Good science here!
The glitazone toxicity needs explanation. Fortunately they retested mitoglitazone, so it seems the earlier findings with that agent may have been a false positive. Either way, I’m reconsidering the benefits of using pio along with rapamycin. This was a surprise.
The rest of the agents I didn’t much expect to succeed, but wouldn’t have bet heavily on failure either. The results are all interesting in their own right, though.
Let us keep in mind, that even if a given med does not prolong lifespan, it may still be vital to take it. We all die of a specific cause. There is no such thing as dying “from old age”. There is always some kind of physiological or organ failure (unless accidental death due to external factors). Even more importantly there is premature death, where you have catastrophic failure of a specific system, while the rest of the body is still physiologically fully functional, like for example cardiac arrest due to arrythmia. If you can identify your particular weakest link(s), you would be wise to take preventive measures such as for example atorvastatin and telmisartan. Mice don’t typically get CVD and hypertension, so these drugs may not move the needle for them in life extension. But in humans, we are looking not just to prolong life (rapamycin: ITP success), but to preventing premature death (atorvastatin + telmisartan: ITP failure), as ASCVD and hypertension related morbidities are overwhemingly weak links in humans. So we may want to take these “failed life extension in the ITP” drugs anyway preventatively even without diagnosed disease, us not being mice and all. Though we may gamble on the ITP successes 
.
Now, we may want to take these preventative drugs anyway as long as they don’t actively shorten lifespan - and this is a far more pertinent question for me in these ITP results. I am not worried by neutral results - I may still take these drugs preventatively. But I am concerned by adverse results. Here apparently a drug like pioglitazone was actively toxic (at least sex dependently - in female mice). If we take ITP results in mice seriously in the positive (rapamycin), should we not also take them seriously in the negative? Here’s where we must turn to human results where we can, however imperfect they may be (NHANES, UK Biobank etc. where for example atorvastatin had a small 9% advantage!.), including long term clinical trials, observation studies, metaanalysis etc. Which is why regardless of what the ITP results say, I do a ton of reading of the literature before I add any drug to my stack, and it takes me unfortunately a long time. Others make faster decisions, but we all are under the gun, as the sand in our lifespan hourglass keeps trickling down, time growing shorter relentlessly. We rarely get to make decisions with all the evidence present, we are forced to gamble - and not taking a given drug is also a gamble. For now I’m sticking with my statin (pitavastatin), telmisartan (although seriously researching substituting with olmesartan), astaxanthin, while of course I never stop re-evaluating as more literature rolls in. For me personally, these recent ITP results have not changed my stack, YMMV.
While I do like cheese, I am not a mouse and agree with this premise.
in 2024, they reported asta extended median lifespan lol
In genetically heterogeneous (UM-HET3) mice produced by the CByB6F1 × C3D2F1 cross, the Nrf2 activator astaxanthin (Asta) extended the median male lifespan by 12%.
glynac works via glutathione the master antixoidant, totally different pathway from NRF2 enzyme AFAIK.
ah okay, this study was different in some aspects…instead of starting on month 12, they started on month 7 and 16 and used different doses.
In a previous ITP study, Asta had increased lifespan in males (12%, P = 0.003) when starting at 12 months at a target dose of 4,000 ppm [10]. Given this result, we wanted to test whether there would be a similar or perhaps greater effect when giving a lower dose (880 ppm) but starting at 7 months and test whether starting later (16 months instead of 12 months) would still have a life extending effect. However, neither intervention led to significantly increased lifespan in either the males or females.
this is about 1.5g asta daily for humans lol. we usually take 4-12mg daily.
I agree with you in general but wanted to add that I don’t really think we need any studies from ITP or any other body for that matter to know that most drugs we are taking preventatively (i.e. Sglt2-i, metformin, acarbose, Pitavastatin, Ezetimibe and few others) have been prescribed in millions annually and barring any accidental dose mistake these drugs have a very safe profile. Now, if I were a doctor I’d want to be much more careful the way I word it but honesty we all know people on these drugs that are doing just fine. I as an example know at least 10 people that I’m related to and take these drugs therapeutically some of them for over 20 years and they are all very healthy. At worst these drugs probably don’t provide any lifespan, but they do help us maintain our health span and that is an important part of the longevity journey IMO.
There is couple iffy ones such as Maraviroc as an example but those ones we just have to proceed with caution and always make sure to check blood markers.
I would caution anyone starting a new medication to start at a very low dose and titrate to desired dose after a while and after you can see that you don’t have any side effect.
The issue is that a lot of medications do cause real, and sometimes deadly side effects. I think that this is where trepidation comes from. However, the meds that are recommended here are not those meds.
If an ITP mouse lives longer due to an intervention, it is probable that it prevents or delays cancer as mice die primarily from cancer. They don’t have heart attacks. That’s why as a human, you have to address cardiovascular disease before going beyond into ITP medications.
Then there is the holy grail of treatments. Those that extend lifespan irregardless of any cancer benefit. This is Rapamycin. The ITP is on the hunt for others as well.
The problem I see with the ITP studies is that even if there was a holy grail med or supplement that is tested by the ITP, if it does not reduce cancer risk, it would never show up in the studies.
Therefore, the ITP studies primarily tell you how to reduce your cancer risk. They just got lucky with Rapamycin that it also extends lifespan.
In order to get valuable results, you need a test organism that does not die primarily from cancer or one single source. Or you need to do interventions on different species that die primarily from diverse reasons. The only known med that increases lifespan amongst multiple organisms is Rapamycin.
Did NR or nmm work on mice hehe
In a way, this is a big advantage of the ITP. I would like to believe that almost nobody on this forum will die from atherosclerosis either, since we aggressively lower our lipoproteins, do calcium scans, CTCAs etc.
Not to sound arrogant, but with my LDL-C and confirmed zero plaque, I feel pretty confident in ruling out ASCVD killing me - which makes me a bit more similar to a UM-HET3 mouse 
I consider 12mg a “high” dose since most studies used 4-12mg. I definitely wouldn’t go higher IMO.
Well, the glitazones caused weight gain. That insulin sensitivity comes at a price. But Rapamycin makes you a bit insulin resistant - so I would say the combination makes logical sense, better than using Pia alone would.
Just to be clear, no, it isn’t. Please look at my post earlier up in this thread. A human taking 12mg/d would end up with >10-fold higher plasma concentrations. The mice don’t absorb the drug well from the dry food, and rodents also metabolise it very quickly. I posted links earlier.
The mice on 800ppm Asta ended up with ~20ng/ml, whereas a human taking 12mg per day has a plasma concentration of more like ~200ng/ml.
You can’t just look at the given dose and convert to human equivalent dose. You need to look at how much dose actually got into the animal.
You can try to get insulin sensitivity enhancement without weight gain - see imeglimin.
Differential effects of imeglimin and metformin on insulin and incretin secretion—An exploratory randomized controlled trial
“Based on these studies, imeglimin may well be expected to improve both insulin deficiency and insulin resistance, suggesting potential for a wide variety of diabetes patients. In clinical trials, imeglimin alone or in combination with other hypoglycaemic agents significantly reduced haemoglobin A1c (HbA1c) without increasing risk of hypoglycaemia and weight gain.”
Dual action of imeglimin on insulin secretion and sensitivity in type 2 diabetes
i take asta daily too and for me it definitely has an effect! the main effect is i feel my brain works better on it, i cant really describe it to you guys but i think through things better. there are studies that show asta really improves cognition in people drastically btw. also for me it seems to increase my physical stamina.
i used to take 12mg but these days tapering down to alternate days or 4mg etc. from what u described, it seems like 6mg would the human equivalent for the ITP mice dosage that worked.
thanks for sharing ur knowledge very useful and logical