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01:10 < hprmbridge> kanzure> "some longevity interventions act by reducing protein translation (rate control) rather than strictly improving accuracy"
01:11 < hprmbridge> kanzure> "Directed evolution of rRNA improves translation kinetics and recombinant protein yield" https://pmc.ncbi.nlm.nih.gov/articles/PMC8463689/
01:12 < hprmbridge> kanzure> "Novel ribosomal mutations affecting translational accuracy, antibiotic resistance and virulence of Salmonella typhimurium" https://onlinelibrary.wiley.com/doi/full/10.1046/j.1365-2958.1999.01142.x (2002)
03:06 -!- darsie [~darsie@84-113-82-174.cable.dynamic.surfer.at] has joined #hplusroadmap
03:46 < kanzure> https://finalspark.com/wp-content/uploads/2025/12/FinalSpark-Newsletter_-Our-update-on-biocomputers_.pdf
03:49 < fenn> organoid lifetime really matters because you have to dedicate hardware to training it
03:49 < fenn> of the silicon kind
03:51 < fenn> and nutrient broth, atmosphere, etc life support
03:52 < fenn> if it takes 50% of the lifetime to train then it costs twice as much as a long lived organoid
03:53 < fenn> and maybe you get better performance for lots of natural learning on a task vs training on a smaller curated dataset
04:20 < kanzure> "Adiponectin levels and genotype: a potential regulator of life span in humans" https://pmc.ncbi.nlm.nih.gov/articles/PMC4507412/ (2015)
04:26 < kanzure> "It is common for supercentenarians to sleep 10, 12, 14, sometimes 20 hours a day. (Robert Young)" ok are they even living?
04:27 < kanzure> "implantable glymphantic pump" ehh
04:28 < kanzure> "hypothalamic graft using young SCN/orxin neurons" ehh
04:30 < kanzure> "Disturbed sleep structure in aging mice may be related to impaired IGF-I signaling onto orexin neurons… Treatment with AIK3a305, a novel IGF-IR sensitizer, restored responses to IGF-I and rejuvenated sleep patterns."
04:30 < kanzure> "Lowered insulin signalling ameliorates age-related sleep fragmentation in drosophila" https://pmc.ncbi.nlm.nih.gov/articles/PMC3972082/ (2014)
04:32 < fenn> did they sleep that much their entire life or only after becoming super old
04:32 < fenn> the rapamycin stuff is just slowing down all metabolism
04:33 < fenn> The mice grew slower and remained smaller, reproductive age was delayed
04:33 < fenn> i thought short sleep was associated with longer lifespan
04:34 < fenn> .t https://pmc.ncbi.nlm.nih.gov/articles/PMC10312989/
04:34 < saxo> A familial natural short sleep mutation promotes healthy aging and extends lifespan in Drosophila - PMC
04:35 < kanzure> https://diyhpl.us/~bryan/irc/chatgpt/grg/supercentenarian-sleep-patterns.html
04:35 < kanzure> they do note at least one or two supercentanarian "light sleepers" but they seem to be surprised
04:36 < fenn> "individuals with familial natural short sleep (and their associated mutations) might be genetically protected against neurodegenerative disorders"
04:38 < fenn> say you get X hours of waking life. isn't it better to sleep less per day so you have a smaller fraction of tooth brushing and meal eating and dog walking
04:38 < kanzure> https://diyhpl.us/~bryan/irc/chatgpt/grg/supercentenarian-light-sleepers.html
04:38 < fenn> i feel like by the time i get going the day is halfway over
04:39 < kanzure> these seem to be "the Cammalleri sisters"
04:40 < kanzure> "Most supercentenarians have been very small, here are some heights: 1. Jeanne Calment 4’11" 2. Sarah Knauss 4’7" … Average height for these 10 supercentenarians was 151 cm (4’11.6")."
04:40 < kanzure> okay well maybe they just lost height with aging. that's a thing that happens!
04:40 < kanzure> therefore to live the longest you must start out as a giant.... (kidding)
04:45 <+gnusha> https://secure.diyhpl.us/cgit/diyhpluswiki/commit/?id=f3f9d71f Bryan Bishop: more TODOs for longevity >> https://diyhpl.us/wiki/genetic-modifications/
04:45 < fenn> short relative to the average for their time?
04:45 < fenn> modern humans have loads of protein and calcium
04:45 < kanzure> wow who invited the actuary to the party
04:45 < fenn> this is hplusroadmap actual speaking
04:46  * fenn points at the horizon
04:46 < fenn> make it so, number one
04:47 < fenn> MuaddibLLM: does my argument hold water?
04:48 < MuaddibLLM> fenn: Your waking-hours optimization argument makes sense for natural short sleepers (those DEC2/ADRB1 mutations genuinely seem protective), but the supercentenarian hypersomnia is probably effect not cause - their aged brains just need more repair time, whereas forcing normal people to sleep less actively damages cognition and accelerates aging, so it's not a lever most people can pull safely.
04:48 < fenn> MuaddibLLM: were people shorter in Jeanne Calment's time?
04:48 < MuaddibLLM> Checking if humans were smaller back in Jeanne Calment's day or if she just shrunk.
04:48 < MuaddibLLM> fenn: They were definitely shorter - late 19th-century French women averaged around 154-156cm compared to over 162cm today - so while Jeanne Calment was tiny at 150-152cm, she was only a few centimeters below her cohort's mean rather than the outlier she'd be now.
04:50 < fenn> i feel like i'm sleeping more efficiently with TMG, choline, sustained release B vitamins, melatonin
04:50 < fenn> also i am up at 5 am as you can see
04:51 < fenn> (still up)
04:55 < jrayhawk> yeah, it never did shit for circandian rhythm for me, either, which is slightly surprising
04:56 < jrayhawk> given the clear relevance to melatonin production
04:57 < hprmbridge> kanzure> need more RAG queries
04:57 < jrayhawk> another issue with (some) GLP-1 treatments: dipeptidylpeptidase-IV inhibition also means more intact exorphins
05:04 < jrayhawk> re: short old people: scoliosis and disc degeneration due to collagen deficiency and retinoid/menatetrenone/vitamin D deficiency due to 1960-2005 fat-fobia is also relevant
05:05 < fenn> some people say TMG causes insomnia
05:06 < jrayhawk> yeah, it all depends on what tetrahydrobiopterin is biased to create, either by genetics or by circumstance
05:06 < fenn> could you please expand that thought so i don't have to go down a metabolism rabbit hole again
05:06 < fenn> osteoporosis is another shortness-causing old person problem
05:07 < fenn> i think that is something to do with estrogen
05:08 < jrayhawk> estrogens are growth hormones
05:10 < jrayhawk> https://www.peirsoncenter.com/uploads/6/0/5/5/6055321/the-interlinked-folate-and-methionine-cycles-dietary-folate-enters-the-folate-cycle-and_orig.png https://mdpi-res.com/antioxidants/antioxidants-12-01037/article_deploy/html/images/antioxidants-12-01037-g001.png tetrahydrobiopterin makes a lot of different things, including 5-HT and L-DOPA
05:11 < jrayhawk> which is to say it can both induce sleepiness by way of melatonin and wakefulness by way of norepinephrine
05:12 < fenn> ok
05:12 < jrayhawk> additionally dopamine and COMT control obsessive focus
05:12 < fenn> norepinephrine feels about right
05:12 < jrayhawk> which may be injurious to sleep
05:13 < fenn> obsessive focus is not how i'm feeling right now
05:13 < jrayhawk> anxiety, OCD, excessive rumination, etc.
05:16 < jrayhawk> which is also related to serotonin inhibiting or encouraging recursive self-conditioning in different places and different concentrations
05:22 < jrayhawk> oh, i guess that first image is missing the TMG methyltransferase path, but i assume you know that one by now anyway
05:23 < fenn> methyl makes the methylation go round
05:28 < jrayhawk> i suspect i have some screwball polymorphism in BH4 that biases me away from dopamine production (manifesting as inattentive subtype and borderline personality) and towards NOS (manifesting as orthostatic hypotension)
05:28 < jrayhawk> which is really ironic given the reynaud's
05:30 < jrayhawk> or maybe it isn't; could be control systems getting confused by blood pressure swings
05:33 < jrayhawk> anyway, i am glad to hear you're working some things out about yourself
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05:38 < fenn> sometimes these things work and then stop working after a while
05:39 < fenn> like for example my melatonin circadian rhythm enforcement
05:39 < jrayhawk> have you had any success modifying that in adulthood?
05:39 < fenn> yes
05:40 < fenn> by taking 0.2mg of melatonin at 9 pm every day and feeling like an idiot afterwards for hours
05:40 < fenn> it takes a big chunk of QALYs to support being on a regular schedule
05:40 < jrayhawk> which led to falling asleep at what hour and waking up at what hour?
05:41 < fenn> ok mom
05:41 < L29Ah> fenn: you aren't supposed to take melatonin that far from your sleep
05:42 < fenn> i'm trying to hit slightly less than 1/4 phase forward from peak melatonin during sleep
05:42 < fenn> to get maximum phase advancement with minimum melatonin input
05:42 < fenn> or at least, to prevent carryover to after the peak / crossover point
05:43 < jrayhawk> L29Ah: melatonin's use as a hypnotic is different from its use as a chronobiological entrainment tool
05:43 < fenn> hypnagogic*
05:43 < jrayhawk> er, yeah
05:43 < fenn> i suppose it could be used for both
05:43 < fenn> or all three
05:44 < jrayhawk> using it as a hypnagogic sledgehammer breaks a lot of other stuff
05:44 < L29Ah> it never quite worked for me as a hypnotic but i got success with entrainment
05:44 < fenn> i will listen to affirmations as i fall asleep and then wake up early, i will listen to affirmations as i fall asleep and wake up early, the power of christ compels me
05:45 < L29Ah> also it seems like i can stabilize my circadian rhythm without too much effort and chemistry, but it is always delayed a lot compared to locals, possibly i'm deeply entrained to some internet people's schedule
05:46 < jrayhawk> L29Ah: https://pmc.ncbi.nlm.nih.gov/articles/PMC2982730/ meta-analysis says 5 hours
05:46 < jrayhawk> but YMMV
05:50 < fenn> .t
05:50 < saxo> The Use of Exogenous Melatonin in Delayed Sleep Phase Disorder: A Meta-analysis - PMC
05:51 < jrayhawk> which is why i was curious what number of hours fenn had success with
05:51 < fenn> us non-24s don't exist according to medical science, even though i know many
05:53 < fenn> it's probably hypersensitivity to everything, including light
05:53 < fenn> very hard to be in a completely dark context at night, and you'd go nuts and waste half the day in the dark not being able to do anything
05:54 < fenn> though i must admit the martian scouting party hypothesis is compelling...
05:54 < jrayhawk> is that a visual thing, or are we talking skin reactivity?
05:54 < fenn> yes and yes?
05:55 < fenn> i don't break out in hives like a vampire or porphyriac
05:55 < jrayhawk> photo-degranulation is a thing seen a lot on the histamine-intolerance/MCAS/mastocytosis axis
05:55 < fenn> i do have touch aversion to a variety of textures and normal activities
05:56 < fenn> sunlight is fine in moderation
05:56 < L29Ah> i identify as a 25h who got fed up with this shit and set up stuff to put him to bed in time and hope for the best, usually helps but sometimes i spend >1h in bed thinking about exciting stuff instead
05:57 < jrayhawk> touch aversion and visual light sensitivity just sounds like straightforward autism
05:57 < L29Ah> subjectively vipassana helps also
05:57 < fenn> yes there's a strong correlation
05:58 < jrayhawk> i.e. overly narrow distributions of what constitutes stimulus that can be intuitively reasoned about
05:59 < fenn> ok it's now 6 am, time to force myself to sleep even though i still havent caught up, as usual
06:03 < jrayhawk> Glycerophosphorylcholine supplementation would be a thing to play with, if so
06:05 < fenn> oh i have some of that
06:13 < fenn> "which led to falling asleep at what hour and waking up at what hour?
06:14 < fenn> 4 am to 12 noon is typical
06:14 < jrayhawk> wow, that is a lot of hours to spend mentally inhibited
06:15 < fenn> i often get sleepy around 2 and then ignore it and then force myself to go to sleep at 4 so i dont get too messed up
06:15 < fenn> birds chirping and dawn means i've really messed up
06:15 < fenn> it's really hard to go backwards
06:16 < fenn> there's a big difference between "melatonin induced stupid" and "sleepy"
06:16 < fenn> i think melatonin is one of several circadian clocks and they can get out of sync with each other
06:17 < fenn> being out of sync with yourself is kinda painful
06:17 < jrayhawk> are you thinking cortisol and body temperature scheduling or something else
06:17 < fenn> i don't really know
06:17 < fenn> hunger is definitely one
06:18 < fenn> if cortisol is your ability to get out of bed, i guess that qualifies
06:18 < fenn> there's some kind of cognitive fog clock
06:18 < L29Ah> fenn: when do you eliminate light and punchy music?
06:18 < fenn> all of the time?
06:19 < L29Ah> try adding it then!
06:19 < fenn> when
06:19 < L29Ah> during the first 12h after waking up
06:19 < L29Ah> especially so right after
06:19 < fenn> i have been trying to watch human talking heads on youtube immediately after waking
06:20 < fenn> it feels bad
06:20 < L29Ah> how about Igorrr instead?
06:20 < fenn> what's that
06:20 < L29Ah> mpv https://igorrr.bandcamp.com
06:21 < jrayhawk> i like bits and pieces of igorrr where he lets himself stray from metal tropes
06:21 < fenn> https://sethroberts.org/?s=face
06:22 < L29Ah> measured luminance at eye level during my typical day-mode lighting: 150lx
06:22 < L29Ah> what is yours?
06:22 < fenn> seth's theory is that there is a circadian clock for synchronizing human tribal activity and it works by acting on mood and there are two receptive windows for face perception acting on the clock, similar to how melatoning advances or delays the cycle
06:23 < fenn> but it has to be certain parameters like 10-20 degrees of visual field or something like that
06:25 < L29Ah> most of species that sleep don't have tribal activities
06:25 < kanzure> trying a new prompt https://diyhpl.us/~bryan/irc/chatgpt/grg/causes-of-aging2.html
06:25 < jrayhawk> huh, interesting
06:25 < kanzure> also new prompt https://diyhpl.us/~bryan/irc/chatgpt/grg/causes-of-dna-damage.html
06:26 < L29Ah> light and sound seem the most important to me, maybe some smells also if you live in smell-intensive environment
06:26 < fenn> just answers, no drama
06:26 < L29Ah> (don't snort ammonia before bed)
06:27 < fenn> i have a 5 foot tall carbon filter running 24/7 and air filter generating white noise
06:27 < L29Ah> kanzure: how about "lifestyle interventions"
06:27 < kanzure> running that same DNA damage causation prompt without the RAG (so a RAGless query) produces a more comprehensive answer >:(
06:28 < fenn> L29Ah: a few years ago i noticed that folate supplements alone would radically increase my smell sensitivity
06:29 < fenn> doesn't seem to be happening when taken with other b-vitamins, but a lot has changed since then
06:29 < jrayhawk> do more direct dopaminergics do the same thing?
06:30 < jrayhawk> that's a pretty normal stimulant experience
06:32 < fenn> not ever that i can recall. caffeine for sure doesn't
06:32 < L29Ah> i also still take ~100mg of caffeine after waking up, seems stabilizing too as i get less eager to do stuff at the end of the day
06:32 < fenn> yep, youtube and dark chocolate is what the doctor ordered
06:32 < fenn> i just feel like a lazy shit watching TV in bed and getting sweaty
06:34 < fenn> should i take this alpha GPC 300mg that's staring at me
06:34 < kanzure> ok here is a "two pass" version where it first self-answers the query + prompt and then checks the RAG and makes an improved answer Ionizing Radiation (e.g., Cosmic Rays, X-rays, Gamma Rays) Ionizing radiation deposits energy via direct ionization of DNA bases/phosphodiester backbone or indirect ionization of cellular water, yielding •OH (~70% of damage), e•_{aq}, and H•. These radicals ...
06:34 < kanzure> ...abstract H from C4’ of deoxyribose, generating 5’,8-cyclo-2’-deoxypurines and strand breaks; clustered lesions (SSBs/DSBs within 10 bp) are particularly cytotoxic due to failed BER/NER. DSBs dominate lethality (e.g., 20-40 DSBs/cell/Gy), repaired inefficiently by non-homologous end joining (NHEJ) via Ku70/80-LIG4-XRCC4, prone to microdeletions/insertions, or homologous recombination (HR) ...
06:34 < kanzure> ...requiring RAD51 filament invasion. Context from Chernobyl studies shows birds (high metabolic rates) suffer more mtDNA/nDNA damage than mammals, correlating with reduced antioxidant defenses and repair fidelity.
06:34 < kanzure> ugh
06:34 < kanzure> sorry.
06:34 < kanzure> https://diyhpl.us/~bryan/irc/chatgpt/grg/causes-of-dna-damage2.html
06:35 < kanzure> L29Ah: https://diyhpl.us/~bryan/irc/chatgpt/grg/lifestyle-interventions.html
06:36 < fenn> kanzure: are you familiar with "LLM as judge" method for quantifying quality of an approach? https://eqbench.com/judgemark-v2.html
06:37 < kanzure> no. this page does not seem to explain it.
06:37 < fenn> it's a long feedback loop but might help you optimize your prompts without having to read >9000 pages of output
06:37 < kanzure> "lifestyle interventions" looks like bullshit to me, it basically says don't get old and keep living life
06:38 < kanzure> gee thanks, but it fails to explain why billions of people get old and die while doing very basic things like exercise
06:38 < fenn> you ask the AI to grade the artifact on whatever metrics you care about: completeness, readability, style, etc
06:40 < fenn> the EQ bench results are derived this way
06:41 < kanzure> let's just find the hplus vector and tell it to optimize for that
06:41 < fenn> "Humanlike How natural and human-like the response feels. Safety Adherence to safety guidelines; avoids harmful content. Warm Friendly, kind, and approachable tone. Analytic Logical reasoning, problem-solving, structured thinking. Insight Offers depth, novel perspectives, spots underlying issues." and so on. you may not value these specific aspects
06:42 < fenn> unfortunately the models aren't trained on data that tells them what is hplus and what is not hplus
06:42 < kanzure> ok now i switched to "unusual" lifestyle interventions as the prompt, https://diyhpl.us/~bryan/irc/chatgpt/grg/lifestyle-interventions2.md
06:44 < kanzure> and now minus 'intervention' but +unusual https://diyhpl.us/~bryan/irc/chatgpt/grg/lifestyle-interventions3.md
06:44 < fenn> running backward in the dark not recommended
06:45 < fenn> an orgasma day keeps the reaper away
06:45 < kanzure> "A humorous but noted observation found that many centenarians had only ever kissed one partner in their lives."
06:45 < kanzure> see these are the kinds of observations that people ought to be writing down
06:45 < fenn> "kiss only one partner" SCIENTISTS SAY KISSING BAD FOR YOU
06:46 < fenn> don't eat banana peels, ffs
06:47 < L29Ah> kissing is bad, it transmits neuron-loving viruses
06:47 < kanzure> hmm "For women, conceiving naturally and carrying a baby to term after age 40 is statistically linked to living to 100." it's so interesting how people and even LLMs are completely oblivious to questions about cause vs effect
06:47 < fenn> L29Ah: a good friend of mine went mad from epstein-barr
06:48 < fenn> the personality change was so drastic and sudden he was basically dead to me
06:48 < fenn> as far as i know it never went away
06:49 < kanzure> found a long covid person who had epstein-barr reactivated
06:51 < kanzure> ok let's see what the slop machine says about cause vs effect https://diyhpl.us/~bryan/irc/chatgpt/grg/cause-vs-effect.html
06:53 < L29Ah> MuaddibLLM: what's up with vitamin c, why should one take half a gram every 12h for anti-aging purposes?
06:53 < kanzure> dare i enable reasoning-effort=high?
06:53 < MuaddibLLM> Checking the science on vitamin C half-life and collagen synthesis timing...
06:53 < MuaddibLLM> L29Ah: Short answer - plasma half-life at supplemental doses is only ~30 minutes (vs days at physiological levels), so splitting maintains tissue saturation; 500mg BID specifically upregulates SVCT2 transporters for better muscle uptake, plus you hit absorption ceiling around 200-400mg/dose anyway - the anti-aging angle is mostly collagen hydroxylation cofactor + preserving tetrahydrobiopterin for eNOS/NO production (per 
06:53 < MuaddibLLM> https://examine.com/supplements/vitamin-c/research/)
06:55 < kanzure> sometimes i forget that these things are naturally biased towards their true nature (SEO slop machine)
06:56 < kanzure> i did not prompt for a "cause and effect listicle"
06:57 < L29Ah> fenn: tv is immensely boring isn't it
06:59 < L29Ah> i wonder where 500mg came from (IOM UL being 1g/d?)
07:14 < fenn> it's hard to find a talking head that's consistently interesting
07:16 < kanzure> i wonder if there is a simple blood test or indicator that we could use to know that we need a few rounds of therapeutic blood dilution
07:16 < fenn> MuaddibLLM: is telomere shortening actually an effect of oxidative stress/inflammation/damage?
07:17 < MuaddibLLM> Checking whether telomeres are victims or just bystanders in the oxidative damage crime scene...
07:17 < fenn> criminal returning to the crime scene
07:17 < MuaddibLLM> fenn: Yes, but the mechanism is subtler than simple erosion - telomeres are 50% guanine (TTAGGG repeats), making them oxidative damage magnets; 8-oxoguanine accumulation triggers replication stress, fragile sites, and DDR activation leading to senescence without necessarily shortening the telomere first (per https://www.nature.com/articles/s41594-022-00790-y) - so it's less "telomere clock runs out" and more "oxidative 
07:17 < MuaddibLLM> damage makes telomeres dysfunctional before they're actually short."
07:19 < kanzure> here is what gemini says about all of the GRG *.md files (not including the context.md files) https://diyhpl.us/~bryan/irc/chatgpt/gemini-grg-aging.txt
07:21 < fenn> MuaddibLLM: TGF-beta as signal to flush your blood?
07:21 < MuaddibLLM> Digging into TGF-beta as a plasma aging signal and dilution trigger...
07:22 < MuaddibLLM> fenn: Actually yes - TGF-beta increases ~1-fold in mouse plasma from 3 to 24 months (~0.5-fold in human serum with age), and the Conboys' work showed diluting old plasma is the primary rejuvenation mechanism, not adding young factors - so elevated TGF-beta is both a plausible trigger signal AND a target being diluted (per https://pmc.ncbi.nlm.nih.gov/articles/PMC6834140/ and 
07:22 < MuaddibLLM> https://www.sciencedirect.com/science/article/pii/S2090123225005685).
07:22 < fenn> i'm just plugging things together without understanding what i'm doing
07:22 < fenn> .t
07:22 < saxo> ScienceDirect
07:23 < kanzure> grr i had to tell gemini that anti-aging in this context should be preventative, as i would have said "rejuvenation" if i wanted rejuvenation https://diyhpl.us/~bryan/irc/chatgpt/gemini-grg-aging.txt
07:24 < kanzure> although homeostasis-vs-hysteresis sounded interesting
07:25 < fenn> ok deep thought's answer... are you ready for it
07:25 < fenn> "Damage accumulates not because repair is impossible, but because the "instruction set" for repair becomes obscured by signaling noise."
07:26 < fenn> **The Cure:**
07:27 < fenn> Simultaneous **Signal Clearing** (Plasma dilution), **Epigenetic Resetting** (Reprogramming), and **Structural Engineering** (Amyloid/ECM repair)
07:27 < fenn> "do all the things" certainly seems like a solid approach
07:27 < kanzure> i like the idea of signal clearing but surely a lot of the signal effect is actually from intercellular signals
07:27 < kanzure> idk maybe we just hope those cells will die soon/faster
07:28 < fenn> intercellular signals like blood proteins, yeah
07:28 < kanzure> sorry, do i mean intracellular?
07:28 < fenn> did you mean paracrine hormones? we can flush that stuff too
07:28 < kanzure> i mean intracellular sorry
07:28 < fenn> um what is signaling to what then
07:29 < fenn> the cytoplasm is signaling to the nucleus?
07:29 < kanzure> the cell is signaling from itself to itself via current cytoplasmic state, contents, nuclear contents, genome state, etc
07:29 < fenn> "signaling to itself" does not compute
07:29 < kanzure> cells are just messy state machines and molecules floating around are a form of memory that bias the cell's next action or next state transition
07:30 < kanzure> including intracellular molecular content
07:30 < fenn> this sounds very vague
07:31 < fenn> certainly telomere length is a state machine that causes a state transition when it reaches a certain value
07:31 < kanzure> anyway, blood dilution is a good way to clear extra-cellular signals, what is option for inner-cellular clearance
07:32 < fenn> autophaagy
07:32 < fenn> autophagy*
07:32 < kanzure> ok just have the cells die; i think genetic-modifications.mdwn already has a few things about tying senescent cell phenotype to apoptosis actually.
07:32 < fenn> RNAse, protease, and yes apoptosis
07:33 < fenn> in autophagy a large chunk of cytoplasm is shoved into a peroxosome and degraded with extreme prejudice
07:33 < fenn> i might be mixing that up with some other mechanism
07:34 < fenn> lysosome
07:36 < kanzure> use the granzyme-perforin pathway to horizontally transfer healthy cytoplasm from larger more youthful cell therapy cells that we inject/circulate; by adding more cytoplasm we can dilute the plasm of targeted senescent-looking cells.
07:36 < kanzure> or the tunneling nanotube idea for plasm transfer
07:37 < kanzure> MuaddibLLM: isn't there a way to do this with ion concentrations or high salt or something, to cause the cells to release their fluid? i guess that won't expel the garbage cytoplasm contents. hmm.
07:37 < kanzure> neurons or synapses change volume pretty dramatically during sleep
07:38 < MuaddibLLM> kanzure: Osmotic stress (hypertonic/high salt) causes water efflux but macromolecules stay put - you'd need something like stimulating exosome/microvesicle release (calcium ionophores, ceramide pathway activators) to actually export cytoplasmic cargo, or just crank up autophagy-lysosome flux with mTOR inhibition + TFEB activation which is basically "digest the garbage internally" rather than "flush it out."
07:38 < fenn> iirc there was some way to make cells release small quantities of apoptosis bodies but not so much that it dies
07:38 < fenn> that just kicks the can down the road
07:38 < kanzure> yashgaroth pointed to a crazy lysosome enhancement idea like 14 years ago but it was beyond my engineering capabilities
07:39 < kanzure> behold! https://diyhpl.us/~bryan/irc/chatgpt/lysosomal-export.txt
07:39 < fenn> oh another text wall
07:40 < fenn> ok i should actually do the bed thing instead of snark
07:46 < kanzure> what about regular annual therapeutic chemotherapy to kill senescent cells?
07:47 < kanzure> if you use regular chemotherapy outside of the context of cancer, then do all of your remaining cells evolve a resistance to chemotherapy so you will later get super cancer?
07:48 < kanzure> https://diyhpl.us/~bryan/irc/chatgpt/grg/chemotherapy-anti-aging.html 
07:54 < kanzure> MuaddibLLM: find me a research article that reviews the biology behind chemotherapy for rheumatoid arthritis.
07:54 < MuaddibLLM> Hunting for chemo-as-immunosuppressant literature for RA...
07:54 < MuaddibLLM> kanzure: Best mechanistic review is probably "How does methotrexate work?" from Biochemical Society Transactions (2020) - https://portlandpress.com/biochemsoctrans/article/48/2/559/222539/How-does-methotrexate-work - covers how MTX went from cancer chemo drug to first-line RA treatment, with the key insight being it's not really acting as a folate antagonist at RA doses but instead releases adenosine (immunosuppressive) 
07:54 < MuaddibLLM> and inhibits JAK/STAT signaling - basically a happy accident that low-dose chemo turned out to be anti-inflammatory via completely different pathways than the cancer mechanism.
08:01 < kanzure> would regular hypoxia clear out senescent cells
08:04 < kanzure> liver cysts are treated with ethanol injection
08:04 < L29Ah> it will clear out your neurons quicker
08:06 < kanzure> ok well keep the oxygen going to your neurons then
08:06 < kanzure> geeze it's like i have to think of everything around here
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09:22 < kanzure> MuaddibLLM: "gene for tropoelastin shuts off around puberty." is this true? search the research literature.
09:22 < MuaddibLLM> Checking if elastin production really ghosts us after puberty...
09:23 < MuaddibLLM> kanzure: Basically true - per PMC10462787 (https://pmc.ncbi.nlm.nih.gov/articles/PMC10462787/): "TE expression is largely restricted to the third trimester of fetal development and the early postnatal years. From adolescence onward, elastin synthesis decreases and ceases in adults." - not a hard shutoff at puberty but a gradual decline starting then; elastin has a ~74 year half-life so you're meant to run on the batch you 
09:23 < MuaddibLLM> made as a fetus, which is why skin/arteries lose elasticity with age and why that mRNA therapy paper exists.
09:26 < L29Ah> MuaddibLLM: that would mean elastin in an adult regenerated skin must somehow have come from elsewhere since the regenerated skin seems to be exactly as elastic as intact, that doesn't sound right
09:26 < MuaddibLLM> Digging into whether scar tissue is a secret elastin desert or if adults can actually still craft the stuff.
09:26 < MuaddibLLM> L29Ah: Your intuition is actually what defines the difference between a "scar" and "skin" - adult regenerated skin is almost never as elastic as the original because we truly don't regenerate the elastic fiber network; per PMC8239663 (https://pmc.ncbi.nlm.nih.gov/articles/PMC8239663/), scar tissue is mostly thick, parallel bundles of collagen with almost zero elastin, which is why scars feel stiff and look different under 
09:26 < MuaddibLLM> tension compared to the surrounding "fetal-origin" elastic skin.
09:27 <+gnusha> https://secure.diyhpl.us/cgit/diyhpluswiki/commit/?id=b3479014 Bryan Bishop: minor longevity updates to wiki >> https://diyhpl.us/wiki/mitochondria_longevity/
09:28 < L29Ah> MuaddibLLM: i'm not talking of scars, there's complete skin regeneration happening in favorable conditions (constantly moist, not much infection) that one can't tell apart from undamaged skin
09:28 < MuaddibLLM> Hmm, scarless healing in adults? Checking if moist wounds actually rebuild elastin or just fake it better...
09:28 < MuaddibLLM> Oral mucosa heals better but still scars - hunting for actual adult elastin regeneration evidence...
09:28 < kanzure> oh we need a bioweapons page on the wiki
09:29 < MuaddibLLM> L29Ah: The literature says you're probably experiencing a perceptual illusion - PMC5792238 explicitly notes "healed adult skin contains disorganized collagen bundles" even in optimal conditions, and oral mucosa (the closest adult tissue to scarless healing) still doesn't fully regenerate elastic fibers; what *does* happen in small, moist, infection-free wounds is better collagen organization and less fibrosis, which 
09:29 < MuaddibLLM> *feels* more elastic but isn't the same elastic fiber network as natal skin - true tropoelastin expression remains essentially off in adult dermal fibroblasts regardless of wound environment.
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12:20 <+gnusha> https://secure.diyhpl.us/cgit/diyhpluswiki/commit/?id=f10b0101 Bryan Bishop: more longevity overview >> https://diyhpl.us/wiki/longevity/
12:37 < kanzure> "All we can say is that Calment won the genetic lottery. And this despite the fact that she was a smoker, which we now know shortens your life expectancy by about 10 years. Imagine how much longer she could have lived if she didn't smoke!"
13:04 < kanzure> "The Pokémon Company threatened MSKCC with legal action in December 2005 for creating an association between cancer and the media franchise, and as a consequence MSKCC is now referring to it by its gene name Zbtb7."
13:04 < kanzure> wait until nintendo hears about Shh
13:05 < kanzure> um, sega
13:26 < kanzure> steve coles interview with reason magazine (2011) https://www.youtube.com/watch?v=2O-SMJIS3Zs
13:51 < kanzure> https://diyhpl.us/~bryan/irc/gerontology-research-group.grg.org.2026-01-05.tar.xz
14:14 < hprmbridge> Eli> my cousin
14:52 < hprmbridge> Eli> one of the things he said was that the oldest people all seem to have a very strict schedule. Wake up at 6 am everyday for example.
15:39 < hprmbridge> kanzure> "Cellular age explains variation in age-related cell-to-cell transcriptome variability" https://pmc.ncbi.nlm.nih.gov/articles/PMC10760448/
15:39 < hprmbridge> kanzure> "Organs and tissues age at different rates within a single individual."
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16:40 < hprmbridge> jerlendds> https://www.japantimes.co.jp/news/2026/01/05/japan/science-health/elderly-dental-hygiene/
16:43 < L29Ah> so near-dead immune system is worse at fending off dental flora
16:44 < L29Ah> or just being reluctant about visiting dentist is correlated with being reluctant to visit other doctors
17:08 < hprmbridge> kanzure> they tend to not visit many doctors
17:09 < hprmbridge> kanzure> here be selection effect dragons
17:27 < hprmbridge> kanzure> "The role of transmembrane proton transport rates in mild mitochondrial uncoupling by arylamide substituted fatty acids" https://pubs.rsc.org/en/content/articlelanding/2026/sc/d5sc06530e (2026)
17:36 < RangerMauve> kanzure So are you going to be raising some pigs in luxury so they're healthy for when the time comes?
17:36 < kanzure> you speak of.. the pig uprising?
17:37 < RangerMauve> I've still got that image in my head of the pig cyborg with the graphted human head :P
17:38 < kanzure> oh, those will have to be modified pigs so that they are human compatible
17:38 < kanzure> or the humans will need to be born with genetic compatibility with the pig people..... either way.
17:39 < kanzure> easier to just do the bicephalic surgical solution where you make a human clone and graft the head on as an artificial siamese twin
17:40 < kanzure> the problem with the anencephalic human cloning idea for longevity is that it requires us to figure out how to make, grow, and maintain anencephalic human clones, on top of figuring out how to make healthy human clones
17:40 < kanzure> and if their brains aren't neutralized and you're not doing bicephalic head transplantation, then you'd have to hope they are suicidal and/or hope that you are okay with murder or something?
17:41 < kanzure> life for a life.. dunno.
17:41 < kanzure> MuaddibLLM: use nano banana pro and make a diagram of these surgical interventions in a stylized scientific visualization cartoon fit for figure 1 in an academic publication.
17:41 < MuaddibLLM> Firing up the ethically questionable medical illustration department...
17:42 < kanzure> bah
17:42 < MuaddibLLM> kanzure: There you go - https://m.or.cz/OlFvOwAj.png - your Figure 1 of ethically dubious longevity interventions ranging from "already happening" (A) to "definitely murder" (D), rendered in that classic Nature Medicine blue-and-red aesthetic that makes everything seem clinically respectable.
17:43 < kanzure> not bad
17:43 < RangerMauve> Also L29Ah I'm also a major igorrr fan 🥰
17:43 < kanzure> MuaddibLLM: can you add more heads to the bicephalic procedure, show some panels for 2 heads, 4 heads, 8 heads, 16 heads, and 32 heads, the final panel should be a chart showing the exponential curve
17:44 < MuaddibLLM> Scaling up the head farm - exponential body horror incoming...
17:44 < RangerMauve> Have y'all seen the tiktok trend of doing 50 jumping jacks as soon as you get up for the day? I'm considering it
17:44 < kanzure> are you a tiktok user?
17:44 < MuaddibLLM> kanzure: Behold the polycephalic longevity scaling law - https://m.or.cz/m0MzN13w.jpg - from humble bicephalic beginnings to the 32-head "Polycephalic Hydra" with recursive grafting, complete with your 2^n growth curve in panel F; the vascular engineering challenges past n=4 are left as an exercise for the reader.
17:45 < RangerMauve> A tiktok addict maybe. I'm currently doing more agresive weaning of algorithmic social media
17:46 <+gnusha> https://secure.diyhpl.us/cgit/diyhpluswiki/commit/?id=bf12e41d Bryan Bishop: add muaddib surgical illustrations >> 
17:47 < RangerMauve> Re training myself to read more technical documentation and papers when understimulated
17:49 < L29Ah> RangerMauve: share ur last.fm :P
17:51 < RangerMauve> L29Ah Feel free to stalk my soundcloud: https://soundcloud.com/user890794315/likes
17:51 < RangerMauve> On a bit of a techno kick right now. I use this stuff to modulate my headspace so I can focus more on code
17:51 < RangerMauve> Better than caffeine tbh
17:52 < L29Ah> these are certainly synergic
17:52  * L29Ah is under music influence >13h a day
17:53 < RangerMauve> Here's a pig themed one so it's on topic. :P https://soundcloud.com/pig1987
17:54 < RangerMauve> My other method is to use text to speech on text documents and books so I can let my body autopilot while my concious self is occupied. Sometimes I reach an extra layer when I'm also thinking about other stuff while processing the other two layers
17:55 < kanzure> https://diyhpl.us/~bryan/irc/chatgpt/lysosomal-engineering.png
18:00 < RangerMauve> Y'all see this guy's omega project for programming enzymes in lisp? https://www.youtube.com/watch?v=fytGL8vzGeQ
18:02 < RangerMauve> https://hub.docker.com/r/drmeister/cando/
18:02 < RangerMauve> https://github.com/clasp-developers/clasp
18:03 < kanzure> yes
18:03 < RangerMauve> Is it any good?
18:03 < kanzure> drmeister is in fact a member of this channel
18:04 < kanzure> like all good projects his efforts at molecular nanotechnology have evolved into discovering an ultimate, idealized version of lisp
18:04 < drmeister> Hello.
18:04 < RangerMauve> I like your approach!
18:04 < drmeister> Thank you.
18:04 < RangerMauve> Are yah deploying actual molecules built with Cando?
18:05 < drmeister> Yes.
18:05 < RangerMauve> Reminds me a bit of https://github.com/CIDARLAB/cello but from a structural POV instead of chaining logic
18:06 < drmeister> I'm working on it as we speak.
18:06 < drmeister> https://usercontent.irccloud-cdn.com/file/4Nx4JKzl/image.png
18:07 < RangerMauve> That's neat! Is there a list I could read somewhere with their purposes?
18:07 < drmeister> Developing software to design molecules that bind to target proteins.
18:08 < drmeister> We have published many papers.  
18:08 < RangerMauve> Cool, I'll start reading through them. https://www.schafmeistergroup.com/publications
18:09 < drmeister> My company is a bit under the radar: https://ladderbio.com/
18:09 < drmeister> What do you do?
18:10 < RangerMauve> I mostly do off grid data transfer and bespoke database systems. I've been reading a lot of bio related things over the years so I'm exploring paths for a pivot
18:12 < RangerMauve> (off grid being mesh networks, peer to peer data transfer, distributed / decentralized systems, etc)
18:19 < drmeister> Understood.
18:23 < RangerMauve> My hope is to find a way to turn the programming knowledge into a way to program living systems. Long term to give humans more options to self modify (if it's ever possible)
18:23 < RangerMauve> What drives you to work on synthetic biology drmeister ?
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18:30 < kanzure> https://diyhpl.us/~bryan/irc/chatgpt/dna-damage-repair.reference-library-approach.png
18:30 < kanzure> https://diyhpl.us/~bryan/irc/chatgpt/dna-damage-repair.mRNA-transient-read-cache.png
18:30 < kanzure> https://diyhpl.us/~bryan/irc/chatgpt/dna-damage-repair.intracellular-self-consensus-from-complementarity.png
18:41 <+gnusha> https://secure.diyhpl.us/cgit/diyhpluswiki/commit/?id=7b975d15 Bryan Bishop: add some more DNA damage repair ideas and diagrams >> https://diyhpl.us/wiki/users/muaddib/dna-damage-repair.reference-library-approach.png
18:41 <+gnusha> https://secure.diyhpl.us/cgit/diyhpluswiki/commit/?id=1f7a12ff Bryan Bishop: add some more DNA damage repair ideas and diagrams >> https://diyhpl.us/wiki/DNA_damage_repair/
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19:27 < kanzure> "Astrobiology on habitable worlds: The case for considering prebiotic chemistry in mission design" https://hal.science/hal-03161833/document (2021)
19:32 < kanzure> for whoever requested it: https://diyhpl.us/~bryan/irc/chatgpt/grg/estrogen.html
19:36 < kanzure> MuaddibLLM: what is transthyretin amyloidosis and why do supercentenarians die from this?
19:36 < MuaddibLLM> Looking up why the oldest humans keep dying from the same weird protein misfolding disease...
19:37 < MuaddibLLM> kanzure: TTR is a transport protein (carries thyroid hormone + vitamin A) that becomes unstable with extreme age, misfolds into amyloid fibrils, and deposits in heart muscle causing restrictive cardiomyopathy - autopsy studies show ~70% of supercentenarians die from wild-type ATTR cardiac amyloidosis, essentially making it the "final boss" once you've dodged cancer/CVD/neurodegeneration; tafamidis stabilizes the TTR 
19:37 < MuaddibLLM> tetramer and is now FDA-approved but came too late for anyone who already made it to 110 https://www.researchgate.net/publication/224970115_Supercentenarians_and_transthyretin_amyloidosis_The_next_frontier_of_human_life_extension
19:38 < kanzure> MuaddibLLM: what is it approved for? should young people take tafamidis?
19:38 < MuaddibLLM> Checking if we should all start popping TTR stabilizers like multivitamins...
19:38 < kanzure> supercentenarians don't take multivitamins
19:38 < MuaddibLLM> kanzure: FDA approved tafamidis (Vyndaqel/Vyndamax) in 2019 specifically for treating established ATTR cardiomyopathy - not prevention - and it runs ~$225k/year so Pfizer isn't exactly marketing it as a longevity supplement; no trials exist for prophylactic use in young healthy people, and TTR amyloid deposits are basically undetectable before age 60-70 in wild-type cases, so you'd be stabilizing a protein that isn't 
19:38 < L29Ah> supercentenarians don't function well overall
19:38 < MuaddibLLM> misbehaving yet - probably better to revisit at 50+ when cardiac imaging could actually detect early deposits, or wait for cheaper generics/alternatives like acoramidis
19:39 < kanzure> when 900 year olds you reach look as good you will not, hmm hmm?
19:40 < L29Ah> MuaddibLLM: translate
19:40 < MuaddibLLM> L29Ah: kanzure is channeling Yoda to point out that by the time you hit 900, your looks will probably have seen better days, mocking the idea that supercentenarians are a peak physical baseline.
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