Ora Biomedical Million Molecule Challenge Results

[AustraliaLongevity]

We have 4 people willing to put the money into this. Just waiting for a response from Ora on this one to get it started.

[John_Hemming]

I thought I would ask chatGPT for a bit more on the process of differentiation of stem cells. I suppose it is not really relevant to this thread as C Elegans adult cells don’t divide.

Hence I have put that here:

Stem cell division

I asked chatGPT for a summary of the processes for stem cell division and thought people might like to see the answer. Q: what are the stages where a stem cell moves from being quiescent to having a somatic cell that is fully differentiated and a stem cell which is quiescent again and how does this link to hypoxia? Below is a generic “life-cycle” that many adult tissue stem cells follow—illustrated with haematopoietic, neural and muscle satellite cells—and the oxygen logic that gates each step. Oxygen tensions are expressed as % O₂ in the niche; atmospheric O₂ is ~21 %. Stage Cell-cycle / fate state Typical O₂ Key HIF / metabolic setting What hypoxia is doing 0 Deep quiescence (G₀) Long-lived, non-cycling stem cell 0.5–3 % HIF-1α (± HIF-2α) stably active; high glycolysis, low mito‐ROS Keeps ROS and replication stress low, up-regulates CXCL12, ID2, PAX7, SOX2, Notch and autophagy genes → preserves stemness and prevents exhaustion (PMC, PubMed , MDPI) 1 “Alert” quiescenc…

[flatlander_woman]

Looks like donations through vida útil.io have been removed. Anyone know why or when they’re coming back?
Sponsor an intervention (Ora Biomedical) | Lifespan.io

[adssx]

This is a question for @Mitchell_Ora

[Mitchell_Ora]

Hello!

To my knowledge, nothing has been changed regarding our fiscal partnership with Lifespan.IO. I will pass along to Ben to have a look.

Thanks for the heads up!

[adssx]

Update: 268% Median Lifespan Increase with Indolepropionamide aka Indole-3-propionamide or IPAM – What this is, and why more studies NEED to be funded! - #194 by AustraliaLongevity

[forceofnature]

[adssx]

New results:

Caffeine

EOS200271 / PF-06840003 (from this Alzheimer’s paper: https://www.science.org/doi/10.1126/science.abm6131 )

Rifampicin / rifampin

Alfuzosin

Amlodipine

Azathioprine

TUDCA

Sodium Phenylbutyrate

Semaglutide

Dapansutrile

Riboflavin (vitamin B2)

Citicoline

L-carnitine

Alpha-GPC

Rasagiline M

Rasagiline

Citric acid (@John_Hemming)

Ivabradine

Rifabutin

Rifapentin

Rifaximin

Melatonin

Calcium pantothenate (vitamin B5)

Chlorogenic acid

Silodosin

Nilotinib monohydrochloride monohydrate

Urolithin A

[adssx]

I’m planning to test next:

• UDCA
• TUDCA
• Pantethine
• Sodium Citrate dihydrate (flies study: Dietary citrate supplementation enhances longevity, metabolic health, and memory performance through promoting ketogenesis - PMC )
• Voxelotor (Hypoxia pill)
• PT2399
• Menaquinone-7
• Methylene Blue
• Lercanidipine dose–response

[CronosTempi]

Some eyebrow raisers. Urolithin A, lol. I take citicoline, hopefully I’m not a worm .

[John_Hemming]

Gpt5: Here you go—concise side-by-side:

Intervention (class)	Mammal (mouse) lifespan evidence	C. elegans result	Notes / why it differs
17-α-estradiol (non-feminizing estrogen)	Extends male UM-HET3 mouse lifespan; benefits even when started late in life.	CITP multi-site testing found it broadly ineffectual across Caenorhabditis strains (one strain exception only).	Likely sex-specific metabolic/endocrine mechanism in mammals that doesn’t translate cleanly to worms.
Acarbose (α-glucosidase inhibitor)	Robust lifespan extension, especially in males, across multiple doses in ITP mice.	No significant lifespan change in any tested Caenorhabditis strain (CITP).	Gut/post-prandial glucose dynamics and microbiome–host interactions differ from worms’ simple gut physiology.
Canagliflozin (SGLT2 inhibitor)	Extends male mouse median lifespan by ~14% (ITP).	No demonstrated worm lifespan benefit; worms lack characterized SGLT transporters—only a GLUT-like transporter (FGT-1) is identified.	Target (SGLT2) not conserved in C. elegans intestine; mechanism unlikely to apply.
Senescent cell clearance (genetic INK-ATTAC; senolytics like dasatinib+quercetin)	Genetic clearance of p16Ink4a⁺ cells extends lifespan; senolytics improve late-life survival/health.	Adult worm soma is largely post-mitotic and does not exhibit Hayflick-type cellular senescence, so there’s no comparable target.	Mechanism is mammal-specific; worms age without proliferative cellular senescence.
Growth-hormone axis manipulations (Ames/Snell dwarf; GHR/GHRH knockouts)	Large lifespan gains (often 40–60%) in dwarf/GH-axis mutant mice; GHR/GHRH disruption extends lifespan.	No GH axis in nematodes (GH evolved in vertebrates); worms instead use insulin-like signaling for growth/aging.	Endocrine lever is vertebrate-specific, so it doesn’t exist in C. elegans.

If you want this exported (CSV/Excel) or expanded with effect sizes and dosing, say the word and I’ll generate it.

[adssx]

@John_Hemming

Gpt5: Here you go—concise side-by-side:

What was the question?

[adssx]

@CronosTempi

Urolithin A, lol.

What’s weird is that a paper found 50% life extension in worms: https://onlinelibrary.wiley.com/doi/10.1111/acel.14424

I’ll ask Ora why such a discrepancy.

Also (as I think John is alluding to): null results are not that significant. But we should care about a significant life extension or shortening and move these compounds to larger animal models.

[John_Hemming]

a) What has been found to extend life in mammals but not in c elegans
then
b) Do table

I also worry personally about the food question. Hence something that helps E Coli can harm C Elegans lifespan. SImilarly if you kill E coli you extend C Elegans life.

[John_Hemming]

@adssx

Also (as I think John is alluding to): null results are not that significant. But we should care about a significant life extension or shortening and move these compounds to larger animal models.

What I think is that the experiments are easy, fast and cheap to do. As a general principle things that are easy, fast and cheap are not good quality and the information we get is not good quality. It is, however, better than having no information at all.

Melatonin, for example, has a good track record in mice.
Citrate, has a good track record in drosophila.

If I get a bit of time I intend reading up on the difference between mtDNA mutations in C Elegans and other species.

I think the relative absence of PINK1/Parkin is probably a key element in the short lifespan.

[adssx]

Felodipine dose-response:

For melatonin and citric acid, it might be a dose issue. Here’s a (low-quality) paper on melatonin: https://www.researchgate.net/profile/Necati-Ozpinar-2/publication/331430600_The_physiological_and_lifespan_alterations_in_Caenorhabditis_elegans_exposed_to_different_dosages_of_melatonin/links/5c78ce90a6fdcc4715a3fdce/The-physiological-and-lifespan-alterations-in-Caenorhabditis-elegans-exposed-to-different-dosages-of-melatonin.pdf

Same authors: https://alz-journals.onlinelibrary.wiley.com/doi/full/10.1016/j.jalz.2013.05.249

Group 6 = 25 mg/dL = 108 µM. I tried 100 µM so should have found the same result. The best is Group 4 = 100 mg/dL = 430 µM. I’ll ask Ora and maybe try 430 µM.

Citric acid:

• There is this paper: Oxaloacetate supplementation increases lifespan in Caenorhabditis elegans through an AMPK/FOXO-dependent pathway 2009. They found +25% with “the citric acid cycle metabolite, oxaloacetate” at 8 mM. I’ll test that.
• I’ll try sodium citrate dihydrate 1 mM, 10 mM, and 20 mM

[John_Hemming]

Melatonin will reduce ROS. It may be that too much melatonin removes too much of the ROS signalling. However, carrying forward dosing issues from C Elegans to humans is a really hard thing to do. I would not really try.

I personally continue with my weekly blood tests and taking between 1 and 2g of melatonin per night. I do think the timing matters although sometimes I take some during the day.

[John_Hemming]

I think what probably happens with the worms is that the damage done to the mitochondria is such that even if you skew splicing decisions to a higher energy state it has no effect on the organism. They basically don’t have senescent cells.

[Goran]

@adssx you are awesome, thank you for your efforts.

[adssx]

Thanks. I’m doing that in a very selfish way for myself If anyone has ideas or suggestions let me know, I’m willing to co-sponsor experiments.