#21

There is not a single thing that Matt Kaeberlein says that I haven’t heard before, but every time I listen to one of his podcasts, I learn something new. I have Peter‘s book. I can’t wait to read it.

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#22

The topics of anti-aging or age reversal are moving so fast, Writing a manuscript then going through the steps to publication takes a long time, maybe a couple of years. Very hard to be current with that lag time. I skipped Sinclair’s book and don’t think I missed out on anything major. Just my opinion.

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#23

I agree, we listening and he is revealing and his use of analogies are quite interesting. About to listen to chapter 5 on rapa.

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#24
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#25

I have reread the sections on nutrition and I believe he is actually saying a great deal. He advocating for following a few simple guidelines; (generally unprocessed food, foods that do not cause large insulin spikes, “healthy “fats, and a fairly high intake of quality proteins). He seems to be saying that if you do these things and eat only enough to not be "overnourished, you will be consuming a diet that will do all a diet can do for the promotion of longevity. Of course, we can’t know if he is correct.

It is interesting though. If Attia is correct, Bryan Johnson and Mike Lustgarten follow incredibly restrictive dietary routines for very little or no benefit. Similarly, if Attia is correct, Valter Longo’s “Longevity Diet” is vastly more restrictive for no benefit.

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#26

I don’t think PA has ever adequately addressed the contradiction between his advocacy for methionine rich proteins (e.g. meat and whey) and literature around methionine restriction:

I do eat methionine rich foods in my ‘normal’ omnivore diet but have recently shifted more towards collagen peptides as a supplementary protein source. Not only is collagen very low in methionine, it has almost 30% glycine which, as we know offers it’s own longevity benefits:

Sure, I might be sacrificing ‘optimum’ muscle anabolism but, based on the literature above, it would seem the superior option for longevity?

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#27

but collagen is not complete protein source and lacks L-tryptophan… as much as I know it is advisable to use it as supplement but not main protein source. I never put much thought into it as I supplement just 6g per day of collagen peptides.

edit:

Found this. Seems you can include more collagen really…

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#28

PA makes a compelling case for lowering (minimising) both ApoB and A1C so I have seriously begun to question the prophylactic use of a drug (Rapamycin) that increases both those markers. For me Acarbose looks like a superior intervention with substantially less risk.

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#29

That argues all the more strongly for Attia’s strategy-over-tactics approach in this book.

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#30

That can be mitigated with a statin though, I didn’t know about A1C increasing, do you have personal experience with that?

I would rather take rapamycin+statin than no rapamycin at all, IMO. As my view is statins are very safe for the vast majority of people, they are longevity/healthspan drugs.

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#31

Yes, I can understand the decision to take statins but I’d just rather avoid polypharmacy.

Yes A1C has been trending upwards at ~2mmol per quarter.

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#32

My a1c was 5.2 immediately prior to starting rapamycin last July. It is currently 5.0. But I don’t take high doses (6 to 8 mg) or inject rapamycin.

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#33

My A1c is stable so far at 5.2

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#34

I agree with you on wanting to avoid the polypharmacy.
Some mouse studies show that the higher blood sugar resolves itself after a length of time, however the mouse study below (admittedly quite old) shows that it does not, is worse in males and becomes somewhat permanent even after the cessation of rapamycin.

Chronic rapamycin treatment causes diabetes in male mice

https://journals.physiology.org/doi/full/10.1152/ajpregu.00123.2014

I wonder how Dr. Attia proposes to deal with this problem as he is a proponent of Rapamycin. I also wonder if treating high lipids and elevated blood sugar with drugs somehow interferes with the benefits of Rapamycin i.e. are they a beneficial feature or a problematic side effect? The male mice in the study above have worse problems with blood sugar control than females, but at the same time achieve greater longevity benefits.

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#35

I agree - we have to be very cautious around polypharmacy… biology is complex, and many drugs affect multiple pathways and processes…

There are many studies in mice showing an impact on blood glucose levels, but the dosing is high and daily typically, and initiated at childhood… so its really unclear how well that data translates to humans… I suspect that if you gave almost any drug at high doses, from childhood on throughout life, that there would be some sort of negative side effects… but that doesn’t mean that its not a helpful drug in many cases.

and of course:

The seeming ability of rapamycin to extend lifespan, while at the same time compromising metabolic function in a manner expected to reduce longevity is recognized as the “rapamycin paradox”

The control diet contained 189 ppm Eudragit, while the rapamycin diet contained 189 ppm (14 mg/kg food) encapsulated rapamycin; mice were started on diets immediately after weaning.

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#36

Me too — or at least I think it merits consideration. Certainly we know that high apoB or diabetes will shorten your life, whereas the lifespan-extending effects of rapa remain hopeful speculation based on animal evidence and extremely limited human data.

Good find — but a pretty extreme situation. “mice were started on diets immediately after weaning” and were given rapa every single day for a full year (through their adolescence and young adulthood) before they were first tested, found diabetic, and taken offf the drug; they were much more mildly diabetic at the 18 week mark, but didn’t test the effect of discontinuation at that earlier time point.

Also, you say the study shows that the higher blood sugar does not resolve itself after discontinuation, but actually the study does find that glucoregulation does improve after cessation, albeit not returned to normal:

Strikingly, after just 1 wk off of rapamycin treatment, the average fasting blood glucose level in male mice decreased significantly [from 250 mg/dl down] to 135 ± 4 mg/dl, although this remained significantly above that of control mice (96 ± 5 mg/dl; Fig. 7A). Similarly, as monitored by successive GTTs, male mice quickly recovered glucose tolerance after the cessation of rapamycin treatment, observable within 2 days off of rapamycin (Fig. 7, C and E). This became a significant change after 1 wk off of rapamycin treatment, however, these mice never returned to the same level of tolerance as the age-matched controls (Fig. 7E). Insulin sensitivity remained the same over the 18-wk period (data not shown).

So humans who monitor themselves regularly can watch themselves for early warning signs and discontinue.

Also it’s not as if everyone taking rapamycin develops either hypercholesterolemia or hyperglycemia: it’s a minority of people even in trials where humans take relatively high doses every day, whereas most people here are taking modest doses weekly or on some other intermittent basis. Dudley Lamming has reported that weekly dosing in male mice has “minimal effects on glucose tolerance, … a reduced impact on pyruvate tolerance, fasting glucose and insulin levels, beta cell function, and the immune system compared to daily rapamycin treatment.”

Presumably he would deal with it by monitoring his patients (he has them all on CGMs and is very vigilant about apoB) and will advise them to either discontinue rapamycin or take corrective action (pharmaceutical or otherwise) should issues arise.

Remember, adding metformin to rapamycin appears to increase lifespan in male mice compared to rapa alone, and adding acarbose to rapamycin had the strongest life extension ever reported in male mice from drugs in the ITP.

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#37

What’s polypharmacy and what’s wrong with it?

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#38

My understanding is that Polypharmacy-multiple pharmaceutical drugs-can have potential undesirable interactions.

#39

You have to be careful that the medications don’t interact in an unintended way. The more medications, the more chances of a negative interaction.

However, I am not sure if this applies to supplements equally as our food is a mish-mash of various different chemicals all providing different natural “supplements”. Also, some medications can be synergistic such as Rapamycin + Acarbose or Metformin.

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#40

Rather than using scary sounding terms like polypharmacy in a vague way, I think it’s better to simply say if longevity drugs like rapamycin, acarbose, statins interact or not.

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