I agree in spirit. 5 may be a bit excessive at this point, but I’d be curious how some of the supported interventions work with new interventions. E.g. acarbose with white kidney bean extract, rapamycin with rifampicin, etc. The only 3 drug intervention I see being viable right now is 17-alpha estradiol, rapa, and acarbose.
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How about rilmenidine? It’s been approved as a blood pressure reducer, but it appears to also inhibit MTORC1. See https://onlinelibrary.wiley.com/doi/10.1111/acel.13774
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Thanks, added it to the list.
-Added a fibrate drug called fenofibrate, which is a PPAR-alpha agonist, and removed PPAR-gamma drugs from the list.
-Fair enough, not really. According to this study though losartan enhanced Klotho levels by 23% in diabetic patients, so there may be something there. Added to the list.
-Noted. I couldn’t find any evidence that deprenyl is a sigma_1 agonist, only that it binds to the receptor (if you could send me some literature suggesting the contrary, I’d be happy to see it). I’m considering adding something like Cutamesine, which is a known sigma_1 agonist.
-Caffeic acid has been tried by the ITP– no observed lifespan benefit from it.
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The ITP needs desperately to consider other types of interventions, foremost among them gene therapy. Liz Parrish’s telomerase and follistatin therapy has already been tested in mice with a 41% life extension.
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Yes, fibrates are possibly interesting. There is a report of some of them being senolytic, too.
Losartan hasn’t been tested in the ITP, though candesartan has been and telmisartan is in progress (both in combination with other agents).
You might be right, I can’t find the primary source for the claim that deprenyl activates \sigma_1. (I didn’t make it up – Wikipedia says the same, citing books I don’t have access to)
Caffeic acid is interesting, but I don’t think it has pharmacologic overlap with caffeine. You might consider cocoa extract, actually.
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My mistake about caffeic acid and caffine! Seems like they’re false cognates. I am hesitant about adding caffeine to the list– it’s been used so universally for so long in people that we probably can conclude it doesn’t have any significant lifespan effects in people.
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ITP Drugs of Interest - Single drug.pdf (58.8 KB)
ITP Drugs of Interest - Multi drug.pdf (56.5 KB)
Here is the updated list! Let me know what you all think.
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Perhaps another drug / compound…
Increased hyaluronan by naked mole-rat HAS2 extends lifespan in mice
Abundant high molecular weight hyaluronic acid (HMW-HA) contributes to cancer resistance and possibly longevity of the longest-lived rodent, the naked mole-rat1,2. To study whether the benefits of HMW-HA could be transferred to other animal species, we generated a transgenic mouse overexpressing naked mole-rat hyaluronic acid synthase 2 gene (nmrHAS2). nmrHAS2 mice showed increase in hyaluronan levels in several tissues, and lower incidence of spontaneous and induced cancer, extended lifespan and improved healthspan. The transcriptome signature of nmrHAS2 mice shifted towards that of longer-lived species. The most striking change observed in nmrHAS2 mice was attenuated inflammation across multiple tissues. HMW-HA reduced inflammation via several pathways including direct immunoregulatory effect on immune cells, protection from oxidative stress, and improved gut barrier function during aging. These findings demonstrate that the longevity mechanism that evolved in the naked mole-rat can be exported to other species, and open new avenues for using HMW-HA to improve lifespan and healthspan.
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Do we know where normal hyaluronic acid
supplements are on the molecular weight scale compared to this?
I noticed that Blueprint includes 300mg hyaluronic acid at the second meal each day and Bryan Johnson uses the brand below.
Does anyone have experience with HA supplements, I was thinking of starting them for my joints (and understand that it may have skin benefits as a “side effect”) if it also has any longevity benefit that would be a good bonus 
https://www.amazon.com/Hyaluronic-tablets-Strength-stronger-tablet/dp/B00GYZ7S2S
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Do you think there is correlation between increased lifespan and increased health span, specifically are there supplements that we should take for health span that will fail ITP. Senolytics for example.
I think oral hyaluronans get broken down into oligomers before absorption, so there’s no way to directly get high molecular weight substance into the body (is HMW even soluble?). That said, I like the idea of supplementing HA. It’s a bit pricey but safe as houses.
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I submitted for Rapamycin + Lithium + Trametinib
Admittedly I didn’t do a great job with the paper, it was the end of February and I got it in just before the deadline, but it was submitted.
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I think some of the most interesting compounds came from that recent nature article that detailed some compounds which inhibit mTORC1 more selectively than Rapamycin.
“Researchers are capitalizing on this knowledge to develop new but still early-stage mTORC1-selective drugs based on molecular and structural information about mTORC1 activation (Fig. 2). One of the best examples of these is the compound NR1, which binds the mTORC1 activator RHEB and prevents it from allosterically activating mTORC1.
One company that screened a library of modified rapalogs identified a compound, DL001, with significantly greater selectivity for mTORC1 than rapamycin120. As expected, mice treated with DL001 had reduced glucose intolerance, dyslipidemia and immune disruption as compared to mice treated in parallel with rapamycin. mTORC1-selective inhibitor DL001, is much better tolerated than the high doses of mTOR inhibitors currently approved for organ transplant and oncology indications, with fewer metabolic side effects and less immunosuppression.
Preclinical trials of one such compound, NV-20494, have reportedly shown efficacy in a mouse model of polycystic kidney disease and in vitro in human three-dimensional cell culture189.
Finally, Rapalink-1, a compound in which an mTOR kinase inhibitor is linked to rapamycin and delivered at a low dose, has shown the ability to inhibit mTORC1 kinase activity selectively.”
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Yes - DL001, as in Dudley Lamming’s top compound 
Thats the compound that this company is working on: https://www.aeovian.com/
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They should also test a strong telomerase activator like TAM-818.
I wonder about the issue of telomere length and longevity… this is from one of the 3 labs that does the ITP studies.
Telomere length in animals is not significantly affected by inbreeding and domestication. It varies across strains and sub-strains of mice, as does lifespan, and there is no direct correlation between telomere length and longevity within a population.
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There have been a few studies, article’s questioning the value of long telomeres.
Hi all,
Sorry for the lack of replies, been busy with the research side of things. Haven’t forgotten about this!
I’ve trimmed down the list significantly, and removed the multi drug interventions, as per Richard Miller’s advice. Will get back to you all soon with the third draft of the list.
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