Yes, agreed. Looking at the actual studies linked in the tweet by Eric Topol, I didn’t see any evidence that GLP1s would benefit a generally healthy person who isn’t overweight.
Having a healthy appetite is, in its own right, a strong marker of health.
I’m not suggesting that it is determinative by I wonder if there are yet undiscovered consequences associated to destroying that normal physiological function. Practically, we see muscle wasting (which can be offset but sometimes only with great effort and not always successfully, and we are now seeing reports of illness associated with different vitamin deficiencies, some (like B-12) not always reversable.
Stepping way back, I think it is possible that GLP-1 agonists will turn out to have been a sort-lived transitional intervention.
3 Likes
That’s my strong suspicion. Way back when, decades ago, I asked the question on the CR list, “might hunger be an integral part of the CR benefits”, which was subsequently dubbed The Hunger Hypothesis. Years of discussion back and forth. My thought was that low energy states are almost always coupled with hunger - evolutionarily it makes sense. If you have a deficit of nutrients, but no hunger and thus no motivation to feed, you don’t survive. Evolution selected for low energy = hunger. Therefore the hunger state is likely a signalling pathway physiologically, deeply enmeshed in the nutrient sensing matrix. And indeed there is a lot of evidence for gherlin and neuropeptide y being neuroprotective and sharpening senses (which makes sense if looking for food) - even subjectively people report heightened senses and faster sensorial processing when fasting (at least acutely). Obviously it’s just a hunch and hypothesis, but I feel uneasy artificially separating the hunger signal from nutrient/energy status - I’m not sure we have a full grasp of this aspect of these kinds of drugs. Again, pure speculation. YMMV,
6 Likes
Sorry to be dense, but I’m not sure I understand this text as written - what are the “it” referring to in these sentences? What increases risk of CVD here?
1 Like
That’s a response to David’s post here: Top 5 - Which Currently Available Longevity Interventions Do You Think Are the Best - #309 by DavidCary
Kidney function / CKD over time. The argument was that kidney function doesn’t matter due to aging and when healthy and thin, because few of those die from it, even if function declines with age. But when it’s very reduced I’ve heard it massively increases risk for CVD where many die from that before dialysis, and it caps max lifespan if one manages the difficult task of avoiding the other diseases.
3 Likes
Ah, got you, and you are 100% correct. Kidney disease independently causes CVD - there was a recent study to that effect, so it makes sense to try to slow down kidney function decline, including age related decline. I originally misread your statement as asserting SGLT2i increase CVD risk - since the opposite is true, I asked for clarification. Thank you!
3 Likes
Lol, I originally thought he meant SGLT2’s as well and had to go back and look to make sure it wasn’t.
I too was confused by the “it”. Now show me the reference where it (kidney failure) independently causes CVD because that would be news to me. And I don’t pretend to know everything at all.
I mean sure, if you don’t handle fluid well because your kidneys are failing, it puts stress on you heart. And sure that can cause arrhythmias and death. And kidney failure can cause heart failure. All this is certainly true. Electrolytes contributing to this also possible.
But all of that is management failure. So I’d want to tease out the data. A bit like high blood pressure causing kidney disease - undeniable - but only if you manage it poorly.
But to truly separate this out would be challenging since most CKD is from the same risk factors as CVD - namely poorly controlled diabetes and hypertension.
None of this means that kidney function doesn’t matter at all. Nothing is black and white. And getting to 120 - maybe those beans are a big deal. But 90 for someone thin, healthy and no specific risk factors, I don’t think it is a huge priority.
Use a mortar and pestle to grind it into fine powder. Sprinkle on your oatmeal, or mix it with fluids (doesn’t really disolve, iirc). Worked for me.
1 Like
It generally works best with a non-wheat diet. No problems with other types of searches and carbs in my experience.
1 Like
Apparently the diseased kidney sends extracellular vesicles to the heart, poisoning it. This shows the directionality of the kidney —> heart axis.
Circulating Extracellular Vesicles in the Pathogenesis of Heart Failure in Patients With Chronic Kidney Disease
“Cardiovascular disease (CVD) causes more than 50% of deaths in patients with advanced chronic kidney disease (CKD). Clinical studies suggest that kidney-derived factors contribute to CVD development in CKD, independently of co-morbidities. However, to date, no kidney-specific humoral risk factor that triggers direct cardiotoxicity has been identified. In this cross-sectional study, we investigate how, in CKD patients, circulating extracellular vesicles (EVs) facilitate pathological kidney–heart communication, thereby causing cardiotoxicity, impairing cardiac function, and contributing to heart failure (HF) progression.”
A popsci article:
Finally explained: Why kidney disease is so deadly for the heart
“Scientists have uncovered why people with chronic kidney disease so often die from heart problems: damaged kidneys release tiny particles into the bloodstream that actively poison the heart. These particles, produced only by diseased kidneys, carry genetic material that disrupts heart function and can lead to heart failure.”
4 Likes
Rapamycin, empagliflozin, and (insert your favorite drug for lowering LDL-C, although I think ezetimibe is superior to atorvastatin/rosuvastatin/etc) are in a class of their own. HRT for early post-menopausal women is probably in this elite tier as well, as well as GLP1RA for anyone who is overweight
In the second tier below that I’d put telmisartan and lithium, along with dutasteride for men.
The third tier would be creatine, magnesium, melatonin, taurine, as well as famotidine for those with GERD.I think you could put psychedelics in this tier for the therapeutic mental reset they offer, in addition to the longevity benefits demonstrated in mice, it’s just that the optimal frequency/dose isn’t clear yet.
I think many of these are very individual-specific though. If you can tolerate acarbose, I can definitely see having it on your list. Buproprion has been life-changing in terms of the productivity boost it’s given me, which I think is a huge factor in longevity, so it’s near the top of my personal list. Similarly, I think if something significantly reduces your stress levels or increases your life satisfaction it could deservedly be there as well.
4 Likes
Let’s say you are taking:
- Rapamycin
- A statin, Bempedoic Acid, Ezetemibe
- An SGLT2I
- A GLP-1
- Dutasteride and Tadalifil
- Acarbose and Metformin
- Galantamine
- You have optimal BP
What would be the next prescription medicine(s) you would add to this stack for longevity? Any other low hanging or potent ones out there beyond these? Exclude supplements. @desertshores @RapAdmin @Agetron
3 Likes
That’s why I gave up on CR after 5 years of misery: constant, gnawing, unrelenting hunger. I just couldn’t stand it.
3 Likes
CR is great except for the constant cold and hunger and outright daily misery that makes you wish you were dead every single moment. 
I’ll take Rapamycin instead for the same benefits and fewer side effects.
4 Likes
Thanks for the kidney references. I am not fully convinced but at least it is a plausible explanation.
1 Like
Definitely Cypionate, testosterone - TRT starting at 50 years. I started at 62 years. Matt Kaeberlein states was the best thing he did … after waiting, next to Vitamin R… rapamycin. He is 54 years in 2 days.
Doxycycline weekly… 100 mg.
2 Likes
I wish sites like this had a commonly editable spread sheet where top NN lists can be in a single place then smeared over 100+ posts. Anyway.
I’m shocked, just amazed that HRT, all hormones replacement therapy was not in any (or I missed) top 5 lists. Both sexes; estrogen (for men, it aromateses from TRT), testosterone, progesterone (no need for men), pregnenelone (LEF loves pitching this) my health coach tips 5mg (not 50) micronized, DHEA and importantly thyroid I take NP thyroid.
=== now hitting
-
DIY self injected exosome sources. Got my 25B exosome delivery on dry ice yesterday. We will split it Sat. $1800 from a private org channeling a top name source. Money no object, said to be best if quarterly… A member of this group just injected 75B dose post shoulder reconstruction surgery.
-
Once hot but now questionable; A product called Cell Factor (googleable). The beneficial insides of exosomes but without the variablity of an exosomee source. TBD
-
plant based exosomes. Several companies have product for topical/skin use. TBD if ever become injectable.
=== Not yet settled protocols pre any TRIM - esk type trials, bearly concensus in private health groups;
-
klotho; my experience with Klotho-a and now klotho-1 is nothing noticable. BUT same with rapa and nearly the same for HRT. Maybe holding flat is a gain in and of itself. :>
-
VD-11; a general systemic up regulator. My order hasn’t arriived and just the coaches reviews of major up regulation, feeling better. TBD
-
Fox-03 yet another compound in the KLOTHO chain in/near the mitochondria
-
met enkephlin (??) an endogenous canabinoid good for pain
-
URB-597 blocks the breaking down of endogenous canabinoids. Another help for pain, anti-anxity BUT feeling better in general. TBD.
-
I’m close to but not in the direct flow of case studies from professional athletes/Olympic folks. In the money no object level; amazing recoveries and performance improvements. Eventually someone close to these folks will leak out the whats.
I suspect theres alot more compounds on the near horizon that are NOT out of patient targeting drug co labs, but out of small labs by genuine benefits driven private chemists.
True #1 line item on this list is sleep, next or close with clean water, clean and nutricious for you (individualized) food. An appropriate typee of exceresize.
But not far down the list are some new compounds more effective then rapa. We just need to get compound names, sources, and more DIY experiements like we have been doing here.
Good luck, curt
2 Likes
I think this pretty much covers it. I don’t think there is any need for more. Maybe could add Selegiline since that has shown potential.
3 Likes
I don’t understand the doxycycline love-in. Doesn’t it disrupt the gut biome like other antibiotics?
1 Like