#41

Great list of questions there! Pick as you say 15 of those and prioritize the ones you really want to ask him and if you have time then you can also take some of the other non-15 questions that you have. Good luck my friend!

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#42

You can probably skip this question… that was a phase 2 study that was successful (small N), mTOR inhibition improves immune function in the elderly - PubMed

and the second study - a phase 3 trial, failed to meet its endpoints (the FDA changed the endpoints between the two studies… ), see this paper:

The phase 3 trial enrolled 1024 individuals aged at least 65 years, who did not have COPD and who were not current smokers, and compared daily treatment with 10 mg RTB101 with placebo. The US Food and Drug Administration requested a change in primary endpoint between the phase 2b and phase 3 trials because of concerns that laboratory confirmation of an infection was not relevant to how patients feel and function. The primary endpoint was hence altered to the proportion of patients with at least one symptom consistent with an RTI. Compared with the phase 2b trial, the phase 3 trial was thus done in patients who were at lower overall risk of RTIs and with a primary endpoint that was less clearly linked to underlying immune function. Perhaps for these reasons, the authors found no significant decrease in RTIs as defined by the primary endpoint

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#43

One down and 7 more to go… :wink: Thanks for the help and input.

#44

I think most of the responses will, as he’s suggested, be “not enough data” is available yet to provide a good response - so you he can probably move through these quickly.

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#45

I don’t think probiotics would be a good idea to test because there are so many different kinds of probiotics that will have different effects not to mention the effect probably depending on the microflora background of the individual animal. Also also the microflora is so different between mice and humans so I think it’s unlikely that you could translate the results to humans.

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#46

Could you share the blood levels you reached with those different doses with or without GF juice? 20-30 ish doesn’t mean anything without specifying what unit it is.

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#47

So, I had my meeting with Dr. Miller last night and I wanted to share with you the results.

First of all, I want to thank Dr. Miller for speaking with me at length. He is a very gracious, understanding, learned and congenial man. He is a man of science and I respect him greatly.

Here are some interesting new things that I learned. I’m going to put the highlights first.

  1. The next cohort of ITP results (2020) are pretty much in. They have been shared in the scientific panel meetings and will be released to the public in October or November of this year. So, something to look forward to. Mark your calendars.

  2. Dr. Miller was highly interested in the following compound - Thioredoxin Reductase (sp?). It seems to be a hallmark of longevity found in most (all?) long-lived species. He will be sending me a paper about it that I will share here.

3.He also highlighted GPLD-1 and studies have shown that this improves cognition and brain cell turnover. Rapamycin increases GPLD-1.

  1. To research a new compound would take about $450,000 USD in donations. $150,000 for each lab. He mentioned you can have just 1 or 2 labs test a chemical as well. $100,000 for the research team/equipment/rats/etc… and $50,000 for the University. The labs would accept donations and grants from outside individuals such as ourselves.

  2. The ideal study for longevity in his opinion is a 5 year dog study. The results of these types of studies should be more applicable to human biology than mouse or rat studies.

  3. They could test injectables, but it would double the cost. They will not do it with NIH funding, but if they received a grant from outside sources, they would consider it.

  4. They are currently doing a study on Rapamycin + 17 alpha estradiol together. The results look interesting.

  5. There is a good paper by Linda Partridge about Trimatenib + Rapamycin on Black 6 mice that is interesting.

  6. He would like us, as a community, to do our best to spread the news about longevity research so that public opinion changes from looking at longevity researchers as “snake oil salesmen” to “informed researchers”. As a community we should try to influence public opinion positively so that we can move forward as a collective with support.

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#48

Very interesting. Thanks a lot for asking these questions.

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#49

Any more color on “interesting”?

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#50

Unfortunately, “interesting” is all I can get. It could be good, bad, or neutral. We have to wait until the official results are announced.

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#51

@Krister_Kauppi thought you’d be interested in this. Maybe you can springboard off of some of these for your interview?

Now for specific questions:

  1. 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?

Answer: Unfortunately, there are too many false positives and negatives in C. Elegans and Killifish to just use this data as a basis for selection. However, this type of data could support the selection of ITP compounds.

  1. 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?

Answer: No comment.

  1. 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?

Answer: No comment.

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

Answer: No comment.

  1. 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)?

Answer: This is a good question. Rapamycin improves cognition and brain cell turnover. They will probably not test everolimus as it is too similar to Rapamycin and they have shown that Rapamycin works.

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

Answer: The second goal of the ITP lab is to catalog cells of long lived species and look for signs that can lead to longevity. This is when he pointed out Thyroredoxin Reductase. (will post paper later).

  1. 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.

Answer: The ITP is currently doing combinations of 2 drugs such as Rapamycin + Acarbose and Rapamycin + 17 alpha estradiol. If they do 3 or more, it would be hard to determine which compounds are doing what (both positive and negative effects).

  1. Do you have any plans to test the Rapalog everolimus or other Rapalogs?

Answer: No. We have shown that Rapamycin works.

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

Answer: The next cohort of data (2020) will be released in October or November of 2023.

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

Answer: Yes, it looks like a great trial once it is available in pill form. Submit a proposal.

Note: Anyone want to write a proposal?

  1. Do you plan to test royal jelly?

Answer: No. There is not enough evidence to back it’s claims.

  1. 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.

Answer: Probably not as mice don’t die of coronary events but instead usually die of cancer. It may not be useful to test these types of medications as it may not show up with mice. However, a human study on this would be useful.

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

Answer: No. Telomerase activators do not have enough scientific backing to be considered.

  1. 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?

Answer: Yes. It would cost $450,000 to test a compound of your choice at all 3 labs. It would cost $150,000 to test a compound at one lab. You can crowdfund this if you like. It would not be under the official ITP name, but it would be done by the same staff.

  1. 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?

Answer: No, not for the ITP. If you wanted to privately fund it, injectables would probably double the cost but could be done. Partial reprogramming is science fiction right now.

  1. 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.

Answer: This is a great idea, but no one has submitted a proposal about it before. He would consider it if it was proposed.

Note: Anyone want to write a proposal?

  1. 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?

Answer: In an ideal world, a 5-year dog study would be done on the compound to reinforce the benefits.

Note: It seems we need a DITP (Dog Interventions Testing Program) to take longevity to the next level.

  1. 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)?

Answer: You should be very skeptical of taking prescription medications as we do not know what they will do in the very long term (20+ years). No specific compounds were mentioned.

Note: It seems like Rapamycin is the exception to this. (Author’s bias?)

  1. Deleted due to a misunderstanding.

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

Answer: He would like us, as a community, to do our best to spread the news about longevity research so that public opinion changes from looking at longevity researchers as “snake oil salesmen” to “informed researchers”. As a community we should try to influence public opinion positively so that we can move forward as a collective with support.

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#52

Epic. Thank you so much @DeStrider

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#53

I think, judging from Richard Miller’s rather scientific and understated approach to things, that this means early results have been positive… but we’ll see.

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#54

At this point, I’d just wait for the results to come in and hope for a winning combo.

#55

Does this combo work only for males?

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#56

I would assume so, but who knows? We will find out eventually…

#57

Fantastic reporting … thanks for sharing!

A few papers I could dig up on Thioredoxin reductase and GPLD1

Mitochondrial thioredoxin reductase 2 is elevated in long-lived primate as well as rodent species and extends fly mean lifespan

In a survey of enzymes related to protein oxidation and cellular redox state, we found activity of the redox enzyme thioredoxin reductase (TXNRD) to be elevated in cells from long-lived species of rodents, primates, and birds. Elevated TXNRD activity in long-lived species reflected increases in the mitochondrial form, TXNRD2, rather than the cytosolic forms TXNRD1 and TXNRD3. Analysis of published RNA-Seq data showed elevated TXNRD2 mRNA in multiple organs of longer-lived primates, suggesting that the phenomenon is not limited to skin-derived fibroblasts. Elevation of TXNRD2 activity and protein levels was also noted in liver of three different long-lived mutant mice, and in normal male mice treated with a drug that extends lifespan in males. Overexpression of mitochondrial TXNRD2 in Drosophila melanogaster extended median (but not maximum) lifespan in female flies with a small lifespan extension in males; in contrast, overexpression of the cytosolic form, TXNRD1, did not produce a lifespan extension.

Thioredoxin and thioredoxin reductase are evolutionarily conserved antioxidant enzymes that protect organisms from oxidative stress. These proteins also play roles in redox signaling and can act as a redox-independent cellular chaperone. In most organisms, there is a cytoplasmic and mitochondrial thioredoxin system. A number of studies have examined the role of thioredoxin and thioredoxin reductase in determining longevity. Disruption of either thioredoxin or thioredoxin reductase is sufficient to shorten lifespan in model organisms including yeast, worms, flies and mice, thereby indicating conservation across species. Similarly, increasing the expression of thioredoxin or thioredoxin reductase can extend longevity in multiple model organisms. In humans, there is an association between a specific genetic variant of thioredoxin reductase and lifespan. Overall, the cytoplasmic and mitochondrial thioredoxin systems are both important for longevity.

Thioredoxin 1 Overexpression Extends Mainly the Earlier Part of Life Span in Mice

We examined the effects of increased levels of thioredoxin 1 (Trx1) on resistance to oxidative stress and aging in transgenic mice overexpressing Trx1 [Tg(TRX1 )+/0]. The Tg(TRX1 )+/0 mice showed significantly higher Trx1 protein levels in all the tissues examined compared with the wild-type littermates. Oxidative damage to proteins and levels of lipid peroxidation were significantly lower in the livers of Tg(TRX1 )+/0 mice compared with wild-type littermates. The survival study demonstrated that male Tg(TRX1 )+/0 mice significantly extended the earlier part of life span compared with wild-type littermates, but no significant life extension was observed in females. Neither male nor female Tg(TRX1 )+/0 mice showed changes in maximum life span. Our findings suggested that the increased levels of Trx1 in the Tg(TRX1 )+/0 mice were correlated to increased resistance to oxidative stress, which could be beneficial in the earlier part of life span but not the maximum life span in the C57BL/6 mice.

And GPLD1

Cap-independent translation of GPLD1 enhances markers of brain health in long-lived mutant and drug-treated mice

Glycosylphosphatidylinositol-specific phospholipase D1 (GPLD1) hydrolyzes inositol phosphate linkages in proteins anchored to the cell membrane. Mice overexpressing GPLD1 show enhanced neurogenesis and cognition. Snell dwarf (DW) and growth hormone receptor knockout (GKO) mice show delays in age-dependent cognitive decline. We hypothesized that augmented GPLD1 might contribute to retained cognitive function in these mice. We report that DW and GKO show higher GPLD1 levels in the liver and plasma. These mice also have elevated levels of hippocampal brain-derived neurotrophic factor (BDNF) and of doublecortin (DCX), suggesting a mechanism for maintenance of cognitive function at older ages. GPLD1 was not increased in the hippocampus of DW or GKO mice, suggesting that plasma GPLD1 increases elevated these brain proteins. Alteration of the liver and plasma GPLD1 was unaltered in mice with liver-specific GHR deletion, suggesting that the GH effect was not intrinsic to the liver. GPLD1 was also induced by caloric restriction and by each of four drugs that extend lifespan. The proteome of DW and GKO mice is molded by selective translation of mRNAs, involving cap-independent translation (CIT) of mRNAs marked by N6 methyladenosine. Because GPLD1 protein increases were independent of the mRNA level, we tested the idea that GPLD1 might be regulated by CIT. 4EGI-1, which enhances CIT, increased GPLD1 protein without changes in GPLD1 mRNA in cultured fibroblasts and mice. Furthermore, transgenic overexpression of YTHDF1, which promotes CIT by reading m6A signals, also led to increased GPLD1 protein, showing that elevation of GPLD1 reflects selective mRNA translation.

Lifespan extension in female mice by early, transient exposure to adult female olfactory cues

Several previous lines of research have suggested, indirectly, that mouse lifespan is particularly susceptible to endocrine or nutritional signals in the first few weeks of life, as tested by manipulations of litter size, growth hormone levels, or mutations with effects specifically on early-life growth rate. The pace of early development in mice can also be influenced by exposure of nursing and weanling mice to olfactory cues. In particular, odors of same-sex adult mice can in some circumstances delay maturation. We hypothesized that olfactory information might also have a sex-specific effect on lifespan, and we show here that the lifespan of female mice can be increased significantly by odors from adult females administered transiently, that is from 3 days until 60 days of age. Female lifespan was not modified by male odors, nor was male lifespan susceptible to odors from adults of either sex. Conditional deletion of the G protein Gαo in the olfactory system, which leads to impaired accessory olfactory system function and blunted reproductive priming responses to male odors in females, did not modify the effect of female odors on female lifespan. Our data provide support for the idea that very young mice are susceptible to influences that can have long-lasting effects on health maintenance in later life, and provide a potential example of lifespan extension by olfactory cues in mice.

Blood-to-brain communication in aging and rejuvenation

Aging induces molecular, cellular and functional changes in the adult brain that drive cognitive decline and increase vulnerability to dementia-related neurodegenerative diseases. Leveraging systemic and lifestyle interventions, such as heterochronic parabiosis, administration of ‘young blood’, exercise and caloric restriction, has challenged prevalent views of brain aging as a rigid process and has demonstrated that aging-associated cognitive and cellular impairments can be restored to more youthful levels. Technological advances in proteomic and transcriptomic analyses have further facilitated investigations into the functional impact of intertissue communication on brain aging and have led to the identification of a growing number of pro-aging and pro-youthful factors in blood. In this review, we discuss blood-to-brain communication from a systems physiology perspective with an emphasis on blood-derived signals as potent drivers of both age-related brain dysfunction and brain rejuvenation.

https://www.nature.com/articles/s41593-022-01238-8

It Seems that GPLD1 is available as a research molecule:

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#58

This looks like the same paper but I don’t see any mention of Trametinib

#59

You are right. That’s not the correct paper. I have asked Dr. Miller for the 3 papers. I am sure he will send them and then I will put them up here.

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#60

Big thanks for sharing your answers to us! Really loved the crowdsourcing question and the answer. Lots of interesting possibilities here to drive research that we want to be done.

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