--- Log opened Sat Jul 27 00:00:05 2024
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01:56 < nsh> (yet this witness this alleged brain functionality)
02:36 < hprmbridge> kanzure> what exactly has this "peak performance" of his accomplished
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07:19 < docl> peak? where'd you get that notion? he's barely hanging in there
07:35 < hprmbridge> kanzure> hm? he says he performs better when calorie loading. so let's see it.
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08:11 < L29Ah> he wrote the sequences back when he was fat, no longer writes much i think
08:11 < L29Ah> https://manifold.markets/levifinkelstein/if-eliezer-yudkowsky-committed-to-d
08:11 < docl> he didn't say anything along about 'calorie loading' there
08:14 < hprmbridge> kanzure> writing a bunch of text is something that almost everyone can do
08:15 < docl> where are you getting that he bragged about his intelligence being higher when he's overeating?
08:15 < hprmbridge> kanzure> facebook, I think. it's been a long time so I don't have the reference.
08:19 < docl> ah, that makes more sense. I had the impression he was just talking about not experiencing atypical cognitive impairment from calorie deficit.
08:21 < docl> isn't sugar considered a mild nootropic?
08:34 < L29Ah> a mild stimulant for sure
09:47 < docl> maybe it's only mild in most people (or most gut microbe colonies)
09:50 < docl> plot device: limitless drug but it's table sugar and only works for a tiny fraction of people and only if they eat so much they grow morbidly obese if not seriously athletic
10:14 < docl> > Doing what I consider okay work means eating enough (if I target it just right) to be "not that hungry during the day; going to bed hungry, but not so starving that it interferes with sleep".  That corresponds to gaining 1 to 2 pounds per week.
10:15 < docl> sounds like it's also connected to a sleep disorder that gets worse when he goes to bed hungry
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11:26 < docl> hmm... when you donate plasma, there's this machine that ends up clogging with fat from your blood. what if you just put the plasma back in and repeat the process several times a day? might be safer / cheaper than liposuction
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11:28 < L29Ah> you only get lots of fat in your blood at times you eat lots of fat iirc
11:30 < hprmbridge> Eli> Fat in your blood? Cholesterol?
11:30 < docl> https://en.wikipedia.org/wiki/Apheresis
11:31 < jrayhawk> excess calories are converted to fat for storage and need to get transported somehow
11:31 < docl> yeah, I just remember seeing it clog up the lines if I ate something fatty beforehand. drinking water would help. I think probably LDL
11:31 < jrayhawk> cholsterol is fat-soluable. it is not itself fat.
11:32 < docl> oh, that makes sense
11:34 < docl> so it'd probably be a mix of choleterol+fat
11:39 < docl> if you inject nonfatty LDL would that pull fat from adipose into the blood?
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11:41 < hprmbridge> Eli> I think the fat in your blood is called cholesterol.
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11:42 < jrayhawk> Cholesterol is a different molecule exported along with fatty acids in lipoproteins.
11:43 < docl> https://my.clevelandclinic.org/health/articles/23229-lipoprotein has a picture
11:43 < docl> so it's these big cholesterol esters with a phospholipid layer
11:45 < docl> .wik Lipoprotein
11:45 < saxo> "A lipoprotein is a biochemical assembly whose primary function is to transport hydrophobic lipid (also known as fat) molecules in water, as in blood plasma or other extracellular fluids." - https://en.wikipedia.org/wiki/Lipoprotein
11:46 < docl> "With a size ranging from 5 to 17 nm, HDL is the smallest of the lipoprotein particles.[2] It is the densest because it contains the highest proportion of protein to lipids.[2] Its most abundant apolipoproteins are apo A-I and apo A-II. A rare genetic variant, ApoA-1 Milano, has been documented to be far more effective in both protecting against and regressing arterial disease, atherosclerosis."
11:48 < jrayhawk> re: safer/cheaper than liposuction: the hypothalamus homeostatically regulates adipose tissue in terms of "what amount of energy is needed to support Y amount of lean mass for X days" where X is measured in terms of inflammatory cytokines (IL4, IL6, NF-κB, TNF-α, etc). Lowering adipose tissue without doing anything about inflammation will upregulate appetite to restore adipose tissue and/or 
11:48 < jrayhawk> decrease lean mass and activity to lower burn rate.
11:50 < docl> so then if you remove LDL and inflammatory cytokines from the blood plasma then return it to the blood, you could lose weight
11:58 < jrayhawk> if you're removing cytokines, there's not much point to removing lipoproteins. appetite would already be downregulated.
11:59 < jrayhawk> additionally, those cytokines exist to manage pathology, so you're dealing with allopathy at that point
11:59 < jrayhawk> the thing to do is to remove the pathology
12:02 < docl> well I'm told it's risky to just nuke the whole gut microbe population, so how?
12:03 < jrayhawk> the low-hanging fruit is to begin evaluating food quality in terms of immunological safety, oxidative safety, micronutrient concentration and micronutrient biolavailability
12:05 < jrayhawk> which you have no natural instincts to do and which nobody is appropriately incentivized to do for you.
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12:09 < hprmbridge> Eli> Docl, people who want to lower cholesterol and triglycerides in their blood often start with statins and ezetimibe. But your body can synthesize fat via glucose. It doesn’t need fatty acids to flow through the blood stream. And those fatty acids can get recycled or removed from the blood already, from what I understand. If you want to lose fat, there are tried and true methods
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12:14 < docl> are there drugs that block fatty acid synthesis? could these be targeted to adipose tissue?
12:15 < jrayhawk> appetite would still be upregulated and/or lean mass and energy expenditure downregulated in that case
12:16 < docl> don't fat cells produce inflammatory effects when they have too much fat in them? this seems like a feedback loop maybe
12:17 < jrayhawk> Oxidative damage from linoleic acid is dealt with by neutrophils and macrophages that involve a bunch of IL-6 signaling
12:18 < jrayhawk> it is wiser to conceptualize that as "the wrong form of fat" rather than "too much fat"
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12:20 < jrayhawk> it is a mostly linear effect that acts as a minor positive feedback cycle on adipose tissue homeostasis in most cass.
12:20 < docl> could you dampen or localize the IL-6 signalling to break the feedback loop maybe? 
12:23 < jrayhawk> dampening the IL-6 would downregulate neutrophils and macrophages and leave peroxidation products of fatty acids unmanaged to cause further recursive lipid peroxidation
12:24 < jrayhawk> additionally, the problems the adipocytes are dealing with are a preview of the problems every other cell in the body inherits as fatty acids get incorporated into phospholipid bilayers
12:25 < jrayhawk> over the course of the next decade
12:32 < jrayhawk> the "mostly linear" "minor positive feedback" can get out of hand in morbid obesity and/or micronutrient deficiency as oxidative damage exceeds defense. there is something to be said for naive interventions like liposuction in that case.
12:35 < jrayhawk> but that's that's "world's fattest people" territory, not the common case
12:35 < docl> think there's any merit to my idea that some gut microbes evolved to create a food rich environment by making their host morbidly obese? could take an inflammatory route
12:37 < jrayhawk> some species have a comptitive advantage in an inflammatory environment, such as h. pylori
12:37 < docl> the key thing would be novel evolutionary pressure, i.e. it's easier to overcome economic counterpressures, particularly where cheap carbs are concerned
12:38 < docl> am thinking it's not something our species has typically had over decades-long timescales before
12:41 < jrayhawk> We exploited sedge tubers pretty aggressively in the transition to savannah 2-3m years ago as seen from increasing amylase copy number variation and carbon isotope ratios
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12:44 < jrayhawk> re: gut bacteria screwing over the host for their benefit: archaea produce methane that inhibits peristalsis, retaining more fecal matter to ferment (to create even more methanogenic archaea)
12:50 < docl> maybe narrow-spectrum antibiotics in suppository form could help? monoclonal antibodies?
12:52 < jrayhawk> it's difficult to make targeted change due to biofilms
12:53 < docl> ahh. I assume disrupting those does more harm than good?
12:54 < jrayhawk> well, it's just not targeted at that point.
12:55 < jrayhawk> biofilm disruptors hit the reset button on a lot of stuff. whether that's good or bad depends upon context.
12:56 < jrayhawk> the approach i have seen that makes sense is delayed-release probiotic pills of the floral profile you're aiming for combined with biofilm disruptors
12:56 < jrayhawk> you could throw targeted antibodies into that mix
13:07 < jrayhawk> i'd be curious to hear more specific mechanisms for your gut bacteria hypothesis. it certainly seems likely that *something* is taking advantage of appetite upregulation.
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13:08 < hprmbridge> Eli> We are fat because we eat too many calories and we don’t exercise. That’s it. If there was a sneaky way to lose fat, big pharma would have done it. There’s no way you’re going to find something novel that they haven’t looked into.
13:09 < docl> it's wild speculation outside my usual wheelhouse, but I wrote up most of my thoughts on the matter here: https://manifold.markets/LukeParrish/gut-microbes-some-strains-have-rece
13:10 < docl> big pharma did find something called semagludite, recently
13:11 < jrayhawk> Eli: No, energy storage and flux is homeostatically regulated by the hypothalamus. There's a bajillion papers on hypothalamic leptin sensitivity. https://diabetesjournals.org/diabetes/article/62/8/2629/34105/Hypothalamic-Inflammation-Marker-or-Mechanism-of is a very accessible read.
13:12 < docl> one way it might conserve appetite upregulation is production of more fecal matter. so then more of the stuff one might wind up exposed to comes from obese people
13:13 < hprmbridge> Eli> Yes, and people lose their lean muscle mass on it. It’s something we give to people once they have a problem that seems to be worse than losing lean muscle mass
13:14 < hprmbridge> Eli> There aren’t any hunter gatherer societies with more than a 5% obesity rate
13:18 < docl> hmm, species with biofilms that benefit from a bigger gut surface more than competing species could also use obesity to their selective advantage. are there specific types of biofilms with that physical property?
13:19 < docl> or ones that do best where lipids are consistently available (since a lot of adipose is close to the gut), or maybe just ones with a need for more calorically dense inputs to form (so they grow when you eat candy bars but not when you eat fruit)
13:23 < jrayhawk> fructose malabsorption is inducible, but I don't know the mechanisms.
13:24 < jrayhawk> gut flora and biofilms are mostly black magic to me
13:26 < hprmbridge> Eli> You can buy a probiotic that is supposed to act as a glp1 agonist. For whatever reason, these bacteria seem to want you to eat less.
13:27 < docl> yeah, maybe it's for selective advantage against the bacteria that do. gotta figure these are all in competition
13:43 < jrayhawk> re: "If there was a sneaky way to lose fat, big pharma would have done it." there is no pill that can generically reverse entropy, but there is a lot of entropy there are "easy ways" to prevent: oxidative stress, CXCR3 agonism/tight barrier (dis)junction, providing immunological communications substrates, etc. Pharma can't, in most cases, market personal responsibility (although Lovaza/Vascepa, 
13:43 < jrayhawk> Deplin, etc. are getting close.)
13:44 < jrayhawk> er, s/entropy there are/forms of entropy that are/
13:45 < jrayhawk> er, shoot, i am too braindead to compose sentences right now
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23:20 < fenn> https://about.fb.com/news/2024/07/open-source-ai-is-the-path-forward/
--- Log closed Sun Jul 28 00:00:05 2024