I expect more good than bad, and the bad being mostly due to improper use.
I believe the official guidelines of constant titration to the highest dose to be foolish. I needs to be individualized. Start low, go slow, increase protein/resistance exercise.
I’ve stated this a while ago but I believe GLP1s will be more efficacious than Rapamycin.
Here is what I don’t understand. Are you suggesting that something could be done before trial starts to ensure that the controls live at least 800+ days? If so what is it and is it predictable? I’m genuinely asking because I have no experience with rodent research. If it can’t be prevented, then are you suggesting that the researchers, after having invested the time and grant money in the study, not publish or conclude that well we got these results but they don’t mean much because our controls did not live long enough.
Sorry to hear that, I’m sure it sucked to go through. I started on a micro dose of rapa, 2 mg per week. I increased it to 3, and got very fatigued so I dialed it back down to 2.
Results should be considered with the caveat that statistically the numbers could look better than they actually are (and that this applies to all interventions with shirt lived ) . See https://www.sciencedirect.com/science/article/abs/pii/S1568163724003301?via%3Dihuby
Yes, absolutely I am suggesting that.
But first the “why” of Matt Kaeberlein’s 900 day mouse rule. Longevity research has been plagued by studies using short lived mouse strains, introducing an intervention which extends the lifespan and then claiming that “hey, we found a life-extending intervention”. All with zero qualifications. Here’s my analogy. Imagine that I took a bunch of teenagers and divided them into “Controls” and “Intervention” group. Now a rule in our world is that at age 20 we deliver a powerful hammer blow to the head to our subjects. For our intervention we have “tie a pillow around the head”. In my trial, it shows that the “Controls” without the pillow all croaked at 20 (as expected) meanwhile, our pillows allowed the Intervention group to live to 80. I can now announce to the world (and perhaps sell!) an amazing life extending pillow. Now Matt Kaeberlein comes along and says, "I will only acknowledge your intervention (say, your pillow) as legitimate life extending intervention, if your CONTROL GROUP lives to at least the average human lifespan (for the US, say, 86 years) - now if you can show your intervention can exceeds that by a significant margin, then it’s a genuine life extending intervention - call it the “86 year human rule” (see: “900 day mouse rule”). Now do you see why we need that rule for all animals? The controls must live at least the average lifespan (mice: 900 days) for the intervention to exceed that target, not exceed a fake rigged target.
In mice research they use all sorts of mice strains for various purposes. Some of these mice strains can have extremely screwed up genetics and be generally very sick animals and consequently are very short lived strains, like, say, 600 days, or 700 days instead of healthy strains 900 days. Now imagine that you have a strain of mice that have severe genetic damage to their pancreas, and can’t produce sufficient insulin and live very short lives, say 500 days. If I now come along and use this strain for my longevity research and my intervention is injecting insulin thus bypassing the genetic flaw, and now the mice live longer, up to 800 or 900 days, can I go out into the world and announce that insulin is a life extending miracle drug? No, because Matt would ask “how long do your controls live?” - only 500 days, and with insulin go to 800 whereas normal mice live to 900… get lost with that dummy intervention. The point is, when dealing with a very short lived strain of screwed up mice, you have ZERO idea if your intervention somehow is not simply compensating for whatever it is that’s wrong with the mouse to begin with - sometimes it’s not even obvious how these drugs interact, perhaps the intervention is not insulin directly but a drug that removes enough glucose to reduce the need for insulin, and this gives you a longer life for the screwed up mouse. Point being, you have no idea what that drug is doing in a short lived strain. Hence we have Matt Kaeberlein’s “900 day mouse rule” for any controls in a longevity trial.
So the first thing to check is that the researchers have used a normal lifespan strain of mice - 900 day minimum (with perhaps a 50 day leeway either way). But what if they used a normal strain mice and their controls only lived 800 days? Well, that means the husbandry was so poor that their experiment is useless because you are comparing poorly cared for mice to the intervention. They’re supposed to live to 900 days, but you didn’t give them enough vitamins and they only live 800 days. Now you give them a vitamin pill and presto - they live to 900 days. Is the vitamin pill a miracle drug of life extension? No, it merely compensates for your shitty husbandry that results in a 800 day mouse from a 900 day strain. Again, the 900 day rule for controls is relevant.
What can the scientists do? First use a normal lifespan mouse strain (900 days), and then take care of them well enough that the controls live to 900 days minimum. Now if your intervention arm exceeds 900 days by a significant margin - go announce your amazing drug/intervention. You ask about “before” the trial - yes, please do select the mouse strain carefully and if you are cr@p at husbandry and your mice are supposed to live to 900 but only limp to 700, you just trashed your study - get better techs to take better care of your mice so they can live to their full 900 day potential. But one thing you should not do is publish your cr@p results - we have enough fraud and useless research as it is.
Bottom line: life is short - it is composed of hours and minutes. If you come across a longevity study where the Control mice cohort is below 850-900 days - stop reading immediately and spare yourself the waste of time. Life is short. You just saved precious minutes.
Thanks for the robust response! I understand Kaeberlein’s 900-day rule. It seems you’re saying you must select a strain with a normal median lifespan of 900 days and care for them properly so they can live up to their potential. Given that C57BL/6 live between 800 and 900 days, we can assume that they were poorly cared for, since the median lifespan of the controls falls at the bottom of the expected range. Did I understand you?
Yes, exactly. It is a dirty secret of labs that an astonishing percentage of them take very poor care of their animals. There is the ordinary neglect, the “convenience” aspect where natual circadian rhythms are violated because lab techs or scientists have their human schedules, but there is also poor feeding protocols, cage proximities causing high levels of stress and every kind of random negative. And then folks do studies and publish results from these subpar labs, the value of which is a confounded unknown. As a result for those in the field, there are reputations, and some labs have poor reputations and some good.
This 900 day rule btw. has very profound implications beyond those that people think of immediately. For example, a frequent argument people raise against, say, CR, is that “how do you know it’s the low calories doing the work and not the animals consuming less of a poor/bad diet, not exercising in a cage etc.” How indeed? Well, if the strain lives max livespan of 850-950 days, and we have no examples of spontaneous 1200 day mouse, and that is with an endless variety of diet and exercise as optimal as has ever been devised, then if your control mouse lives to 900, clearly it did not have a life-shortening bad diet and husbandry - it lived its max for the species. So that objection dies. That’s important. Meanwhile if your mouse cohort dies out at 800 or below, something went wrong, and your results are sus, and in longevity research are outright disqualifying - don’t publish those.
Meanwhile we should pause in a one minute reverent awe at the wisdom of the ITP design by Richard Miller. They use a heterogenous mix of genetics in their mice, so you don’t have odd genetics that might impact a drug, because it just so happens that a given strain of inbred mice react strangely to a particular drug. And the vast majority of labs use single strain inbred mice in any given trial… makes life easier… and is substandard. And the ITP account for lab variability by running the same intervention in three different labs simultaneously, for possible unknown lab variables. Now, that is a solidly run trial. Which is why an ITP result is treated with so much respect. Of course in a perfect world every trial design would look like the ITP design, but alas.