Another Example of Induced Pluripotency Reversing Mitochondrial Damage in Aging

In the past researchers have shown that reprogramming adult cells to create induced pluripotent stem cells sweeps away some specific forms of damage observed in old cells. In particular it seems to clean up damaged mitochondria, which is of considerable interest given the role of mitochondrial DNA damage in aging. It is possible that this has some connection to the aggressive cleanup that takes place in early stage embryos, stripping out damage inherited from parental cells. There may be the basis for a future therapy somewhere in here, but is also possible that finding out how to apply this sort of process in isolation to adult cells safely is going to be very hard, and the end result impractical in comparison to other technologies: if induced pluripotency as it currently stands somehow happened to many of your cells, you would certainly die.

I've linked to the open access paper rather than the publicity materials because I think that the latter are misleading as to what was accomplished and the significance of the research. The researchers theorize that the ability to restore mitochondrial function, and then break it again when you take the induced pluripotent stem cells and redifferentiate them back into ordinary cells, means that mitochondrial DNA damage is not a primary source of harm, but rather something under the influence of the state of nuclear DNA and thus some other cell process. For example, perhaps epigenetic changes in nuclear DNA are mediating the pace of replication-induced DNA damage in mitochondria.

All in all it is interesting work, and programmed aging supporters, who theorize that aging is largely caused by epigenetic changes, will no doubt find it encouraging, though I think that at this stage there are other possible interpretations of what is taking place here. For example, in how reprogramming restores function and how that function is lost again: one could proposed clearance and damage mechanisms rather than direct regulation mechanisms. The researchers are in most circumstances looking at mitochondrial function (via oxygen consumption rates) rather than at mitochondrial DNA damage, which greatly muddies the water. The two do not have a straightforward relationship, and there are any number of simple drug treatments that can tinker with the results of measures of mitochondrial function without touching the issue of damage. I'd like to see the same work done again with mitochondrial DNA damage assessments at each stage and each intervention, and also animal studies rather than just cell line studies in the case of the interventions in ordinary aged cells - which seems to be where this research group is heading in any case:

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. Our previous studies proposed that the age-associated respiration defects found in human fibroblasts are caused not by mtDNA mutations, but by nuclear-recessive mutations. However, these findings can also be explained by assuming the involvement of epigenetic regulation of nuclear genes in the absence of nuclear-recessive mutations. Here, 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.

In the case of epigenetic regulation, expression of mitochondrial respiration defects would be reversible and restorable with reprogramming. To examine this possibility, we randomly chose two young fibroblast lines and two elderly fibroblast lines and used them to generate human induced pluripotent stem cells (hiPSCs). These cells were then redifferentiated into fibroblasts and their mitochondrial respiratory function examined. We reprogrammed human fibroblast lines by generating iPSCs, and showed that the reprogramming of fibroblasts derived from elderly subjects restored age-associated respiration defects.

We also showed that age-associated mitochondrial respiration defects were expressed in the absence of either reactive oxygen species overproduction in the mitochondria or the accumulation of somatic mutations in mtDNA. One explanation for the absence of an age-associated increase in somatic mutations in mtDNA is the presence of a dynamic balance between the creation and segregation of somatic mutations in mtDNA during repeated cell division. This absence could also be a consequence of the preferential growth of cells possessing mtDNA without somatic mutations during repeated division of the primary fibroblasts obtained by biopsy. Here, however, our focus was on the causes of respiration defects expressed in elderly human fibroblast lines, and respiration defects were still expressed even after repeated divisions of cells from the primary biopsy samples. The question that then arises is: What causes age-associated mitochondrial respiration defects by epigenetic regulation?

Our findings revealed that epigenetic downregulation of nuclear-coded genes, including GCAT and SHMT2, which regulate glycine production in mitochondria, results in respiration defects. Our previous studies showed that the age-associated respiration defects in elderly fibroblasts are likely due in part to reduced translation activity in the mitochondria, but not in the cytoplasm. Therefore, defects in glycine metabolism in the mitochondria as a result of a reduction in SHMT2 and GCAT expression would be partly responsible for the reduction in mitochondrial translation, resulting in the expression of age-associated respiration defects. Because continuous glycine treatment restored respiration defects in elderly human fibroblasts, glycine supplementation may be effective in preventing age-associated respiration defects and thus benefiting the health of elderly human subjects. To confirm this hypothesis model mice deficient in GCAT or SHMT2, or both, would need to be generated to examine whether they expressed respiration defects and premature aging phenotypes and, if so, whether these disorders could be prevented by continuous glycine administration.



It has long been very obvious that mito dysfunction in the elderly is hardly at all caused by mutations (since they are too rare) and rather, by elimination, almost entirely by “deliberate” (i.e. regulated) nuclear gene expression changes, occurring as an adaptation to other things that are going wrong. That’s not to say that mito mutations are harmless though, not at all - but that their harm is via other means, such as my “reductive hotspot hypothesis” from 1998.

There is one interesting result in the paper, namely that glycine supplementation partly rejuvenates mito function - but I don’t think the authors believe that the result is robust, because they have relegated it to one sentence at the end of the results and one supplementary figure.

Posted by: Aubrey de Grey at May 27th, 2015 6:31 AM

@ Aubrey So in other words this is a downstream effect of damage or dysfunction happening upstream which is where we should be focusing on? eg, fix that and this wont be a problem? How that upstream is targeted is another matter but is this what you are driving at?

Posted by: Steve H at May 28th, 2015 7:04 AM

@Steve H: Yes :) .

Posted by: Michael at May 29th, 2015 3:30 PM

@Aubrey: Are you sure the result was not robust? Because I looked at supplementary figure 6 (it's on page 11 of the supplemental pdf) and if I'm reading it correctly the 10 days of glycine supplementation more than doubled the O2 consumption rate of the 97-year-old cell line (TIG102) so that it was back up to a bit more than half the level of the youngest fetal cell line. (TIG3S)

That sounds fairly robust to me. Or am I reading the situation incorrectly?

Posted by: MB at June 1st, 2015 2:16 AM

Counterintuitive large amounts of glycine per day makes you young again

Posted by: john mcdonald at November 11th, 2016 9:08 AM

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