#21

Ok, you’ve convinced me. I was kind of hoping someone would change my mind when I posted that, to be totally honest, since it’s an expensive enough supplement anyway (the Ca-AKG specifically) so I suppose I’ll drop it when I run out.

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#22

The ITP really should study PQQ. I think that one has some pretty good potential.

Substantial benefits in mitochondrial biogenesis

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#23

I totally understand the tendency to prefer human studies over mouse studies - so you’re not wrong in that predisposition. This is one of the less common situation where the mouse study is so much better than the human study that I think we have to defer to the mouse study. Of course - I welcome other input and data that other people here might be able to bring to the discussion. I always try to admit that I too may have made a mistake, as I frequently do.

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#24

Brian Kennedy comes off as a pretty honest guy to me so I like the think the Rejuvenant study was done in good faith but it’s true they have a lot to lose from a study like that failing.

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#25

Yes, I agree that that would be very valuable! We’d need to know whether not having SGLT1i matters or not.

Everolimus and Sirolimus are probably more similar to each other in that mTOR inhibition is clearly hit cleanly by both of them vs Cana and Empa having some big known differences (re whether they have a mechanism via gut and SGLT1 see below).

But also in the case of Evero and Siroli I’m not sure how confident we can be in that they will give the same effects.

Think that might be an over generalization. Think it depends on how similar the given drugs are within a class. When there are differences in mechanisms within a class the differences in effect can be larger. And in the case of Cana there are some meaningful differences vs Empa.

Totally, this is the very crux we have weigh and learn as much as possible about. Above is a key difference between Cana and the SGLT2-“only” inhibitors like eg Empa.

Another key difference that is important to me is that there is Mendelian Randomization data for Cana lowering mortality but we have not yet seen that for any of the SGLT2-“only” inhibitors. Since all of the SGLTi trials have been in non-healthy/sick/specifically at risk populations we can only rely on them to a certain extent when triangulating to healthy populations seeking a gerotherapeutic.

I won’t rehash the different considerations here and there was some disagreement on how important to weigh different parts of evidence, but for what it is worth my conclusion at this point in time is that there may or may not be similar benefits from “only” SGLT2i via e.g. Empathy and Dapa on longevity in humans as there (may or maynot) be for SGLT1i combined with SGLT2i / Cana where we do have multiple ITP studies + MR data.

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#26

There was no control group in that study…

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#27

100%. Cana and empa/dapa are very different. Many papers also suggest that SGLTi’s benefits might be off-target. So dapagliflozin and empagliflozin should definitely be tested.

Unfortunately, the test on C. elegans didn’t help us much as they all failed to increase lifespan without significant differences. However, I sponsored canagliflozin (instead of canagliflozin hemihydrate used by humans) and dapagliflozin (instead of dapagliflozin propanediol hydrate used by humans). Is there any reason to believe that these will perform differently? Should I sponsor these as well?

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#28

Here is a study comparing Canagliflozin vs Empagliflozin.

5 CONCLUSION
In the limitations of the NMA, this study showed that
empagliflozin 10mg/25mg once daily might be better than
other SGLT2 inhibitors with low risks of all-cause mortality
and cardiovascular events in patients with T2DM suggesting the
need for ad hoc RCTs.
https://www.ahajournals.org/doi/10.1161/circ.140.suppl_1.9733#:~:text=Introduction%3A%20Sodium%20glucose%20cotransporter%202,2%20diabetes%20mellitus%20(T2D).

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#29

On another note, the bodybuilding world would have gone crazy if DNP showed a lifespan benefit :joy:

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#30

It didn’t detect anything in ITP, I don’t remember if it was you @Olafurpall who were critical about the ITP dosage or if it was someone else or had to do with something else.

#31

How about : Chemically induced reprogramming to reverse cellular aging.

Seems that our biological clock can be turned back by a combination of small molecules influencing the Yamanaka genes. Turning on three of these genes without increasing the c-Myc-gen seems possibly safe. The combination of the four OSKM abbreviated can possibly only been stimulated for a short time like 3 or 4 days; after this short period cells will refind their old identity supposedly.
I think his should be tested on some larger animals that have grown old on a natural way.
Any ideas?

#32

I think a key issue is SOX2 stimulating autophagy.

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#33

Yes, but where can regular people who don’t work in a lab obtain them?

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#34

Hmmm… my thoughts too on AAKG…what the hell? Lol.

Sticking to Taurine and Acarbose daily.

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#35

This is what I’d like to know. This info is less exciting when the thing mentioned is not attainable.

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#36

Do you, or does anyone, have prospective data demonstrating that these “metabolic clocks” actually predict aging/mortality in humans? Even prospective dog data would help.

If not, I will continue to file these under “aspirational”.

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#37

Lifespan.IO writeup on the ITP results:

Estrogen Metabolite Robustly Increases Lifespan in Male Mice

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#38

Matt Kaeberlein did a review of the study in his Optisapn Podcast:

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#39

What interests me is 16-α Hydroxy Estradiol (discussed @ 35:20) as an alternative to 17-α Estradiol studied in an earlier ITP.

16-α Hydroxy Estradiol is also known as the drug “estriol.” It’s available by prescription everywhere outside of US and Canada. Although not FDA approved, it can be prepared by compounding pharmacy for off label use in female hormone replacement therapy and is approved for dogs in the US under the brand name Incurin. Estriol is sometimes called a weak estrogen owing to its low 10-20% binding affinity for the estrogen receptor when compared to the stronger estrogens estrone (E1) and estradiol (E2). There is even lab and saliva tests for it.

Although life extension in male mice was little lower for 16-α (15%) than for 17-α Estradiol (20%), it seems estriol could be an alternative to 17-α Estradiol which is only available as a research chemical. I’m assuming it has a similar non-feminizing impact as 17-α owing to its weak binding affinity, but that is not discussed, so as a guy that identifies as a “he” who would like to retain my secondary sex characteristics, I’d need to verify this before trying it, ha ha. Also, you’d need figure out what serum or salvia range to target for longevity.

Thoughts?

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#40

@ageless64 We should probably avoid aromatase inhibitors. Raise testosterone in other ways if that’s a thing. Estrogen is good and important for men too. Lose the body fat if that’s the cause of too much AI.

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