A highly saturated fat-rich diet is more obesogenic than diets with lower saturated fat content
and is looking at this graph:
Again, this post is pure speculation. I don't even know if the lab had a janitor.
The red oval highlights a serious "That's odd" moment. With this sort of finding you can
a) Say "That's odd" and think about investigating it based on what probably happened.
b) Report it, accept that you have no idea what it is all about and say so.
c) Pretend it didn't happen, but leave the anomaly in the graph without mentioning it in the results or discussion.
d) Falsify the data.
To their credit the group took option c), as far as I can glean after making myself read the results and skim-read the discussion section. The didn't take option d), to their slight credit.
Why do I find this so interesting?
Because rats, subjected to a 40% reduction (down to 165kJ/d) in available calories from their preferred calorie intake (270kJ/d) quite suddenly, after about 10 days of clearing the food hopper, started to leave some of the full (but small) amount of offered food.
In real terms this means that, suddenly, they weren't hungry. During a 40% calorie restriction.
Just think about that.
Nothing at all is reported to have changed at the time point of the sudden drop in hunger.
Oooooh, now that's a challenge if ever I saw one. The change was transient and the rats were almost back to clearing their hopper at the time they were executed ("euthanised" under CO2 anaesthesia).
Aside: If you have an anaesthetic machine with a CO2 regulator and a cylinder of CO2 you can easily dial a 50:50 mixture of CO2:O2 and try inhaling it. I would suggest that is no fun. No fun at all. I guess the study's ethics committee have never tried this. Maybe they don't have an anaesthetic machine with a CO2 regulator to try it with. The way I used to have. End aside.
Anyhoo. Here's a Powerpoint of lines popping up on diagrams.
TLDW?
The janitor turned up the heating. Day 109.
Peter
PS this wouldn't work in humans, not even transiently. We're too big, we live very close to our thermoneutral point compared to rats.
Links to papers briefly used in the presentation.
Mouse EE graph from https://pubmed.ncbi.nlm.nih.gov/26042200/
Mouse to rat EE conversion from
Apologies for the totally off-topic question. Is this new information, and is there anything to it, about distinct subpopulations of mitochondria?
ReplyDeletehttps://www.nature.com/articles/s41586-024-08146-w
https://www.youtube.com/watch?v=QKOdGCy34Xw
Hi cave,
ReplyDeleteI'd not come across that but it fits perfectly well with the clash between ox-phos and anabolic functions of the mitochondria which Nick Lane discussed in Transformer. We also know that ATP for growth can (and is, under tissue repair for example) be derived from glycolysis in addition to ox-phos. I can conceive that sub populations exist where some mitochondria do ox-phos and some do anabolism in the same cell.
As another thought: If you assume that cancer is response to an unsuppressable growth signal then I can see a drive to subsume all mitochondria to the anabolic state, decrease cristae and use glycolysis or glutamate catabolism for substrate level phosphorylation of ADP. That might end up giving you the grossly abnormal mitochondria seen in EMs of aggressive cancer cells. Just a thought...
Peter
BTW on the Youtube page was a link to China licensing two experimental thorium reactors, so that was another rabbit hole. I seem to have been corrupted by Arnaud Bertrand on X to modify my MSM influenced discomfort about China. Though they clearly did as badly as the rest of us over Covid!
@Peter wrote: "As another thought: If you assume that cancer is response to an unsuppressable growth signal then I can see a drive to subsume all mitochondria to the anabolic state, decrease cristae and use glycolysis or glutamate catabolism for substrate level phosphorylation of ADP. That might end up giving you the grossly abnormal mitochondria seen in EMs of aggressive cancer cells. Just a thought..."
DeleteMy bias is you've got the nail close to the head.
I've looked at mitochondrial development during embryonal development and there are a lot of similarities to cancer metabolism and mitochondria.
Even look at induced iPSCs. The mitochondria aren't 'grossly abnormal' per se, given that it's a part of normal development, of PSCs, ESCs, etc, but replace 'abnormal' with 'immature' and it may be closer to the mark. Stealing from my notes:
PSCs display mitochondria that are fewer in number, immature, globular, display a perinuclear localization, contain poorly developed cristae, and have an electron-lucid matrix. In contrast, differentiated cells display mitochondria that are higher in number, mature, elongated, dispersed in the cytoplasm, contain numerous cristae, and have an electron-dense matrix. Reprogramming mature cells into iPSCs results in the remodeling of the mitochondrial network resembling the characteristics of ESCs. Studies have also observed an induction of mitochondrial biogenesis during the differentiation of PSCs.
I think the normal progression of development is unlimited proliferative potential of the cell -> mature specialized differentiated cell -> and the transition from SLP (via glycolysis in the cytosol) and mSLP (via oxidative Krebs cycle; succinylCoA -> succinate step) to OXPHOS effectively is a proliferation <-> differentiation switch. It allows the mitochondria to develop in a proliferating cell and contribute ATP and building blocks as it ferments glutamine. As mtOXPHOS develops, there's an overall or net mSLP -> mtOXPHOS shift in terms of preponderance of ATP synthesis. I think there's a lot of confusion in the embryogenesis and cancer metabolism fields because of this (researchers assume ATP synthesis in the mitochondria and the ANT working in forward mode - mtATP -> cytATP confirms to them that mtOXPHOS is driving ATP synthesis.)
Not only is there a lot of mSLP likely derived from glutamine, the ATP synthase is working in "reverse" to maintain membrane potential likely due to immature or abnormal mitochondria (or even CI degradation etc like you've mentioned Peter of Nick Lane's papers on glutahiolation.) ATP -> ADP. ATP dervide from mSLP is a "bail-in" for the mitochondria as Seyfried's colleague Christos calls it (I'll see if I can paste his fascinating talk on this...). Otherwise the mitochondria would not be able to keep the lights on and/or be unable to export ATP to the cytosol. ANT would go in reverse, feeding more ATP to the matrix, mitochondria would consume it via ATP hydrolysis at CV.
Christos's talk: https://youtu.be/rsrnlqWqhxg?si=nt9t0A7lmj9_pl6H
…continued…
…continued (sorry)…
DeleteI hadn't thought about decreased cristae in this context - but - wouldn't 'robust' cristae increase surface area, increasing the need for more robust proton-pumping activity in order to maintain MMP? Reducing cristae I think should reduce the proton demand and allow the mitochondrion to maintain voltage with fewer protons pumped accoss the IMM, no? CI, CIII, and CIV may still be semi-functional and may ease the burden on CV ATP consumption to pump protons across the IMM. (You may even see an increase in production of ATP synthases in order to more efficiently CONSUME ATP, not synthesize it.)
At least on the face of it, the title of Craig Thompson's paper you provided @cavenewt (excited to read it when I can get full text) is nothing new. ATP hydrolysis by CV is likely happening in all of us to some extent. It's not either/or. A big argument is that cancer cells use glutamine for reductive carboxylation of the TCA for lipid synthesis. That almost assuredly occurs at some level. But so too does oxidative decraboxylation and GTP/ATP synthesis at succinylCoA -> succinate in the bargain. Keep in mind that even a single miutochondrion has several ATP syhthases and there's varying mV in varying pockets of the mitochondrion. Even when things are going well in the cell, I believe you'd find most sytheisizing ATP from ADP, but a few doing the opposite when mV drops below ~150ish (see Chinopoulos, 2010 'forward operation' paper).
Christos 2010 paper: https://pmc.ncbi.nlm.nih.gov/articles/PMC2887268/
Anyway, the ROS hypothesis has opened my eyes wide to the role of mitochondria in modulating ROS and therefore - and you'll see this in relatively mainstream cancer metabolism and embryonal metabolism papers - mitochondria dictate cell fate...and the simplest explanation to me (after reading 3000 protons posts!) is most of ROS generation AFAIK is mitochondrial-mediated.
@cavenewt
ReplyDeleteI've ended up thinking that most cancers are a type of MT disease - the mutations being a result rather than the cause of cancer. (Any time we see causation in a narrative - it is good practice to consider reversing the arrow of causation as an alternative!).
Also, on my rather long list of possible causes of the T2D pandemic ( I believe the damage is permanent) is permanent changes to MT. One suspect is if we burn too much LA - perhaps chronic exposure to ROS or 4HNE?
@Petro
Excellent forensics! I wonder if the authors might comment here? What I will add to the story - the volume to surface-area ratio is why small mammals burn so much energy to stay warm - (and might make them a poor model for human carbohydrate studies - I would think they have a higher MT leakage rate) - this same ratio explains why small children get cold so fast and why 10um droplets evaporate in only a second or two ( leaving naked virions) - why the tiny parts in a cell interact differently than was supposed - wrapping ones head around the physical world inside cells is a bit non intuitive.
I only follow a few on X - Arnaud Bertrand is also on my list! The corporate news has become about 95% propaganda. I can add a bit about China (my wife and I hosted international students for some 30-years - many Chinese students). The US is spending something on the order of $1B/year on anti-China propaganda. China can be a bully - but the culture is really focused on doing business - making money. The last thing they want is to win via war. (war is very bad for business - makes EVERYONE poorer) (It is also a very high-context culture). The US wants China to become a vassal state - they don't want to. The US can't compete much anymore, but instead of looking at why(cultural collapse) - it is easier to blame outsiders.
karl, I struggle to think of a war which the USA has "won" in my lifetime. Its purpose seems more about making a few people richer by printing money they don't have to supply arms to conflicts abroad without making their own citizens' children in to canon fodder (at least since the Vietman debacle). I see the USA national debt cited as >30 trillion dollars a year ago and goodness only know how much they have spent in the middle east this last year...
ReplyDeleteOh, I guess Afghanistan was a boots on the ground, coffins in the ground scenario... my bad.
ReplyDeleteBob. You make sense. The final simplification is whether a level of ROS is the signal to grow or whether lipid derivatives are. I favour the former.
ReplyDeleteI also think of SLP as being primitive, at the level of CO2 +H2 -> CH3.COOH -> CH3.COO-P (ATP surrogate before ATP) at the end of the Wood-Ljungdahl pathway. But not glycolysis, that's highly evolved. Seyfried drives me up the wall here!
Re ROS and mitochondrial, the NOX enzymes seem to be controlled by the mitochondria too...
P
Hi Peter, acetyl phosphate, good point. Can we have similar acetate switch as bacteria? Acetate is the key.
ReplyDeleteJaromir
"The Acetate Switch"
https://doi.org/10.1128/mmbr.69.1.12-50.2005
Saved the paper.
DeletePeter said "I seem to have been corrupted by Arnaud Bertrand on X to modify my MSM influenced discomfort about China."
ReplyDeleteThanks to the whole Covid debacle, I'm modifying my MSM-influenced discomfort about a whole lot of things. I just voted for a Republican for president for the first time since 1972*. Paradigm upheavals are uncomfortable, but ultimately very liberating.
* Well, actually, I was voting for an Independent via the Republican.
Yes, in Covid the lying became utterly bare faced. I've had to examine some uncomfortable aspects of the Ukraine war too, being of Ukrainian descent. I've stopped listening to the radio at all (used to have it on for the drive to work on work days) but the crap they talk is too nauseating nowadays. Don't start me on the BBC, plant based and saving the planet. Disgusting.
DeleteIn other news, rapa increases your resting heart rate
ReplyDeletehttps://x.com/bryan_johnson/status/1857131261980270933
Mikhail Blagosklonny passed away last month. I always think of him when I see ‘rapa’ pop up. Seemed like a remarkable guy in many respects.
DeleteI also remember being struck by him grappling and trying to explain away that rapa, “puzzingly,” can induce insulin resistance. I think he literally said that rapa can induce insulin resistance without insulin resistance.
He seemed to be at Peter’s protons door but ashamed to knock on it. I’ll find it.
Fasting and rapamycin: diabetes versus benevolent glucose intolerance .
From the Abstract: “Puzzlingly, rapamycin can induce insulin sensitivity, but may also induce insulin resistance or glucose intolerance without insulin resistance. This mirrors the effect of fasting and very low calorie diets, which improve insulin sensitivity and reverse type 2 diabetes, but also can cause a form of glucose intolerance known as benevolent pseudo-diabetes. There is no indication that starvation (benevolent) pseudo-diabetes is detrimental. By contrast, it is associated with better health and life extension.”
Alt, I tend towards drugs as recreational tools. To think we're clever enough to find spanners which might fix the works seems somewhat unlikely. I'll settle for healthy ageing...
DeleteThe protons theory might be challenged if the pre-print study Johnson mentions last (but doesn't link to) is legit and rapa increases aging in humans. We shall see.
ReplyDeleteThat would be good!
DeleteThe challenge to Protons, that is!
DeleteI think this is the study: DNAm aging biomarkers are responsive: Insights from 51 longevity interventional studies in humans.
ReplyDeleteSee Figure 3.
Last time I looked into epigenetic clocks — granted, it was five years ago — I did not find them legit. And the thought of using 16 broken clocks doesn’t inspire confidence in me. I could be wrong — and perhaps we should all go on a vegan diet after we quit smoking (see Figure 3 again).
I believe at the time, Levine’s clock was presumably the “best.” That’s the same Morgan Levine who first-authored this dumpster fire with Valter Longo on the lead. It’s possible she had little to do with the worse than nonsense that occurred in that paper. But look at the people who put their names on that paper. Luigi Fontana, Pinchas Cohen, Brian Kennedy, Eileen Crimmins. These are the aging experts we’re dealing with.
I’m out of the loop as far following anti-aging peeps, but I just looked up Bryan Johnson and Gemini suggests he’s employing roughly 467 interventions simultaneously, so…
I don’t really have a strong opinion on rapa, but I think I share one with Peter which is that if one wants to intepret the results of interventions that seem to extend life in mice, they should probably consider that mice tend not to fall off ladders so frailty is not so relevant when you sit in a cage, but very relevant for humans that don’t.
Also a drug which works in the face of a 60% starch rodent diet may not work in the face of a 80% fat, low PUFA, human diet. There may be nothing left to gain...
Delete