I've also got a number of ideas I want to get written down about the differences between hydrogenated coconut oil driven obesity and linoleic acid driven obesity. Plus I'm about to run out of free time in the very near future so argh...
Anyhoo, Tucker sent me the link to this discussion he and Brian Kerley had with Dalton Graham.
As in
Ability of high fat diet to induce liver pathology correlates with the level of linoleic acid and Vitamin E in the diet
discussed in a slightly tangential way here
Insulin mimesis without NOX enzymes (5) MCT plus linoleic acid
Which gives me about four more things I'd like to blog about but might not get time for. Especially listen to what chow does to liver fat content in the long term and about unpublishable but highly enlightening observations. Oh, and a shared view of peer review. Oh and what it's like to be junior linoleio-phobe in a conventional lab. Oh, and... Never mind, just give it a listen:
11 comments:
Quite interesting. One takeaway - something I have known for a while - is that using a standard chow as the control is not real science.
Both the control and the variable diet have to be tightly control.
To do a real diet study - you would need a diet that is tightly controlled and then add (or subtract) the variable from it. Sadly, this is rarely done..
Yes!
The chow, often ~7% LA, still gives NAFLD but in slow motion. High fat diets supply the fats ready to esterify in to trigs, appears to be a faster easier process.
Peter
Thanks to many years of reading Hyperlipid, I've learned to view control chow as another variable in an experiment. Dittos cell culture substrate, if that's the right term.
Has anyone ever done a study comparing lab chow to a natural diet, and the effect on rat/mouse health and longevity? That might be interesting.
Slightly off topic: Peter, are you familiar with Bret Weinstein's mouse telomere theory? I guess he tried to publish it, or did publish it, around 2000, and was pretty much dissed. Apparently someone has now independently proposed or demonstrated the same idea, that telomere length determines the ability of an organism to heal (or something to that effect) and lab mice have unnaturally long telomeres, making them, for instance, more resilient to pharmaceutical abuse, with obviously impact on the validity of pharmaceutical tests. He brings that up often in his podcast and I've been wondering what you thought about it.
Hi cave, Re Brett Weinstein, karl sent me the link to
https://odysee.com/@BretWeinstein:f/bret-and-heather-188th-darkhorse-podcast:b
and I went back to the previous podcast they mentioned and also downloaded the 2002 paper via our lovely Kazakhstan facility. I also have seen extreme criticism of his concept on X-Twitter, which makes me feel it has some credibility. My main problem is that it appears to tell us a great deal about the potential cause of death in old age but less about the age at the time of death.
The game changer for peak longevity (in mice) is growth hormone signalling, with the cost being dwarfism. But a sideways approach is to minimise insulin signalling which controls the induction of IGF-1 in the liver (at least) in response to a given level of GH production from the brain.
So interesting but not fundamental. Overall I would be loathe to consider a telomerase blocker or agonist as a longevity drug. Or accept a telomere length change as being a surrogate for an intervention being Good or Bad.
Re wild rats vs chow. Trying to decide what a wild rat diet might be is not as simple as it sounds. You would need a non-human modified environment where wild rats are in a stable relationship to that environment. Doesn't sound easy.... There might be multiple such environments or none!
Peter
As per the telomerase ideas, it is attractive to craft a simple narrative of how it works. Real biology has other ideas - wrapped in these feedback/control loops is the total history of evolution - hyper-complexity is the rule - not the exception.
My current thinking is to look at the MT-N-epistasis(Mitochondrial–nuclear epistasis) - but we don't know much. This match of DNA might give hints to what matters with the telomerase saga as well? I'm also thinking that some of the match has to do with which haploid zygotes get selected. (Fertility seems to be the first thing to go in hybrids where MT-N-epistasi tends to be mismatched).
Asexual and sexual propagation both have advantages - Right now I'm thinking that the male haploid zygotes are taking the role of asexual competition - running a gauntlet that selects for the fittest.
Savanna cat hybrids end up with sterile males all the way to the F4 generation. Sadly, all I'm finding a vague hints that this about the MT.
What makes this appealing is the small size of the MT-DNA - on the other hand, knowing which N-DNA matters is another huge puzzle. I do think that attempts to understand MT-N-epistasis may illuminate our understanding of MT including the telomerase-length riddle.
I do think Weinstein's has a valid point that using mice with abnormal telermerase length is not a valid drug safety screen.
Hi karl,
I haven't had chance to read Lane's N-Mt DNA mismatch paper so don't really feel up to speed there. But re control systems you might enjoy this paper I was alerted to by Tucker. It's fascinating and metabolic control is slightly complex....
Metabolic sensing and control in mitochondria
https://www.cell.com/molecular-cell/fulltext/S1097-2765(23)00119-3
Peter
“I also have seen extreme criticism of his concept on X-Twitter, which makes me feel it has some credibility.” 🤣
“I do think Weinstein's has a valid point that using mice with abnormal telermerase length is not a valid drug safety screen.” On the couple of podcasts where I've seen him talk about it, that has been his main concern. Not even so much that he gets no acknowledgment for his earlier work on it, although he always does point that out, rather understandably.
I've started following him on Twitter. He makes a lot of sense. You can never agree 100% with anyone but I do like his outlook.
Peter
I also appreciate that he freely admits he was completely taken in by Covid panic at the beginning. Some of his podcasts from that time have him praising bandannas for masking, etc.
@Cavenewt
One of the things that separates a good scientist from those that merely parrot narratives is true scientists change their opinions as new data becomes available - the parrots tend to double down in order to save face. I've thought that some system to encourage researchers to publicly proclaim errors would help science. (A good MD is a scientist - but they are socialized to never admit errors or ignorance. The public would disagree, but a MD that tells you he isn't sure what to do is a good sign)..
One of the tells that our institutions have failed is the lack of humility - no one backs up when things go wrong.
,.,.
I'm troubled that as I age, groking new information is slower than it used to be. Not sure it is all my fault. There is way to much in papers in the pattern of needlessly multiplying terminology (an example - the huge number of terms given to blood clots) - I think much of this has to do with egos rather than science.
,.,.
I'm thinking again about asexual vs sexual reproduction - and MT use asexual reproduction, but it is possible that N-DNA controls may be part of managing which MT succeed and which are eliminated. So for cells with few MT the accumulation of dysfunctional mutations seems a problem. (I've wondered if some ability to pick and choose MT by the N-DNA run cell might exist? Some gauntlet that MT have to run in order to replicate?)
,.,.
But if I reframe MT-N-epistasis as a symbiotic relationship - I sense a bias for N-DNA control of MT in the papers - where the opposite is also true. (That MT are key for apoptosis seems part of this balance of power?).
Karl—“One of the things that separates a good scientist from those that merely parrot narratives is true scientists change their opinions as new data becomes available - the parrots tend to double down in order to save face. I've thought that some system to encourage researchers to publicly proclaim errors would help science.”
In a footnote at the end of chapter 2 of Transformers, Nick Lane says “Peer review is often lionised as the ‘gold standard’, and at its best can indeed work extremely well. But it is also intrinsically conservative, as long argued by Don Braben (I would strongly recommend his books, notably Scientific Freedom). The problem is twofold. First, peers are frequently antagonistic towards each other, as they are by nature competitors (or, just as bad, collaborators) for fame and fortune (papers and grants), all of us being human. Second, any revolutionary ideas, by definition, overturn the applecart, meaning the lifetime achievements of peers are diminished, even disproved. The greatest of scientists – the greatest human beings – will put their own emotions aside, stand on a soapbox, and proclaim their errors and misinterpretations. But it’s normally less clear-cut than that, and as we’ve seen here, scientists often fail to rise above our own baser instincts. For these reasons, Braben argues that we need to develop better ways of assessing radically new ideas in science – the kind that lead to fundamentally new ways of seeing the world, and which did so much to revolutionise our understanding of life, the universe and everything in the twentieth century.”
Sounds like Braben might be worthwhile reading.
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