Drop some burning questions for Richard Miller below!

I will ask about this!

Good question. will ask

Also try ALL the drug combos + calorie restriction? (does it have additive/synergistic effects on all the relevant assays like cap-independent translation)
High-fat/MUFAs + acarbose

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How about asking the ITP to test alpha ketoglutarate ala Brian Kennedyā€™s study at Buck Institute before he went down to NUS (where he is now doing human trials)? In terms of gender differences, that one actually favored females. That study was 2% w/w in the chow ad lib, so not much in terms of even rodent mg/kg dosage info, let alone extrapolating to humans, but the overall data was encouraging on healthspan, and I think at least one Chinese group has also evaluated AKG for longevity benefit in mice. Kennedy is helping market a dose of the calcium salt, but the recommended dose looks way low (not to mention expensive).
It seems like it shouldnā€™t matter what salt was used, so Arg-AKG (a favorite of bodybuilders because of presumed NO benefits) likely would work as well, and is much less expensive.

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Another question for Richardā€¦

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Mice do not have atherosclerosis according to Miller. Interpret that as you wish

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It is not the responsibility of the ITP to do omicsā€“ they happily share tissue cultures from ITP mice with labs that do proteomics + transcriptomics though.

He suggests looking at Vadim Gladyshevā€™s work for transcriptomics work.

Indeed what he said about this :slight_smile:

There is the case to be made for some drugs that are less bioavailable though. But a lot of drugs are lethal when injected straight into the bloodstream, hence why most are done orally

https://phenome.jax.org/projects/ITP1 < This is a list of compounds tested

Iā€™d love to know if they will do further research into the cause of the gender differences in lifespan increases seen with canagliflozin, 17-alpha estradiol and acarbose.

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It would be interesting indeed! This review of his goes into it a little bit: Rapamycin, Acarbose and 17Ī±-estradiol share common mechanisms regulating the MAPK pathways involved in intracellular signaling and inflammation | Immunity & Ageing | Full Text

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Yes - like rapamycin.

Any other tidbits of information from your talk with Richard?

@invivo Very interesting! Thanks so much for sharing.

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Unfortunately not much else I could share that doesnā€™t delve into the realm of proprietary information. There are some interesting choices for the next ITP cohort though, so stay tuned!

If you want an idea of some research directions his lab is going into, I recommend looking at Gonzalo Garcia and Xinna Liā€™s newest papers on cap dependent/independent translation.

He is also pretty excited about this paper:

Rapamycin treatment during development extends life span and health span of male mice and Daphnia magna

https://www.science.org/doi/10.1126/sciadv.abo5482

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This paper?

Yes, thatā€™s the one.

My conversations with Richard and the rest of the ITP program leaders is a little frustrating at timesā€¦ Richard gives some really interesting information, but then says ā€œoh, but thats not public information yet and you canā€™t publish itā€ā€¦ which almost defeats the purpose. He sends me longevity curves on compounds but then - no, you canā€™t share that with anyoneā€¦ Iā€™m sure they have good reasons, but its just frustrating because I want to get the good news out to where it can help peopleā€¦

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I just noticed this commentary by Richard Miller in an interview:

Do we have any idea why most geroprotective drugs seem to work better in one sex than in the other?

While we donā€™t know why several of these drugs either work only in males or work better in males, there are several clues. Let me tell you about three of them.

One has to do with improvements in function like balance and grip, strength, and endurance on a rotating rod. Michael Garrett has studied several of these in mice treated with either 17Ī±-estradiol, which is male-specific for lifespan, or acarbose, which males respond to better.

He finds that most of the performance measures are improved by acarbose and 17Ī±-estradiol only in male mice. But there are a few that are improved even in female mice. In this way, you can begin to sort out what aspects of improved health are seen in both sexes and what aspects are seen only in males and presumably contribute to their lifespan benefit.

Similarly, people in my lab like Gonzalo Garcia have evaluated biochemical indices. Gonzalo has looked at enzymatic cascades in particular. Heā€™s looked at two sets of kinases, one of which is really important in inflammation and the other in terms of protein translation.

When you look at the cascade that is important in inflammation, all the drugs, rapamycin, acarbose, or 17Ī±-estradiol, cause benefits in that particular set of cascades in both males and females. So thatā€™s not likely to be a key element of the lifespan control pathway because 17Ī±-estradiol does not improve lifespan in females, itā€™s males only, and yet it does improve this kinase cascade.

The other kinase cascade, the one that focuses on protein translation, does show sexual specificity for 17Ī±-estradiol in Gonzaloā€™s assays. Only the males benefit from 17Ī±-estradiol. So, this is a hint that of the many cellular changes that these drugs produced, some, like the ones that lead to protein translation, at least show the same pattern of behavior as lifespan and may be important to lifespan. Others, like the inflammatory kinase cascade, respond to all the drugs, and that means that theyā€™re probably not involved in the lifespan effect, which is male-specific for this. The more drugs we have that can be thrown into this analysis, the more likely it is that weā€™ll zero in on the specific pathways by which these drugs produce health benefits and lifespan improvements.

Our current search is to look for biochemical and physiological changes that are produced by all those drugs, as well as by four single-gene mutations that extend lifespan, and by caloric restriction. So, we have eight such changes so far ā€“ things that you can measure in young adult mice after drug treatment, or in the four mutants, or after calorie restriction. And they all change in the same way.

Most, though not quite all of them, are sex-specific for the 17Ī±-estradiol treatment. We think that these physiological changes are our best glimpse as to what aspects of biology have to be changed, at least in mice, to get a lifespan increment.

This is also a link to human biology because you can ask, okay, Iā€™m giving this drug to humans. Do any of these changes happen? If the answer is yes, thatā€™s a sign that the drug may be very important in terms of controlling the human aging processes or at least links to the human biology and human diseases.

Source:

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Thanks so much, Rapadmin. I had not seen that post before - very interesting.

The ITP highly cares about the quality of their results. Iā€™m sure they have good reason to keep unpublished data private for analysis + peer review until they feel itā€™s ready to be shared.