Make versions of rapamycin that are variously lipophilic and fat soluble and a version that is water soluble, these taken together reach more tissues than regular rapamycin.
Rapamycin has long squiggle lengths of alkane or alkene form, change the length of these and test for longevity effects.
Really different than modifying rapamycin is modifying the mtor inhibiting peptides, about 9 of them are published. These mTor inhibitor peptides can be tested, both to increase longevity effects and to make a compound peptide like longevizing epithalon or thymulin attached to to the mtor1 inhibiting peptide, possibly with an enzymatically degradable linker.
There is even the possibility of attaching epithalon or also thymulin directly to the regular rapamycin molecule, possibly with an enzymatically degradable linker, that could be even more longevizing than rapamycin alone. Two studies cause 60% longevity increase from just rapamycin, and epithalon longevizes perhaps near 24%. These combined in one molecule could longevize 80% or a greater from that one molecule.
Fluorination, replacing hydrogen with a fluorine atom is a well known way to increase the dose potency and affordability of a drug.
Some other approaches to making longevity testable rapamycin variations are:
yeast digests, new probiotic makes rapaycin, enteric coated, the three cycles change the 6 carbon cycles to 7 carbon cycles, swap out some O with S or even Se,
Leave a comment if you would like me to explain these.
What are you, the reader’s ideas on new rapamycin variants?
If rapamycin really ends up proving to work for CVD/cancer risk, the main issue I would expect is dementia. There is limited data on rapamycin crossing the BBB in humans. The one study I’m aware of for brain tumors in human suggests it can to an extent, and we know in mice it inhibits mTOR in the brain.
It’s possible rapamycin may only be effective at delaying AD, if treatment is started at the MCI stage when the BBB is leakier. I suppose some people are going with very high dose levels like 60+ mg and believe LDL increases are benign. But rapamycin derivatives are an option for hedging. Unfortunately, not everyone can wait years for the results of the Dog Aging Project to look at biomarkers of CCD and get a better guess at it.
There are just too few incentives to test this one out and put it in the literature - someone could do an ultra-low dose PET scan (ML) with custom synthesized radiolabeled rapamycin to figure this out. Another option I’d like to observe would be a few people using IV ketamine 0.5 mg/kg + very high dose of rapamycin + baseline hs-CRP + MADRS depression testing.
Drug design efforts may be a little more than most of us here are familiar with… do you have experience in the area?
Here is a paper the covers many of the mTOR inhibitors currently being used and new ones being tested (with the goal of treating cancer, but of course, these can also likely be used as longevity drugs as rapamycin and everolimus are used):
There have been quite a number of startup companies that have formed over the past few years focused on mTOR inhibitors for anti-aging… rapamycin, but without the side effects. At least one came out of the Buck Institute, and was later shut down I believe, due to lack of success. Others are still going and have raised many tens of millions of dollars in VC money to fund their development and testing efforts. Its a hot area given the success of rapamycin :
Thanks for the reply, i don’t work for Pharma, I’m just a guy who audited Organic Chemistry and read some papers.
Here’s the longer version of some of the previously mentioned items. New probiotic makes rapamycin, rapamycin itself was first found as a bacterial product. Putting the genes to make rapamycin into the largest gram mass bacterial GI tract species as well as multi year durable probiotic bacteria like B. Durans makes a rapamycin based durable probiotic that is verified at mice as causing greater longevity and youthspan.
Enteric coated rapamycin reduces disintegration, if any, in stomach acid, with the enteric coating or capsule releasing the rapamycin in the small intestine.
Rapamycin with a co-dose of piperine to heighten dose effect several times, curcurmin combined with piperine called Biocurcurmin is absorbed 30 times better. I do not have any idea of what the dose multiplier effect of piperine is on rapamycin. If it is 2 times then your rapamycin dose is twice as affordable.
The thing longevity rapamycin users can do now is to put their rapamycin in enteric capsules(ebay) with 200 mg of piperine. Piperine is also on ebay
Biotransformation of rapamycin to unregulated longevity supplements, use yeast or bacteria with rapamycin at the culture medium to transform the rapamycin to new chemicals and rapamycin conjugates, this is testable at mice to verify longevization. This procedure produces unregulated supplements that have rapamycin’s longevity effect. It is even possible the longevity effect could increase from screening 111 different yeasts, bacteria, and fungi to find the 98th percentile of longevization.
Rapamycin has 3 <=> hexagonal cycles, just changing those to pentagonal or 7 carbon cycles changes the biological activity, those variants can be tested to find greater longevity effect, or higher dose potency.
A new opportunity for rapamycin users is ordering mTOR1 inhibiting peptides online as custom produced peptides. $210 gets 1 gram of 7 amino acid mtor1 inhibiting peptide, abiscientific.com. Peptides are sometimes given in 1mg/24 hours dose so $210 is 2.5 years of daily dosing. Last time i looked there were 9 mtor1 inhibitor peptides at a database.
There are already many options for increasing bioavailability of rapamycin - but the results are highly variable (in the case of grapefruit juice we’re it varies by type of grapefruit, fresh/frozen, and individual biology of people - so unfortunately its really imprecise and ultimately pretty risky if you are taking any other medications as it can cause you to overdose on a drug if you’re not really careful. See details here: Improve Bioavailability of Rapamycin (pt 2)
You mention:
Biotransformation of rapamycin to unregulated longevity supplements, use yeast or bacteria with rapamycin at the culture medium to transform the rapamycin to new chemicals and rapamycin conjugates, this is testable at mice to verify longevization.
Yes - those are possibilities - but it costs a lot of money ($500,000+) to do a reasonable sized mouse longevity study for a single compound (this estimate from the NIA ITP program), and 4 years of time… these are not trivial projects.
Ultimately these are possible, but beyond the scope of possible for biohackers. More like to be corporate / academic lab pursuits.
Never heard of these, but sound interesting. Do you have references where they were studied in any animal model for longevity?
Is this below an example?
Conclusions
Taken together, the current findings revealed that pentapeptide FLPNF enhanced autophagy via inhibiting mTOR by direct interaction with FRB domain, and thus, promoting the hIAPP degradation and protecting the INS-1 cells from hIAPP cytotoxicity. Therefore, peptide FLPNF may serve a potentially effective therapeutic compounds for T2D.