Why Is There Insufficient ATP?

I picked up this gem of the paper from, of all places, a blog with limited passion for ketogenic eating somewhat. I’ll just feel the results portion of the paper, giving a staccato summary of every paragraph, because you have to make certain of exactly what an organization has found before you consider whether you trust their conclusions.

These mice lack the capability to form prelamin A properly, instead they form a protein, plus they age very rapidly. A mutation which damages nuclear architecture and causes premature aging also increases autophagy. The abnormal protein formed (that prelamin A precursor known as protein) is apparently the reason for premature aging and to be associated with increased autophagy (in this model). Other models, CSB/XPA and XPF, of rapidly aging mice (both with defective DNA repair processes) do a similar thing but without accumulating protein, especially they increase basal autophagy.

So this upregulated autophagy is common to several types of premature aging, not the prelamin A model just. TOR signaling is switched off. The PI3K-Akt pathway, which usually activates mTOR, is not the explanation. AMPK is switched on. Stopping the response to DNA damage (p53 knockout) does not stop improved AMKP activity.

So we are not taking a look at the extra autophagy to recycle broken DNA. We can get on to glucose Next. The five-hour starved level of glucose is low, around 38% of the control value. Insulin too is low. In the liver things are strange. Phosphoenolpyruvate-blood sugar-6-phosphatase and carboxykinase are up-regulated, both are essential for gluconeogenesis.

Pyruvate kinase (a glycolysis regulator) is not up-regulated. So where is the glucose going, whether it’s not heading to glycolysis? Glucose from gluconeogenesis seems to end up in the liver as glycogen granules, without requiring glycogen synthase to be up governed. This glycogen can be accessed if needed. At the same time fatty acid producing genes are governed up.

Glucose has been converted to fatty acids. Genes associated with fatty acid oxidation are up regulated too. And a fatty liver develops. Pyruvate dehydrogenase kinase-4, a key for switching from glucose to fat reducing, is strikingly upregulated. These mice get rid of fat. They reject blood sugar. And they die of precocious maturity! Every one of the “good” markers indicating durability in many models are fantastic in these mice. The ultimate end product is early loss of life. Metabolically, everything seems to come to PGC 1-alpha down. It’s production is very regulated.

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This cofactor seems to responsible for the change from glucose to fat based metabolism. End of results summary. That’s where the paper stops. Based on these findings a concern expressed in the discussion is that elevated PGC 1-alpha drives autophagy, which is at first adaptive but might become maladaptive when activated chronically. The authors are well aware that the reason behind rapid aging is the genetic defect in nuclear architecture formation.

This leads, indirectly, to genomic instability which immediately places this model into the same category as other premature maturing models such as XPF and CSB/XPA, both of which have flaws in DNA repair, as mentioned above also. Why do the cells of these animals go directly into a state of AMPK driven, mTOR inhibition dependent, persistent autophagy?