LukeMV
#81
This is devastating news to me since I take Empagliflozin, Telmisartan, AND Ezetimibe. I don’t know what to make of this.
I wouldn’t worry about it at all. I think these drugs have already shown their value to people, and in some case Mice. The fact that canagliflozin has done well in mice is of much more value to me than whether it worked in nematodes or not.
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LukeMV
#83
Didn’t taurine show significant life extension in nematodes? While these drugs did not?
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LukeMV
#84
Do worms have hearts? SGLT2’s are supposed to be good for the heart too
Neo
#85
I don’t think so, see for example below:
It is true that
genes and molecular pathways underlying both species are very similar.
So some learnings can be had for things that might be conserved over hundreds and hundreds of years evolution (which key parts of aging likely are)
But please note that we are massively far from each other in many, many ways
nematodes and humans differ in many ways
C. elegans reaches only about 1 mm in length and doesn’t have a heart or circulatory system
(So many of the effects of Telmisartan and Ezetimibe may not be helpful to study in this organism - similarly cardiovascular aspects of SGLT2i might be more valuable to study in other systems)
the roundworm has 959 cells and a life cycle of only three days
(The adult human body is composed of nearly 37 trillion cells)
https://biology.ucdavis.edu/research/model-organisms/roundworm#
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LukeMV
#86
Thanks for the explanation. Well if they don’t have hearts or kidneys, then I take these results with less than a grain of salt.
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Neo
#87
Where the worms and human are similar (eg AMPK, mTOR, IGF-1 equivalents, need to eat (so fasting, calorie restriction, etc) these models might be more helpful
Where we are fundamentally different (kidneys, hearts, brain/neocortext, etc) these models are probably less helpful
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Remember that if a drug shows promise to C. Elegans, it may show promise to mice and humans. If it doesn’t show promise, it doesn’t mean it won’t show promise to mammals. Canagliflozin and the other drugs that didn’t work for C. Elegans may work for mice and humans as the ITP has shown.
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Big thanks and nice that we have found one top performer of the six mTOR inhibitors I tested. The thing that I will focus on before we start the scaling up the Longevity Cocktail project on Rapamycin Longevity Lab is to get the Rapamycin dosing right so that we get to around 15-20% of median and maximum lifespan. After that I feel comfortable in starting the development of longevity cocktails where we combine different compounds with Rapamycin to create an even bigger lifespan effect. Step by step forward and a really nice discovery around GSK2126458 
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adssx
#90
Quite nice that you joined the leaderboard with a random compound!
Benidipine, another dihydropyridine calcium-channel blocker (D-CCB), extended lifespan, while the most common D-CCB, amlodipine, decreased lifespan 
D-CCBs are considered beneficial for dementia and Parkinson’s prevention (see, for instance, Calcium Channel blockers are associated with reduced risk of Parkinson’s disease in patients with hypertension: A population-based retrospective cohort study 2021). So I’m considering sponsoring other D-CCBs, such as isradipine (reasoning here) and lercanidipine (it ranked well in Association between prescription drugs and all-cause mortality risk in the UK population 2024).
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@Krister_Kauppi another potential compound , a PAM mTOR inhibitor:
- In December 2023, Celcuity presented data from nonclinical studies evaluating gedatolisib and other PI3K/AKT/mTOR (PAM) inhibitors in breast cancer cell lines during a poster session at the 2023 San Antonio Breast Cancer Symposium (SABCS). In a panel of breast cancer cell lines, gedatolisib was found to be more cytotoxic and at least 300-fold more potent, on average, compared to the single node PAM inhibitors.
https://www.globenewswire.com/en/news-release/2024/03/27/2853589/0/en/Celcuity-Inc-Reports-Fourth-Quarter-and-Full-Year-2023-Financial-Results-and-Provides-Corporate-Update.html
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Berberine is another HDAC inhibitor.
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It was a surprise, but in my opinion with a million molecules, someone must sponsor the ones that are completely a mystery. The fact that not all CCBs have an impact on the lifespan of worms is that there are unknown targets of some CCBs.
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@Krister_Kauppi will you submit GSK2126458 to the ITP?
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One plan is to screen 200 mTOR inhibitors this year to find better ones than Rapamycin. So based on that results we can write some interesting ITP proposals on the best mTOR inhibitors. My guess we will find some interesting ones.
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@Krister_Kauppi Have you thought about submitting a proposal to Hevolution?
They plan 115 mln $ for longevity research - maybe it would be possible to get some money for grant:
https://hevolution.com/
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I had some contacts with them but the focus on supporting human clinical research so we will not get help from them in the initial stages of the research but we could get maybe grants from Impetus Grants (https://impetusgrants.org) and Hevolution grants money to them. We will need all the help we can get to finance the early stage of the research. The really nice thing is that it’s not so much money that is needed. For the screening of mTOR inhibitors in worms we need 60k and that is nothing for the big magnitude of valuable data which we will deliver to the field. I think that will be the first project to do. But first before we start scaling things we need to understand why Rapamycin lead to decrease in median lifespan. After that we can start scaling things
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It seems like the combination of Rapamycin and Taurine had no significant effect on lifespan. Very curious.
Why isn’t Rapamycin prolonging the lives of these nematodes?
Well, at least it’s not harmful.
Order-8622_Rapamycin-15uM-and-Taurine-50uM_report_final.pdf (428.3 KB)
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It could be that they dont have that good a process of autophagy so increasing it has less of an effect.
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I’ve talked to other nematode / longevity researchers at conferences and they were telling me that its actually quite hard to get rapamycin taken up in nematodes. I forget the reasons why - but its hard. He was asking me if I knew of any ways to increase the bioavailability / uptake in these worms. (You know they’re scraping the bottom of the barrel when they are asking me about worm biology & rapamycin pharmacokinetics.). This is likely why you always see them use Metformin as the default comparison point in many of the Ora Biomedical comparison graphs, and not rapamycin. Its just too finicky.
I wonder if the issue that the nematode researchers have with rapamycin may be more generalizable to other mTOR inhibitors?
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