These data bring to 7 the list of ITP-tested drugs that induce at least a 10% lifespan increase in one or both sexes, add a fourth drug with demonstrated mid-life benefits on lifespan, and provide a testable hypothesis that might explain the sexual dimorphism in lifespan effects of the SGLT2 inhibitor Cana.” !
Paper results: (paywalled) - if someone can get a full copy, please upload to this thread.
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Good news for the men.
Nothing for the women though. 
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What changed for AKG? Even kaeberlein thought AKG looked interesting.
Too much Cana is a negative. What’s too much? <1x, 1x, 10x, 100x a normal human dose? Too many healthspan positives for sglt2 inhibitors to pause on that one (especially for a male).
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jakexb
#4
Wow nothing for AKG? Seemed to be a lot of signal there.
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Lost
#5
I’m still trying to get a look at the paper proper. Out of this cohort I was most interested in nebivolol. Brief comments to expand after reading (is anyone able to share a copy with me?):
- AKG and DNP are both intended to poke at cellular metabolism. This failure mildly confirms my view that aging is best understood at the tissue and whole organism developmental level, and cell based hypotheses often lead to null results.
- As a few folks know, I’ve been trying unsuccessfully to drum up interest in Fasudil. HYD has some overlap in function, so would be a valuable comparison if a ROCK inhibitor ever gets tested appropriately. Or it could indicate that line too is a dead end.
- NEBI was especially interesting in that Spindler ran a well regarded experiment showing life extension for a beta-blocker, and there really isn’t an accepted explanation of how it worked. If that finding is not robust, maybe it’s not worth thinking about too much.
- I don’t know what research the ITP’s pursuit of SO_2 signalling is based on, I don’t think the full argument is in the publicly available literature, maybe someone on the conference circuit has heard? Anyways, it seems interesting, but they keep trying it, with THIO this time, and keep getting null results.
- I don’t know the details of estrogen signaling well enough to comment on the difference between OH_Est and other estrogens.
- The claim of late-life toxicity from CANA due to kinetic issues seems reasonable. Translationally, I don’t know the argument for humans using CANA as opposed to lifestyle levers and acarbose, but presumably that appears in this forum somewhere.
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LukeMV
#6
I find it frustrating they continue to study Canagliflozin and not Empagliflozin, which is much more commonly used in humans.
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All interventions are responsive to dosing. AKG already exists in cells at a given level hence moving the needle would require quite a high dose. Do we know what dosing was used?
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What I’m getting from this is that lower dose SLGT2i is probably better for longevity than a higher dose.
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20,000PPM so quite a high amount and fed throughout the day. Considering that the ITP does test whether AKG is readily absorbed into the bloodstream, it appears that the citrate cycle is not a limiting aspect for lifespan.
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I suspect they believe the mechanism of action will be the same on both medications because they are so similar, and would likely produce similar results (similar reason why they don’t test Everolimus vs. sirolimus). They feel they would gain more information from different dose/ timing interventions than trying an almost identical molecule.
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AnUser
#11
Yeah, the generalizability of study results between the same class of drugs is probably very high.
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So the takeaway from this round is that men should be on a SGLT2I and women shouldn’t.
Also, another estradiol is also good for men.
I’ll be starting 12.5 mg of daily Jardiance Empagliflozin this August.
Let’s hope the next round of ITP experiments pays off bigger. However any steps forward are good. Even baby steps.
I’m bummed about AKG as well. It seems whenever I buy a year’s supply of something, it’s doomed to be useless. 
Honestly, I’m starting to put more faith in the human RCTs for longevity drugs like empagliflozin and Telmisartan more than mouse trials.
Although I’m very thankful to the mice and ITP for Rapamycin. 
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Different krebs metabolites have different effects. AKG is a substrate for the TET enzymes.
20,000 PPM is to be fair about 2% of food which is quite high. AKG is quite complicated because it exists in a pool with glutamine and glutamate. I am not sure that AKG can get past the plasma membrane, but it does get into the cells, but probably as something else.
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ORRAPA
#14
Can we get a list of the seven pinned?
There were a number of healthspan signals, but the only mammalian lifespan study was Brian Kennedy’s, which reported a very small effect on lifespan (though a larger effect on frailty) in female mice, and a negligible effect in males.
https://www.cell.com/cell-metabolism/fulltext/S1550-4131(20)30417-4
That’s a reasonable guess. It may also be that they started with cana because cana was the first one approved. It’s worth remembering, however, that cana also cross-inhibits SGLT1, leading to reduced glucose absorption from the gut — more like acarbose, another male-specific ITP winner.
Based on what they reported (“blood levels of Cana were approximately 20-fold higher in aged females than in young males, suggesting a possible mechanism for the sex-specific disparities in its effects”) , and the fact that there’s no signal for an inferior effect in diabetes or kidney disease for human women in trials, I’d say it’s more that therapeutic drug monitoring might be useful for women.
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Pat25
#16
That is the takeaway for rodents, but also for humans? Take for example the research that discusses the potential renoprotective mechanisms/effects of SGLTi, and/or cardiovascular and metabolic effects: do they indicate a difference between males/females?
And do we know at all whether these differences in blood levels of Cana between (aged) females/young males the ITP found in their rodents, are also seen in humans?
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Good point. We see a similar large blood level variation between male/female mice for rapamycin that doesn’t seem to translate to humans.
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LukeMV
#18
In regards to AKG. Maybe I’m being too optimistic here but a human study showing the subjects were 7 years younger according to an age clock to me is worth more than a (well conducted) rat study showing no lifespan increase.
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Yes - probably too optimistic.
The study was done by the company, they got to choose the biological clock they used. Did they “shop” to find the best possible results from a any of the many different biological clocks? I certainly would if my entire company’s future depended on it. Think about it - they’ve already gotten millions of dollars of investor’s money. Would there really be no financial incentive to try to get the best possible results from this small, short “clinical” study? They could have easily used 5 different biological clocks (the top 5) but they chose not to. They chose 1. Or at least they only revealed one.
And they got to choose the participants in the study (did they choose less fit, more ill people?) Brian Kennedy has said that less fit benefited more from AKG and they saw no benefits in healthy populations. The new ITP study is actually pretty consistent with the results Brian Kennedy has reported from his mouse trials (not the company-sponsored, company managed study with people).
And the company study was a small population over a short period of time.
I put much more emphasis on independent 3rd party studies who have no financial stake in the outcome. And large repeated studies (remember, the ITP studies is actually 3 simultaneous studies) with 300 mice in each group in the studies, and it was done for the entire life of the mice (compared to a few months in the human studies done by the company Rejuvant).
In summary:
The ITP study is:
- Very large sample size - three studies with 300 mice in each study.
- Done by an independent group with no financial stake in the outcome
- Done in 3 studies of three independent populations that were chosen completely randomly
- Done by 3 fantastic groups of scientists at three different leading scientific institutions
- Is a lifelong studies (actually 3 studies at once), so three lifetime studies. Lifespan increase is what we really care about, not some theoretical “biomarker” that is in its preliminary testing stages that has little functional validation mapping to real lifespans.
the Rejuvant company study:
- Small sample size
- Short duration (few months)
- Non-randomly chosen participants
- Managed by a company with a huge financial stake in the outcome
- Endpoint was a chosen biomarker by the company (of hundreds of possible biomarkers/clocks) that in themselves are also not trusted. (Biomarkers / clocks are still a work in progress and none of the experts think they are ready for “prime time”.)
- Study done by a small recently-funded company, perhaps contracted with a small third party contract research organization (I don’t know what CRO actually did the study - perhaps someone can find out, and what their level of expertise in these types of studies are).
From a scientific standpoint, there really is no comparison between these two studies. The ITP study is a real study, the Rejuvant study is just a marketing effort.
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AKG is complicated because it probably does not get into cells as AKG. However, metabolised it does get into cells. The pool it is in with Glutamine and Glutamate is quite transferrable and AKG itself is a substrate for demethylation enzymes.
Hence it seems to have merit as an indication of cellular energy levels.
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