Stem Cells Age as Well
Today I thought I'd point out an interesting post from the Buck Institute team on the topic of stem cell aging. The good news here is that the characteristic age-related decline of stem cell function is an issue that the research community has to engage with on the way to developing effective treatments based on their work. It is unavoidable: the majority of regenerative medicine based on the use of stem cells is most applicable to age-related diseases, yet the old and damaged tissue environment disrupts stem cell activity.
What happens to adult stem cells as a person ages? Can they always maintain their regenerative capacity? The answer is no. Adult stem cells maintain tissue homeostasis and differentiate into the cell types that make up the tissue in which they reside, however these processes become less efficient over time. Adult stem cell dysfunction caused by aging has been reported in many organ systems including the heart, muscle, and bone marrow. Some adult stem cell populations like neural stem cells in the brain and melanocyte stem cells in hair follicles actually decline with age. Both adult stem cell dysfunction and a decline in number translate to a reduced regenerative response to tissue or age-related damage.
A few of the culprits: DNA damage occurs in aging stem cells over time because of factors present inside and outside of the cells and because of exposure to genotoxic stress (chemical factors that cause genetic mutations). The machinery that repairs DNA in older stem cells does not function as precisely, and this can cause genomic instability, cell death, or even cancer if a person is really unlucky. Cellular senescence is a term that refers to cells that have entered a state where they can no longer proliferate and divide. Senescence occurs in older stem cells because of elevated cellular stress. Senescent stem cells are bad news because they secrete factors that can cause inflammation and stem cell dysfunction, which further exacerbates symptoms of aging and disease. Then there is mitochondrial dysfunction. Mitochondria are the batteries that power our cells. Mitochondria have their own genome, and in aging stem cells, mitochondrial DNA can be damaged, which impairs mitochondrial function and consequently, adult stem cell function.
So how do we solve the problem of aging stem cells? One obvious approach is to rejuvenate adult stem cells by preventing DNA damage, cellular senescence, and mitochondrial dysfunction. Another strategy is to transplant healthy adult stem cells from a donor into a patient with disease or damaged tissue. However, the issue with adult stem cell transplantation is that the environment (called the niche) into which you transplant healthy stem cells may contain toxic factors (caused by disease or damage) that will kill off the newly transplanted stem cells or impair their function. Thus, a better approach would be to fix or reverse aging phenotypes in the surviving stem cells and other mature cells in that niche, and then transplant healthy donor stem cells into a rejuvenated, healthy environment.
One last thing to consider as one addresses the aging adult stem cell issue is when to intervene therapeutically. Trying to restore adult stem cell function in already diseased or older tissue might not be as effective as preventing damage from accumulating in the same stem cells earlier in life. Prevention of stem cell aging would be a promising strategy to fight aging itself, but that would require the ability to predict or diagnose disease onset in healthy people, which is a huge and complicated endeavor.
Armstrong et al. (2014) suggests that stem cell aging might not be related to DNA damage and might be relatively easy to reverse (that is, stem cell decline might be more of a consequence of some uphill effects than a cause of aging):
"These data imply that the age-related decline in satellite cell function may not arise because of irreversible errors such as the accumulation of DNA damage but may be due to reversible epigenetic changes. Moreover, the satellite cell population shows little evidence of DNA damage accumulation in older animals. Enumeration of DSBs by detection of γH2A.X foci showed no differences between satellite cells of 4-month-old mice when compared with 24-month-old animals . In addition, SCID mice, which have well-characterized defects in DNA repair, have similar myogenic characteristics to non-SCID mice supporting the idea that DNA repair defects or accumulation of unrepaired DNA damage does not influence satellite cell function when the damage is restricted to the satellite cells. An alternative explanation for the effects of microenvironment on stem cell function could be the senescence-associated secretory phenotype [86, 87] in which the progressive accumulation of senescent cells within a tissue alters the microenvironment by secreting various factors such as interleukin-6. The regulation of senescent cell accumulation and impact upon the progression of an aged phenotype are not clear but published data suggest that that removal of senescent cells can prevent or delay tissue dysfunction . For these reasons, studying satellite cell function in mice derived from iPSC generated from truly aged HSC as proposed above will be a valuable and timely undertaking.
The rejuvenating effects of a young systemic environment do not appear to be restricted to the skeletal muscles. Neurogenesis is subject to an age-related decline in the murine central nervous system [89-91] but this seems to be partially rescued in heterochronic parabionts . Again, the decline in neurogenesis seems to be reversible by other factors since deletion of the Wnt antagonist Dkk1 (whose expression increases during normal ageing of the CNS)  can increase the self renewal of neural stem cells and contribute to improved spatial learning and memory in older mice, while increases in the level of the cytokine CCL11 in the blood of young mice are sufficient to reduce neurogenesis and CNS function. These observations appear to support an epigenetic contribution to ageing but at present there are insufficient data from which to draw clearer conclusions."
Elabd et al. showed that oxytocine could rejuvenate old muscle tissue, probably by rejuvenating the relevant stem cells:
"The regenerative capacity of skeletal muscle declines with age. Previous studies suggest that this process can be reversed by exposure to young circulation; however, systemic age-specific factors responsible for this phenomenon are largely unknown. Here we report that oxytocin—a hormone best known for its role in lactation, parturition and social behaviours—is required for proper muscle tissue regeneration and homeostasis, and that plasma levels of oxytocin decline with age. Inhibition of oxytocin signalling in young animals reduces muscle regeneration, whereas systemic administration of oxytocin rapidly improves muscle regeneration by enhancing aged muscle stem cell activation/proliferation through activation of the MAPK/ERK signalling pathway. We further show that the genetic lack of oxytocin does not cause a developmental defect in muscle but instead leads to premature sarcopenia. Considering that oxytocin is an FDA-approved drug, this work reveals a potential novel and safe way to combat or prevent skeletal muscle ageing."
I guess the big difference between this Buck author's view and that of the SENSRF is that DNA damage itself is an important cause of aging and further damage.
I guess that SENS would say that DNA damage is not important unless it results in cell death or senescence.
I think these are old arguments though and the quickest way to settle them would be to remove the 7 SENS classes of damage and see if aging still occurs. That seems far easier than maintaining and checking DNA integrity throughout an animals body over time.
Jim I actually think that is a great idea. Test the seven deadly SENS on some cells and see what happens. We are at a point where the differences between the programmed aging and the wear and tearers needs to be resolved so things can move forward.
Does anyone have a suggestion for an experimental protocal we can test to confirm SENS would lead to rejuvenation? ADG was recently saying in a recent paper that this difference of opinion needs resolving and Reason has said this before too. So is there some way this can be resolved? Things are occurring in the field which means its vital this is answered.
This is a very interesting article and I know that Irina and Michael Conboy are also working on the problem of the aged Stem cell niche inhibiting young Stem cells being transplanted to the body. I agree with Reason that this is a problem that needs dealing with irrespective of which aging camp you are in.
Could rejuvenation of the Stem cell niche represent a project that unifies the research community to work collaboratively? It certainly seems to be something that both programmed aging and damage camps both need to happen and a common ground to work from.
I'm curious as to whether Reason (or others reading this) think banking/freezing your stem cells in middle-age is worth it. You mentioned donor stem cells being transplanted from other people but nothing about possible rejection issues. I was just curious if rejection of transplanted stem cells is seen as a big hurdle in the field. If so, then banking seems reasonable.
@KC: I think not worth it. By the time you'd want them, decades from now, the state of technology will have advanced to the point at which they are useless and irrelevant in the context of therapies. You'll either get your own older stem cells rejuvenated outside the body before reintroduction or stem cell transplants in general will be superseded by means of reprogramming and repairing cells in situ.