New update of Aubrey de Grey’s great longevity study (RMR 1). The goal with the RMR 1 study is to extend maximum lifespan in middle-aged mice by combining different longevity interventions with each other.
The toplist is sorted by what works best in both genders and I will update the list as new data is presented every month. Here is my takeaway on the latest data that has been published.
Rapamycin seems to still have a key role in the different cocktails on the list. The big question is why is Rapamycin no longer extending lifespan in male mice? The results show even a slight lower effect than none treatment mice. This is an important thing to investigate further to see if new interesting insights around Rapamycin can be done here. One interesting thing to look at is if the cause of death differs between the Rapamycin and control group. Has for example some specific type of disease increased in the Rapamycin group?
I looked a bit quickly at the research around Rapamycin in the mice strain which is used in the RMR1 study and it does not exist much on that (pubmed: 37142830). This makes me wonder if the dose of Rapamycin may be too high or too low for the male mice.
There are many different things that can play in here and does anyone else have any thoughts around this
I think we have identified a) the key mechanism through which Rapamycin extends lifespans and b) those which are harmful
a) Is improving mitchondrial efficiency
b) Is reducing cell division and renewal through stem cells. (be they WBC, RBC, nail or other stem cells).
This is all dose and timing dependent. I wonder whether they are cycling rapamycin or doing daily dosing and what the human equivalent doses are.
If you stop cell division that will harm the creature. There will, therefore, be thresholds.
I have looked this up:
Design : Mice in treatment groups will receive 42ppm Eudragit S100 enteric-coated rapamycin in chow (Purina 5LG6), using the same encapsulation provider and formulary as ITP studies. Food will not be irradiated. We have selected oral delivery in chow over other delivery methods in order to be minimally invasive and so that the drug can be administered continuously.
A dose of 42ppm has been chosen on the basis of sex-specific dose effects [PMID 33145977], particularly the observation that male mice receive minimal or no benefit from lower doses of 14ppm [PMID 24341993], and higher doses have not shown any detrimental effects.
I don’t know how that compares to a human dose, but it is not cycled.
When you say we have identified, can you elaborate on that more. Are you refering to the discussions here or to research studies? If it’s discussions here I would be more humble around that we have identified something. Curious to hear more on this
I think comments on here which are underpinned by research (as the above two are) are reliable.
When we have discussed these I have found the relevant original research. I accept that my hypothesis about the mechanisms of aging is my original work and although it has been published in various places it has not appeared in a journal. However, it is underpinned by the literature (and research I have done myself).
Taking, however, the two points above:
Rapamycin
a) Is improving mitchondrial efficiency
b) Is reducing cell division and renewal through stem cells. (be they WBC, RBC, nail or other stem cells).
I would call it a interesting hypothesis to test and do studies around. Would be very interesting to see some kind of clinical trial around these areas.
Time for an update of Aubrey de Grey’s great longevity study (RMR 1). The main goal with the RMR study design is to speed up the discovery of interventions that increase both median and maximum lifespan with at least 40% in middle-aged mice.
The below toplist is sorted by what works best in both genders and I will update the list as new data is presented. Here are my two takeaways on the latest data that was recently published.
Most likely the discovery that will have the best lifespan effect will be a combination of different interventions. Even if a future RMR iteration will discover a single intervention which shows really good lifespan effects I think there will be a potential to improve that effect with a combinational approach in some way. My guess is that Aubrey has similar thoughts because of how the RMR studies are designed.
The current RMR data point towards that Rapamycin is currently an interesting intervention for male mice to enhance efficiency when it is combined with other interventions. When it comes to female mice then Rapamycin as a single intervention works as good as the top two combinations.
One interesting side note is that when I was at the Longevity Fellowship Biotech (LBF) camp no in May I listened to a great talk by Caitlin Lewis about the RMR study and her work with it. She showed some very interesting pictures of both mice with and without interventions. The control mice looked really old. One interesting thing was that the Rapamycin mice were obese. She also mentioned that the male mice also had higher glucose levels. But despite these conditions the mice lived longer. In the next RMR iteration they will see if they can minimize these conditions.
If you look at row 4 then without senolytics you have a slightly better results in males than row 1 when all interventions are combined. So based on this study with that specific senolytic and dose protocol the data is not impressive.
Navitoclax is I think clearly a senolytic. It is not an HDAC inhibitor (which I think are senomorphic). My preferred hypothesis for the majority of senescent cells is that they are stuck in the process of differentiation. I think the body needs them to be differentiated.
Hence considering Navitoclax as equivalent to an HDAC inhibitor is IMO a mistake
The original study plan indicates these groups (male animals, positive treatment) are less than 25 animals? I haven’t run the numbers, but it seems likely that with all the comparisons some differences would happen by chance. I assume they haven’t published a statistical analysis yet?
I would call it a interesting hypothesis to test and do studies around. Would be very interesting to see some kind of clinical trial around these areas.