The idea that stem cells will be used to rejuvenate aged bodies shows signs of becoming the conventional wisdom among stem cell researchers. Writing in the journal EMRO reports of the European Molecular Biology Organization two recent articles address this prospect. First, researcher Nadia Rosenthal examines "Youthful prospects for human stem-cell therapy" for both disease prevention and life extension.
It is the year 2053. A mere century after James Watson and Francis Crick resolved the structure of DNA, scientists at the forefront of medical research have just announced the first successful regeneration of a human heart. After re-routing the blood of Jón Sigurdsson, a terminal heart-failure patient, to an advanced cardiac assist device and removing most of the damaged organ, doctors thawed a frozen tube of Jón's personalized stem cells—established in 2013 from embryonic stem cells created through somatic nuclear transfer—and injected them into his chest. Thanks to a sophisticated cocktail of growth factors, the new stem cells target the damaged area and rapidly get to work, perfectly rebuilding a youthful heart. Several weeks later, Jón is discharged in excellent health. Regenerative medicine provided him with a new kidney ten years ago, and subsequent double knee regeneration gave him renewed mobility. Now his new heart will soon have him running a six-minute mile again. Jón Sigurdsson is 100 years old.
Rosenthal foresees a future in which stem cell-based therapies rejuvenate aged parts of the body and allow much longer lifespans. Stem cell research seems inevitably to lead to such thoughts. Stem cell researchers want to develop youthful, genetically undamaged, and flexible stem cells. Once they accomplish this for a wide range of stem cell types it is hard to avoid the conclusion that many parts of the body could be repaired by sending in youthful cells to gradually replace the old cells. She even discusses the future use of stem cells to dissolve scar tissue and build new 3 dimensional scaffolding for tissue types which have suffered decay in larger scale structures.
Most of the rest of the article is a tour through recent advances in stem cell research and what they portend
Reproductive cloning is not envisioned in humans, but the lessons learned from cloned animals may be important for therapeutic applications of nuclear transfer. Large deletions involving millions of base pairs have been found in ageing post-mitotic tissues, such as the heart (Vijg, 2004), thus removing large numbers of genes, which leads to cellular degeneration. If such defective nuclei from senescent tissue were used to generate personalized stem cells for therapy, they could cause more harm than good. Moreover, nuclei from patients with inherited diseases, such as haemophilia or muscular dystrophy, may first need to be manipulated to correct the genetic defect before they can be used in clinical settings.
Such a transfer, with subsequent manipulation of genes in human ES cells using human viral vectors and other techniques, could be used on aged nuclei to avoid creating stem cells with dangerous mutations. Any strategy for introducing genetic changes must be applied with care, however, due to the possibility of these genes randomly integrating into the host genome, causing even more serious mutations. To circumvent this danger, techniques for gene-specific modifications that are routinely performed in mouse ES cells have recently been applied to human ES cells, thereby providing the opportunity to correct genetic mutations in stem cells derived from nuclear transfer before administering them to patients.
Adult stem cells are being found an increasing number of locations the human body and in other mammals. At the same time, the tools we have for identifying adult stem cells still leave much to be desired.
In parallel with studies on ES cells, a concerted search for similar adult stem-cell lineages has yielded a flood of recent publications. These challenge the classical concept that stem cells in the adult are present in only a few locations, such as the skin or bone marrow, and are committed to differentiate into the tissue in which they reside. Nevertheless, rigorous criteria are required to distinguish an adult stem cell from partially committed cells with limited potential. True stem cells are self-renewing during the lifetime of an organism and they undergo asymmetric division, so that one daughter cell maintains the stem-cell lineage while the other daughter cell matures into a specialized cell type. The criteria for defining stem cells in the adult are still difficult to satisfy experimentally. There is no predictable location for stem cells in most adult tissues, and we still have only limited tools for identifying them.
For purposes of regeneration we need to know a lot more about adult stem cells. Most obviously adult stem cells are an important source of cells for use in regeneration therapies. However, less obviously, we need to know all the types of adult stem cells and all their locations in the body in order to develop and deliver youthful replacement adult stem cells into all the reservoirs that hold them. Therefore we absolutely need to delineate all the differences between the many different kinds of adult stem cells.
The emotional political debate about the limitations and advantages of embryonic stem cells versus adult stem cells and ethical arguments about embryonic stem cells tend to distract attention from the fact that we need to solve many problems in adult stem cell manipulation. Regardless of how replacement stem cells are made they have to get converted into the various adult stem cell types in order to replace aged stem cells of each type with more youthful cells. Well, how to create adult stem cells of each needed type? How to grow them in sufficient number? How to cheaply and easily test to know that a conversion to a needed cell type succeeded? Then the created cells must get delivered to all the many (and probably mostly still undiscovered) stem cell reservoirs in the adult body. How to get stem cells to go just where we want them to go? Will they have affinity for their natural habitats? Or will they require methods of injection or ways to tag them to give them affinity for the desired target areas? All these problems need solutions.
We need many new technologies to make manipulation of all stem cell types easier. We need automated ways to separate out the many stem cell types from other cell types and to nurture and grow them. We need ways to rejuvenate stem cells. Stem cell research does not exist in a vacuum separate from other avenues of advance in biological sciences and biotechnology. We need advances in DNA sequencing technology to make it cheap and easy to test the DNA of stem cell lines for correctness and completeness. We need gene therapy techniques that can repair and improve the genome of stem cell lines.
Rosenthal's article reviews many recent reports on adult and embryonic stem cell research. In is worth reading in full.
Another article in EMRO reports by Anthony D. Ho, Wolfgang Wagner & Ulrich Mahlknecht of the University of Heidelberg, Germany is entitled "Stem cells and ageing" with the provocative subtitle "The potential of stem cells to overcome age-related deteriorations of the body in regenerative medicine".
Although the vulnerability to infectious disease and cancer is caused by a decline of the immune system, the latter is in turn a product of interactions among haematopoietic stem cells and the microenvironments in the bone marrow and the thymus, as well as in the mucous lining of the bronchus and gut systems. Hence, all ageing phenomena—tissue deterioration, cancer and propensity to infections—can be interpreted as signs of ageing at the level of somatic stem cells. As the regenerative prowess of a living organism is determined by the ability and potential of its stem cells to replace damaged tissue or worn-out cells, a living organism is therefore as old as its stem cells.
These researchers outline a number of technical obstacles which make identification and study of non-embryonic stem cells difficult.
Lab tests which can measure a stem cell line's regenerative potential are needed.
Furthermore, by contrast to ESCs, which can be derived from cell lines established from 4- to 7-day-old embryos, somatic stem cells are elusive. The need for in vitro assays to identify human haematopoietic progenitors increased with the advent of haematopoietic tissue transplantation to treat leukaemia. Any assay to measure stem cells must compare the properties of the cells analysed in vitro with those of repopulating units tested in vivo after a lethal dose of irradiation—an experimental approach that is obviously not possible in humans (Ho & Punzel, 2003).
The problem with stem cells in older bodies does not appear to be so much diminished numbers as diminished abilities in those stem cells which remain.
Various studies have indicated that even though similar HSC concentrations could be found in young and old bone marrow, it is the functional ability per cell in the repopulation model that shows a significant reduction with increasing donor age. HSC senescence is regulated by several genetic elements mapped to specific chromocytes (Chen, 2004). These elements may differ among species, strains and even individuals in the mouse model. In humans, HSC senescence and related pathological effects might not be as obvious as in the mouse model because individual primitive HSC clones can produce progeny that sustain life-long mature blood cell production, which is especially obvious after bone marrow or HSC transplantation.
The older the donor of bone marrow cells for transplantation (e.g. for leukemia) the worst the chances of success.
The success of any bone marrow transplantation correlates with the quantity of HSCs in the graft, which are able to reconstitute the blood and immune system after myeloablation. On the basis of our extensive experience in HSC transplantation since 1984, we have found that age represents the main variable and worst prognostic factor for clinical outcome of transplantation. Recent evidence indicates that there is a decline with age in the quantity and quality of the CD34+ cells harvested. There is also a change in the ratio of fat to cellular bone marrow with age, which has been well known since the turn of the twentieth century. One way to overcome this problem would be to expand the human HSC population ex vivo before transplantation. There have been numerous such attempts, but progenitors with self-renewal capacity are very demanding. Reports of successful expansion of HSCs derived from human marrow in the laboratory have thus far been controversial. By contrast, CD34+ cells derived from umbilical cord blood have been shown to be expandable to a limited extent, which is another indication that the potency of HSCs declines with ontogenic age.
As we age we all would benefit from infusions of youthful stem cells carefully selected to have few DNA mutations. We'd gain stronger immune systems, less risk of anemia, and probably stronger bones as well. More generally, the development of genetically sound and youthful stem cells for all the stem cell reservoirs of the body would partially reverse aging and substantially increase life expectancies.
|Share |||Randall Parker, 2005 August 10 06:12 PM Aging Reversal|