Abstract
Age-associated accumulation of somatic mutations in mitochondrial DNA (mtDNA) has been proposed to be responsible for the age-associated mitochondrial respiration defects found in elderly human subjects. We carried out reprogramming of human fibroblast lines derived from elderly subjects by generating their induced pluripotent stem cells (iPSCs), and examined another possibility, namely that these aging phenotypes are controlled not by mutations but by epigenetic regulation. 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.
Highlights
Age-associated accumulation of somatic mutations in mitochondrial DNA has been proposed to be responsible for the age-associated mitochondrial respiration defects found in elderly human subjects
Because we observed no age-associated overproduction of mitochondrial reactive oxygen species (ROS) and no age-associated accumulation of somatic mutations in the mitochondrial DNA (mtDNA) of the human fibroblast lines we used (Fig. 1b and c), neither was associated with the mitochondrial respiration defects found in the fibroblast lines derived from the elderly subjects (Fig. 1a)
These age-associated phenotypes found in elderly fibroblasts are regulated reversibly and are similar to differentiation phenotypes in that both are controlled by epigenetic regulation, not by mutations in either nuclear or mtDNA
Summary
Age-associated accumulation of somatic mutations in mitochondrial DNA (mtDNA) has been proposed to be responsible for the age-associated mitochondrial respiration defects found in elderly human subjects. The mitochondrial theory of aging proposes that age-associated overproduction of reactive oxygen species (ROS) and the resultant accumulation of somatic mutations in mtDNA are responsible for aging phenotypes including age-associated mitochondrial respiration defects[1,2,3,4,5]. These findings can be explained by assuming the involvement of epigenetic regulation of nuclear genes in the absence of nuclear-recessive mutations We addressed these controversial issues by reprogramming fibroblasts derived from elderly human subjects and examining whether age-associated mitochondrial respiration defects could be restored after the reprogramming
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