The mitochondria within each human cell are the energy source for the cell. Mitochondria have their own DNA which is subject to mutations during the aging process. The Mitochondrial Theory of Aging states that mitochondria become dysfunctional due to the mutations in the mitochondrial DNA.
A team of researchers from the University of Tsukuba in Japan published a study that found that the respiratory defects in mitochondria are due not to mutations in mitochondrial DNA, but to epigenetic regulation or changes in gene expression. 1
Professor Jun-Ichi Hayashi from the University of Tsukuba in Japan was the lead researcher of the study entitled: Epigenetic regulation of the nuclear-coded GCAT and SHMT2 genes confers human age-associated mitochondrial respiration defects, Scientific Reports 5, Article number: 10434 (2015) doi:10.1038/srep10434. Professor Hayashi and his team examined the function of the mitochondria in human fibroblast cell lines.
They derived fibroblast cell lines from two groups:
- Young people: Ages Fetus to 12 years old
- Elderly people: Ages 80 to 97 years old
In each age group, the researchers looked at the following:
- Mitochondrial respiration
- DNA damage in the mitochondria
The researchers expected to find reduced respiration and DNA damage in the elderly group. The elderly group did have reduced respiration yet there was no difference in the amount of DNA damage between the elderly and young groups.
These astonishing results led the researchers to attempt to reverse the epigenetic changes in the mitochondria of the elderly group. They did this by reprogramming the fibroblast cell lines from both groups to an embryonic stem cell like state. Once in this stem cell like state, they turned the cell back into fibroblasts and found that the fibroblasts from both groups had respiratory rates comparable to the embryonic fibroblast cells. In effect, they determined that the defects had been reversed .
The next task of the researchers was to determine the genes that could be controlled epigenetically to either induce or restore mitochondrial function in fibroblast cell lines. Epigenetics is the study of external or environmental factors that switch genes on and off and how cells read genes instead of being caused by changes in DNA sequence.
The researchers found two genes that regulate glycine production in mitochondria. These two genes are:
- Glycine C-acetyltransferase (CGAT)
- The degradation of L-threonine to glycine consists of a two-step biochemical pathway involving the enzymes L-threonine dehydrogenase and 2-amino-3-ketobutyrate coenzyme A ligase. L-Threonine is first converted into 2-amino-3-ketobutyrate by L-threonine dehydrogenase. This gene encodes the second enzyme in this pathway, which then catalyzes the reaction between 2-amino-3-ketobutyrate and coenzyme A to form glycine and acetyl-CoA.
- Serine hydroxymethyltransferase 2 (SHMT2)
- This gene encodes the mitochondrial form of a pyridoxal phosphate-dependent enzyme that catalyzes the reversible reaction of serine and tetrahydrofolate to glycine and 5,10-methylene tetrahydrofolate. The encoded product is primarily responsible for glycine synthesis. The activity of the encoded protein has been suggested to be the primary source of intracellular glycine. The gene which encodes the cytosolic form of this enzyme is located on chromosome 17.
These two genes affect age-associated mitochondrial defects, and by controlling them epigenetically, they could restore mitochondrial function. This was exactly what the researchers found when they administered the amino acid glycine for 10 days to the culture medium of the 97 year old fibroblast cell line.
This resulted in the restoration of the fibroblast mitochondria respiratory function. The researchers suggested that perhaps glycine supplementation could reverse the age-associated respiration defects in the elderly human fibroblasts.
The abstract from the Study concluded as follows:
“Here, we show that reprogramming of elderly fibroblasts restores age-associated mitochondrial respiration defects, indicating that these aging phenotypes are reversible and are similar to differentiation phenotypes in that both are controlled by epigenetic regulation, not by mutations in either the nuclear or the mitochondrial genome. Microarray screening revealed that epigenetic downregulation of the nuclear-coded GCAT gene, which is involved in glycine production in mitochondria, is partly responsible for these aging phenotypes. Treatment of elderly fibroblasts with glycine effectively prevented the expression of these aging phenotypes.” 2
This study suggests that mitochondrial dysfunction and senescence is controlled by epigenetic (environmental) factors. It also suggests that mitochondrial dysfunction and senescence can be reversed by epigenetic factors. Further study is required, however, in this case glycine supplementation reversed mitochondrial dysfunction.
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