#121

I find luteolin being a very promising substance to test in the ITP. It shows potential to activate autophagy and apoptosis through a many pathways in many cell-lines. .

"Luteolin inhibits tumor growth by targeting cellular processes such as apoptosis, cell-cycle progression, angiogenesis and migration. Mechanistically, luteolin causes cell death by downregulating Akt, PLK-1, cyclin-B1, cyclin-A, CDC-2, CDK-2, Bcl-2, and Bcl-xL, while upregulating BAX, caspase-3, and p21. It has also been reported to inhibit STAT3 signaling by the suppression of STAT3 activation and enhanced STAT3 protein degradation in various cancer cells. "

" The autophagy process is classified into different types i.e., micro, macro and chaperone-mediated autophagy that transmits to the lysosome. Macroautophagy is a metabolic process that wraps protein cells to form autophagosomes with a bilayer membrane, the membrane fuses with the lysosomal membrane and degrades the wrapped protein by hydrolyzing [42]. Luteolin affects various pathways, i.e., it is involved in autophagy that includes nucleation and elongation that prevents the progression of cancer. Luteolin attenuates Wnt signaling (Wingless-related integration site) pathway for the upregulation of fizzled class receptor to downgrade cancer cells. Beclin1 plays an important role in autophagy, a process involved in cell survival that increases during cell stress and decreases over the cell cycle. The Beclin1 regulates autophagy during the initiation step that suppresses tumors and downregulates the Beclin1 expression in cells. Luteolin affects the ER chaperone binding and activates stress sensors and induces autophagy [43]. The Beclin1 promotes protein light chain formulation that effects elongation steps through the downregulation of light chains. Autophagy can also help in the survival of cells in cancer cells with Beclin1 downregulation [44]."

Impressive data from Luteolins role in autophagy.

5 Likes
#122

What’s the list of things they’re considering for 2024?

I’ve just created this prediction market to identify the most successful interventions: ITP: Which drug(s) will increase median lifespan the most in males by 2030? | Manifold

Please add your prediction(s)! Hopefully, the “wisdom of the crowd” will converge towards what’s best… And then we can suggest that…

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#123

I saw Nathan Cheng suggest the market prediction idea yesterday… its a good idea, if you can get some critical mass of “voters”.

I found it very interesting to hear Richard Miller (on the recent Peter Attia podcast) mention they only had 28 submissions for the ITP program last year. It would be nice if there were a lot more ideas submitted… we have until Feb. 28th of 2024 to get our suggestions in… see here: Feb. 28th Cutoff For NIA ITP Aging Drug Submissions - Ideas for New Testing?

1 Like
#124

I must say that I didn’t even know Nathan Cheng, shame on me… His concept is amazing, we could have self-funding trials thanks to that:

https://twitter.com/realNathanCheng/status/1735762470575251481

I’ve been following prediction markets for the past few years, mostly on geopolitics and economics, and they tend to be more correct (or at least directionally correct, and more so than so-called “experts” in the media), even with a relatively small number of “voters”. I set my critical mass at about 25–50. Below 25, I don’t pay attention. Above 50, I somehow “trust”.

This paper puts the critical mass even lower, at n = 20! “We have shown that increasing the crowd size improves the quality of the data. This effect occurs especially with small n. From about n = 20, the improvements are only very small and rather not worthwhile in relation to the costs since the costs grow linearly with n. For n greater than 20, even a deterioration of the F1 score can be observed, which is mainly explained by the increase of FP.”

The most famous example is, of course, Francis Galton’s Vox Populi: 800 voters were accurate within 1% of the true result: Vox Populi | Nature

If we can get to these numbers, it would be amazing, but again, even small numbers may be informative. So please all vote :wink: => ITP: Which drug(s) will increase median lifespan the most in males by 2030? | Manifold

1 Like
#125

Thank I’d never seen this

#126

I didn’t expect to see DNP on this list. That’s an interesting one. It’s used in the bodybuilder to burn extreme amounts of fat in record time but it can be fatal if you use too much. Also makes you drench in sweat.

#127

Really a shame that white willow bark isn’t being tested since it could end up being the best longevity compound out there

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#128

I’m not surprised. While DNP is best known as a very powerful fat loss agent, and a dangerous one at the doses used for that purpose, a much lesser known fact is that DNP has been found to extend lifespan in rodents at doses about hundred times lower than used for dieting. Such doses are safe and inexpensive and at such low doses it induces mild mitochondrial uncoupling which may be beneficial for longevity. I’v been waiting for DNP to be tested more for longevity and am glad to see it in the ITP.

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#129

About 1 month left. Should we do a wiki? (see Canagliflozin - Another Top Anti-aging Drug - #350 by adssx ) Or just list ideas here?

Anyway I’d love to see:

  • Taurine
  • Oral semaglutide
  • Selegiline low dose
  • Rapa + cana
  • Ambroxol
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#130

and safest in humans and (closest to generic too?) non Cana SGLT2i

(Would help also disentangle whether Cana is unique or whether it could be that the SGLT1 part of Cana is key and not just (or not at all) the SGLT2 part)

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#131

I’d like to see alpha cyclodextrin. I know mice don’t die from heart disease, but it makes SCFA and reduces inflammation. Should help.

#132

It’s probably too early in the research to confidently test rejuvenating small-molecule cocktails, but down the line, I think this will be a very promising avenue for the ITP to test

One of the most effective current rejuvenation cocktails is VC6TF, which consists of valproic acid (HDAC inhibitor), CHIR-99021 (GSK-3 inhibitor), E-616452 (TGFβRI inhibitor), tranylcypromine (irreversible MAO inhibitor that also inhibits the histone demethylase KDM1A), and forskolin (adenylyl cyclase activator currently being tested in the ITP).

Right now we have results on various cocktails showing rejuvenation in human fibroblasts, but we need to know which of these cocktails can also rejuvenate transcriptome and reduce epigenetic age in various mice tissues, without loss of cellular identity. We also need to know the minimum concentrations needed for each component of the cocktail, to make delivery feasible and minimize off-target toxicity.

Follow-up studies are underway to elucidate the cellular machinery that mediates these rejuvenative effects, with an emphasis on the mechanisms by which cells apparently write then later read a “backup copy” of earlier epigenetic information to reset chromatin structures and reestablish youthful gene expression patterns.

^ There is more work being done on this as we speak.

Although I don’t find it a convincing idea that cells contain a backup of epigenetic information, perhaps they meant that as an analogy? I think that cell type-specific epigenetic marks are (obviously) thermodynamically favorable, at least in newly differentiated cells. This is due to cell type-specific complements of transcription factors and other DNA-binding proteins which favor certain loci and create stable methylation patterns at those loci, and this steady-state is obviously favored in the presence of youthful metabolome, youthful proteome, and youthful values of other high-level information like electric and ionic gradients.

Over time, or perhaps even shortly after differentiation, some of those loci-specific DNA-binding proteins are lost, and the youthful patterns of DNA methylation are no longer thermodynamically favorable. This in turn further changes the patterns of DNA-binding proteins, which further changes the DNA methylation. It’s a vicious cycle.

From this perspective, cellular rejuvenation is more like folding a protein than it is burning a CD. If you can push the proteome (and especially the DNA-binding subset of the proteome) and the metabolome towards a newly differentiated/youthful state, you get youthful DNA methylation for free, since those patterns of DNA methylation are favorable under those conditions.

So it’s about finding small molecules which can mimic or induce that initial set of DNA-binding proteins, and perhaps that might be a different set of molecules for each cell type. And as far as essential organs go, you’re only as good as your weakest one, so you would have scheduled pulses of each cocktail for each organ to avoid interactions and minimize extended exposure (in this view you’re resetting the clock and not just slowing the rate it ticks, so pulsing should work just fine).

5 Likes
#133

As I see it the key to methylation patterns is how frequently a gene is transcribed. Hence if you have genes that are rarely transcribed they will be more heavily methylated.

Limits on transcription come from diffentiation, whether the cell’s logic systems require a gene to be transcribed and indicated energy levels (indicated by acetyl-CoA levels).

Hence when energy levels are lower (at a cellular level and often because of mitochondrial damage) then genes will end up more methylated.

This, however, is not a question as to whether there is a “backup of epigenetic information”, but a metabolic question.

1 Like
#134

I think you can look at it from different levels, and the causes in one level will be the effects in another level. It’s all interconnected.

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#135

I see that AKG is in the 2020 and then they are doing another cohort in 2022 - has that generally meant that there was a signal the first time?

Has anyone seen or heard anything about the 2020 cohort data - especially on AKG, but more in general too?

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#136

That’s also my assumption. The trials are not double blinded I guess so they can see early if one intervention is super successful. Same for CANA and STS in 2020 btw.

Does anyone know when the deadline to submit an application is? And is it really worth applying? I assume that they already have in mind the compounds I’m interested in (taurine, GlyNAC, oral semaglutide, empagliflozin, sotagliflozin, selegiline, fenofibrate, rapa + CANA) so applying might be useless…

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#137

Application Instructions

The submission deadline occurs once per year on the last weekday in February.
The next deadline is Wednesday, Feb. 28, 2024.

Is it worth applying? Hard to tell, right? Sadly they really don’t share much information on the applications - past or present, unless chosen… It would be nice to know what had been submitted in the past and turned down, every year.

But - they start sharing information, pro and con, on the chosen compounds when they are about half way through the trial…

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#138

Should I submit an FOI request? Submitting FOIA Requests | National Institutes of Health (NIH)

Just the name of the compounds submitted + the application year. And maybe as well the compounds under consideration for the next batch?

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#139

See my earlier post:

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#140

Thanks. I’ll do the FOIA request. I’ve never done it in the US but non citizens can do it and I’ve have experience of similar requests in the UK, France, and the EU (including up to the European Court of Human Rights :joy: HUDOC - European Court of Human Rights ).

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