Aubrey De Grey has announced more details on the Robust Mouse Rejuvenation project that his new foundation is launching in the new year. I covered this initially in the report back from the Longevity Summit the other week, but this goes into much more detail on the plan:
LEV Foundation’s flagship research program is a sequence of large mouse lifespan studies, each involving the administration of (various subsets of) at least four interventions that have, individually, shown promise in others’ hands in extending mean and maximum mouse lifespan and healthspan.
We focus on interventions that have shown efficacy when begun only after the mice have reached half their typical life expectancy, and mostly on those that specifically repair some category of accumulating, eventually pathogenic, molecular or cellular damage. The first study in this program is starting in January 2023.
I was talking to a father of another child at my son’s school who is a molecular biologist and he said that if I did a pHD at his University I could experiment on mice and not have to experiment on myself. I found this odd because I wanted to be healthy myself rather than have a lot of healthy mice as pets.
I do understand the logic of what is done with these experiments, but the advantage of biohacking is that I can change the protocol on a daily basis. What I do is a bit like debugging a computer and I adjust the inputs
a) To work out what causes particular outcomes
b) To achieve the outcomes I wish to see.
It is difficult because there are lots of variables, but it works.
But sometimes it takes a long time to see the results… Both positive and negative. If you are the mouse and you make a mistake…
Better to try things on a mouse… Or a thousand of them. Once you know it works, then try it on yourself. Too many theories are wrong and may be dangerous.
Rapamycin has been we’ll tested on many model organisms, so that’s why I will try it and anything else that science shows is safe and beneficial.
I am actually quite cautious and I study the previous research quite assiduously. However, there is actually quite a lot of research out there and there are ways of seeing objective measurable changes in reasonably short timescales.
My concern before I try something is that it should not do harm. It remains that there are questions and I have had side effects even from things like vitamins B6 and D3.
I was experimenting with cholecalciferol and I took 12,000 and 24,000 iu (on two separate occasions. This disrupted my sleep for a day or so. In fact even 6,000 was a bit high. Hence I have obtained some 25OHD (Dedrogyl) and I use that to bring my D3 up every so often. On a daily basis I take 3,000 which I find my body can process without side effects. My initial conclusion is that cholecalciferol itself is mildly toxic until processed into 25OHD.
The background is that I wanted to get an idea as to how quickly my body converts large doses of cholecalciferol into 25OHD and how long the benefit lasted (which I measured by the impact on my sleep).
Why such a high dose?
I’ve received my rapamycin today and it came with a vitamin d3 ‘Bomb’ cholecalcierol sixty thousand iu
is this to boost immunity whilst on rapa?
The reason I took 12,000 and 24,000 was to see what happened. I think of the metabolism as a system in flux rather than something static. To me it is obvious that there would be a limit on processing from D3 into 25OHD. I wanted to see what that limit was.
I am continually experimenting with all sorts of metabolic processes.
I do check first that it is unlikely that any serious harm will be done, but I don’t get stressed with side effects. I can always stop what I am doing.
I now have a good vitamin D protocol which enables me to keep my 25OHD levels up around the top of normal. If I stopped my weekly blood tests I would have some idea what to do to achieve that.
Looks like HSCs work much better with males than with females. But it definitely very reassuring that “all” works the best for both.
Aubrey in his interviews mentioned the costs of the experiment, but I’ve forgotten. Do you know by any chance?
Am I misunderstanding or is HSCs just straight up infusing stem cells into the mouse? I’m shocked that is doing anything at all, much less going head to head with rapamycin.
Rationale: A reduced regenerative capacity of stem cells is widely believed to contribute to age-related morbidity and functional tissue decline. Numerous studies have shown stem cell transplantation to have rejuvenating effects in mouse tissues, and several additionally show a lifespan extension effect [PMID 32012439, 31031800].
Design: The study design is largely (but see below) based on the protocol utilized by Guderyon et al. 2020 [PMID 32012439] and consists of mobilizing the recipient bone marrow niche followed by transplant of lineage-depleted hematopoietic stem cells (HSCT).
Bone Marrow: We have opted to use lineage-depleted bone marrow HSCs as opposed to additional selection for and expansion of long-term self-renewing HSCs. This was on the basis that 1) prior lifespan studies used whole or lineage-depleted bone marrow, which may include MSCs or other beneficial cells promoting engraftment, and 2) expansion protocols have not been extensively validated.
Mobilization Protocol: We will follow the mobilization protocol for recipient mice as outlined in Guderyon 2020, consisting of G-CSF + AMD3100. Although other newer mobilization reagents require fewer injections, efficacy is not well established; the current protocol is most common for chemical mobilization, has been used in aged mice, and remains the current standard of care for mobilizing HSCs from human BM donors.
# of cells: Each administration will consist of ~2x10⁷ HSCs, derived from 8 sex-matched C57Bl/6J PEP-BOY (CD45.2) donor mice per injection. This number is four-fold greater than the Guderyon study, however in line with other HSCT studies [PMID 31031800, 18491294]. Additionally, it is demonstrated that % donor cell engraftment is largely based on competition with mobilized recipient cells; thus, increasing the donor to recipient ratio in the blood may allow for increased engraftment with each administration allowing for fewer transplants overall and thus less stress on the animals.
Number of Transplant Injections: While the lifespan cohort of the Guderyon study received a total of 8 HSCTs, each round administered only 5x10⁶ lineage-negative (long-term repopulating) donor cells. We wish to minimize the number of administrations for each mouse. Therefore, we will perform 2 rounds of HSCT, a month apart, and then assess the % donor-derived cells (CD45.2) in peripheral blood after 4-8 weeks (timing to coincide with planned blood draw). Whether or not additional rounds of HSCT are performed (for a given experimental group) will be decided based on percentage engraftment in recipient mice.
