RNAi epigenetic demethylation drug drug causes c elegans to live twice as long as unmodified c elegans going from 30 day lifespan to 60 day lifespan; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4889222/figure/F1/
The longest lived c elegans compared to undrugged c elegans is called vector + CCO1 daf2e1370, daf2e1370 did better at median but they both doubled longevity; isp1 (qm150) had greater surviving near median, but was like 58%
CCO1 RNAi was a single treatment rahter than a combined treatment
“Across eukaryotic species, mild mitochondrial stress can have beneficial effects on the lifespan of organisms. Mitochondrial dysfunction activates an unfolded protein response (UPR(mt)), a stress signaling mechanism designed to ensure mitochondrial homeostasis. Perturbation of mitochondria during larval development in C. elegans not only delays aging but also maintains UPR(mt) signaling, suggesting an epigenetic mechanism that modulates both longevity and mitochondrial proteostasis throughout life. We identify the conserved histone lysine demethylases jmjd-1.2/PHF8 and jmjd-3.1/JMJD3 as positive regulators of lifespan in response to mitochondrial dysfunction across species. Reduction of function of the demethylases potently suppresses longevity and UPR(mt) induction, while gain of function is sufficient to extend lifespan in a UPR(mt)-dependent manner. A systems genetics approach in the BXD mouse reference population further indicates conserved roles of the mammalian orthologs in longevity and UPR(mt) signaling. These findings illustrate an evolutionary conserved epigenetic mechanism that determines the rate of aging downstream of mitochondrial perturbations.”
So like they did this thing to mitochondria, and the epigenetics had more demthylase going on, so there were some histone DNA areas that got more demethylated, They demethylased the c elegans when they were larvae, suggesting a possible human prenatal longevity chemical (epigenetic), or noting epigenetics, something the mother can do for her children, or possibly something a grandmother can do for her grandchildren, mitochondrial stress causes c elegans to live twice as long and mice have the same genes, notably I read that nucleotide riboside (NR) or a lipid rich diet change the mitochondria from many and diminuative (NR) to plump and few (lipids), and that at the many and diminuative version the energy producing ability of the organism, and this has been verified with humans taking Nicotinic acid combined with ribose, could have similarities to the “mitochondrial stress” that makes the c elegans live twice as long, that suggests primate research, like on marmosets could find out if something like a NR enriched, or possibly just nicotinamide with ribose enriched, or just nicotinamide enriched diet or possibly just ribose enriched beneficial at mice and marmosets diet during pregnancy is beneficial, along with the studies of people with naturally demethylated mitochondrial uncoupling areas at their histones found at databases guiding enhanced preoptimization human genetics and epigenetics
Notably it is possible to grow human oocytes from a cheek swab, so a woman can do a cheek swab, grow some oocytes (eggs), have their epignetics modified, notably as well as among others, with particular demethylases, then her direct progeny get the longevity benefit; this immediate progeny longevity epigenetics benefit could be verified with mice as well as finding out that actual amount of lifespan increase at a mammal; notably it is possible that the demethylases that cause mitochondrial protein uncoupling UCPmt epigenetics that double the longevity of the c elegans may also have completely different beneficial effects, if these demthylators have other beneficial effects then along with the longevity benefit they might have cell culture oocyte babies to say, prevent heart disease, or halve cancer risk when there is a previous generational occurence, so this longevity epigenetic modification to human oocytes has both a “conservatively get rid of illness” attraction component as well as a “my children will live a really time” component, which combined or separately reaches more people
Note though they have to figure out the benefit of demethylation that effects (uncouples) mitochondrial function possibly looking at medical records of individuals epigenetics at health maintenance organzations records or other databases to find hundreds or thousands of people, out of hundreds of thousands or millions of people, that have these histone demethylase epigenetics naturally; then measures like g (like iq), big five personality type, subjective well being, quantifications of beneficial or aversive life events, n external, if possible video based quantification of social fluency nd attractiveness, noting mitochondrial energy regulation during preganancy could effect birth weight, facial feature development, and body proportions; If all of these are at first standard deviation (about the same as 2/3 of other people), or have a higher concentration of characteristics to the right of one standard deviation, that is better than 2/3 of people, then demethylation of areas of oocyte (egg) histones is a highly beneficial thing people could actively seek. Also fiding out the epigenetic variants amongst those that naturally have demethylated epigenetics of mitochondrial uncoupling, the notable benefit being longevity, could find versions among humans that are actually better than the published data on mice and nonmammals, like there could be an genetic or epigenetic subgroup that has 40% more lifespan extension at their parents and grandparents ages than the other demethylase epigenetic humans, who also are quantified living longer than the 2019 population median; also subgroups of the long lived demethylation histone group that have higher g (like iq),
It is also possible that when screening databases to find people with naturally occuring demethylase of mitochondrial uncoupling persons high ceoncentrations at some regions, lifestyles, or direct genetics may be found, that could be because because it is possible genetics can also drive epigenetics, and then groups of those people could be looked at to find out if they have some endogenous production of an epigenetic modifier that demethylates the genetics of their oocytes as well as of the rest of their body,
Making sure this is beneficial to humans is suggested at, “One of the most dramatic examples in which early events have effects on longevity is found in the nematode C. elegans, in which mitochondrial stress during development can cause nearly a doubling of the animal's lifespan (Dillin et al., 2002a). The timing and degree of mitochondrial dysfunction is highly selective: it must occur during a specific L3/L4 larval transition in order to cause lifespan extension, a time during which a heavy amount of germline-specific mitochondrial biogenesis also occurs (Rea et al., 2007; Tsang and Lemire, 2002). In contrast, mitochondrial dysfunction that is too severe or which is implemented too early or late can have a negative effect on lifespan. In many cases, titrating a level of dysfunction is absolutely required in order to observe an extension of lifespan (Rea et al., 2007). Longevity caused by mitochondrial dysfunction also often fails to generate universal health benefits, as organisms may live longer but exhibit developmental delay and a drastic reduction in reproductive fitness (Dillin et al., 2002a; Lee et al., 2003). These effects are surprisingly conserved: in yeast, flies, and mice, mitochondrial dysfunction can delay the aging process (Copeland et al., 2009; Dell'agnello et al., 2007; Dillin et al., 2002a; Feng et al., 2001; Kirchman et al., 1999; Lee et al., 2003; Liu et al., 2005), but, when occurring later in life, has deleterious effects and is associated with age-onset neurodegenerative diseases, directly contributing to their pathologies (Schon and Przedborski, 2011).
The researchers noticed mice have these genes as well
Longevity technology: Just as a person would value and utilize taking more than one longevity drug to make sure different kinds of tissues were simultaneous benefitting from a longevity drug, say lipophilic and hydrophilic rapamycin variants (rapalogs), This multi-agent technology at gene therapy and purposed epigenetic modification is also beneficial, doing gene therapy on different genes that effect one system has benefit, like longevizing different genetic compositions of daf1,daf2,daf3, and others as well as sirt1, sirt2, sirt3, and others rather than just one; at epigenetics, addressing the epigenetics of mitochondria with simultaneous agents to modify other things at mitochondrial genetics besides just the UCPmt genes could be characterized as to human well being, notably groups of subgroups at a population of databased epigenetic health records having a subgroup above the median, a subgroup above the first deviation, as well as a non subgroup quantified physyiological and psychometric quantification at the standard devaition of variance as the entire database of all the records;
the paper says, “One of the most dramatic examples in which early events have effects on longevity is found in the nematode C. elegans, in which mitochondrial stress during development can cause nearly a doubling of the animal's lifespan
Rescueing children: curing, preventing and treating diarrhea saves childrens lives and makes them feel better; notably Oral Rehydration Therapy (ORT) is published as being among the things that saved more lives than any nonvaccine technology during the 1990s;
a complement to ORT is pieces of paper, available at 1/10th of 1 cent per dose, to be affordable globally and at the developing world, attractive to distributors, with anti-diarrheal peptides like octapeptide octotrieotide, mu-opiod anti-fever peptides, or new screened molecular variants or the antipyretic protein lipocortin1;
As an alternative to the anytipyretic lipocortin1 the drug liposomal-active transport protein-ethynyl-naproxen (ELA-naproxen) could be developed; naproxen is a 12 hour antipyretic, ethynylising sex hormones at things like contraceptives gives them 600 nanogram dosages (1/1000 of a microgram per nanogram), compared with .625 micrograms, so the dose efficiency increases 10 times, active transport is a phenomena where cells actively use energy to pull molecules into the cytoplasm, it is 1000 times as active as diffusion, so that is also 700-1000 times greater dose efficiency, optional is dry liposomalization, where the drug is surrounded with a tiny sphere of a phosphatidyl (food) molecule molecule and dried, I have read online that dried liposomes are good for months, that causes about 4 times greater physiological availability and passage through the membranes of the small intestine; together 220 mg of naproxen at the new antipyretic is 10 times 700 times 4 times fewer mg per dose, of about 7.9 micrograms per dose;
the anti-diarrheal anti-fever one dose per 1 cm paper things also have smiling faces on them They are 1 cm^2 (1 cm square, like LSD), or as another form, pieces of yummy candy about 2-3 mm on a side like Nerds (tm);
Notably other peptide and microgram dose drugs are printable, the GABA receptor activator phenibut causes happier mood, is anxiolytic, increases some cognitive abilities (nootropic), increases social fluency, reduces symptoms and itch of dermatitis like atopic dermatitis, and is absent regulation because of its nonhabituating character; GABA receptor active peptides are published, and a library of 3000 variants could be screened sequentially at 100 mice, each taking 30 different peptides/24 hours for a month, or in-vitro GABA receptor activation could be quantified, and possibly multiple simultaneous radiolabelled versions of GABA peptides at positron emission tomography could be traced to their locationization at the brain, spinal cord and dermis, noting which brain structures and therefore ability heightening (nootropic), relaxing, anxiolytic, anti-itch and screening a library of 10,000 to 100,000 different GABA peptide variants to find the one in vitro that most nearly matched mild, nonhabituating, human appreciated phenibut could be done with microfluidic technology like the microfluidic chip I read about;
To globally equal or exceed the incentive of candy companies in the developed world that currently make and distribute candy, at a 1/10 of 1 cents a dose, the US dollar store candy has value; At a regular grocery you can get one entertainingly wrapped metallized paper Andes mint for 10 cents, I perceive the Andes mint company might get 5 cents for it and the distributor to the grocery store might get 7 cents for it; on ebay a 4 pound container of Andes mints is 7.06 per mint;
Along with the Andes mint version is the 400 Nerds(tm) candy per box version, a 3-4 ounce box of candy at the dollar store in the US can have hundreds of pieces (perhaps 400) per $1.00 box, and the dollar store is incentivized enough to have a large candy section.
The fiscal value of 10 to 100 micrograms of octotrieotide (anti-diarrheal) combined with 1 milligram of the the antipyretic protein lipocortin1 (active at 50 micrograms per kilogram) at $1000-$10,000 a kilogram at 1.01 mg of drug, is, if it were a $1 a gram, 1/1000th of a cent a dose, and if the drug ingredient is $10,000 a KG then the active drugs combined are 1/100th of 1 cent a dose.
The paper component, for an 8.5 x 11 sheet of paper with drugs inkjet printed or silkscreened onto it is 7 cents per sheet, 567 happy face 1 cm ^2 doses per sheet, makes the paper value per dose is about 1.2/100ths of one cent. It is possible that the paper, the most financially prominent part of the anti-diarrhea, anti-pyretic, and with GABA active peptide drug dose form is actually 3 cents rather than 7 cents, which would double the 87% profit margin to the distributors;
Together the drug and paper is 1.3/100ths of one cent, so at retail to the family of child or adult each 1/10 of 1 cent dose at the nearest distributor, which might be a place with carbohydrate staples and sweet treats, has a profit margin of 87%, far above many items than perhaps most items at the US dollar store;
The piece of paper has enteric (stomach passing) polymer ink coating as the base layer, (one polymer possibility is the polymer used to make enteric drug capsules available now) then a 2 milligrams of ink (1.01 mg drug and 1 mg vehicle), then another enteric layer, then a cheerful graphic layer; the piece of paper reaches the small intestine, where the pH goes up to 8-8.5 and the pH enteric polymer ink dissolves, letting the drug reach the circulation; The ink used to print the 1 cm^2 dose can have a sucralose ink layer to make the paper taste sweet and good;
A children’s happy face has a child’s dose each, an adult happy face has an adult dose, if the thriftiness is popular, an image of water and a face can mean both are on the same piece of paper, and it is kinder to give children the antipyretic with the antidiarrheal drug; The antidiarrheal and antipyretic, and the GABA comfiness causing version could have three images on it;
At one version the ELA-naproxen version uses an anipyretic with 12 hours function (naproxen), I think it would be kinder to children to make the antipyretic last 24 hours, there are a few ways to do this, one is to have the sweet layer printed on the upper surface of the paper dose have ELA-naproxen combined with a flavoring, the child would then enjoy, and perhaps swish around in their mouth, or even chew the piece of paper so that the few microgram dose of ELA-naproxen was administered immediately, then the thickness of the enteric-coated base layer and mid layer with the drugs between it would be constructed to dissolve 11 hours after ingestion, it would then release a second dose of ELA-naproxen and the child would get 24 hours of continuous antipyretic activity; Another approach is to print the immediate dose of ELA-naproxen right on the surface, and then print a transparent stomach-dissolving layer on it, that way instead of thinking ELA-naproxen is delicious enough to dissolve in your mouth, the dosing paper tastes neutral or, with the sucralose print layer, sweet
Notably I think it is possible to make the piece of paper at least kind of chewable, for one thing, swallowing a piece of paper is less easy than swallowing a good tasting eentsy wad, it is possible printing a kind of micro dot array, where the dots are mostly so small chewing does not disrupt them very much; also, at a dot array, the administration effects would be measured and the dots have a quantified ability to administer drugs;
Chewability engineering might be something to skip; making it as simple as possible as a technology so that there is a minimum of effort and it reaches people more rapidly and affordably; making it simple enough so that it is designed and built with 2 months or less between corporate approval and the ability for the company to bulk print it; if it is simple then the companies making it perceive it as, and it actually is, a minimal investment, high profit, easy to distribute item;
simple rapid corporate process suggests making it simple enough to minimize corporate redesign and dosing studies; I think it can be tested in parallel with just a few humans, inkjet or silkscreen printing; Based on a computer file as simple as a jpeg of dots, print 576 slightly different versions that fit on one sheet, and each of the 576 versions can be printed with slightly different enteric thicknesses, and at the drug part, different geometries like dots of different sizes; use taggants (a known thing, sometimes little chemical fragments, sometimes fluorophores, some I think are even stable isotopes); omitting the actual drug; using the taggants one person can test 40 versions simultaneously, the paper doses sequentially swallowed , 40 in an hour, and a few hours later, 320 versions have been swallowed, then the taggants can be read, possibly in urine, to find out which versions stood up to chewing, sodas, hot beverages, and the effects at people in the normal range with with double or half the usual gastrointestinal motility, and the different sizes and lengths of children's GI tracts;
one simple approach to taggants is to just have a person with a paintbrush who only has to dip the brush in the taggant, give a quick dab to the particular 1 cm^2 dose, 576 times, let the page of tagged doses dry, then load it in the printer again to put the mid layer of enteric ink on it;
Incentive to distribute: An andes mint package, if it can contain two, 1 times 2 cm square happy face doses, and have the paper layers be 16 layers then it is 64 doses per pack, and has the visual advertising function, product freshness and physical bundling adequacy, the proven first world distribution incentive adequacy, of an andes mint in Seattle Washington;
One drug area that may be beneficial; the antidiarrheal and antipyretic are, unless ELA-naproxen is used, peptides; peptides can be engineered to be orally deliverable drugs and the FDA oral drug desmopressin (vasopressin) combines having a D-chiral amino acid at the peptide with removing three atoms at one of the amino acids, that causes stomach enzymes not to degrade it making it an orally available peptide medication; it is possible that larger doses of the enteric coated peptide could be quantified as to effect, skipping some effort, or perhaps the mu-opiate peptide is already fully active at the small intestine to end diarrhea without further engineering and can be combined with ELA-naproxen; there is also the version where D amino acid, possible deaminated (atom removed) version of mu-opiod and octotrieotide to produce GI tract passing oral peptide drugs
Another possible peptide drug paper dose enhancement heightens the likeliness that the unwell person will stay alive; the peptide AEDG (Epithalon) when combined with the peptide thymosin is published as causing people to be four times less likely to be unalive after six years; epithalon is also published as making mice live 24% longer; the four times more likely to be alive was among adults, I do not know the effects on unwell children but it is possible that quantifying lives saved and physiological harmlessness (noting 24% greater longevity) utilizing mice could qualify these peptides as causing more children to live
Engineering the mu-opiod containing antidiarrheal, antipyretic, and comfort-producing GABA active paper dose form to be harmless to people unintentionally or intentionally taking large quantities or children eating a bunch of sweet paper is to make the peptides have a protein, or another peptide attached to them that unless removed keeps the drug peptides from being active; there is an amount of some naturally occuring enzyme at either the GI tract, or, possibly more functionally, the circulatory system where the amount of enzyme circulating is only sufficient to cause four doses of peptide drugs at once to have the passivation protein enzymatically removed at the circulation and the mu opiod peptide and antipyretic peptide made physiologically available, if if a person ate an entire sheet they would still only experience four doses
It is possible screening a library of mu-opiod peptide variants at mice could find the most anti-diarrheal one that is the most well tolerated as an alternative to octotrieotide which is a multifunction drug and I think has a different dose than goes well with printing