Aging Research and Drug Discovery Conference 2023 - Reporting

[RapAdmin]

I will provide some summaries of the presentations with a few slide captures, over the coming week. My focus is on rapamycin and other high-impact and actionable approaches to longevity.

Targeting availability to consumers in the next few years…

Tornado in-licensed a bunch of compounds from Novartis (because Novartis has decided not to pursue aging as a target at this time).

Lead compound is to enter the clinical trials next year… the endpoints being targeted; oncology/cancer and aging immune system. Their goal is to come out with an mTOR inhibitor that inhibits mTORC1 better, and mTORC2 at a much lower level than can happen with rapamycin (or a negligible level).

From the consumer perspective (i.e. longevity enthusiasts), the key issue will be the cost/benefit comparison of any new drugs from Tornado to rapamycin and everolimus. What is the marginal benefit compared to the marginal cost over existing generic mTOR inhbitors? Everolimus recently went off patent (in the past two years) and the price prior to going generic was in the $15,000 to $20,000 per month range. I believe prescription generic rapamycin (sirolimus) is in the $200 to $400 per month range, for a month’s supply.

Most of the information below in the slide presentation is well known to fans of rapamycin:

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The key issue (that rapamycin, etc.) is addressing is that with increased age, mTOR gets activated most of the time in cells (i.e. becomes disregulated), which (in other sources I’ve read) people have compared to having the gas peddle on the car pressed down all the time, even when you don’t need to go fast. In young mice, mTOR is only activated when there is a good nutrient supply. in older mice mTOR becomes activated all the time, even when older mice are on a fast / nutrient deprived. Rapamycin acts as an mTOR inhibitor.

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Joan says they are seeing very low toxicity with their new candidate molecule TOR101, as shown below with even very high dosing of 250mg/kg, so things are looking good.

I hope they are successful, as we need all the longevity drugs we can get. I’m just not optimistic that most people will be able to afford it, if and when it becomes available.

[DeStrider]

@RapAdmin Thanks for the summaries. I think we really need some RCTs to determine optimal dosing strategies. Right now everyone is making their own WAG. Is it too much? Is it too little? It depends on the person.

But, you’re right. Any new Rapalog is probably going to be maximized for maximal profit. They need to offer something above and beyond generic Rapamycin, and I’m not seeing anything that moves the needle for me.

[Walter_Brown]

THANK YOU! You are amazing in all the time and effort you dedicate. You are adding to the people on this site (cumulatively) decades of human thriving (and I count myself as one of those lucky ones)

[John_Hemming]

I am also remotely attending ARDD whilst going through a bit of a transport crisis (with my flight from France to UK being cancelled). I am not able to listen to all of the presentations, but some are quite good.

It appears that there are around 4,000 virtual attendees.

“Expanding the horizons of proteins in aging research: energetics and splicing variants!” by Luigi Ferrucci, National Institute on Aging was particularly interesting to me because it fits with my own hypothesis that acetyl-CoA shortages as a result of energy limitations (through SLC25A1) drive changes in proteins (the reduction of long proteins) which cause the phenotypes of aging.

The plasma proteome as sensor of organ physiology and aging by Tony Wyss-Coray , Stanford University, USA also looked at the changes in protein production and the impact of that on plasma so it fitted into the same area.

[RapAdmin]

@DeStrider

They need to offer something above and beyond generic Rapamycin, and I’m not seeing anything that moves the needle for me.

Actually, as I watch the full presentation, the new data from Joan Mannick is pretty compelling, as much as I might hate to admit it (I like the fact that everyone who is interested can afford rapamycin and that definitely won’t be the case with Tornado drugs when they are approved).

In her new presentation she’s saying that they’ve dosed as high as 250mg/kg in non-human primates (for 14 days, so its ongoing…) without any significant side effects yet. While its still early, if that holds true over the longer term I think they may have a winner of a product (but sadly, its unlikely I’ll be paying $15K to $20K/month for it).

If you truly can dose their new rapalog drug candidate at 250mg/kg, it suggests that you may be able to get to the higher levels of equivalent lifespan increases that we are seeing in mice at the highest dosing levels of rapamycin (or perhaps higher even, than the 30% median lifespan increase we are seeing in mice). I hope someone has started doing a mouse lifespan study with the Tornado therapeutics candidate molecules!

Just to refresh everyone - here are the results we’ve seen in the past with rapamycin; the higher the dose (generally), the higher the lifespan extension. The downside (for humans) is that we don’t live in a pathogen-free environment (like lab rats / mice). So with higher doses we risk immune suppression and bad (potentially deadly) infections. So the mouse results don’t translate directly to humans.

Most of people currently using rapamycin seem to be (in mouse equivalent dosing) in the low levels tested (note: mice were dosed rapamycin in their food, daily, so that is another difference - vs. us using rapamycin dosed once weekly or so). As you can see, there is a dose/longevity effect for higher dosing of rapamycin and longer lifespan. Many researchers think that is likely due to increased mTOR inhibition, but I wouldn’t say all researchers in this area agree with that theory.

Transient rapamycin treatment can increase lifespan and healthspan in...

Here are the National Institutes on Aging Results from their rapamycin studies (these are the best rapamycin studies):

Sirolimus Dose	mg/kg/day Dose	Blood/Sirolimus Level	Male Median LS Increase	Female Median LS Increase
4.7ppm	∼2.24	3 to 4 ng/mL	3%	16%
14ppm	~6.67	9-16 ng/mL	13%	21%
42ppm	~20	23-80 ng/mL	23%	26%

Here are results from all the higher dose studies I could find:

Sirolimus Dose	Mouse mg/kg/day Dose	Mouse: Blood/Sirolimus Level	Human mg/kg/day Dose	Dose for 60kg Human	Daily Dose adjusted for longer half-life (/4)
4.7ppm	∼2.24	3 to 4 ng/mL	0.182 mg/kg	10.92 mg	2.73 mg
14ppm	~6.67	9-16 ng/mL	0.542 mg/kg	32.54 mg	8.135 mg
42ppm	~20	23-80 ng/mL	1.626 mg/kg	97.56 mg	24.39 mg
126ppm	~60		4.878 mg/kg	292.68 mg	73.17 mg
378ppm	~180	45 to 1800 ng/mL	14.634 mg/kg	878.04 mg	218 mg

Based on the FDA animal to human dosing conversion guide here.

Note: ½ life for sirolimus in mice is approx. 15 hours, vs. approx. 62 hours in humans. So, mice metabolize sirolimus approximately 4 times faster than humans.

[DeStrider]

@RapAdmin You are correct, sir. I wish them all the best. I just know that the sticker shock for any new treatment they find is going to give me a heart attack.

Hopefully Rapa will take me to a point in the future when their discovery will become a generic!

[anon16510610]

@RapAdmin

its unlikely I’ll be paying $15K to $20K/month for it).

Who will? What is the indication for which they intend to sell this?

[RapAdmin]

Cancer and respiratory infections… big markets, they will pay.

[RapAdmin]

Day 5 is Starting… listen in by clicking on the livestream link below (Start time 9am CET)

Welcome to day 5 of ARDD.

Live Streaming
Here is the link for the 5th day of ARDD, 1st of September:

ARDD 2023 – Friday - Københavns Universitets Videoportal

Questions and networking
You are encouraged to use Slack to ask questions of speakers and panelists. Please use this link to access the channels to chat with other participants, if you are having technical issues, or if you want to ask questions to the speakers:
https://tinyurl.com/4azdp9ae

Schedule
We know your schedule is very busy and that you may not be able to attend every session. However, we do encourage you to participate as much as possible. For your convenience the full program can be found here: https://agingpharma.org/program2023

[RapAdmin]

You Are Likely To Live Longer Than You Think: Day Two Of The 10th ARDD Meeting

[Jonas]

I wish there was someone there to interview the attendees on rapamycin and their supplement stacks = that’s what counts for us.

[RapAdmin]

I suspect that most of the scientists at these types of meetings are doing minimal efforts in the way of taking longevity drugs and supplements. If you look at our list of the health and longevity people you’ll tend to find that those who are taking rapamycin typically don’t take much else. I think most scientists are more interested in the science and the pursuit of knowledge than they are longevity enthusiasts (wanting to live much longer). Who in the Health and Longevity Field are Taking Rapamycin (part 2)

The more Pharma-oriented the person (e.g. Joan Mannick) the more likely it seems they will want to have the double blind, placebo-controlled clinical studies to back up the use of the the drug or supplement (and since they are rare on the supplement side, that means few of them take the supplements).

My scientist friends are all much more rigorous in wanting to see the data from long term clinical studies… and are much less interested in the risk/reward analysis that I think is more common in the engineering / technology types (at least this seems to be the case from my experience in the SF Bay Area / Silicon Valley). In the “Bay Area” longevity is seen as an engineering challenge and we’ve seen many of those solved over the decades so this seems like nothing too different. Of course its an order of magnitude more complex…

[Jonas]

@RapAdmin

I think most scientists are more interested in the science and the pursuit of knowledge than they are longevity enthusiasts

You are probably right but it could also be those who do take it are not willing to advertise it for fear of ridicule or disclosure. Sinclair had reluctantly admitted taking rapamycin only Peter Diamandis put him on the spot in that interview.

[John_Hemming]

I think you are right about the risk reward type of calculations. Entrepreneurial techie sort of people (such as myself) balance the risk of doing nothing against the risk of experimentation that goes wrong and experimentation that goes right.

I would say, however, that my focus is specifically on health at the cellular level (ie health span).

[RickCohenMD]

100%. There were very few that have a functional optimal health background and are mostly very conservative. It is the mold they were trained and live. Even the physicians running some of the new clinics don’t seem to have a true personal longevity passion and “biohacking” experience. There were a few MDs like me there that were fit and had functional experience. Alex Z. is looking quite fit and strong. he must of put on 25lb of LBM since I saw him last in 2019. His personality has changed so I can guess… Retro Bioscience is the one company that I heard that is focused on practical longevity measures sooner than later.

And while RTC are nice they don’t address each person’s individual needs and priorities. So facetiously unless we are testing whether everyone needs oxygen, water and food to live we need n=1 protocols that track improvement.

There are only a few clinics now that truly are combining multiple interventions however I expect in the next few years this will increase as assessments continue to improve. I was impressed at the power of proteomics and new mitochondrial markers coming on board.

[RapAdmin]

From Alex @biogerontology :

In case you missed the world’s largest 5-day meeting on aging research in Copenhagen, here is a day-by-day coverage of this epic event. Over 750 delegates joined on-site and over 7,000 online.
Hope to see you there next year; it will be epic! All the top scientists and biotechs will be there again:

Day 1: Leaders In Longevity Medicine Convene In Copenhagen
Day 2: You Are Likely To Live Longer Than You Think
Day 3: You Are Likely To Live Longer Than You Think: Day Three Of The 10th ARDD Meeting Featuring Dr. David Sinclair
Day 4: You Are Likely To Live Longer Than You Think: Day Four Of The 10th ARDD Meeting Featuring Minister Mette Kierkgaard
Day 5: You Are Likely To Live Longer Than You Think: Day Five Of The 10th ARDD Meeting Featuring Eli Lilly And Novo Nordisk

Regards,
Alex

[RapamycinCurious]

@RapAdmin

[Mannick is] saying that they’ve dosed [Tornado’s lead rapalog] as high as 250mg/kg in non-human primates (for 14 days, so its ongoing…) without any significant side effects yet. While its still early, if that holds true over the longer term I think they may have a winner of a product (but sadly, its unlikely I’ll be paying $15K to $20K/month for it).

If you truly can dose their new rapalog drug candidate at 250mg/kg, it suggests that you may be able to get to the higher levels of equivalent lifespan increases that we are seeing in mice at the highest dosing levels of rapamycin …

Just to refresh everyone - here are the results we’ve seen in the past with rapamycin; the higher the dose (generally), the higher the lifespan extension. The downside (for humans) is that we don’t live in a pathogen-free environment (like lab rats / mice). So with higher doses we risk immune suppression and bad (potentially deadly) infections. So the mouse results don’t translate directly to humans.

I agree with the general thrust of this argument. I would introduce two caveats and one strengthening factor.

On the caveat side, some might unconsciously read in a 1:1 dose equivalence of TOR101 with rapamycin. But her IC50 graph suggests you’d need ≈8 times higher milligram-for-milligram dosing of TOR101 to get equivalent mTORC1 inhibition.

Another caveat is that your human values assume a body weight of 60 kg; “Among all men, mean age-adjusted body weight was 89.8 kg (197.9 lb) in 2015–2016 … Among all women, mean age-adjusted body weight was 77.4 kg (170.6 lb)”
Mean Body Weight, Height, Waist Circumference, and Body Mass Index Among Adults: United States, 1999-2000 Through 2015-2016

Weights were lower in Matt Kaeberlein’s group of off-label rapamycin users (178.0 ± 29.5 lb in males and 136.9 ± 24.1 lb in females), which is likely more representative of people on this forum:

Evaluation of off-label rapamycin use to promote healthspan in 333 adults -...

But that’s still 81 and 62 kg, respectively.

Conversely, TOR101’s mTORC2 inhibition is vastly lower than that of everolimus. If that reflects chronic dosing, that does suggest a lot of room to push the dose — at least on blood sugar regulation.

[Olafurpall]

@RapAdmin

In her new presentation she’s saying that they’ve dosed as high as 250mg/kg in non-human primates (for 14 days, so its ongoing…) without any significant side effects yet. While its still early, if that holds true over the longer term I think they may have a winner of a product (but sadly, its unlikely I’ll be paying $15K to $20K/month for it).

If you truly can dose their new rapalog drug candidate at 250mg/kg, it suggests that you may be able to get to the higher levels of equivalent lifespan increases that we are seeing in mice at the highest dosing levels of rapamycin (or perhaps higher even, than the 30% median lifespan increase we are seeing in mice). I hope someone has started doing a mouse lifespan study with the Tornado therapeutics candidate molecules!

Why would anyone want to use these drug candidates when rapamycin is a clean mTOR inhibitor that is relatively low cost and much more studied? It’s not like rapamycin is a dirty drug with lots of off-target effects creating a need to design an mTOR inhibitor that is more clean. It seems to me the only reason they are creating other mTOR inhibitors is to make money. If they were focused purely on longevity then it makes much more sense to test rapamycin more. It’s sad to see how profit driven all drug developments are.

[RapAdmin]

Here is Joan Mannick’s MTOR drug presentation from the ARDD Conference this year - which I posted some slides of earlier:

Joan Mannick at ARDD2023 - Longevity Medicine Day: Longevity medicine therapeutics applied gero...