Human Intervention Testing Program phase A measurement?

Their is a need for a Human Intervention Testing Program. Currently the ITP (Intervention Testing Program) which is done in mice checks if an intervention increases median and maximum lifespan in their initial phase A studies. What would be a good measurement to check for when testing intervention in the Human Intervention Testing Program instead of lifespan? We can not use lifespan as our measurement because that is way too inefficient and costly. What creative way/s can we do this instead? All feedback is welcome.

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I totally agree, there must be a human intervention testing program. I imagine testing could be done in a similar fashion to that being done currently with metformin where they are looking for statistical changes in the occurrence of negative health outcomes over time. That approach, however, would only work for interventions that are beneficial started later in life. Interventions that are effective if started in a humans 20’s or early youth would be extremely difficult to test and if tested the testing might have to last 40 or 50 years.

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I was thinking about this last night. I still can’t get my head around the astronomical cost of clinical trials. It’s so prohibitively expensive that only a very small amount of drugs get tested for conditions that pharmaceutical companies believe will maximize profit. We’re missing out on so many treatments for all sorts of conditions as there’s no financial incentive to do the trials.
A human intervention trial is a great idea, I think the challenge is that traditionally there’s been no way to measure any meaningful effect on biology. But I think that’s about to change. I don’t want to derail the thread but I listened to a couple of Dr. Kara Fitzgeralds did with Dr. Vittorio Sebastiano who is the CEO of turn.

Interestingly, he has been working solely on humans cells for his cellular reprogramming platform as he rightly points out that there’s so much translational failure between mice and humans in what seems like promising treatments that extend life in rodents. In the second interview he talks about a genome clock his company has produced. Which is tracks changes over the epigenome. As an aside, he mentions that Rapamycin works on a different part of the genome than caloric restriction. One of the bottlenecks to meaningful human interventions testing is a measurable clock that tracks changes. But, it sounds as if we’re getting a lot closer. I think turn seems to have a really interesting product. If you have access to these clocks then I think it will be much easier to do small scale trials of interventions on small cohorts of people much more cheaply. Bryan Johnson is attempting a trial through his blueprint protocol right now and while it can’t be too rigorous, it’s definitely a step in the right direction.

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Realistically we are all participating in a human intervention testing programme. We have different interventions, but we can agree on certain measurements that are useful.

a) C Reactive Protein - I think this is particularly useful if measured on a number of occasions to make sure you are not responding to infection.

b) Cystatin - C this is another particularly useful measure. It does not suffer from all the variations that hit creatinine.

c) Physical function tests (such as sitting on the floor and standing up)

These are a few simple tests that people can do. I think we started on this process previously, but it is worth identifying simple outcome measurement that people can do and then tracking results. This sort of happens in this forum, but could be more structured so there is an agreed set of outcomes.

The XPrize will also do something like this. All the teams will have their participants tested in the same way. That will be a useful process.

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Since cardiovascular disease and stroke is the number one killer, youthful / neonatal levels of apoB too.
If you can’t reverse increase in apoB from neonatal then it is not good.

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You could probably do it, using bio markers in blood, urine and tissue. using different aging clocks etc. How would using Rapamycin, Taurine, Gato Kula, Green Tea extract etc affect these bio markers after 2 years of use in different strengths etc.

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I agree with this line of thinking. Of course we don’t know how to weight the various metrics, and some metrics overlap with each other. But a sensible and manageable list would make sense and be practical. I don’t like black box metrics that seem to predict aging for a population but fail at the individual level.

Blood markers: albumin, hsCRP, NRL ratio, RDW, apoB, TG, iron
Urine: pH, protein, calcium
Organ function: lung (spirometer test), heart (RHR), arteries (BP), pancreas (HbA1c), kidney (cystatin-c, eGFR), liver (ast/alt/ggt), eyes (blood vessels), skin (AGEs levels), bones (bone density), etc
Physical capabilities: hang time, co2 tolerance, max HR, jump height / length, balance, sleep

Who will do it?

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Because some of these markers have u shaped ACM curves it is probably best to look at them individually rather than to try to generate a formula.

Albumin also is sensitive to short term food intake. If you are to some extent calorie restricted you might find albumin is lower, but that may not be a negative point.

AST is very sensitive to exercise.

Ferritin is also an interesting one.

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It’s very frustrating that we don’t have good ways of validating things in an efficient way. One thing that I have started to think about was that it would be interesting if it was possible to take some kind of photo of different cells and get an image of their state of age. We can for example today differ between young and old cells. Would not one interesting measurement be to take for example different cells photos and see how their state was impacted by an intervention?

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What we are looking at for cells is the aggregate efficiency of mitochondria combined with the effect of sensecence on SLC25A1.

I don’t think that would be possible to capture with a camera.

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Would it be possible to do a muscle biopsy in an inexpensive way? To look at mitochondria density etc. Is a microscope needed?

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How do they compare for example skin cells? Is it with some kind of special camera or something else to get a image of the cells?

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Of course we need this. We also need a Dog ITP program (for faster results). I talked with Matt Kaebelein about the idea of the dog ITP program, and a few years ago he said yes, its needed, but it wasn’t going to be him.

The issue of course is cost. Nir Barzelai has been working for almost a decade to get an ITP program (basically) but just on Metformin (the TAME Trial) going… without much success. I forget the exact cost… but its something like $60 Million for a single compound. To recreate the ITP program… say 5 new compounds a year, would need a “Hevolution Foundation” sized budget .

Its not going to happen.

In fact, this may be the key potential benefit / rationalization for biohacking… early data in areas where clinical trials are not realistically fundable (due to generic drugs / supplement and lack of IP potential for companies).

So the issue is, given these limitations, how do we move the science forward faster. I agree with John here… The only real option is via Biohackers like people here, but somehow doing it with better data in a controlled fashion so that we can get better data so we can parse out what the real benefits or downsides are.

I’ve thought about doing a proposal to Hevolution fund for a Biohacker’s Longevity App that allows you to easily track your results (i.e. data from Fitbit/oura/GCM, etc.) , and your interventions (supplements, drugs, etc.). Over time, with enough people, it might gain some meaningful data. I spoke with Andrea Maier (NUS) at the recent Longevity Summit and she liked the idea and was interested in partnering. But I’m still unsure about it… and I don’t have the time right now, but it seems like a reasonable way to go, given our constrains in this market segment. I’ve done an app like this for a Pharma company looking to validate real-world outcomes on a new drug (Patient reported outcomes are a big thing for the FDA; they want to see a measurable improvement in quality of life for patients, so this type of app was going to be very helpful for them, and I think the same is true broadly across the Pharma industry).

We could integrate these forums right into the app, so it would be an app that you interact with frequently.

What are people’s thoughts?

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My plan for biohacking.tools is to move that in the direction of managing health. I intend to use this for the biohacking team, but am happy to work with rapamycin.news in doing all of this.

Given the challenges of managing multiple intervention protocols I think a system which manages a large number of individual testing protocols is the best way forward.

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John, I think what you’re doing is great, but what I’m talking about is a reasonably professional grade iPhone/android app like you’d see from a typical app startup company, and I think it would take an investment of $500K to $1 Million to create,(and test, and iterate, and test and test) and really a year or two of dedicated work by a small team (depending on time commitment).

And part of the issue is that there isn’t a really good business case for an app that gathers data on longevity and biohacker interventions. So, it has to be a non-profit type of situation, funded by a group like Hevolution.

The key challenge/issue in all of these efforts is to make something that large numbers of people will adopt and use on a regular basis so that you get a large dataset of reasonably structured information on outcomes and input variables.

And you need a large number of users because Biohacker data is well-known to be a group of people that are really hard to track…the data is really “dirty”. Biohackers tend to try all sorts of different supplements or drugs, they change their dose frequency and usage patterns of these interventions frequently, so you need a large number of people so that you can separate the signal from the noise, in finding what treatments are actually effective, and what side effects are real.

Kevin Perrott (formerly of SENS) has started a project similar to what you are doing: Open Cures
The Platform In fact you might want to talk to him and use his platform in your biohacker effort with the XPRIZE, since his is a non-profit, I suspect he’d give you the data you need from his platform.

The key issue is that its web-based, its a pain in the ass to get your data into it, and nobody is going to use it (or very small numbers of people). Kevin’s a nice guy, but his work experience is a family snow mobile selling business in Canada, then he got into “Longevity” and studied biology, but he has no experience developing a App / or software platform that gets adopted by large numbers of people, and is continued to be used by large numbers of people years after launch.

I have worked in the Internet field for many years… its really hard to develop something that large numbers of people will use for a long time (think years). Think about how many apps or websites you engage with over a period of years in an intensive way… perhaps a half dozen apps, out of the tens of thousands (millions of websites). And think about how much money likely went into developing and supporting that short list of websites and apps you actually have used for years? Typically we’re talking tens of millions of dollars if not more…

It takes a lot of usability testing… and optimization to make it really, really easy to gather the information you need from people without making it a burden for the user. Its really hard to make things easy, and still get the data you want.

We already get 15,000 to 25,000 people a month coming to this website, doubling every 6 months to a year, of people who are interested in longevity… so I think moving from this to a RapamycinNews app/website combo has some potential. But its still really hard and a ton of work getting adoption of an app. There isn’t an obvious revenue model, so its basically a non-profit effort. And most apps and website fail… like 98% of them… so its a risky use of someone’s time and effort.

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Love the idea :two_hearts:

I, for one, would have no qualms at all about using such an app and sharing my testing protocol and results with everyone.

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There is the possibility of citizen science studies, with a ‘do-it-yourself’ placebo-control built into an app.

The study’s innovative ‘do-it-yourself’ approach to placebo control may serve as a template for future citizen science studies on other popular phenomena where positive expectations and social factors could play a role, such as cannabidiol (CBD) oils, nootropics and nutrition.

Implementing placebo-control even like this probably creates more credibility for some interventions.

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How should ageing be classified? Thanks to the incredible support of @impetusgrants, we are working to answer this. On 19th February we will be holding our first consensus meeting with experts from around the world to define the criteria for an ageing-related pathology.

https://x.com/bbentley_1/status/1750619075208708242?s=46

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I think there is hope that the healthspan X-Prize will be the ITP equivalent in humans. I think the potential is certainly there, given that there will likely be hundreds of teams with probably as many combinations as there are teams

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