Bone Marrow Transplant from Young to Old Mice Extends Remaining Life Span
Here, researchers report on the results of transplanting cells from young bone marrow into old mice. The bone marrow came from genetically identical young mice, so there was no risk of rejection. Unlike the usual process for bone marrow transplants, there was no ablative chemotherapy to kill existing stem cells. This strategy led to a high degree of integration of young stem cells into the aged bone marrow, with cells of young origin making up a quarter of the bone marrow by the end of the study. This sizable integration is likely because old bone marrow has much smaller active stem cell populations, and thus their comparatively feeble efforts to produce daughter cells were outpaced by the activities of the transplanted cells.
As a result of this procedure, the maximum life span of the aged mice population was extended by nearly 30%. We can envisage many mechanisms by which this improvement can occur, such as greater production of immune cells, leading to a more active and competent immune system, or improved systemic signaling that may affect all organs, not just the bone marrow. The authors of the paper use these results to argue for the adoption of a similar therapy for old human patients, bone marrow transplantation without the ablative chemotherapy that characterizes its usual use in cancer patients, in order to achieve some degree of rejuvenation of tissue and immune system.
Increase in maximum lifespan (MLS) is the most significant indicator of hitting the basic mechanisms of aging, in particular, regarding age-related loss of stem cells and cell damage accumulation. In this study, a significant (30%) increase in maximum lifespan of mice was found after nonablative transplantation of 100 million nucleated bone marrow (BM) cells from young donors, initiated at the age that is equivalent to 75 years for humans. Moreover, rejuvenation was accompanied by a high degree of BM chimerism for the nonablative approach. Six months after the transplantation, 28% of recipients' BM cells were of donor origin. The relatively high chimerism efficiency that we found is most likely due to the advanced age of our recipients having a depleted BM pool.
In addition to the higher incorporation rates, there are more reasons why the nonablative setting is preferable for old recipients. These are lesser risks of infections and of graft-vs-host disease, threatening to ablated patients, while graft rejection by nonablated recipients is less probable in the elderly than at a younger age because of naturally weaker immune system in the elderly. Even in the absence of histocompatibility, when allogeneic BM was used in a nonablative experiment instead of syngeneic BM, no lifespan shortening of the experimental group was observed.
Obviously, at an old age the immune system is already too passive to reject donor BM, but it still efficiently suppresses infection and graft-vs.-host reaction, which makes it unnecessary and undesirable to use ablative conditioning in the elderly. On the bases of the above and our data, we advocate a more rapid implementation of nonablative stem cell transplantation into the clinic not only for pathology treatment, but also for rejuvenation.
This is a pretty big deal if it means we no longer need to kill existing bone marrow stem cells before implantation. The ablative treatment is the biggest risk for elderly patients.
Longest lived control lived 19.3 months. Something wrong with those mice.
@Mark
Correct. The ablation is a nasty stuff. Probably still can do a partial ablation of there bc is some autoimmune disease, though.
Now the question is how well it will translate to humans....
@ale
Yeah, could be an issue with the population size. But probably we can look for some sort term improvements that don't require a longevity study. Those by definition take a long time
Using donated BMSCs looks like a stretch to me. But wth partial epigentic reprogramming it may be possible to generate younger BMSCs from the patients own tissue, perhaps eventually in vivo.
Combined with Repair Biotechnologies thymus rejuvenation using FOXN1 and possibly 3D printed lymph nodes and perhiperal T and B cell abaltion, older patients could get something approaching a fully rejuvenated immune system, which could massively cut rates of cancer.
It would be interesting to see the competition dynamics for example in myleofibrosis for young mesenchymal stem cells vs the fibrotic cells that outcompete old MSCs.
We do not see those kinds of effects in human subjects post BMT, even with reduced conditioning protocols. So either ablation damage supersedes the rejuvenation effects from the younger bone marrow, or this mechanism is not active in humans
Treatment for graft versus host disease using stem cells already does this - no need for 100 % ablation of the BM before administration - can do a partial ablation - could be done serially for relatively gentle treatment of tbe very elderly.
Use allogeneic cells - cheaper and less bother.
30% is quite a result, and it is a non-metabolic treatment, so we have a shot at seeing improvements in longer lived animals, like ourselves. But Ale pointed out the controls died early, which makes makes the results more questionable. 19.3 months for the longest lived mouse. How long do they usually live?
B10 mice usually live ~700 days
https://mazeengineers.com/c57bl-10j-mouse-strain/
@ Gregory 'We do not see those kinds of effects in human subjects post BMT, even with reduced conditioning protocols' - how do you know?
To my knowledge no study has been done to this effect; current treatments presumably do reduce mortality due to the specific disease the the BMT is addressing, and such effects would be hard to unpick from the proposed anti-aging effect.