Ora Biomedical Million Molecule Challenge Results

[John_Hemming]

I have had discussions about C Elegans at BSRA and it is clear that it will not be a good model for senescence.

[adssx]

@Josh

@adssx when you sponsor custom stuff is it still 100$ per chemical, assuming they have the supplies since those are extra? Hopefully they can get a quantity discount at a certain point…

I don’t know because I said “I sponsored” above but actually they haven’t sent me the quote yet…

[forceofnature]

It’s two single interventions, not combined

[Krister_Kauppi]

Here is some of my thoughts around the topic which I posted on my channels.

Rapamycin Longevity Lab has made an interesting experiment with the Ora Biomedical’s WormBot-AI technology. The lab has pushed the median lifespan above the 50% line by combining the PI3K/mTOR inhibitor GSK2126458, a new longevity compound Rapamycin Longevity Lab discovered earlier this year, with the compound Allantoin. You have probably not heard of the compound Allantoin before but researcher such as Alex Zhavoronkov (pubmed: 29165314), João Pedro de Magalhães (pubmed: 26676933) and Jan Gruber (pubmed: 30269951) has done some interesting longevity research around this compound. It seems to have similarities with metformin which has glucose lowering effects.

I have previously shown research that combining a mTOR inhibitor with a glucose regulator may be an interesting combo. But I would like to see the above experiment replicated because the untreated worms were a bit short lived (14.5 days median lifespan). I also think a higher dose around 250µM instead of 50µM may result in a better longevity effect. That type of dose has also been tested in other papers successfully (pubmed: 26676933, 30269951). One other thing is that someone should write a publication on roundworm experiments and create a similar “900-day rule” as for untreated mice when it comes to median lifespan (doi: 10.1101/2023.10.08.561459). That way we get guidance if untreated worms are too short or long lived. Thereby we can interpret the lifespan results in a better way. So step by step we improve and push things forward.
Source: x.com

[forceofnature]

It’s a very interesting compound. Some information online makes it seems like oral consumption is possible:

This was interesting as well

Allantoin reduces cell death induced by cisplatin: possible implications for...

and here

https://journals.sagepub.com/doi/pdf/10.1177/1091581810362805

[adssx]

I’ll try to sponsor PF-06840003 ( https://www.caymanchem.com/product/25003/eos200271 ) which is supposed to be this miracle compound that can reverse Alzheimer’s: Predicting Alzheimers (and minimizing risk) - #186 by RapAdmin

[adssx]

Some great results!

Amlodipine lowered lifespan, but I think the dose was too high:

Felodipine, another DHP CCB, did way better at a low dose (even though controls lived longer than usual!):

And yet lacidipine failed:

So there are weird differences among DHP CCBs.

Ambroxol, studied for Parkinson’s disease, lowered lifespan a lot:

CoQ10: nothing

Gemfibrozil looks good:

Doxazosin as well:

Hydralazine:

And the best… the immunosuppressant azathioprine… +41%!:

So I’m now sponsoring low-dose amlodipine (to see if it can do better than other CCBs), alfuzosin and terazosin (to see if they’re better than doxazosin) and three azathioprine combinations:

• azathioprine + nilvadipine
• azathioprine + sulforaphane
• azathioprine + GSK2126458

I’m still waiting for the following results:

• Telmisartan + Amlodipine Besylate
• Lercanidipine
• Urolithin A
• Methyl-B12
• Methotrexate sodium
• UDCA (ursodiol)
• Lactoferrin
• Chlorogenic acid
• Nebivolol
• GlyNAC
• Ezetimibe 100 µM
• Fluoxetine 50 µM
• Fluoxetine 0.2 µM
• Caffeine 5 mM
• Sulforafane 100 µM
• Sitagliptin 2 µM
• Selegiline (L-deprenyl) 10 µM
• Selegiline (L-deprenyl) 100 µM
• Sildenafl citrate 50 µM
• GlyNAC (Glycine 8 mM + N-acetyl-L-cysteine 3.7 mM)
• Sertraline 10 μM
• Rilmenidine 200 μM
• Alfuzosin HCl
• Silodosin
• Carvedilol + Doxycycline HCl
• Sulforaphane + Nilvadipine
• EOS200271 / PF-06840003

[DeStrider]

@adssx Great job! You are a longevity hero!

[adssx]

Thanks, but nothing heroic here; it’s pure selfishness: I just want to live healthier and longer!

I’m now quite confident we’ll find a combination that doubles the lifespan in worms in the next few months. But… what’s next?

[Yoo]

Does anybody know the absolute record (in days) for control and intervention C.Elegans?

It’s would be great to know these figures (and perhaps even a leaderboard) to compare against.

Otherwise we risk being tricked by short-lived controls as outlined in the mouse ‘900 day rule’.

Long-lived animals vital in aging research | Lifespan.io

[adssx]

I don’t understand your question, you can see all the controls here: Million Molecule Challenge Results and Leaderboard – Ora Biomedical, Inc.

If there’s a great result with short-lived controls Ora Biomedical would likely rerun the study.

[Yoo]

Ok from the leaderboard it seems that the record for controls is 20 days.

Record for intervention is 22.9 days for GSK2126458 at 10 micromolar concentration.

So a 14.5% extension over historic controls. Not that impressive.

[adssx]

Why should we compare to the record control? What’s the record for controls in the ITP?

I’ll ask Ora Biomedical while lifespan seems longer for these few combinatorial interventions.

[Yoo]

1. Because it ensures we are looking at a true ‘life-extension’ effect, rather than just a ‘life-restoring effect’.

Have you read the paper linked in the article above? It caused a paradigm shift in how I interpret lifespan studies

2. The longest for C57BL/6 and HET3 (ITP) strains cluster around 900 days on the high end, though there might a few outliers around 950.

By this definition only rapamycin and rapamycin combos and truly life extending in the ITP

[adssx]

I read the article but it’s not very convincing. The average lifespan in all sites is 840 days (I summed the 6 values they give). But for whatever reason instead of saying “the 840 day rule” they “believe that, although masked by husbandry and related issues, the true median lifespan of untreated healthy mice, for both the UM-HET3 and Black 6 strains, is close to 900 days. Therefore, they propose the institution of a “900-day rule”, plus or minus 50 days, for lifespan extension studies in mice.”. 900+/-50 is pretty close to 840, but why 900 and not 890 or 910 or 840?

At no point they say “Let’s look at the longest our controls have ever lived”. No, they take the average across all sites + 7% to have a “round” number that is simple to remember.

If you follow the same methodology for C. Elegans then calculate the average median control lifespan of worms. And add 7%. I guess you’ll get about 16 days. And the top compounds therefore do about +50% vs this.

[Yoo]

Not sure I understand what you are arguing for nor the rationale for taking the average of different cohorts (I don’t believe they did this either).

The idea is to find the longest living cohort of control mice (as we believe this more closely mimicks a person living the perfect lifestyle) and see if we can extend past this.

Otherwise are we really slowing aging or just making a fat, diabetic mouse more healthy?

The full study demonstrates that the relative lifespan improvement in mouse studies is mainly driven by how short the control lifespan is rather than how long the intervention lifespan is.

In other words we have lots of drugs against the effects of an unhealthy lifestyle (i.e. metformin) which do not work against aging.

And a few drugs with a small relative lifespan improvement (which are glossed over) but are nonetheless ‘anti-aging’…

[adssx]

@Yoo

The full study demonstrates that the relative lifespan improvement in mouse studies is mainly driven by how short the control lifespan is rather than how long the intervention lifespan is.

Which full study?

@Yoo

The idea is to find the longest living cohort of control mice (as we believe this more closely mimicks a person living the perfect lifestyle) and see if we can extend past this.

That’s not what they say in the article you sent unless I misunderstood. Where does the 900-day rule come from? And what would be the equivalent in C. elegans?

(I agree with the rest of your post of course.)

[Goran]

azathioprine is very very interesting, ITP should jump on this.

[medaura]

I’d love for people with more time than me to follow the rabbit hole — and I hope I don’t sound self important about the value of my time, just that I’ve got an infant to care for — to pretty please with a cherry on top look into rifamycins. As if the name didn’t sound close enough to rapamycin to tease out your interest (zero etymological connection, however), this class of antibiotics is a very powerful buster, not mere preventer, of advanced glycation end products. It is also showing remarkable promise for Alzheimer’s. I expected to find a lot on rifampicin on this forum but there was barely any mention.

[ng0rge]

@medaura

rifampicin

My search here for rifampicin showed 11 links - many mentions by @PolishGentleman on the combination of rapamycin, rifampicin and allantoin.
See this article:
“A combination of rapamycin, rifampicin and allantoin resulted in an impressive 89 percent lifespan extension. A combination of psora-4, rifampicin and allantoin even resulted in a 96 percent lifespan extension, far more than each ingredient separately.”

https://novoslabs.com/why-combinations-of-longevity-drugs-are-the-future/

But here’s one I didn’t see posted on rifampicin and AGEs:

Rifampicin reduces advanced glycation end products and activates DAF-16 to increase lifespan in Caenorhabditis elegans

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4406675/

Aging is an inescapable process in all living beings. Although most animals exhibit signs of age-related decline in body functions, some interestingly show negligible visible signs of senescence (e.g., some tortoises, sea anemones, lobsters). One of the hallmarks of aging is the accumulation of altered proteins (Hipkiss, 2006). With advancing age, cellular homeostatic processes that restrict damage caused by altered proteins decline in their efficiency, leading to various age-related pathologies (Thornalley, 2008). Importantly, modern lifestyle also contributes immensely to this process of disease development. One such posttranslational alteration of protein, which is at the center of many age-related diseases including type II diabetes, atherosclerosis, renal disorders, Alzheimer’s disease, and rheumatoid arthritis, is the formation of advanced glycation end products (AGEs) (Thornalley, 2008; Luevano-Contreras & Chapman-Novakofski). AGEs are a complex and heterogeneous group of molecules formed via a series of parallel and sequential nonenzymatic reactions involving glucose or glucose-derived products and amino groups of proteins, lipids, or DNA.

Thus, pharmaceutical interventions that can suppress AGE formation may be an effective way to increase lifespan and health span (Semba et al., 2010). In this study, we show that rifampicin (RIF), a potent glycation inhibitor (Golegaonkar et al., 2010), dramatically increases lifespan (up to 60%) as well as improve health of C. elegans by preventing AGE modifications of important cellular proteins. This is by far one of the largest increases in lifespan obtained using a pharmaceutical reagent. Apart from possessing antiglycating activity, RIF activates the FOXO transcription factor DAF-16, possibly through JNK pathway, to modulate transcription of a unique set of target genes, those that are not controlled by the Insulin-IGF-1 signaling pathway. Together, our study shows that the dual ability of RIF to reduce glycation as well as activate DAF-16 makes it a potent lifespan-extending intervention.

In this direction, our study shows that rifampicin and its analog rifamycin SV, developed initially as antibiotics to treat tuberculosis, are effective interventions in extending health and lifespan. Additionally, lifespan extension was also obtained when the drug treatment was started well into adulthood. It will be interesting now to evaluate their efficacy in higher organisms and determine whether RIF treatment late in adulthood can bestow benefits of health as well as longevity on these animals. Thus, the multidimensional effects of RIF result in one of the most dramatic effects of a drug on longevity in C. elegans.