The Challenge of Predicting Outcomes when Mixing Longevity Therapeutics - How are you thinking about this?

Dr. Kennedy in this recent video brings up the interesting problem that he’s seeing which is that its very hard to predict how two “longevity therapeutics” interact and how widely varied the outcomes are.

He says in their lab that the outcomes they see are all over the map, and he cautions people to be careful in assuming that just because one drug or supplement has a positive effect, and another has a positive effect, combining the two together will also have a positive. In fact it can also have a negative or neutral effect (cancelling each other out). And of course the issues of combining more than two drugs or supplements are even more complex and difficult to predict.

How do you integrate this type of data into your own life and longevity strategy?

I tend to try to focus on drugs with the largest effects, and that seem to have largely discrete and differential pathways. My thinking is that these types of therapeutics are more likely to be additive in impact and less likely to be canceling each other out, or causing an “overdosing” of effect.

E.g Rapamycin - with its MTORC1 focus, and SGLT2 inhibitors which seems to work via blood glucose reductions (among other pathways that are still being determined). Similarly, this is why I’m very interested in 17-alpha estradiol, as it is yet another well differentiated pathway with significant longevity effects (at least in males).

And for supplements - I de-emphasize these because they don’t provide (in mouse studies) nearly the lifespan effects that these previously mentioned drugs do.

Here is the part of the interview with Brian Kennedy where he discusses their results of mixing multiple longevity therapeutics in their lab, and his recommendations of caution:

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Have you had a chance to try 17-alpha estradiol yet?

Not yet. I have sources lined up and biologist friends who can purchase it for me - but I think I’ll try it later in the year.

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Okay! Looking forward to hear your experience.

Btw, I’ve been using pantostin topically to maintain my hair (since the last 6 months) and I’ve noticed 0 side effects. But of course it would be a different issue if one were to consume it.

I did wonder if I could just take pantostin orally :sweat_smile:
But other ingredients in it in addition to 17-alphaestradiol include Isopropanol, Glycerol 85%., and Inositol.

So, I thought thereafter that maybe I should wait to hear other reports and get it via a lab.

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Yes, even if the drugs or supplements affect different pathways, there may be an overlap that leads to cancellation or excess. The same potentially applies to rapa combined with lifestyle interventions like keto and fasting of various types. Right now, for the first time, I’m combining my every-6-week fast-mimicking 5-day diet with weekly rapa. I’ll get a general blood panel a few days later to if there is anything unusual.

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I try to combine fmd/fasting and rapa too.

How are you doing this? Rapa at the beginning of the fast or Rapa in the middle of the fast or Rapa after the fast? I’ve done each of them at different points for different reasons lol

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I had rapa at the beginning of the fast for two reasons.
First, there is some evidence that rapa enhances stem cell regeneration and activation, such as here:

My major goal of the fasts is to ameliorate my type 1 diabetes. Stem cell activation and dedifferentiation-then-redifferentiation of pancreatic endocrine cells is part of this.

Second, at the end of the fast when rapa is lower, TOR is needed for rebuilding and redifferentiation. In mouse fasting (not rapa) studies, Longo has found this effect in some tissues like the heart, liver, and pancreas.

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I had not viewed rapa + fast from this angle! This is useful.

When I combined them:
a) at the beginning of the fast → I looked at this in terms of autophagy induction. Generally speaking the first day or two of a fast is spent depleting glycogen. I felt that kickstarting a fast with rapa would make this more efficient and synergestic

b) at the end of the fast → I felt rapa may help prevent any binge eating and also reset the weight point more effectively. I’ve on occasions started fasting with an intention to make it a five day extended fast. But if I’ve instead broken my fast say after 2 or 3 days, then instead of going back to normal eating, I try to make the remaining 3 days a short fmd (with rapa). I felt 5 days extended fast should be equivalent to 2 days extended fast + 3 day fmd (+rapa)

But that said, I think I like your stem generation argument more. It’s more convincing and deals with measurable biomarkers as opposed to my autophagy and set points.

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I, too, am interested how your 17-alpha estradiol experience goes (when you do start).

Right now I’m combining acarbose, empagliflozin and rapamycin. I added them in that order with a 6-month lag between each in order to get blood tests and a more scientific sense of how each was modifying things. Diet has remained “keto plus fruit.”

17-alpha estradiol was the fourth intervention I planned on adding in, but unlike the first three I struggled to find either a source or the same level of safety studies for human males.

Agreed – also very concerned about interactions and things that cancel each other out, or maybe even make things worse than nothing at all. I still take multiple supplements which lower LDL cholesterol and risk of vascular disease (citrus bergamot, amla extract, aged garlic, grapeseed extract, taurine, ashwagandha and a few others). The potential issue is that all of these also have complex antioxidant effects. While I consider those effects to be very different than taking high doses of Vit E, Vit C, etc (some might actually work as weak pro-oxidants, stimulating antioxidant defenses via hormesis), it’s still concerning to me that for all I know, they could be completely blocking the beneficial effects of rapamycin, etc.

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What did you infer from your blood panels? :slight_smile:

So far it’s been all positive. I had been on an upward trend in HBA1C and fasting glucose despite frequent exercise. When I switched to a near keto diet, that started very slowly coming down. When I added the pharma interventions, the improvement accelerated. Kidney function also improved somewhat. I tend to have high creatinine due to the exercise, which translates into low eGFR.

Here’s fasting glucose. The big recent drop is acarbose and then empagliflozin. I did my last bloods on Dec 15 and started rapa Dec 17. I plan to check every quarter now, so I’ll have another new reading in a couple of months.

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This is an interesting thread. I still take NMN as well as rapamycin despite the former making zero difference to any health markers after 12 months. The only reason I continue taking it is that one study on aerobic performance (Im a competitive cyclist). It’s an expensive placebo!!

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Have been on rapa for 5 years. The experts are going to higher doses less often such as 20 mg every 14 days. 75 yo male in good health, no problems. 71" 165 lbs., Got this way taking rapa, controlling glucose levels i.e. inflammation (Metformin 1,000 mg. daily (inhibits glucose production in liver, Canaflozin 300 mg to inhibit glucose uptake back into blood stream after being filtered in kidneys, and Acarbose 100 mg. when I eat a high carb meal. Now I am at my ideal weight will cut Canaflozin to 100-150 mg. Have lost 10 kg. this way in last 4 months. It is essential to get weight and glucose down. Controlling B/P is also, paramount. I want mine from 100-110 systolic. If you can control it will lifestyle great, but if not use drugs to get where you have to be. Exercise, anaerobic and weights. Not very excited about any other interventions except for diet such as keto. Should also mention, I take baby aspirin and 5 mg Crestor daily because I have plaque. If you have plaque, you are at risk period no matter how low plaque is. Aspirin, and Statin reduce inflammation thus inhibit build up of plaque in arteriies of entire body.

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Have you considered taking 30 to 50g of olive oil rather than the aspirin? In theory the oleocanthal should have a similar anti inflammatory effect. Also, there’s evidence that EVOO reduces blood pressure…

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You are right that kickstarting autophagy with rapa at the beginning of a fast might make a difference.

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i would think rapamycin would be far better than any fast… it’s pretty much THE signal that there ain’t no food now or in the forseeable future. what your cells do during a fast you would THINK they’d just do a lot harder with rapamycin. but of course this is just me guessin. cuz our scientists really don’t seem to care about this stuff. or at least they are sure takin’ their sweet time :confused: