Robert Pappas is an independent filmmaker currently in the final stage of updating his film To Age or Not to Age. This is a film on longevity research featuring interviews with prominent researchers. Two days ago, Robert asked me to generate a short presentation on my own pet theory for extraordinary longevity for inclusion in the film. This is the Closing the loop in the stem cell supply chain theory described in the blog entries The stem cell supply chain – closing the loop for very long lives , Progress in closing the stem cell supply chain loop, and mentioned in several others. The presentation had to be simple and suitable for non-technical viewers and was needed immediately. It will be shown on Dish TV and will likely be exposed to a couple of million viewers. I prepared the presentation yesterday and for that purpose I created two explanatory graphics. For the benefit of my less-technical readers I present the graphics and more or less the same explanation here, though not quite as simplified for the film and with some hyperlinked references.
Normal Progression of Cell Types
The first diagram is a simplified explanation of how cells relate to one another in the course of a normal lifetime. At CONCEPTION of fertilization (upper left corner) the GERMLINE CELLS, sperm from father and egg from mother come together to form an embryo containing at a very early stage EMBRYONIC STEM CELLS. These are pluripotent cells, which means they are capable of eventually differentiating into all of the body’s some 200 different types of cells (blood cells, nerve cells, heart cells, skin cells, etc.). During EMBRYONIC DEVELOPMENT this cell differentiation occurs. In this simplified description three categories of cells are produced: ADULT STEM CELLS, PROGENITOR CELLS and SOMATIC BODY CELLS. These categories of cells will be around the rest of our lives although the specific cells in them will continue to change due to cell division, cell death and, except for adult stem cells, cell replacement.
SOMATIC BODY CELLS for the purpose of this presentation are the working cells of the body: neurons, glia, red blood cells, immune system cells, muscle cells, skin cells, liver cells, thyroid epithelial cells, heart cells, etc. etc. – excluding stem and progenitor cells.
ADULT STEM CELLS can differentiate on an as-needed basis to make replacement SOMATIC BODY CELLS or PROGENITOR CELLS, and they do this throughout a lifetime. ADULT STEM CELLS come in different varieties, such as hematopoietic stem cells which are found in the bone marrow and give rise to all the blood cell types and neural stem cells which give birth to new neurons in the brain and other parts of the body and other related nerve-associated cells like astrocytes and oligodendrocytes. Typically, ADULT STEM CELLS in any category can differentiate into a limited number of target BODY SOMATIC CELL types. They divide like all other cell types and can also morph into PROGENITOR CELLS and SOMATIC BODY CELLS in response to signaling. ADULT STEM CELLS tend to live in stem cell niches which care for them and function like storehouses. Adult stem cells may remain quiescent (non-differentiating although dividing) for substantial periods of time until they are activated by a normal need for more cells to maintain tissues, or by an emergency need induced by disease or tissue injury(ref). The storehouses are always ready to replenish SOMATIC BODY CELLS – that is, as long as a supply of quality ADULT STEM CELLS still exists.
PROGENITOR CELLS are ones intermediate in their range of target differentiation capability between ADULT STEM CELLS and SOMATIC BODY CELLS. They tend to be more specific in what they can differentiate into. For some cell types there is a hierarchy of progenitor cell types and some PROGENITOR CELLS are short-lived intermediates created in the process of differentiation of ADULT STEM CELLS into SOMATIC BODY CELLS. For simplicity of presentation I have shown them as a single box in the diagram although their properties vary widely.
A few factors are important for this discussion:
1. In us humans and other mammals, renewal of our SOMATIC BODY CELLS through differentiation of ADULT STEM CELLS and PROGENITOR CELLS is required throughout life. In the course of a year, virtually all of our blood cells turn over. If ADULT STEM CELL and PROGENITOR CELL differentiation were to stop, we would soon die. No problem during most of normal life, as long as the stocks of ADULT STEM CELLS and PROGENITOR CELLS are plentiful and the cells are young enough that they will readily differentiate. With advanced aging, those conditions may no longer exist. Disease and death may follow.
2. Cells in all of these three categories (ADULT STEM CELLS, PROGENITOR CELLS and SOMATIC BODY CELLS) age with progressive cell divisions. That is: a) there are major shifts in their global gene expression patterns ; hundreds if not thousands of genes get upregulated or downregulated, b) their telomeres (caps at the ends of chromosomes) generally get shorter, c) there are multiple changes in the epigenome, i.e. methylation of promoter regions of genes and changes in histone (spools around which DNA is wrapped) acetylation and histone morphology, and d) once a critical number of replications occur the cells become senescent or dysfunctional or destroy themselves or turn cancerous.
3. With aging ADULT STEM CELLS and PROGENITOR CELLS become less ready to differentiate resulting in the stream of renewal for SOMATIC BODY CELLS slowing down and also the resulting replacement cells being epigenetically older. As cell renewal slows down and the number of senescent cells increases, so does organ renewal slow down or become impaired and disease susceptibility increases. The processes shows up as what we normally call aging and accelerates as the years roll on. Eventually life cannot be sustained and the organism dies.
4. The process is once-through in nature, as is life as we know it. All our cells age and there is nothing in place to keep them young. Up to this point aging has been absolutely insurmountable. But we may be able to change that.
The longevity intervention – closing the loop
The second diagram is the same as the first with additional boxes overlaid and shaded in orange showing the possible longevity intervention. I have described the intervention in previous blog entries(ref)(ref)(ref) but will repeat it here with reference to the diagram.
The first step is to COLLECT A SMALL SAMPLE of SOMATIC BODY CELLS from an individual of any age, perhaps in a drop of blood perhaps in a tiny scraping of skin. All of us have experienced collection of such samples.
The next step is to CORRECT THE COLLECTED CELLS FOR GENETIC DEFECTS. This is now a fairly well-understood procedure(ref)(ref). Any mutated genes that confer disease susceptibilities is snipped out of the DNA and a healthy versions of the same gene is re-inserted in its place. See the blog entry Treating genetic diseases with corrected induced pluripotent stem cells.An option is to perform the last two steps in reverse order. Also, at either stage the number of cells could be multiplied by standard laboratory processes.
The next step is REVERSION TO IPSC STATUS, that is, reversion of the collected corrected cells to being induced pluripotent stem cells. Using one of a number of known approaches, the cells are reverted to being undifferentiated cells that are, apart from correction for damaging genetic mutations, functionally, genetically and immunologically equivalent to the original EMBRYONIC STEM CELLS for the donor of the tissue sample. Reversion to iPSCs is an exciting stream of technology development that has been underway 3-4 years now. See the recent blog entry A breakthrough in producing high-fidelity induced pluripotent stem cells. A key point is that the iPSC cells at this point are young cells like the original EMBRYONIC STEM CELLS. It the reversion job is done right they no longer have any of the markers of aging that were associated with the cells they were made from. This is “the fountain of youth” on the cellular level.