Nutrigenomics and the Future of Nutrition Proceedings of a Workshop (2018) / Chapter Skim
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2 Nutrigenomics and Chronic Disease Endpoints
2 Nutrigenomics and Chronic Disease Endpoints
Pages 11-28
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From page 11... ...
, which either do or do not exist across all cells in an organism, the epigenome changes over time and across organs and cell types. "So we have something much more difficult to deal 1 CpG is a coupling of a cytosine and guanine nucleotide in linear sequence; the cytosines in CpG dinucleotides can be methylated, unmethylated, or hemimethylated, with methylation status affecting gene expression.
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From page 12... ...
• However, mitochondria are constantly replicating, and as they do so, muta tions accumulate, the "wiring" loosens, and energy output decreases. Results of several studies suggest a central role for mitochondrial mutations and bio energetic dysfunction in human disease.
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From page 13... ...
He cited the lactase persistent gene as the classic example of this phenomenon, with different ethnic groups having more or less prevalence of the gene depending on past access to dairy products. The same is true of the fat-related APOE gene, he noted, with respect to its prevalence among groups with a hunter-gatherer versus agricultural history, as well as of alcohol-related ADH1B.
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From page 14... ...
The fact that this same pattern has been seen in six independent populations and five ethnicities across the world indicates, he said, that "this is a p olymorphism that may have a significant impact in terms of personalized recommendations." However, he again cautioned that this is only one piece of the complex nutrigenomics puzzle, which he predicted probably will not be completed any time soon. "But at least we have a better idea of where the pieces fit together," he said.
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From page 15... ...
. Ordovás then turned from the Dutch Hunger Winter, a set point in history, to parts of the world that experience yearly seasonalities, reporting that investigators have found similar changes in the DNA methylation patterns depending on the season of conception.
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From page 16... ...
. More specifically, with a 1 percent increase in EPA, individuals with the CC genotype experienced decreased methylation, increased gene expression, and increased HDL cholesterol, in contrast to the increased methylation, reduced gene expression, and lowered HDL cholesterol experienced by individuals with the GG genotype under the same conditions.
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From page 17... ...
He suspects that perhaps the problem is not the effort expended, given the trillions of dollars that have been spent trying to under stand human disease, but the basic assumptions the scientific community is making in addressing the problem. According to Wallace, the first basic assumption upon which Western medicine is premised is that disease is organ based, an assumption that goes back to Andreas Vesalius.6 For example, if one has a headache, one is 5 Voltaire was an 18th-century writer, historian, and philosopher.
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From page 18... ...
According to Wallace, however, these ideas may not be sufficient. While it is true that anatomy is encoded by Mendelian genes and that there are specific disease mutations that gave rise to the newborn screening program, he observed, this knowledge does not appear to be helping with the common complex diseases.
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From page 19... ...
, they pump protons from inside the m itochondrial matrix, across the mitochondrial inner membrane, and into the intermembrane space, thereby creating a positive, acid exterior and a negative, alkaline interior. This membrane potential can be used for many functions, Wallace added, one of which is to make adenosine triphosphate (ATP)
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From page 20... ...
, then another electron, provided by a transition metal, will bind with it to produce a hydroxyl radical, a reactive oxygen species and a potent damaging agent. Wallace noted that some people take vitamin C, vitamin E, beta carotene, or coenzyme Q (CoQ)
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From page 21... ...
Thus, Wallace said, "the tissues in our bodies are a mosaic of different mitochondrial genotypes, with different tissues having different percentages of mutant and normal mitochondrial DNAs." And as the number of mutant mitochondrial
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From page 22... ...
"We believe these are markers for mitochondrial lineages that adapted human energy metabolism to live in different environments," Wallace said. Finally, Wallace explained, as people age, they accumulate somatic mutations.
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From page 23... ...
Wallace and his team wanted to know whether a change in heteroplasmy in a cell could affect these different phenotypes, so starting with normal cells, or cells with zero percent heteroplasmy, they made what are known as cytoplasmic hybrids, or cybrids -- cells with the same nucleus but different percentages of mutant mitochondrial DNA. They characterized the cybrids physiologically, then performed RNA sequencing and examined all the transcription factors that were regulated in the different cell lines.
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From page 24... ...
. The researchers then created pluripotent cytoplasmic hybrids by, first, taking a cell with mutant mitochondrial DNA, removing its nuclei, and keeping the cytoplasmic fragment with the mutations and, second, making a female embryonic stem cell, killing its mitochondria, and then using cell fusion to substitute the mutant mitochondria (from the cytoplasmic fragment)
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From page 25... ...
"So simply converting a homoplasmic cell to a heteroplasmic cell, of perfectly normal mitochondrial DNAs," he said, "severely altered the neuropsychiatric pattern of those animals." Geographic Constraints of Human Mitochondrial DNA Wallace pointed out that because mitochondrial DNA can be transmitted only from mother to daughter, the only way it can change is by sequential mutations. So, he explained, if he were to sequence the mitochondrial DNA of any two individuals, the number of changes would be equivalent to the generations since those two individuals shared a common mother.
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From page 26... ...
Not so for mitochondrial variation." He characterized mitochondrial variation as "our adaptive e ngine. It allows us to adapt our energy to environmental changes." Wallace went on to talk about an A-to-G mutation that arose 10,000 years ago in Europe in the tRNA glutamine gene (Hutchin and Cortopassi, 1995)
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From page 27... ...
start running but fall down because of the progressive accumulation of abnormal mitochondria. The mutant mice also have been shown to exhibit highly dysrhythmic cardiomyopathy, as opposed to the wild type.
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From page 28... ...
Based on this mitochondrial view of disease, he and his colleagues are now looking at traditional Chinese therapeutics. For 5,000 years, he said, Chinese medicine has been based on the idea of Qi (Chi)
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