There is an intriguing amount of evidence to suggest that the stem cells remaining in the tissues of old people are still quite capable. If removed from the old cellular environments, many aspects of their behavior become similar to those of the same type of stem cell taken from a younger individual, at least in some reports. There is a greater level of accumulated cellular damage in old stem cells, but much of the evidence suggests that this does not provide as great a contribution to degenerative aging as do diminished numbers and diminished activity. Stem cell activity in the old is much declined from youthful levels, as I'm sure regular readers know. This activity is necessary for the support of tissues, supplying replacement somatic cells and generating signals that adjust cell behavior. The loss of regenerative capacity and consequent slow failure of tissue function an important part of the processes of aging.
As to whether the principal problem is loss of stem cells or that the stem cells are present but become perpetually quiescent, the evidence is varied. The situation is probably different for different stem cell populations, and to muddy the waters further, these are most likely overlapping issues. The stem cell populations react to the aging of tissues, meaning the rising level of damage and the changing signal environment that results from that damage. This reaction may be to self-renew less readily, decreasing the size of the stem cell population, or to remain quiescent and inactive for ever longer periods, decreasing the number of active stem cells at any point in time. Or both. The consensus theory on this process is that it is a part of the evolved balance between aging and cancer. As damage grows, so too does cancer risk, and stem cell decline can serve to reduce cancer risk at the cost of a slower decline into frailty and death.
Whether old stem cells are inherently dysfunctional is a question of considerable relevance to the practical development of stem cell therapies. The present direction in therapies is to use a patient's own cells, to take existing stem cells to generate more of the same for transplant, or to use those stem cells to create differentiated cells and tissues, again for transplantation. If aged stem cells are inherently dysfunctional, that would greatly limit the ability to use this class of therapies for older people, those who most need such treatments. But if, as seems to be the case, old stem cells are still capable in and of themselves, then this approach to regenerative medicine for age-related disease has a brighter future. Of course, the influence of the aged tissue environment still means that a challenging problem must be to solve to build effective regenerative therapies for the old: how to ensure that the fate of transplanted cells isn't just a repeat of what has already happened to the native cell populations? The regenerative medicine industry has to grapple with the causes and mechanisms of aging in one way or another, given that the vast majority of patients are in fact old, and the state of their aged tissues impacts cell therapy effectiveness.
Stem cells are found not only in embryonic or fetal tissues but also in all adult tissues in relatively high numbers. These cells are committed to tissue repair throughout adult life. Although the number of cells and their capabilities decrease over time, rich stem cell niches remain such as bone marrow and adipose tissue. The observation that stem cells differentiate into several cell lineages reveals their potential for use in regenerative medicine. More importantly, stem cells harvested from adult tissue can be used for autologous transplantation and can also avoid immunological rejection. However, whether stem cells from elderly people have similar capabilities as those found in younger people is yet unknown. Some studies suggest that elderly people have fewer stem cells and that they have lost their capacity for growth and differentiation in vitro. Other evidence indicates that sufficient numbers of stem cells remain throughout adult life, providing an alternative for use in cell therapy.
Self-renewal in vitro is one of the main stem cell characteristics that occur after harvest. Healthy adult stem cells grown in vitro have a high proliferation capacity. However, stem cells from elderly subjects show less proliferation potential. Several studies have reported a decrease in the number of colony forming units in mesenchymal stem cell (MSC) cultures from donors aged ≥40 years. In vitro doubling times are longer in cells taken from elderly patients than those from younger donors and show a substantial decrease in proliferation rate. Similar observations have been reported for lipoaspirate samples obtained from adipose tissue. In vitro doubling times differ depending on donor age and are longer in those collected from older donors. The relationship between the decrease in number and functionality of stem cells could be a consequence of the loss of proper environmental signals. In addition, decreased telomere length and an increased rate of apoptosis and its signals have been reported in MSCs harvested from elderly donors. In addition, the definition of MSCs requires the presence of specific cell membrane antigens, as well as human leukocyte antigen class II. Until now, flow cytometry has been performed on MSCs from younger and elderly patients to confirm the presence or absence of these specific stem cell markers. The overall conclusions from these reports are that MSCs from elderly donors have less capability to grow.
Differential expression of stemness genes on MSCs from elderly donors may be ultimately responsible for the decline of the stem cell proliferation rate. Stemness genes characterized in bone marrow-derived stem cells from patients with amyotrophic lateral sclerosis (ALS) show decreased expression of two genes related with pluripotential for the transcription factors OCT4 and NANOG. In addition, decreased expression of trophic factors have been reported. Similar observations have been reported for adipose-derived stem cells (ADSCs) from healthy patients aged from 50 to 60 years. However, others have reported no difference in the expression of NANOG or OCT4 between MSCs isolated from the bone marrow of children and those obtained from adults. Despite these controversial reports, the general consensus supports that the expression of stemness genes is lower, but their activity is sufficient for growth and self-renewal.
Several studies have shown that healthy adult stem cells grown under specific culture conditions will differentiate into various cell lineages in vitro. The bone-forming capacity is similar in cells obtained from younger and older donors. One hypothesis proposes that the senescence-associated decrease in bone formation is due to a defect in the bone microenvironment. Chondrogenic differentiation is also controversial, as some studies have shown independent age-related responses or reduced capacity with age. Other stem cell sources, such as muscle-derived stem cells obtained from young (age 9 years) and old (age ≥60 years) humans, replicated 20- to 30-times in vitro and differentiated into different tissue lineages. These cells (satellite cells) are found in aged human skeletal muscle and are capable of regeneration. Stem cells from elderly donors do not have as much pluripotential as cells from younger donors. Nevertheless, these cells are capable of self-renewal and differentiation into osteoblasts, chondroblasts, adipocytes and other cell lineages.
Samples of pluripotent stem cells for autologous transplantation have been obtained from several tissues of differently aged donors. The most abundant and relatively accessible sources for adult stem cells are bone marrow, peripheral blood and adipose tissue. Samples from elderly people have been obtained, applied to autologous transplantation and have improved some degenerative diseases. The beneficial effects of autologous cell transplantation have been reported in patients with neurodegenerative diseases, including those performed on elderly patients. The stem cell subpopulations selected for treatment may have improved the outcomes. Several clinical trials have been performed on cardiomyopathies in patients greater than 50 years old. The most promising among those trials included infusion bone marrow-derived stem cells or MSCs from peripheral blood in patients suffering a myocardial infarction, in whom a moderate but significant improvement in left ventricular ejection volume was observed. There is no consensus about the best MSC subtype to treat ischemic heart disease. Nevertheless, all studies in this area have reported improved cardiac function after autologous MSC transplantation.
In summary, stem cells obtained from elderly patients retain pivotal membrane cell markers and have in vitro self-renewal and differentiation capabilities in adipocytes, osteoblasts and chondroblasts. In addition, stem cells from elderly patients express the transcription factors responsible for cell proliferation, such as SOX2, NANOG and OCT4. Some reports have indicated that these genes are expressed at lower levels in elderly subjects than stem cells obtained from younger donors. Nevertheless, the cells respond to induced differentiation as well as those obtained from younger donors. Several trials are currently being performed using autologous MSCs in elderly patients. Until more data are gathered indicating some beneficial effects, there is no consensus on the utility of stem cells as a gold standard treatment, but stem cells from elderly donors have similarly capabilities to growth and differentiation as younger donors.