On Rejuvenation of Muscle Stem Cell Function
This review looks at a range of investigations into the effects of aging on stem cell populations supporting muscle tissue, and various attempts to restore those populations to active duty. Stem cell populations decline with age, becoming less active and more damaged. In recent years, researchers have demonstrated that a variety of approaches can be used to instruct dormant stem cells to be more active: stem cell transplants, altered GDF11 signaling, and so forth.
Elderly humans gradually lose strength and the capacity to repair skeletal muscle. Skeletal muscle repair requires functional skeletal muscle stem (satellite) and progenitor cells (SMSCs). Diminished stem cell numbers and increased dysfunction correlate with the observed gradual loss of strength during aging. Recent reports attribute the loss of stem cell numbers and function to either increased entry into a pre-senescent state or the loss of self-renewal capacity due to an inability to maintain quiescence resulting in stem cell exhaustion.Earlier work has shown that exposure to factors from blood of young animals and other treatments could restore SMSC function. However, cells in the pre-senescent state are refractory to the beneficial effects of being transplanted into a young environment. Entry into the pre-senescent state results from loss of autophagy, leading to increased reactive oxygen species (ROS) and epigenetic modification at the CDKN2A locus due to decreased H2Aub, up-regulating cell senescence biomarker p16ink4a. However, the pre-senescent SMSCs can be rejuvenated by agents that stimulate autophagy, such as the mTOR inhibitor rapamycin. Autophagy plays a critical role in SMSC homeostasis. These results have implications for the development of senolytic therapies that attempt to destroy p16ink4a expressing cells, since such therapies would also destroy a reservoir of potentially rescuable regenerative stem cells.
Other work suggests that in humans loss of SMSC self-renewal capacity is primarily due to decreased expression of sprouty1. DNA hypomethylation at the SPRY1 gene locus down regulates sprouty1, causing inability to maintain quiescence and eventual exhaustion of the stem cell population. A unifying hypothesis posits that in aging humans, first loss of quiescence occurs, depleting the stem cell population, but that remaining SMSCs are increasingly subject to pre-senescence in the very old.
"These results have implications for the development of senolytic therapies that attempt to destroy p16ink4a expressing cells, since such therapies would also destroy a reservoir of potentially rescuable regenerative stem cells."
This is the other side of the Senolytic coin and is exactly why MMTP wants to combined Senolytics followed with stem cell replacement shortly after. This is our ultimate plan once we conclude our senolytic study and the effects of that on stem cells.
Michael Fossell also recently suggested on singularity 1 on 1 that Senolytics was not a good idea but to my mind removing the SASP and inhibiting factors therein would be a good thing.
I would be interested to hear Michael's thoughts on this counter argument to the SENS proposal of clearing out these cells?
It would seem a particularly good idea to use Senolytics then follow up with Stem Cell therapy to replace loses too. Aubrey indeed seemed quite keen on this idea.
And I mean Michael from SENS not Fossell! Too many Michaels!
The concern is potentially legitimate, but is premised on a false dilemma. We don't and shouldn't have to choose between ablating senescent cells to protect ourselves from the SASP, vs. holding on to damaged cells in hopes of forcing those cells to re-enter the cell cycle: we can happily purge the dead wood away and then use cell therapy to replace ablated muscle stem cells with pristine new ones (and I mean here true cell replacement therapy, not infusion of generic, non-replacing bone marrow-derived stem cells and suchlike). This is why both interventions have always been central to the SENS platform of rejuvenation biotechnologies. This includes replenishment of muscle stem cells, whether they are lost by injury, age-related attrition, or conversion into senescence.
It's worth noting, in any case, that all the evidence of restored muscle stem cell function in aging mice via such metabolic jiggery-pokery - whether via parabiosis, or pharmacological inhibition of p38α/β MAPK, or the disputed GDF-11 findings, or oxytocin, or whatever - comes from studies in "younger-old" mice (18-22 mo old) - or 24 mo old ones, if you're willing to grasp at the most elaborate metabolic mousetrap (muscle stem cell biopsy, followed by small-molecule p38α/β MAPK inhibition, followed by exposure to an actual or simulated young niche, followed by re-transplantation).
By contrast, such interventions fail in truly old (28-32 mo) mice's muscle stem cells once they have suffered sufficient DNA damage to progressed into a state of truly irreversible sensescence ("geroconversion"), making the point ultimately moot.
And, of course, manipulating the senescence machinery to restore cell proliferation in cells whose proliferation has been shut down by programming intended to protect the body from cancer is itself a tradeoff, and an even more foolish one. Remove the damaged cells and then replace them with pristine, youthful ones.