There are 2 broad types of stem cells in our body: 1. embryonic stem cells (ESC) and 2. adult or somatic stem cells (SSC)– the undiffrentiated cells found in adult tissues. Embryonic stem cell is pluripotent meaning it can differentiate differentiate into any of the three germ layers: endoderm (interior stomach lining, gastrointestinal tract, the lungs), mesoderm (muscle, bone, blood, urogenital), or ectoderm (epidermal tissues and nervous system) while adult or somatic stem cells (and progenitor cells) is multipotent meaning it has the capacity to generate (all) the cell types of certain organ/tissue (blood, skin, intestnal tissues) from which they are derived through cell division, potentially regenerating the entire organ from a few cells. For example, hematopoietic cell — a blood stem cell can develop into several types of blood cell. Stem cells (and progenitor cells) functions as a repair system for the body, replenishing specialized cells/tissues, and also maintain the normal turnover of regenerative organs.

Then, how adult or somatic stem cell functionality is implicated in human aging or somatic cellular senescence? Recently more and more evidence suggests that the genetic and biochemical alterations in somatic stem cells and its decline in differentiation when we age contribute to the all ageing phenomena—tissue deterioration (reduced capacity to regenerate injured tissue), susceptibility to cancer and cardiovascular disease and increased propensity to infections. Major types of SSC includes: mesenchymal stem cells, neural stem cells, endothelial stem cells, dental pulp stem cells, and hematopoietic stem cells. SSCs are capable of differentiation to produce progenitor cells and then to normal somatic cells though they normally engage in cell division without cell differentiation. Under conditions of signaled stress such as injured tissue, SSCs will be triggered to produce a differentiated cell through signal transduction and then certain gene being turned on. At the same time, a copy of the SSC is also produced along with the new more-differentiated progenitor cell. The number of SSCs stays the same. However, with aging the population of adult stem cells declines and the rates of differentiation into somatic specialized cells also declines, thereby reduce our ability to replenish tissue cells.

Then, what are these genetic and biochemical changes causing SSC senescence and make them dysfunctional or defective in cell differentiation ? As a logical reasoning, the main causes of our normal cellular senescence should also apply to SSC (free radical, glycation, methylation, DNA damage or mutation, mitochondrial damage). In addition to these molecular changes, we will discuss 3 more biochemical and/or genetic changes which contribute to declined SSC differentiation function in aged humans. They are 1. shortened telomere length, 2. replicative senescence 3. certain tumor suppressive proteins, 4. DNA damage.

Telomere length shortening is one of the most important biomarkers of aging or cell senescence. Telomeres are non-coding regions at the tips of chromosomes. Its function is to cap the ends of chromosomes to prevent chromosome fusions. The correlation of telomere length shortening and aging/cell senescence lie in the fact that DNA polymerase (the enzyme responsible for DNA replication) could not fully synthesize the 3′ end of linear DNA known as the end-replication problem. This end-replication problem would result in telomere shortening with each round of replication and that this mechanism could be the cause of replicative senescence (RS) which means somatic (stem) cells can not divide indefinitely. Telomerase is a reverse-transcriptase enzyme that reverse transcribe RNA back to DNA at the tip of chromosone whose function is to elongate the telomeres and thus corrects the normal telomere shortening. In the bone marrow, hematopoietic cells express telomerase. Telomerase activity is higher in primitive progenitor cells and then downregulated during proliferation and differentiation. A decline in telomerase activity was reported in blood mononuclear cells with age. Therefore, somatic stem cell, though better than fully differentiated cells, also have a declining telomerase activity and hence shortening length of telomere with aging which in turn cause replicative senescence.

Replicative senescence refer to the aspect of cellular senescence in that cells can only divide finite number of times. This loss of division potential and the simultaneous change in morphology was termed replicative senescence, also known as hayflick limitation. For example, fibroblasts can only divide about 50 times over the life span. Unlike embryonic stem cells which has unlimited division potential, somatic stem cell has limited potential in division. Biomarkers of replicative senescence include: the most obvious biomarker is growth arrest, i.e., cells stop dividing), they are growth arrested in the transition from phase G1 to phase S of the cell cycle. This growth arrest is irreversible in the sense that growth factors cannot stimulate the cells to divide, even though senescent cells can remain metabolically active for long periods of time. Another important biomarker is cellular morphology. Other markers of cellular senescence include: abnormal behavior of enzyme β-galactosidase, increased percentage of polyploid cells–i.e., with three or more copies of chromosomes, increased mutations/deletions to the mitochondrial DNA (mtDNA), decreased ability to express heat shock proteins, the change of the expression levels of several genes, an increased activity of metalloproteinases, and shortened telomere length as described above. To wrap this paragraph up, when the somatic stem cell enters replicative or more broadly cell senescence stage, they can no longer divide and differentiate into progenitor and/or specialized cells to replenish damaged or dead cells and act as the components of tissue repair system.

Increased amounts of certain tumor-suppressor proteins in somatic stem cells is another cause for concern regarding the longevity of stem cells. A new line of research focuses on four genes implicated in both cancer and stem cell activation: Ink4a, Arf, Hmga2 and let-7b. P16/Ink4a, a tumor suppressor gene, appears to become increasingly active with age. It is a known mediator of cell senescence and biomarker of aging as well as a possible promoter of aging. P16/Ink4a works together with the three other genes to simultaneously protecting against cancers and shutting down adult stem cell’s regenerative capacity in aging tissues. Expression of Ink4a and Arf in the absence of a protein Bmi1 results in loss of self-renewing stem cells. The four genes appear to turn on and off in a coordinated way depending on age. Along with this and other parallel research a new concept is emerging: that age-related changes in the stem cells in many body organs may be responsible for deterioration and decline in functionality of those organs.

One experimental evidence that associates stem cell aging with DNA damage is the melanocyte stem cells (MSC). It is found that gray or white hair is due to age-related depletion of melanocytes which is a direct result of depletion of melanocyte stem-cells (MSCs). This depletion of MSC is the direct result of DNA damage. MSCs, living in hair follicles, can normally both reproduce new stem cells and differentiate into mature color-producing melanocytes. Experimentation suggests that DNA damage to MSCs causes them to stop reproducing and instead terminally differentiate into melanocytes. As the melanocytes in hair follicles die off, there are no new melanocytes to replace them when there are no more MSCs to make them.

In summary, the somatic stem cell theory of aging gains much attention in the scientific community recently. With aging the population of adult stem cells declines and the rates of differentiation into somatic specialized cells also declines, thereby reduce our ability to replenish tissue cells. (Somatic) stem cells have great potential and implications in regenerative medicines for treating age-related deteriorations.

Classical stem cell therapies based on using other people’s bone marrow stem cells for treatment of leukemia has been in routine use today. The more practical approach to stem cell therapy is to reintroduce autologous (a patient’s own) somatic stem cells back into the body to avoid problems of immune system rejection encountered when other people’s stem cells are used.

It may still a long way to go before good news for longevity treatment using SSC since there are reports of failure and cancer development in patients who was subject to stem cell therapies in clinical trials. However, small-scale experiments are beginning to show the power and potential of this simple, inexpensive and non-invasive techniques to clear up formerly intractable diseases.