Rules of Thumb?

#1

Has the group ever tried to collect useful “rules of thumb” related to longevity interventions? I found several references here to individual RoT but no list.

I like @desertshores RoT: If a supplement provides no subjective benefit in 30 days, drop it.

I also think his idea of keeping the number of supplements (drugs?) down is smart and could be codified as a RoT. I think the RoT should be something like have a max number of drugs taken every week <30 and stick to it. Drop old ones to add new ones.

Relatedly, only add one new drug at a time.

In my thinking, a drug is any synthetic chemical or chemical concentrated beyond what is in food or is injected.

For my diet:
30 different plants (veg, seeds, nuts, fruit, spices) every week
40g fiber per day
1.5g of protein per kg body weight daily average, but shifted to more after resistance training and less around rapa dosing
No/ limited added sugar
No/ limited added fat
No/ limited UPF

For my “safety”:
Get comprehensive blood tests at least every 3 months. More frequently to match a faster pace of new drug additions.

What can you contribute?

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#2

Keeping lipids down is the most important part of any longevity intervention. It won’t matter if you have a telomerase activator or kept your body young using rapamycin if you die in your 70s from heart disease.

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#3

I agree. My goal is apoB <60 on every test while avoiding the muscle aches of rosuvastatin (EOD dosing at 10mg). What’s a solid RoT?

I’m at ~65 now.

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#4

According to Attia, keeping your apoB at the same levels you had as an infant would be ideal and likely eliminate ASVCD completely. Stanfield suggests keeping your LDL-C well below 50.

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#5

That’s a great start for an RoT

I think on the drugs/supplements taken daily there should be a lower limit like 10-12. What I wouldn’t include in that limit are those supplements only taken occasionally e.g. I love oily fish like sardines, herring and salmon, and I eat one or the other just about every day of the week. Occasionally though I might end up not having consumed any for several days and this is then the only time I will take a fish oil (EPA/DHA) supplement.

On the one new drug/supplement at a time, only start after one of the quarterly blood tests and keep it going until the next one (unless another adverse symptom appears) as 3 months would be enough to notice any positive or negative difference whilst I feel 30 days is a bit on the short side. (It was 6 weeks before some specific negative side effects of statins hit me).

Just then need to add RoT on exercise (2-3 hours zone2 cardio, 20-30 mins HIIT, weight training 2-6 hours (depends on how long one rests between sets)) and RoT on sleep (always try to go to bed at the some time and don’t set an alarm to wake you in the middle of a 90 minute sleep cycle).

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#6

I’ve been thinking about this more generally as it relates to rapamycin and dosing protocols. I’ve posted earlier about some general heuristics when it comes to dosing, but I’m also thinking we need to pull together some ideas on dosing adjustments for rapamycin that are conditional upon testing outcomes or side effects…

For example I started dosing rapamycin with this approach:

  1. start at 1mg/week and increase 1 mg/week until I’m at median dosing levels (6mg/week) and then hold there for 3 months, testing blood every 3 months (standard panels for Levine Phenotypic calculations). Also test APOB levels.

  2. If minor side effects (e.g. rash, apthous ulcer in mouth), pause increases in dosing but continue current dose unless side effect continues all week and still at time of next dosing (in which case skip a dose until things clear up).

  3. If a more significant side effect becomes evident (Like with our Swedish community member: Selling my rapa (Sweden) ), perhaps some alternative dosing schedules (other than weekly) are in order. E.g. Lower Dosing (e.g. pause until problem clears up, then try dosing at 50% problematic dosing level, or less frequent dosing schedule, e.g. once every two weeks).

  4. If you encounter lipid or glucose disregulation (e.g. higher lipids / APOB) or higher fasting glucose levels or glucose response… you have the options of either modifying dosing frequency or levels to reduce the disregulation, or adding a treatment to counter the disregulation (e.g. statin or blood glucose medication like acarbose, canagliflozin or metformin). There are no evidence-backed rules of thumb in this area yet. I was talking with Andrea Maier at the University of Singapore about this as they were designing the protocol for their rapamycin clinical trial and they too were asking about this. So nobody really knows what the right approach here is, so its still up to us to try what we feel confortable with until more data comes out.

One note here is that I did see a Bryan Johnson adjust his rapamycin dosing schedule to one week of higher dose (13mg dose one week, 6mg dose the next week). So, another approach we can consider.

Here is my earlier post (from the Rapamycin Dosing Thread):

Its really early as far as dosing heuristics, but here are some of the ones I’ve seen floating around.

  1. The older the person, the higher the dose needed of rapamycin. This is based on the idea that mTOR tends to get overactivated with age (i.e. doesn’t return to a low baseline after activation), so as you get older mTOR tends to be active all the time, which is not good. Thus the idea that the older you get the more you need to block the mTOR activation so your body isn’t always in “growth” mode. I think this is related to the hyperfunction theory of aging: The hyperfunction theory of aging: three common misconceptions - PMC

  2. The higher the weight / Mass, the Greater the Dose. In the Rapamycin dog trials they dose by mg/kg because there is a relatively large range of weights and sizes (see here: How Do I Get Rapamycin for My Dog? )
    In the human medical field I think they tend to go for simplicity, so they may tend to go for simpler dosing strategies to increase adherence, but i also see many doctors increasing the dose of the rapamycin depending on the weight of the person.

  3. Side effects driven by the trough (not the peak) value of rapamycin in the blood. There is a hypothesis that most of the side effects of rapamycin are driven by mTOR2 inhibition, which happens in a non-direct way when mTOR1 is inhibited at a higher level chronically for a longer period of time (I’ve not seen any greater detail on this but would love to see specifics). So if you take rapamycin daily, you have much higher risk of side effects than pulsed dosing weekly or every two weeks.

Some related threads that may be of interest:

here: To have less side effects, are there any ways to increase Rapamycin elimination rate? (Ex: drugs? fasting?...)
here: Make your arguments for Rapamycin dosed Once Weekly vs. Once Every Two Weeks
here: Rapamycin Update - Summary of Recent Matt Kaeberlein, Dr. Green, Blagosklonny Conference Call (June, 2022)
here: Rapamycin and Beyond: Presentation by Dudley Lamming & Adam Konopka

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#7

Thanks. That makes sense. The exact number of drugs is important but it is separate from the importance of having a limited number to force a prioritization. My thought process is something like: can I get it in a food? Am I already getting this mechanism with some other drug? Does this drug #1 provide more benefits than drug #2 (seek fundamental/ hallmark of aging effects)?

You might be right on the length of time to assess a new drug. Anyone else?

Exercise can certainly have RoT:
Exercise every day, mostly low intensity but hit max heart rate periodically (90/10?)
Emphasize activity (sports, outdoors, rough trails, free weights) over “exercise” (limited brain stimulation)

Perhaps there should be a set of RoT on honoring biological/ evolutionary cycles (90 minute Utradian for attention; 24 hour circadian for sleep and more; seasonal food variations, etc.)

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#8

This is great. The most important thing I learned from rapa is that I don’t have to take drugs everyday. I can make the schedule plus the dose fit me and my schedule.

I have shifted my rapa to a higher dose (6mg plus fatty meal plus other boosters) but a longer cycle (9/10 days). I weigh 200 lbs; I have no side effects but I want a very low trough.

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#9

All the Geroscientists I talk to tend to think people who take many longevity supplements and/or drugs are vastly front-running (i.e. out in front of) the evidence.

So, given this and the gaps in the evidence, my tendency is to go light on the supplements and longevity drugs (admittedly, everyone’s idea of 'light" on the supplements and longevity drugs is different).

But I’m wondering if there is a case to be made for taking more of these supplements and longevity drugs, but creating a very specific blood testing regimen (and functional testing regimen) to watch for any detrimental side effects and just catch them early…

@Joseph_Lavelle you seem to have what I would consider a fairly aggressive approach to longevity supplements and drugs (from what I hear in your posts).

I’m wondering if we, as a community, might develop some very specific “rules of thumb” for testing on a drug by drug basis, both for efficacy and also for any potential negative side effects. I’m thinking we’d need to do this on a drug / supplement by supplement basis. So - every time we add a new drug we review all the important risk factors for that drug/supplement and try to develop a list of key blood tests that map to those key risk factors.

For example, given what we know about rapamycin the rule of thumb might include the following;

  1. Regular testing of blood glucose levels (by finger prick or CGM) to watch for any potential disregulation.
  2. Regular blood/lipid testing to watch for any potential disregulation.
  3. Periodic Blood/Sirolimus levels for trough levels (and perhaps for peak, though that is less valuable).

Efficacy testing might be things like Levine Phenotypic testing, and others…

I’m thinking maybe we develop something like this for all the positively tested ITP longevity drugs and supplements.

The goal here would be to develop a safer and systematized means of expanding our longevity therapeutic use, and tracking the results.

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#10

@RapAdmin I like this. My “aggressive” approach is more from sliding down the slippery slope rather than a logical, rational thought process. I started off as very healthy in so far as aging.ai and Levine can be relied upon. And I haven’t helped or hindered that yet (4 mos in on rapa). My fear level is abnormally low (I have enjoyed and suffered from this much of my life). I would like to be more careful, and I think the approach you describe is a good one.

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#11

First drug should be Rosuvastatin 5 mg/day or Praluent 150 mg 1x/month.
Increase dose or add other drugs like Ezetimibe if needed for optimal levels.
Of course lifestyle changes are encouraged at the same time.

Once lipids are optimal add in Rapamycin 1 mg/week, until 5 mg/week.
If lipids go outside the optimal range, either reduce rapamycin or increase dose/add drug for lipids (apoB).
Consider lifestyle changes.

If lipids still not optimal and decreasing dose of rapamycin doesn’t work, stop taking rapamycin or maybe try another mTOR inhibitor like everolimus which I don’t know if it will help.

With optimal lipids and possibly an mTOR inhibitor, add in Acarbose in small doses before each meal until 100 mg before every meal. If stomach doesn’t function properly decrease dose or change what you eat, try not eating for example wheat.

Check apoB peridoically, maybe once a year or every two years depending on changes or how stable it is.

After this, add in 17-Alpha-Estradiol using OTC hair gel bought from Germany if you don’t have genetic risk for autoimmune disease or lupus. Take DNA test at Ancestry ($99), then upload to Nebula Genomics to see risk, billed monthly, cancel after one month ($15).

Once this is complete, increase protein intake to 1.6 g/kg, use protein powders, and resistance train 3 times a week to gain strength and muscle mass. Once muscle mass and strength is in 90th percentile for age, add in exercise like cross trainer, bicycle or swimming for 90th percentile VO2Max, and with a couple hours of Zone 2 exercise a week, preferably longer.

Entire journey focus on happiness, meditation, journaling, gratitude, relationships. Limit intake of alcohol, news and don’t smoke. Invest money in the stock market for retirement and older age, stick to index funds with low costs. Use that money for retirement and future longevity drugs.

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#12

Not sure I understand or agree with that one. Many supplements and medications will not show any results. If you’re taking something to prevent cancer, are you going to stop after a month?

My ROT is to regularly review current literature on each supplement I take and decide whether to continue.

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#13

@KarlT It’s a thought but where does it end? I’m looking for a rough but logical rule for staying in control of my emotions.

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#14

“There is a hypothesis that most of the side effects of rapamycin are driven by mTOR2 inhibition”
I agree, but the question is even with the side effects of mTORC2 inhibition how much is it actually inhibited?

Dr. Blagosklonny expressed the opinion that there is not much evidence for rapamycin suppressing mTORC2 significantly.

I guess the definition of chronic administration is mostly related to lab experiments.
Most people in the forum are pulse dosing or daily dosing and taking breaks, which is not in my opinion “chronic” dosing.

My own unscientific personal observation is this:
When I was taking high weekly pulse dosing, definitely noticed a longer time for wound healing and a slight increase in blood glucose levels.
Since the wounds healed and my glucose didn’t rise significantly, (though worrisome to me), I must conclude that mTORC2 suppression is modest.

I have tried several different dosing patterns. For the past two weeks, I have been trying 1mg daily, 7 days on 7 days off. Yes, the AUC is greater than a 7mg pulse dose, but I think that it is a good thing.

The result so far is I feel good every day and there has been no discernable change in my fasting glucose levels. As per the article I am referencing, I am using my daily fasting glucose levels to check for any excessive mTORC2 suppression.

“inhibition of mTORC2, specifically in the liver, causes the negative effects of rapamycin on glucose homeostasis”

When I was pulse dosing I usually did not feel good for 1 or 2 days and often had loose stools. At high doses, I also had mild diarrhea.

Rapamycin-mediated mTORC2 inhibition is determined by the relative expression of FK506-binding proteins - PMC.

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#15

Shouldn’t the dosing be based on surface area rather than mass? I think they use mass only because it’s simpler.

#16

Yes - I’ve read surface area is better, its just a little more complex and much of the data on dosing (in animals for longevity) is ppm (parts per million) of food, or mg/kg of animal weight.

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#17

Here is a good one from @Boldi

“For example, he insists that I never make more than one change (whether to dose or drug) per quarter, with clear blood panels before and after”

Source: https://twitter.com/Boldizar/status/1679556321962790912?s=19

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#18

:+1: great detail in info!

Regarding the 90th percentile of strength and VO2 max, how do you measure that and what matrix do you compare it to?

#19

I agree here and this feels little bit like the longevity research is trending to evalute interventions on a short period of time. I see risks that we miss out the slow and long term term compounding interventions this way. But also that we miss long term bad effects on interventions which seems promising in short term. Its very tricky thing to navigate in this jungle.

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#20

You really can’t really rely on Aging.ai IMHO. My HBA1C and LDL levels shot into high territory but my age did not change. I hope Aging.ai is correct, but it makes me doubtful.

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