sweden queried archives and living descendents of Overkalix, a small, isolated, impoverished Swedish village near the Arctic circle—a part of the world that is vulnerable to crop failure and severe famine—where village elders had kept meticulous records over the centuries of birth, deaths and harvests6.

Scientists found a strong link between a grandfather’s food supply and his grandson’s chance of diabetes death, as follows: grandson was four times more likely to die of diabetes/diabetes-related illness if grandfather had plenty to eat in his own late childhood.

This finding was the first to suggest that environmental exposure in men directly affects male offspring. And with that, the straightforward cause-and-effect role of one’s daily diet became a lot more tenuous, and the questions about nutrition and genetics a lot more complex.

The researchers were homing in on sensitive periods of development. And, to make the picture even richer—and more exciting, we think—further analysis showed that among the nutritionally impoverished, the sensitive developmental period is different for a male and for a female. The grandmother, it seemed, was susceptible while she was still in the womb; the grandfather was susceptible in late childhood. Perhaps, if not probably, epigenetic marking is related to the formation of egg—during early prenatal life—and sperm, during the transition to puberty.

Of further interest from this study? Grandsons of men who experienced famine at age ten lived longer than those that who had plenty to eat as a ten year old. This curious note brings to mind the idea of calorie restriction, which is the only intervention known to extend mammalian life7. Yet the granddaughters died far earlier if their grandmothers experienced famine in the womb. So, the grandsons of men who endure famine live longer, while the granddaughters of women who endure famine are shorter lived.

It seems that the impact of famine (or any nutritional state in fact) is captured in the egg and sperm and retained, passed along to influence offspring two or more generations later8. Well then, how much does what we eat in our own lifetime affect our health? Or what our mothers eat? The impact is fundamental, Robert Waterland told us.

image1YOU ARE WHAT YOUR PARENTS ATE
After reading the Dutch Hunger literature, Professor Robert Waterland, Associate Professor of Molecular and Human Genetics at Baylor College of Medicine and Associate Professor, Department of Pediatrics; USDA/ARS Children’s Nutrition Research Center in the United States, set out to study the relationships among diet, behaviour and weight in early life. He specu-lated that dietary deficiency of methyl donors such as folate during post-weaning development would cause hypomethylation of DNA, and therefore dysregulation in a growth factor locus.

He took as a working assumption that nutrition during development may induce persistent changes in the epigenetic regulation of genom-ically imprinted genes. He found that indeed this was the case. And for the first time, demonstrated this in vivo8.

One of the most surprising—and we think potentially significant—findings was the epigenetic impact of three diets: a natural diet, a synthetic diet with comparable levels of methyl donors and synthetic diet without methyl donors. Professor Waterland assumed that of the three, only the methyl donor-deficient diet would produce the dysregulated state. But, only the natural diet resulted in normal epigenetic outcomes. Even the methyl donor-rich synthetic diet did not produce the properly methylated state.

Why did an ostensibly nutritionally-replete synthetic diet early in life cause persistent changes in gene expression? What are the implications of this for processed “modern” foods? Synthetic dietary supplements? No answers yet, though clearly, mimicking mother nature can be tricky.

From here Professor Waterland turned his eye directly on obesity. He knew that, in mice, obese agouti viable yellow mothers produced offspring that tended to obesity. He set out to identify the developmental timing and physiological basis of the obesity-promoting effect.

In this study9, he and his co-workers found that female offspring of obese mothers became obese in adulthood, but male offspring did not—in the females fetal growth restriction was followed by adult-onset obesity.

The central analysis focused on the female wild-type offspring, which interestingly did not have an abnormally increased appetite that fueled their obesity. The source of their obesity instead appeared to be their blunted activity.

The implications are as curious as they are fascinating. In the lab, female mice are more physically active than males. They choose to run on the wheel more often than the males, and in general are more spontaneously active. This finding suggests that fetal growth restriction affects some developmental pathway that changes the female’s natural drive for physical activity.

In a further groundbreaking observation in the same study, Waterland’s group showed that the obesity-promoting effect definitively occurs during fetal development and not during early life. Shortly after birth, litters of lean and of obese mothers were cross-fostered. An obese female’s lactation is impaired, which results in persistent stunting of the offspring, yet even when reared by a lean, fully-lactating mother, the offspring of obese females still became obese in adulthood. It appears the pattern of fetal growth restriction followed by sufficient nutrition causes a developmental mismatch, and in adult females, obesity prevails.

It has been found that there is a similar pattern in humans. Humans who are growth restricted in utero show a greater risk of metabolic syndrome/type 2 diabetes as adults. It is postulated that the suboptimal uterine conditions create limited nutrition, so the fetus redistributes blood flow to help in the development of vital organs. This is called the brain-sparing effect9.

But what is altered in these patterns? Professor Waterland is hunting for the answers. His hunch is the hypothalamus10 and he is now on the path to discover the source of dysregulation through the neuronal development of this brain structure, which links the nervous and endocrine systems. The hypothalamus coordinates hormonal and behavioural phenomena, including food intake, energy expenditure and circadian rhythms.

image2YOU ARE WHAT YOU (AND YOUR BACTERIA) EAT
When you eat, food gets broken down in the stomach and then passes to the body’s sorting centre, the gut, whereby enzymes from the pancreas and the gut break it down further. The gut’s prodigious bacterial population, called the microbiota, processes what remains by fermentation and sends the results out to nourish your body.

What’s important here is that optimum function—processing, extracting nutrients and absorption by the body—all depend on processing by the entire gut, which is quite long and varies in its bacterial populations from one segment to the next. Furthermore, what is broken down, and where, may provoke epigenetic responses in your genome and that of your gut bacteria.

Here’s why this matters to health. The human intestinal system evolved when people ate food in a natural state, like leaves, fruits, whole grains and roots. These are fibrous, and the gut digests them in several stages. So each section of the gut progresses digestion and each section of the gut has specific microbial populations dedicated to their part of the task. Collectively the whole is designed to extract maximum nutritional benefit from what we eat.

But what happens if you consume food that doesn’t require the multi-phase digestion? For example, what happens when you eat simple sugars and starches and highly processed foods that all break down quickly, such that digestion finishes in the upper gut?

The processing essentially acts as a pre-digestive, which leaves much less digestion to the intestines and the gut bacterial population begin to alter. Imbalances can mean overpopulation of deleterious microorganisms that make people feel, and often get, sick.

Research has shown that a properly balanced gut microbe population is the key to a healthy immune response; and, interrupted processing causes a host of negative changes including inflammation, altered hormonal release and undesirable epigenetic changes.

“The gut is what modern nutritional science is about”, Dr Michael Müller, Professor of Nutrigenomics and Systems Nutrition at the University of East Anglia and head of the Food and Health Alliance, told us. Professor Müller studies the impact of food on epigenetic mechanisms, and he is especially concerned about the effect of food choices on chronic disease.

“The ways to keep the gut healthy are simple and time-tested. Eating slow foods—foods that take time to digest over the length of the gut, feeding all the various microbiotic populations, not only sustains health, but triggers greater satiety. Incorporating fermented foods into our diets directly supplements our microbial gut populations. Even feeding our microbiota directly is now considered part of the path to sustained good health”.

Only one day of dietary change—shifting from an animal-product diet to a plant-based diet, for example—shifts the diversity of the gut microbiota11. “We need to re-learn how to consume plant foods”, Dr Müller says with a good deal of passion. “Plant-based diets confer gut health, but also play a larger role. Plants have internal defences to keep themselves protected from being eaten by insects. For example, a secondary plant metabolite causes the plant to have a bitter taste. This metabolite creates a response in our human bodies—it is stress inducing—and upregulates our chemoprotective mechanisms. Transcription factors recognise this and upregulate the antioxidant response. So the hormetic effect appears to be a large part of our homeostasis, and larger health dynamic.

“The older we get, the more the protective mechanisms slip, inflammation goes up and we lose resistance to disease”. If our guts are not protecting us and working with us, we will succumb to aging and disease much more quickly. “Ideally there is a dietary protocol for every individual based on these responses and keeping the microbiota active and in balance. This will be the new medicine”.

NEW MEDICINE
But what of the future? Obesity is 27.7% in the US and climbing rapidly, 22% in Europe, and rising fast in China and India, not to mention rates of diabetes. Fetal development and the first 1,000 days of life are the most important time, the days of greatest plasticity. Everything is essentially programmed from there; certainly there is still room for impact and for change, but there is much less flexibility after this.

A majority of the literature and calls-to-arms is about how to move forward with treatment. But with the work of these two investigators, we can clearly see that the causes are deeply seated in early life development, and only further disturbed by the modern diet. This substantially changes the nature of the traditional concept of “treatment”.

Prevention and metagenomics are, it seems, the way ahead. That means you have a personal profile of your epigenetic marks and your microbes, how you got them through birth and breast feeding, your first foods, episodes of antibiotic use—which collectively shapes the gut, and therefore long term health. In our view, the more we adapt to seasonal food patterns, diversity of diet and whole foods, the better our chances for health for ourselves and our children.

Presently Dr Waterland is collaborating with Richard Simerly at University of Southern California in the US to study epigenetic mechanisms regulating the formation of hypothalamic neuronal pathways12. In an attempt to disentangle the methylation patterns associated with healthy pathways and healthy gene expression in foetal and early post-natal life, they will be profiling DNA methylation in genes that regulate differentiation of specific classes of hypothalamic neurons. If this team can build a picture of the dysregulation—the epigenetic marks on genes that alter neuronal development that lead to obesity—perhaps they will be able to find a way to normalise these patterns before they affect the developing child.

Professor Waterland is an optimist. He is betting that it is possible to modulate the mechanisms of disease, because epigenetic mechanisms are inherently malleable. “It might be possible, for example, to prescribe pro-methylation supplements during critical developmental periods, to prevent the epigenetic dysregulation (obesity) from continuing”, he says. “In time we will find the answers that will help break the trans-generational cycle of obesity”.

REFERENCES

  1. Lumey, LH, Stein, Aryeh D, Kahn, Henry S et al. Cohort Profile: The Dutch Hunger Winter Families Study. International Journal of Epidemiology, Volume 36, Issue 6 pp. 1196-1204. http://ije.oxfordjournals.org/content/36/6/1196.full#ref-2
  2. Smith, George Davey and Susser, Ezra. Zena Stein, Mervyn Susser and Epidemiology: Observation, Causation and Action. International Journal of Epidemiology, Volume 31, Issue 1, Pp. 34-37. http://ije.oxfordjournals.org/content/31/1/34.full
  3. Stein, Zena; Susser, Mervyn; Saenger, Gerhart; Marolla, Francis. Famine and human development: The Dutch hunger winter of 1944-1945. New York, NY, US: Oxford University Press. (1975). xx 284 pp. http://ije.oxfordjournals.org/content/36/6/1196.full#ref-2. http://www.pnas.org/content/107/39/16757.full.pdf
  4. Kelly, H and Kelly, Laura E. Can Life Experience Shape the Genes We Pass Along? ALN World. http://www.alnmag.com/articles/2014/06/can-life-experience-shape-genes-we-pass-along
  5. Heijmans, Bastiaan T., Tobi, Elmar W, Stein, Aryeh D. Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc Natl Acad Sci U S A. Nov 4, 2008; 105(44): 17046–17049. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2579375/
  6. The Ghost in Your Genes: The scientists who believe your genes are shaped in part by your ancestors’ life experiences. http://www.bbc.co.uk/sn/tvradio/programmes/horizon/ghostgenes.shtml
  7. Heilbronn, Leonie K, de Jonge, Lilian, Frisard, Madlyn DeLany, James P. Effect of 6-mo. calorie restriction on biomarkers of longevity, metabolic adaptation and oxidative stress in overweight subjects. JAMA. Apr 5, 2006; 295(13): 1539–1548. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2692623/
  8. Waterland, Robert A., Lin, Juan-Ru et al. Post-weaning diet affects genomic imprinting at the insulin-like growth factor 2 (Igf2) locus. Human Molecular Genetics. 2006 Mar 1;15(5):705-16. Epub 2006 Jan 18. http://www.ncbi.nlm.nih.gov/pubmed/16421170
  9. Baker MS, Li G, Kohorst JJ, Waterland RA. Fetal growth restriction promotes physical inactivity and obesity in female mice. Internal Journal of Obesity (London). 2013 Aug 8. doi: 10.1038/ijo.2013.146. [Epub ahead of print]. http://www.nature.com/ijo/journal/vaop/ncurrent/full/ijo2013146a.html
  10. Roza, Sabine J., Steegers, Eric A. P., Verburg, Bero O. What Is Spared by Fetal Brain-Sparing? Fetal Circulatory Redistribution and Behavioral Problems in the General Population. International Journal of Obesity (8 August 2013) | doi:10.1038/ijo.2013.146. http://aje.oxfordjournals.org/content/168/10/1145.long
  11. David, Lawrence A., Maurice, Corinne F., Carmody, Rachel N. Diet rapidly and reproducibly alters the human gut microbiome. Nature 505, 559–563 (23 January 2014) doi:10.1038/nature12820. http://www.nature.com/nature/journal/v505/n7484/full/nature12820.html
  12. Waterland, Robert A. Early Nutritional Influences on Hypothalamic Developmental Epigenetics and Energy balance. 7th Annual Meeting of the International Society of Nutrigenetics and Nutrigenomics, Québec City 2013. http://quebec.isnn2013.org/wp-content/uploads/2013/11/S24-Waterland.pdf

ADDITIONAL READINGS

  • Li G, Kohorst JJ, Zhang W, Laritsky E, Kunde-Ramamoorthy G, Baker MS, Fiorotto ML, Waterland RA. Early postnatal nutrition determines adult physical activity and energy expenditure in female mice. Diabetes. 2013 Aug;62(8):2773-83. doi: 10.2337/db12-1306. Epub 2013 Apr 1.
  • Nielsen, H Bjørn, Brunak, Søren, Ehrlich, S Dusko et al. Identification and assembly of genomes and genetic elements in complex metagenomic samples without using reference genomes. Nature Biotechnology, 2014; DOI: 10.1038/nbt.2939

Laura E. Kelly L.Ac is a Primary Care Physician in Los Angeles, California in the US. She is presently undertaking a research project on the epigenetic effects of the immortality herbs in the Chinese materia medica. LauraKellyLAC@gmail.com

Helen Kelly is an ALN World Contributing Editor reporting on news in biomedical science, health and management worldwide. HelenKellyLtd@aol.com

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