It's amazing what you can find on the internet when you click on a link. I stumbled over this recently:
Premature aging in mice activates a systemic metabolic response involving autophagy induction
I picked up this gem of a paper from, of all places, a blog with somewhat limited enthusiasm for ketogenic eating. I'll just go through the results section of the paper, giving a staccato summary of each paragraph, because you have to be sure of exactly what a group have found before you consider whether you agree with their conclusions. These mice lack the ability to form prelamin A correctly, instead they form progerin, and they age very rapidly. Here we go with the results section:
A mutation which damages nuclear architecture and causes premature aging also increases autophagy.
The abnormal protein formed (that prelamin A precursor known as progerin) appears to be the cause of premature aging and to be associated with increased autophagy (in this model).
Other models, XPF and CSB/XPA, of rapidly aging mice (both with defective DNA repair processes) do the same thing but without accumulating progerin, especially they increase basal autophagy. So this upregulated autophagy is common to several models of premature ageing, not just the prelamin A model.
mTOR signalling is switched off. Really switched off.
The PI3K-Akt pathway, which usually activates mTOR, is not the explanation.
AMPK is switched on. Really switched on.
Stopping the response to DNA damage (p53 knockout) does not stop enhanced AMKP activity. So we are not looking at extra autophagy to recycle damaged DNA.
Next we get on to glucose. The five hour starved level of glucose is low, around 38% of control value. Insulin is low too.
In the liver things are strange.
Phosphoenolpyruvate carboxykinase and glucose-6-phosphatase are up-regulated, both are important for gluconeogenesis.
Puryvate kinase (a glycolysis regulator) is not up-regulated. So where is the glucose going if it's not going to glycolysis?
Glucose from gluconeogenesis appears to end up in the liver as glycogen granules, without needing glycogen synthase to be up regulated. This glycogen can be accessed if needed.
At the same time fatty acid producing genes are up regulated. Glucose is being converted to fatty acids. Genes associated with fatty acid oxidation are up regulated too. And a fatty liver develops. Very interesting.
Pyruvate dehydrogenase kinase-4, key for switching from glucose to fat burning, is strikingly upregulated. These mice burn fat. They reject glucose. And they die of precocious aging!
All of the "good" markers indicating longevity in many models are fantastic in these mice. The end product is early death.
Metabolically, everything appears to come down to PGC 1-alpha. It's production is very upregulated. This cofactor appears to responsible for the switch from glucose to fat based metabolism.
End of results summary.
This is where the paper stops.
On the basis of these findings a concern expressed in the discussion is that elevated PGC 1-alpha drives autophagy, which is initially adaptive but might become maladaptive when chronically activated. This is a potentially valid concern (there is an autophagy triggered form of cell death distinct from apoptosis and necrosis) but we have to bear in mind that there is zero data to support this specific concern provided in the paper. That's all of the results section summarised up above.
The authors are well aware that the reason for rapid aging is the genetic defect in nuclear architecture formation. This leads, indirectly, to genomic instability which immediately puts this model in to the same category as other premature aging models such as XPF and CSB/XPA, both of which have defects in DNA repair, also as mentioned above.
So why do the cells of these animals go in to a state of AMPK driven, mTOR inhibition dependent, persistent autophagy?
They do this because they have a severe ATP deficit. High levels of AMP per unit ATP drive AMPK.
Why is there insufficient ATP?
Let's have a read at Nick Lane's essay Mitonuclear match: optimizing fitness and fertility over generations drives aging within generations. Here's the quote:
"Oxidative phosphorylation involves the transfer of electrons through a succession of redox centres in respiratory chains, from an electron donor such as NADH, to a terminal acceptor such as oxygen. A slowing of electron transfer means that respiratory complexes become more highly reduced, which increases their reactivity with oxygen, corresponding to a rise in free-radical leak . A slowing of electron transfer is the most likely outcome of any mismatch between mitochondrial and nuclear genomes. The reason relates to the mechanism of electron transfer. If the gap between adjacent redox centres in respiratory chains is increased by just 1 A, electron transfer by quantum tunnelling slows down by an order of magnitude  and free-radical leak should rise accordingly. Given that hydrogen bonds and Van der Waal’s forces act over distances in the range of 1–2 A, it is likely that any changes to optimal subunit interactions would disrupt the distance between redox centres by more than 1 A, slowing electron flow and increasing free-radical leak. Thus, a rise in free-radical leak is the predicted outcome of virtually any subunit mismatch, and indeed has been reported [27, 28]"
Question: How well might the electron transport chain function in the mitochondria of a cell which has a permanent defect in its ability to repair nuclear DNA damage?
Answer: Three separate mouse models, engineered to have defective DNA repair, have chronically activated AMPK.
I think these mice are "starving" with full stomachs because they cannot generate ATP. They have progressive un-repaired changes to the nuclear DNA coding for (amongst many things) electron transport chain components which means these proteins simply don't fit the proteins from mtDNA.
Soooooooo. Essentially all of the changes in these mice could be traced back to inadequate ATP generation, with the added bonus of excess ROS generation to further damage the "unrepairable" DNA.
The extended autophagy is a total red herring, sort of.
I picked this paper up as a FB link "liked" by Chris Highcock. The linked blogger is so impressed by the lethal effect of autophagy that he appears to consider that diet-induced autophagy is a "worthless dogma" and avoids it, not liking dogma. That's fine by me, we all have our quirks.
Unfortunately for this autophago-phobic concept, and possibly for the poor chap himself, it turns out that if you take a prelamin A mutant mouse and treat it with rapamycin you will actually promote even MORE autophagy. So, if autophagy is the cause of premature aging, things should get worse. Yes? The actual result is that:
"Here, we report the discovery of rapamycin as a novel inhibitor of progerin [defective prelamin A], which dramatically and selectively decreases protein levels through a mechanism involving autophagic degradation. Rapamycin treatment of progeria cells lowers progerin, as well as wild-type prelamin A levels, and rescues the chromatin phenotype of cultured fibroblasts..."
or just have the title:
Autophagic degradation of farnesylated prelamin A as a therapeutic approach to lamin-linked progeria.
As an approach, it works. Further increasing autophagy rescues prelamin A mutant mouse cells. RIP autophagy as a "cause" of accelerated aging.
I like Chris a lot, he's a really nice chap. Luckily the sort of hill walking he does (still love your Pentland pictures on FB, if you read this Chris) he will be regularly and repeatedly activating AMPK with subsequently increased autophagy. Exercise does this. So does the "misery" of ketogenic eating.
Actively changing your diet to avoid autophagy, based on a progerin model which can actually be rescued by increasing autophagy, just might be a booboo. Imitate with caution.
BTW It's sort of nice looking at technical papers which (superficially) challenge my low carbohydrate biased perspective. Knowing you are in a correct paradigm makes dissecting them a rather relaxed process when you start form a position where the world makes sense. Perhaps this is dogma.