--- Log opened Mon Sep 22 00:00:47 2025
00:02 < fenn> somehow this is the only alzheimers graph i can find that goes back before 1991 (Age-standardised dementia mortality (incl. Alzheimer's disease) in finland 1969-2010) https://stat.fi/til/ksyyt/2010/ksyyt_2010_2011-12-16_kat_003_en_007.gif
00:03 < hprmbridge> kanzure> is that adjusted for all other cause mortality?
00:03 < fenn> no, and finland made huge strides in cardiovascular disease
00:04 < fenn> it's from this collection of graphs which show the other causes of mortality https://stat.fi/til/ksyyt/2010/ksyyt_2010_2011-12-16_kat_003_en.html
00:05 < fenn> supposedly because they added magnesium to the salt by default
00:06 < fenn> nsh: is this true? people have "pansuola" on the table?
00:06 < hprmbridge> kanzure> "I will guarantee that my future children will be free of Alzheimer's." https://x.com/Jiankui_He/status/1966714303840768473
00:08 < hprmbridge> kanzure> huh, all the APOE stuff is scattered https://diyhpl.us/wiki/genetic-modifications/
00:08 < fenn> APOE variants are only like 2x higher risk
00:10 < hprmbridge> kanzure> no? some of them are protective.
00:10 < nsh> no idea, but i just checked three containers of salt here and none mentioned it. which doesn't preclude that they're doing it in secret, or just that my partner doesn't buy salt very often, which would be probably less surprising
00:12 < nsh> this does remind me however that i should obtain some magnesium and potassium
00:12 < nsh> ty
00:13 < fenn> i'd expect it to be obvious from the label if it contained magnesium and potassium
00:13 < hprmbridge> kanzure> something, something lithium oxolate and alzheimers
00:13 < fenn> orotate
00:14 < hprmbridge> kanzure> gesundheit.
00:14 < fenn> "Switching to Pansuola in cooking is an easy, Finnish choice. As a sign of Finnishness, Pansuola has been awarded the Key Flag symbol."
00:14 < fenn> i find this highly amusing for some reason
00:15 < fenn> i pestered our dear bot the other day about lithium and it has something to do with getting glucose into brain cells
00:18 < hprmbridge> kanzure> "Lithium deficiency and the onset of Alzheimer’s disease" https://www.nature.com/articles/s41586-025-09335-x recent article. it wasn't this, i forget why lithium/alzheimers is in my working memory.
00:19 < fenn> a monthly lithium pill seems a lot easier than genetic engineering
00:21 < fenn> so is alz.org the AHA equivalent in terms of funneling research up all the wrong trees
00:21 < hprmbridge> kanzure> ah, it was email from that "nutrition investigator" linked above, "report from the Buck Institute claiming that lithium orotate (1000mcg lithium) will prevent Alzheimer's, Parkinson's and dementia."
00:22 < fenn> 1mg?
00:22 < fenn> per what
00:23  * fenn notes that lithium is not in the USDA food database
00:32 < hprmbridge> kanzure> fenn> let's add lithium to the water! what could go wrong?
00:32 < hprmbridge> kanzure> and L29 posted the Alzheimer's/lithium result about a month ago.
00:34 < fenn> that was probably me complaining about fluoridation
00:37 < hprmbridge> kanzure> i still want more modern diet digestion/metabolism mods for the wiki, nobody is tracking this changelog :/
00:37 < fenn> like phytase?
00:38 < hprmbridge> kanzure> who is that?
00:38 < fenn> an enzyme that degrades phytic acid, an antinutrient, as seen in EnviroPig
00:38 < fenn> or do you mean like, upregulating PON1 to proactively deal with all the garbage people are going to eat
00:39 < fenn> our environment is the technosphere and we better adapt to it
00:39 < hprmbridge> kanzure> both? why not put phytase into the genome?
00:39 < fenn> it seems like a good idea to me...
00:40 < hprmbridge> kanzure> so yes then. throw it into the page.
00:42 < fenn> why is "Digestion of branching carbohydrates" an entire section
00:42 < fenn> how are we supposed to separate out dietary stuff from disease stuff
00:43 < fenn> like PON1 is needed because of seed oils, and it protects against heart disease etc
00:43 < hprmbridge> kanzure> this document has been poorly organized for a long time.
00:43 < fenn> is that a digestion mod or a disease prevention mod
00:43 < fenn> this is the tag vs hierarchy problem
00:43 < hprmbridge> kanzure> throw it into TODO if you must.
00:44 < hprmbridge> kanzure> not every time editing a file should be an occasion of debilitating ontology anxiety.
00:45 < hprmbridge> kanzure> only 1 out of 15 occurrence maybe.
00:47  * fenn yak shaves the PMC figure embedder instead
00:48 < hprmbridge> kanzure> i added a longevity section to https://diyhpl.us/wiki/mitochondria/
01:17 <+gnusha> https://secure.diyhpl.us/cgit/diyhpluswiki/commit/?id=6708e982 fennwiki: a little reorganizing >> http://diyhpl.us/diyhpluswiki/genetic-modifications/
01:21 <+gnusha> https://secure.diyhpl.us/cgit/diyhpluswiki/commit/?id=07dfab79 fennwiki: type 1 and type 2 are very different diseases, best not to mix them up >> http://diyhpl.us/diyhpluswiki/diabetes/
01:28 <+gnusha> https://secure.diyhpl.us/cgit/diyhpluswiki/commit/?id=1d34de60 fennwiki: phytase and k2 >> http://diyhpl.us/diyhpluswiki/genetic-modifications/
02:03 <+gnusha> https://secure.diyhpl.us/cgit/diyhpluswiki/commit/?id=bd79acd9 fennwiki: PON1 >> http://diyhpl.us/diyhpluswiki/genetic-modifications/
02:14 <+gnusha> https://secure.diyhpl.us/cgit/diyhpluswiki/commit/?id=dee394ca fennwiki: edit PON1 >> http://diyhpl.us/diyhpluswiki/genetic-modifications/
02:16 < fenn> so this chemist takes a huge dose (120mg iirc) of extremely lethal acetylcholinesterase inhibitor just to see what would happen, then gets instantly paralyzed and can't take the antidote right in front of him
02:19 < fenn> RIP Helmut H. Velbinger https://www.chemistryworld.com/opinion/a-cautionary-tale-/2500174.article
02:20 < fenn> By Sally Bloodworth
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06:04 < fenn> "This study showed that vitamin C can potentially be used up to 24 hours after exposure to high levels of ionizing radiation in life threatening situations" https://pmc.ncbi.nlm.nih.gov/articles/PMC4479387/
06:06 < fenn> equivalent to roughly 2-8g for a human
06:07 < fenn> that'll make you poop your pants, so fancy liposomal C or injection
06:11 < L29Ah> i don't think i pooped my pants from 2g of ascorbic acid
06:11 < fenn> yeah probably not
06:11 < fenn> you don't want to be the unlucky mouse though, better to take 8g
06:12 < fenn> i wish the survival curves went longer
06:12 < hprmbridge> kanzure> what about something before the radiation?
06:12 < fenn> that's almost certainly better, i'm still reading
06:18 < hprmbridge> kanzure> what if we just walked around with iron plates strapped on because, ya know, the flesh is vulnerable to radiation
06:18 < fenn> depends on the radiation
06:18 < fenn> lead blocks gamma rays but not neutrons
06:19 < fenn> metals can shatter incoming high-Z cosmic ray particles into a shotgun blast of smaller particles which are more likely to interact with cell material
06:19 < fenn> in space, cosmic rays do less damage with no shielding at all
06:21 < fenn> radiation risk is overblown and unscientific. the linear no threshold dose model is used to justify enormous expenditures on safety systems and quality control of nuclear plant construction, making it uncompetitive by definition (the ALARA cost ratchet)
06:21 < fenn> if you expect there to be a high chance of high levels of radiation, it'd be better to just not go out of your bunker
06:22 < fenn> sit in a bathtub full of water or something
06:23 < fenn> i have one of those fancy iron claw-foot bathtubs, i knew it would come in useful some day!
06:47 < fenn> i was confused. "This study" refers to the authors' previous study, which used a higher dose (13Gy vs 8.8Gy) and gave C before and after the radiation. 0% of mice only given C afterwards survived. 40% of mice given C before and after surfived. 20% with pre-treatment only. 100% with before, after, and a shot 8hr before (injection?)  N=15 in each group
06:48 < fenn> .t https://pmc.ncbi.nlm.nih.gov/articles/PMC3821576/
06:48 < saxo> A Combination of Pre- and Post-Exposure Ascorbic Acid Rescues Mice from Radiation-Induced Lethal Gastrointestinal Damage - PMC
06:49 < fenn> i'm having trouble interpreting this word "engulfment"
06:52 < L29Ah> were these regular mice or C-synthesis-knockout ones?
06:55 < fenn> Male C57BL/6 mice
06:56 < fenn> "the most widely used and best-selling mouse strain"
07:08 < jrayhawk> also https://scholar.google.com/scholar?q=%28+l-glutathione+OR+N-acetylcysteine+OR+glutamylcysteine+%29+high-dose+radiation
07:36 < kanzure> MuaddibLLM: what was elton john's reason for gold plating his kneecaps..?
07:37 < MuaddibLLM> He had them surgically removed for double knee replacement (his surgeon said they were "the worst knees he's ever operated on") and turned them into gold jewelry because he thought it would be "fun" and create "timeless pieces that will last for centuries" - one became a necklace with a cheeky Latin inscription "I will no longer bow to any man." https://www.today.com/popculture/news/elton-john-jewelry-kneecaps-rcna231408
07:40 < kanzure> that's very metal?
07:40 < jrayhawk> very glam, very rock
07:43 < jrayhawk> re: methylene blue: it bypasses electron transport chain complexes. the only way it would result in increased ATP production is if something is going catastrophically wrong with those complexes in the first place.
07:48 < jrayhawk> methylene blue is an MAO-A inhibitor, burdens riboflavin, upregulates Nrf2 by crashing glutathione, and is a vasoconstrictor. it is a profoundly messy treatment for which there are better alternatives in almost every case.
07:54 < jrayhawk> the rare legitimate treatment class being some specific genetic ETC disorders
08:10 -!- catalase9 is now known as catalase
09:42 < hprmbridge> Eli> Yeah, apparently complexes 1-3 have problems in alzheimers, which MB can bypass. MB is also claimed to increase complex IV work better, so, you are getting more ATP just from that. And decreased ROS because MB binds to ROS that slip out the ETC. THat's the theorized MOA. Might increase mitochondrial biogenesis via PGC-1α modulation. I don't know if the recent TauRx LUCIDITY trial will result in
09:42 < hprmbridge> Eli> reg approval for alzheimers. We shall see.
09:42 < hprmbridge> Eli>
09:42 < hprmbridge> Eli> I think for the vasoconstriction treatment, they are using large doses. Most people aren't going over 70 mg. And, I guess people are even microdosing at < 5 mg. The MAOI gives me pause, but I'm kind of wondring if it's relevant at the doses biohackers are taking. Personally, if I was a certain age and facing cognitive decline, I would seriously consider it. Life doesn't have a lot of purpose if
09:42 < hprmbridge> Eli> you can't recognize your loved ones. I'm guessing people under a lot of cognitive stress might benefit most (founders, grad students, wall street people, ...). MB likes to accumulate in the CNS, and the CNS is consuming like, a huge amount of ATP.
09:42 < hprmbridge> Eli>
09:42 < hprmbridge> Eli> I was curious why, teleologically it would even make sense for mitochondria to even respond to a synthetic drug this way. Apparently, ATP generation is made to be pretty flexible in single celled organisms, so, they can survive in different environments. MB seems to work during hypoxia, and is proposed for CO and cyanide poisoning.
09:42 < hprmbridge> Eli>
09:42 < hprmbridge> Eli> I'm running so many parallel experiments on my body that I don't currently have the ability to experiment with MB without affecting other variables. Would be nice if it was patentable so that we saw more studies from big pharma. If only I was a billionaire so I could run studies on non-patentable stuff ...
09:42 < hprmbridge> Eli> https://cdn.discordapp.com/attachments/1064664282450628710/1419725504151293982/mb_etc.png?ex=68d2cde9&is=68d17c69&hm=71d9ca679d1057a933a18ece347342846ccfa73af3d7738548072a9ddb59675d&
09:44 < hprmbridge> Eli> If embryonic gene editing takes off, we could pretty much eliminate alzheimers. We've discovered some long tail mutations that seem to be pretty protective. And, just getting rid of APOE4 from the population would get rid of a lot of alzheimers. Ultimately, I optimistic that big pharma will get some treatments approved in the next ten years. Maybe in next five years.
09:47 < hprmbridge> Eli> Obviously, just lifestylemaxxing would get rid of a lot of alzheimers.
09:49 < kanzure> in what way is that obvious? just curious. i don't know much about it.
09:51 < jrayhawk> https://scholar.google.com/scholar?q=bredesen+dementia it's in the lifestylemaxxing memeplex at this point
09:52 < jrayhawk> oh https://scholar.google.com/scholar?q=bredesen+cognitive+decline captures more of the corpus
09:53 < hprmbridge> Eli> Well, we already know that people with type 2 diabetes have major increases in risk alzheimers. So, based on this pretty strong data, we are confidant that a good diet would decrease risk. I want to say data on GLP1RAs just proved decrease in risk of alzheimers for these people. So, that's another data point that we can alter trajectory of this disease. Educational attainment is correlated with
09:53 < hprmbridge> Eli> reduce risk, maybe due to cognitive reserve. Almost like sarcopenia of the brain. So, exercising the brain likely changes disease trajectory. I have strong priors that increasing VO2 max and eliminating sleep apnea will decrease risk. So, exercise and sleep mask. Same with HRT therapy, decreasing UTIs in women likely helps. And, as jrayhawk mentioned, just stuff that reduces inflammation, and
09:53 < hprmbridge> Eli> other personalized medicine stuff likely helps. I think theres other data points that are pretty strong, but, this is a good start.
09:54 < jrayhawk> amyloid and tau are both inflammatory defense proteins, and inflammation is highly environmentally determined
09:54 < jrayhawk> the strongest genetic correlate, ApoE4, is an inflammation gene
09:55 < hprmbridge> Eli> Yeah, just living in a place that doesn't have a lot of air pollution probably helps. The epidemiology data on that is pretty crazy.
09:58 < jrayhawk> er, s/inflammatory defense/immunological defense/
10:09 < hprmbridge> Eli> People with type 2 diabetes have about 1.5–2× higher risk of developing dementia, with the risk skewing higher for vascular dementia (≈2–3×) than for Alzheimer’s disease (~1.5×).
10:09 < hprmbridge> Eli>
10:09 < hprmbridge> Eli> GLP1RAs reduce risk by 10-40% for these people, if my stats are correct. Vascular dementia gets even better improvement. But what happens if we go from high normal HbA1C to low normal HbA1C? What if we do VO2 maxxing and everyone does the Mediterranean diet? What if we are all "better than good"? Do we reduce risk even more? My bias would be that, yes, we probably would. I think everyone would be
10:09 < hprmbridge> Eli> suprised if that wasn't the case. It's also why I think we could increase average lifespan by 10-20%.
10:09 < hprmbridge> Eli>
10:09 < hprmbridge> Eli> Just need to figure out a few more things like how to regenerate the immune system. We kind of have figured out a lot of other things to extend life.
10:12 < jrayhawk> re: alzheimers/diabetes correlation: https://scholar.google.com/scholar?q=ketone+alzheimers+trial
10:13 < jrayhawk> "type 3 diabetes" was being tossed around as a term for alzheimers
10:15 < hprmbridge> Eli> Yeah, switching the metabolic pathway is interesting. One thing I’m curious about is if taking exogenous ketones would change fat storage? Like, if we become fat adapted, does the body think it’s starving and then increase conversion of glucose to fat? I actually have no idea how that works. I’m curious to try the keto esters.
10:22 < jrayhawk> the big hominid c3->c4 arboreal->grassland transition and emergence of tool-based selective animal butchering was 2-2.5mya; what would've triggered apoE ε2/ε3 haplotype emergence and proliferative competitive advantage 200-300kya?
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10:26 < L29Ah> https://www.lesswrong.com/posts/sPceWmHudmkSAA9Ba/diabetes-is-caused-by-oxidative-stress
10:26 < L29Ah> tfw i'm confident i got this link from this channel but can't find it in the logs
10:30 < jrayhawk> i don't recall having seen it before
10:32 < jrayhawk> it's an oversimplification regardless; t2d is induced by any of oxidative stress, inflammation, or micronutrient insufficiency (especially electron transport chain co-factors)
10:34 < jrayhawk> all of which feed back into eachother in various ways
10:37 < jrayhawk> i guess human populations were pretty small until recently, so maybe the haplotype emergence taking millions of years to respond to increased SFA consumption is more explicable
10:56 < hprmbridge> kanzure> "The mechanosensitive adhesion G protein-coupled receptor 133 (GPR133/ADGRD1) enhances bone formation" https://www.nature.com/articles/s41392-025-02291-y another strong bone variant.
11:35 < RangerMauve> L29Ah Re: being plugged in 24/7 I've had decent success walking around with my GPD WIN4 + Viture. It's not amazing for high outdoor brightness or medium indoor brightness. I don't feel confidant in Zucks new glasses but the band is pretty cool
11:37 < RangerMauve> Anxiety about alzheimers / dementia seems pretty big if folks aiming to off themselves sooner than their "natural lifespan". It'd be great if there were treatments for it before I need them. :P
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11:42 < RangerMauve> re: fixing stupidity with brain surgery I have a hope that implanting bits of brain grown from ones own cells but rejuvinated could help with the whole "brains are hard to fix" issue with long lifespans. I also wonder if there's room for adding neuroplacticity via this method to address the "people just die instead of changing their minds" issue which I think is spot on
11:53 < kanzure> for whole-body transplantation, if fusogen-based nerve fiber repair is working then you don't necessarily need to murder a clone... you can just hitch a ride.
11:54 < kanzure> oh wait, no that was for pig. if you are hitching a human ride but piggyback then you don't need nerve fiber repair.
11:54 < kanzure> RangerMauve: i don't have a good reference for the gradual replacement strategy for brain. people have talked about it but i have no canonical reference to cite or read.
11:55 < RangerMauve> kanzure: I'm only aware of the mouse implantation so I'm purely speculating that something could come from it in our lifetime
11:56 < RangerMauve> I imagine that the start will be attempting to repair brain damage with grafts. That seems to be the vibe with the organoid research
11:58 < RangerMauve> I think I'd rather hitch a ride on a pig and have my senses re-routed to digital prosthetics rather than die. But I don't think I'd choose it if I had pretty much any other option :P
11:58 < kanzure> if you introduce the donor cells during early fetal development (very early), then maybe the organism will be receptive to brain cell donation later in life, like from a smarter donor.
11:59 < kanzure> piggyback on a pig would not require your senses to be digitized because it would be a head transplant to their belly or back, not a brain transplant.
11:59 < RangerMauve> BTW I'm thinking of doing a startup for VR based humanoid robot telepresence if anyone wants to invest / use such a thing
11:59 < kanzure> there are many companies doing that though. what are you doing differently or better?
11:59 < RangerMauve> Regarding piggyback, I don't think life would be bareable if I was literally stuck on top of a pig and had to conform to the pig form factor for world interaction
12:00 < kanzure> okay well you know what's more unbearable? death
12:00 < RangerMauve> Yeah that's what I mean. Defs preferable to death
12:01 < RangerMauve> Regarding the telepresence, I have some ideas for making the immersian / latency better, but also have a more resilient / decentralized baseline. e.g. franchise bot deploy + decentralized marketplace for renting, sovergn to countries / private nets without a central cloud
12:02 < RangerMauve> Embed the pig body into a robot body as a prosthesis. Like, remove more and more of the pig. Robocop style
12:03 < RangerMauve> https://facts.net/wp-content/uploads/2023/08/20-facts-about-krang-teenage-mutant-ninja-turtles-1692245135.jpg
12:03 < RangerMauve> This but it's your head on top and the brain in the belly is a pig brain you feed apples or w/e
12:07 < RangerMauve> re: preferable to death, I think it's easy to bring a bunch of quality of life additions on top of the baseline pig graft. Easer than the grafting at least
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13:05 < kanzure> gonna chat with someone working on the breeding and domestication of raccoons, any questions you want me to queue up?
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13:52 < L29Ah> MuaddibLLM: what's the current state of the research of MAO-B inhibitors for brain health?
13:53 < MuaddibLLM> Error - API error: Cannot connect to host api.anthropic.com:443 ssl:default [[SSL: SSLV3_ALERT_HANDSHAKE_FAILURE] sslv3 alert handshake failure (_ssl.c:1010)]
13:53 < L29Ah> MuaddibLLM: are you under MITM?
13:54 < MuaddibLLM> Unclear, but SSLV3_ALERT_HANDSHAKE_FAILURE is more often TLS/cipher/SNI mismatch than MITM - run: openssl s_client -connect api.anthropic.com:443 -servername api.anthropic.com (if the cert issuer is your org proxy, it’s MITM), also check system clock, ensure TLS 1.2+, and try from a different network/VPN to compare fingerprints.
13:54 < L29Ah> MuaddibLLM: what's the current state of the research of MAO-B inhibitors for brain health?
13:55 < MuaddibLLM> Error - API error: Cannot connect to host api.anthropic.com:443 ssl:default [[SSL: SSLV3_ALERT_HANDSHAKE_FAILURE] sslv3 alert handshake failure (_ssl.c:1010)]
14:02  * L29Ah handshakes pasky
14:57 < hprmbridge> .monokhrome> Why don't billionaires put more money into life extension research? There are a lot of them, and they're mostly middle aged or older, they should care about it.
15:08 < hprmbridge> Eli> To some degree I think they are
15:10 < hprmbridge> .monokhrome> Like who? It doesn't seem like life extension is overflowing with funding
15:17 < hprmbridge> kanzure> retro, new limit, altos
15:36 < L29Ah> ask them; also money isn't everything, and management of a large-scale research program is dark magic
15:37 < L29Ah> also https://arcinstitute.org/
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16:28 < hprmbridge> kanzure> https://www.spermracing.com/
16:29 < hprmbridge> kanzure> "To enhance the spectator experience, we project the leading sperm’s position frame by frame onto a more visually engaging 3D-rendered track." what
16:31 < hprmbridge> kanzure>  https://cdn.discordapp.com/attachments/1064664282450628710/1419828386683031552/share_7495370144821924245.png?ex=68d32dba&is=68d1dc3a&hm=d6f9e1d022d7333037618836ca1aa85fd07a486ec9ea879aaf3f6e978631d5cb&
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17:49 < hprmbridge> kanzure> "Fourth, DEEPSERVE includes optimizations such as pre-warmed pods, DRAM pre-loading, and NPU-fork, which allow DEEPSERVE to scale up to 64 instances in seconds."
18:06 < hprmbridge> kanzure>  https://cdn.discordapp.com/attachments/1064664282450628710/1419852405784449095/file_00000000e61c61fba09fb349e12d62d9.png?ex=68d34419&is=68d1f299&hm=36bc8137131c91a9014d5473c9a7876cade706f0c854d7ac0d85270a601300e1&
18:06 < hprmbridge> kanzure>  https://cdn.discordapp.com/attachments/1064664282450628710/1419852418023424030/file_000000001574622fb4bfcd4fb2f697df.png?ex=68d3441c&is=68d1f29c&hm=5bff0520ccc536179734973f508db53be642b467bd13fd670df64d910e4f1858&
18:07 < hprmbridge> kanzure> eh, probably teleoperation.
18:22 < hprmbridge> kanzure> what about adding uricase into the human genome?
18:23 < hprmbridge> kanzure> or cellulase?
18:26 < L29Ah> i think you should start with viral gi tract cellulasification like that lactase guy did
18:33 < hprmbridge> kanzure> keratinase, chitinase, uricase, better lysozymes, oxalate oxidase, ligninase.
18:34 < hprmbridge> kanzure> better proteases.
18:34 < hprmbridge> kanzure> can we just slap in a better myoglobin?
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