#21

By all means, please help to rewrite them in a way that you think we’d get a better answer. I might be too much to the point and not as circuitous as needed. Just post your versions here… :slight_smile:

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#22

Any more questions for Dr. Miller? (bump)

#23

Any plans to test other SGLT2 Inhibitors besides canagliflozin?

The reason being, Canagliflozin was chosen for ITP is because of it’s unique mimicry of acarbose of blunting glucose peaks by delaying its uptake from GI tract, Other SGLT2i don’t actually blunt the postprandial spikes in healthy humans or mice. By testing them we can more definitively know if the glucose peaks are the culprit. We’ll also know if Dapagliflozin or empagliflozin will have any benefit in humans.

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#24

Here are two more:

  1. After the ITP identifies a compound that is effective to anti-aging, how is that information used? In an ideal world, what would be the next steps? In a practical world, what would be the next steps?

  2. Are there any ITP compounds that extend longevity that humans should not take (like NDGA)? Are there any compounds that should not be taken together? Are there any compounds that are beneficial to take together (like Rapamycin + Acarbose or Metformin)?

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#25

Could you inquire whether he intends to test any potent telomerase activators, such as TAM-818? Could it possibly give us some of the same perks as gene therapy?

#26

Does he know what the dosing equivalent of rapamycin is for everolimus? There seems to be some mixed opinions what dosage of everolimus is equivalent to rapamycin. The mannick trial used for example 5 mgs of everolimus a week with few side effects, what is his best bet that would be for rapamycin?

Overall everolimus is cheaper than rapamycin, so this could be an important question.

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#27

I would like to hear Dr Miller’s comments regarding oral absorption—need for enteric coated tablets vs compounded Sirolimus capsules.Other means to enhance absorption such as grapefruit juice or other CYP3A4 inhibitors

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#28

This might also be a question for Dr. Miller:

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#29

In the past, the Miller lab has been interested in comparative studies at the cellular level. Along these lines, I have two questions:

  • To what degree do you think that differences in lifespans between species can be tied to cell-autonomous mechanisms?

  • In your opinion, what is the best way to combine insights from long lived species with experiments in short lived ones?

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#30

Interesting… was not familiar with this. Here is a presentation covering it:

http://genetics.wustl.edu/bio5491/files/2019/01/Cell-Autonomy.2019.pdf

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#31

Serves me right for trying to sound smart. To elaborate, for obvious reasons much of the experimental study of long-lived animals is done with cell cultures (try getting funding for a bowhead whale colony in your lab). But cell cultures only show some things – mostly but not entirely the behaviors that cells can exhibit in isolation (cell autonomous in a loose sense). It’s conceivable that bowhead whale cells are grossly similar to mouse cells individually, and that either the environment in the organism cues them to age less or the whale is better at replacing them as they get old. In any case, to confirm what’s going on you probably want to generate hypotheses that can be expressed in terms of mouse lifespan.

A nice example is the recent work with naked mole rat hyaluronan, where a phenomenon that is difficult to test in vitro was partially addressed in transgenic mice.

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#32

Do you have a podcast? Is this going to be recorded and available for audio download or streaming?

Q: In various podcasts Dr. Miller has repeatedly and emphatically discouraged aging people with no clinical indication for rapamycin or other successful ITP candidates from taking these agents off-label for anti-aging purposes. Yet in his recent GEN session, he said that aging people with no clinical indication for rapamycin taking it off-label for anti-aging purposes was likely one of the only ways we would ever get evidence supporting or ruling out the use of these drugs for that purpose in humans. How does he suggest resolving this dilemma? Without advising any particular individual to take these drugs, does the situation not demand that people experiment and that scientists collect observational data? If not, is the ITP and his life’s work not likely to be wasted?

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#33

Ask Dr. Miller is there could be any consideration of doing non-dietary interventions. Zolendronic acid has recently been found to be senolytic for fibroblasts and other cells in older mice and also improves grip strength. (First reference below). It has been shown to increase lifespan in elderly humans who have undergone surgery for fractures (2nd and 3rd references).

Since it is given once a year intravenously for age-related prevention of osteoporosis, it should be pretty cost-effective to give an infusion one time to a cohort of aged mice. (As opposed to having a substance mixed in with chow).

In vitro and in vivo effects of zoledronic acid on senescence and senescence-associated secretory phenotype markers

#34

I would like to hear Dr Millers thoughts on the fact that there has been great success with substances that target how the human body handles glucose.(alone or in combination with Rapamycin). Since cardiovascular disease is the nr one killer of humans, I wonder if rapamycin could be considered in the ITP program in combination with substances that have known effects, targeting directly on the cardiovascular system. Rapamycin combined with Captopril, Tadalafil, Sildeanfil, starting midlife or late life. This since sildenafil usually is started later in life and even with this late start, it is correlated to improved brain health.

Or Could one first step be totest Tadalafil and Sildenafil alone. Starting midlife/late life.

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#35

Really interesting questions! One thing that can be good to have in mind when you have the interview with him is that I don’t think you will get so much information on Rapamycin application on humans from Richard. My feeling is that he don’t like to speculate about things outside his ITP research and mice data or about sharing anecdotal things. It can be good to have this in mind. Will you share the interview?

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#36

We’ll, I am not an internet personality like you are, so I was just going to have an informal off the record discussion with him. I wasn’t planning on recording the interview, but just take notes and share them here. He offered to do a zoom interview with me. Would you like to do it, @Krister_Kauppi . I can refer you after our informal talk? You can do a more in depth zoom interview with him later for your podcast?

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#37

My recommendation is that you do it by using zoom and record it. Then you can focus more on the conversation with Richard rather than taking notes. Afterwards you can listen to the private recording multiple times and make better summary notes of that interview which you share with us :pray:

My plan is to interview Richard in the autumn so he is in podcast pipeline :slightly_smiling_face: Big thanks for trying to help out :pray: Looking really forward to read your summary notes! Keep up the great work!

6 Likes
#38

Final Draft:

Questions for Dr. Miller

05/25/2023

About Rapamycin Longevity News

Rapamycin News is based in the San Francisco Bay Area. We are a group of professionals interested in longevity and healthspan, especially as it relates to the use of rapamycin. We are dedicated to healthier, longer lives through a good diet, regular exercise, and longevity medicines. We are advocates of geroscience research and of greatly increased funding for National Institute of Aging ITP program and clinical trials of generic compounds showing promise.

Doctors have, in the past few years, started to prescribe Rapamycin to people off label, and early adopters are testing it for themselves. In these forums we share our personal experiences and results with rapamycin and other anti-aging drugs. Most of us are not doctors and no medical advice is given. This site is for informational purposes only.

Questions from the Community:

  • Have you considered using a model such as the WormBot, proposed by Dr. Matt Kaberlein, to help identify potentially life-extending molecules by testing a multitude of compounds on C. Elegans or Killifish first?

  • If you were an average 50-year-old man, and money was not an issue, which supplements would you take for health span and longevity? Are there any successful ITP molecules you would avoid taking?

  • If you were to provide input for a clinical trial in humans focused on longevity outcomes, what would your thoughts on dosages (1mg, 6 mg, 9 mg, etc.) and blood levels of Rapamycin? What levels are best for human longevity and healthspan? Daily dosing? Weekly? Bi-weekly? Monthly?

  • Any other information that would be helpful to determine dosages of Rapamycin for humans for a clinical trial?

  • Could we pick your brain about rapamycin bioavailability in the brain please? Maybe a higher dose of everolimus would be better for that (higher peak/shorter half Life)?

  • In your opinion, what is the best way to combine insights from long lived species with experiments in short lived ones?

  • Polypharmacy is a contentious issue with many members. Have you considered doing a trial with all (or most of) the successful ITP compounds to see if their effects are additive or subtractive to lifespan? We feel this information is important especially for those taking many medications and/or supplements (the kitchen sink approach) to determine if it is helpful or harmful.

  • Glycine was shown to increase life expectancy by the ITP. Baylor College of Medicine has done their own research with glycine + NAC and shown much larger increases in mouse life expectancy (20%+) in addition benefits have been seen in humans as well. Could the ITP trial the combination of Glycine + NAC to confirm or repudiate these claims?
    GlyNAC supplementation reverses aging hallmarks in aging humans | BCM

  • Do you have any plans to test the Rapalog everolimus or other Rapalogs? Does you know what the dosing equivalent of rapamycin is for everolimus?

  • Can you give us the status of the drugs currently being tested by the ITP? Do any look especially promising?

  • Do you think GLP-1 agonists would work well with Rapamycin?

  • Do you plan to test royal jelly?

  • Since cardiovascular disease is the #1 killer of humans, I wonder if rapamycin could be considered in the ITP program in combination with substances that have known effects, targeting directly on the cardiovascular system. Rapamycin combined with Captopril, Tadalafil, Sildenafil, starting midlife or late life. Since sildenafil usually is started later in life and even with this late start, it is correlated to improved brain health. Or could one first step be to test Tadalafil and Sildenafil alone. Starting midlife/late life.

  • Does the ITP intend to test any potent telomerase activators, such as TAM-818?

  • If there was a crowdfunding effort or philanthropic donors that could expand their budget would they be able to scale and test more compounds across the three sites in a cycle? If so, roughly how much would be needed per extra compound?

  • Is there any chance that they’d consider including some non-orally eaten compounds (eg partial reprogramming/OSK therapy or GDF11)? If that is tough based on budget constraints, would it be possible if funded per above?

  • Any plans to test other SGLT2 Inhibitors besides canagliflozin? The reason being, Canagliflozin was chosen for ITP is because of it’s unique mimicry of acarbose of blunting glucose peaks by delaying its uptake from GI tract, Other SGLT2i don’t actually blunt the postprandial spikes in healthy humans or mice. By testing them we can more definitively know if the glucose peaks are the culprit. We’ll also know if Dapagliflozin or empagliflozin will have any benefit in humans.

  • After the ITP identifies a compound that is effective for anti-aging, how is that information used? In an ideal world, what would be the next steps? In a practical world, what would be the next steps?

  • Are there any ITP compounds that extend longevity that humans should not take (like NDGA)? Are there any ITP compounds that should not be taken together? Are there any other compounds that are beneficial to take together (like Rapamycin + Acarbose or Metformin)?

  • In his latest interview, Dr. Matt Kaberlein stated he needed the help of some data scientists to parse through the data of the Dog Aging Project. In one of your interviews, you mentioned the Google data team offered to help the ITP parse data. Would it be possible to send Dr. Kaberlein the contact info of the Google team that offered to help the ITP with data analysis? It may be of help?

  • There was a mouse and a human study that showed that pre-treatment with Rapamycin before a vaccine improved the effectiveness of vaccines in the elderly (Mannick). Why do you think that the medical community hasn’t adopted this pre-treatment before vaccination?

  • Is there any way our online community can help you or the ITP?

Thank you for your time and consideration. I look forward to speaking to you soon.

I did not use this question, because I just don’t know enough about the subject to have an informed discussion. Maybe @Krister_Kauppi Krister can ask it?

6 Likes
#39

Update from Dr. Miller

Hi, Chris:

Thanks for sending me these questions. We will have only an hour and 15 minutes or thereabouts, and I am not sure we will be able to get to all of them, so you may have to do some prioritizing. It may help to know that for many of the questions my answer will be quite simple - “I really don’t know” or “I don’t know any evidence on that”, which may help us move on to the next question.

Looking forward to our conversation.

Rich

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#40

I think we need to narrow it down to 15 questions tops.

1 Like