By Vince Giuliano
This blog entry is about somatic stem cells, the natural kind that reside in adult bodies, the factors that affect their health and longevity, the changes they undergo in the process of aging, and the roles they possibly play in overall human aging. Further, it outlines how epigenetic interventions in such stem cells could possibly contribute to longer human lifespans. In the interest of presenting a comprehensive overview, I review previously-reported findings as well as several newer ones.
Somatic stem cells, also known as adult stem cells are multipotent cells, that is, a type of somatic stem cell that can differentiate into cells belonging to several different related cell lineages but not into all ultimate body cell types. They generally live in stem cell niches, protective microenvironments in the body unique to the kind of somatic stem cell involved. Important types of somatic stem cells include:
· Hematopoietic stem cells (HSCs) which are “multipotent stem cells that give rise to all the blood cell types from the myeloid (monocytes and macrophages, neutrophils, basophils, eosinophils, erythrocytes, megakaryocytes/platelets, dendritic cells), and lymphoid lineages (T-cells, B-cells, NK-cells)(ref).
· Mesenchymal stem cells, or MSCs, which are “multipotent stem cells that can differentiate into a variety of cell types, including: osteoblasts (bone cells), chondrocytes (cartilage cells) and adipocytes (fat cells)(ref).”
· Endothelial stem cells. “Endothelial Stem Cells are one of the three types of Multipotent stem cells found in the bone marrow. They are a rare and controversial group with the ability to differentiate into endothelial cells, the cells which line blood vessels(ref).
Adult stem cells belong to a major category of cells in what I have called the stem cell supply chain. In my treatise I related: “In a simplified model, think of the 210 kinds of cells found in the human body as falling in five categories:
B. Relatively undifferentiated multipotent somatic stem cells, such as may exist in bone marrow or vascular walls (e.g. hematopoietic stem cells, mesenchymal stem cells and pericytes). These multipotent adult stem cells are each capable of differentiating into a variety of kinds of somatic cells.
C. More differentiated stem and progenitor cells (e.g. endothelial progenitor cells, myoblasts or satellite cells in muscle tissue). These are cells capable of differentiating only into more-specific somatic cell types.
E. Senescent cells, ones which no longer can divide.
The list is in order of increasing cell-type specificity and decreasing potency to differentiate into other cell types. Starting at conception and throughout life, all cells on this list except the senescent ones will selectively reproduce and possibly differentiate into cells of types further down in the list.”
Adult stem cells of a given type under conditions of youth and health typically differentiate to produce a defined mix of daughter cell types. For example, hematopoietic stem cells (HSCs) “give rise to all the blood cell types from the myeloid (monocytes and macrophages, neutrophils, basophils, eosinophils, erythrocytes, megakaryocytes/platelets, dendritic cells), and lymphoid lineages (T-cells, B-cells, NK-cells(ref).” As discussed below, aged or damaged adult stem cells may give rise to a skewed mix of daughter cells.
There are a few key topics that I do not treat here though to some extent they have been discussed in past blog entries, including disease therapies based on use of adult stem cells and practical dietary and lifestyle interventions that can contribute to adult stem cell health. Without doubt, these will be discussed further in future blog entries.
I organize this post by major observations, attempting to be fairly comprehensive in coverage. Some of the observations are quite basic and I have written about them before in my treatise and in multiple blog entries. I will cite relevant past writings as they apply to such observations. Other key observations are based on research published only in the last six months.
The 2011 publication Manifestations and mechanisms of stem cell aging reports “Adult stem cells exist in most mammalian organs and tissues and are indispensable for normal tissue homeostasis and repair. In most tissues, there is an age-related decline in stem cell functionality but not a depletion of stem cells. Such functional changes reflect deleterious effects of age on the genome, epigenome, some of which arise cell autonomously and others of which are imposed by an age-related change in the local milieu or systemic environment. Notably, some of the changes, particularly epigenomic and proteomic, are potentially reversible, and both environmental and genetic interventions can result in the rejuvenation of aged stem cells. Such findings have profound implications for the stem cell–based therapy of age-related diseases.”
Health and longevity of somatic stem cells is critical for human organismal health and longevity
This point has been known for some time and is discussed in the Section on the 14th theory of aging in my treatise ANTI-AGING FIREWALLS – THE SCIENCE AND TECHNOLOGY OF LONGEVITY. “Health for older people requires continuing operation of the stem cell supply chain at some levels throughout life. If an injury is sustained, mesenchymal stem cells must make new tissue cells. If there is loss of blood, hematopoietic stem cells must make new blood cells. And cells that die of attrition trauma or apoptosis must be replaced by new ones. “Hematopoietic stem cells (HSCs) are responsible for blood cell production throughout the lifetime of an individual(ref),” and the same is true for other types of stem cells. 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. As a simple example, new research suggests 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) which in turn is the result of DNA damage. It has been known for some time that ” – hair graying is caused by defective self-maintenance of MSCs(ref).” These stem cells, living in hair follicles, can normally both reproduce making new stem cells and differentiate into mature color-producing melanocytes. The new research based on experimentation with mice 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 because there are no more MSCs to make them.”
“As multicellular organisms age, there is a gradual loss of tissue homeostasis and organ function. Throughout life, populations of adult stem cells maintain many tissues, such as the blood, skin and intestinal epithelium. Therefore, it is likely that the decrease in tissue homeostasis can be attributed to an age-related decline in the ability of stem cells to replace damaged cells. Although cell autonomous changes occur as the organism ages that result in the inability of stem cells to proliferate or self-renew, or of daughter cells to differentiate along a specific lineage, local and systemic changes can also affect the ability of stem and progenitor cells to function properly (Energy metabolism in adult neural stem cell fate 2011).”
The 2011 review article Manifestations and mechanisms of stem cell aging relates “Aging is accompanied by a decline in the homeostatic and regenerative capacity of all tissues and organs (Kirkwood, 2005; Rando, 2006). With age, wound healing is slower in the skin, hair turns gray or is lost, skeletal muscle mass and strength decrease, the ratio of cellular constituents in the blood is skewed, and there is a decline in neurogenesis (Sharpless and DePinho, 2007). As the homeostatic and regenerative activities of these tissues are attributable to the resident stem cells, these age-related changes are reflections of declines in stem cell function (Bell and Van Zant, 2004; Dorshkind et al., 2009; Jones and Rando, 2011). Clearly, in terms of organismal aging, the focus on stem cells is most relevant for those tissues in which normal cellular turnover is very high, such as epithelia of the skin and gut, as opposed to tissues, such as the cerebral cortex and the heart, in which cellular turnover in adults is exceedingly low (Rando, 2006). There is also an increasing interest in the therapeutic potential of stem cells to treat age-related degenerative diseases or conditions, further highlighting the importance of understanding the relationship between stem cell function and the properties of aged tissues. Within this context, it is essential to understand how the local environment influences stem cells, how aging affects stem cell number and function, and the extent to which aspects of stem cell aging may be reversible.”
Stem cells reside in niches and there is a close interplay between stem cells and their niches in determining stem cell health, their differentiation capabilities and their fates.
Again from my treatise “Adult stem cells live in niches – stem cell microenvironments and the health of the stem cells and their ability to reproduce or differentiate both depend upon and condition the states of their niches. The behavior of stem cells can be expected to be very different within and without their niches. “Interaction of HSCs with their particular microenvironments, known as stem cell niches, is critical for maintaining stem cell properties, including self-renewal capability and ability for differentiation into single and multiple lineages. In the niche, the niche cells produce signaling molecules, extracellular matrix, and cell adhesion molecules and regulate stem cell fates(ref).” “Various niche factors act on embryonic stem cells to alter gene expression, and induce their proliferation or differentiation for the development of the fetus. Within the human body, stem cell niches maintain adult stem cells in a quiescent state, but after tissue injury, the surrounding microenvironment actively signals to stem cells to either promote self renewal or differentiation to form new tissues(ref).” For example, “Haematopoietic stem-progenitor cells (HSPCs) reside in the bone marrow niche, where interactions with osteoblasts provide essential cues for their proliferation and survival(ref).” Among the other places where niches of adult stem cells can be found are hair follicles (see the blog entry Hair stem cells) and in dental pulp (see the blog entry Dental pulp stem cells).”
Adult stem cells are subject to aging and stock depletion like other dividing cells types
In general, adult stem cells either divide like normal body cells do (mitosis) or differentiate in which case a stem cell produces another like stem cell and a progenitor cell which further differentiates and divides to make normal somatic body cells. “Differentiation dramatically changes a cell’s size, shape, membrane potential, metabolic activity, and responsiveness to signals. These changes are largely due to highly-controlled modifications in gene expression. With a few exceptions, cellular differentiation almost never involves a change in the DNA sequence itself(ref).” In other words, differentiation involves a significant shift in epigenetic state of a cell to a more specific less-potent status.
“Adult stem cells are exposed to many of the same factors that lead to age-related changes in their replicative or postmitotic progeny, but stem cells must resist those changes as a self-renewing population to assure proper function and normal tissue homeostasis across the lifespan (Rando, 2006; Sharpless and DePinho, 2007; Jones and Rando, 2011). As a replicative population that may have prolonged periods of quiescence (Fig. 1), stem cells must possess defense and repair mechanisms that are relevant to both highly proliferative cells and to long-lived postmitotic cells (Rando, 2006) — During prolonged periods of quiescence and by the process of self-renewal to establish a cellular continuum, stem cells experience chronological aging caused by the accumulation of damaged or aberrant intracellular molecules. During the process of asymmetric cell division and self-renewal, stem cells also experience replicative aging, which is particularly important in tissues with high turnover rates. — In long-lived animals, adult stem cells, particularly those in continuously renewing tissues, undergo many rounds of cell division to maintain normal tissue homeostasis (Fuchs et al., 2001; van der Flier and Clevers, 2009). During each round of DNA replication, processes that underlie replicative aging, including telomere shortening, chromosome rearrangements, and single base mutations (Ben-Porath and Weinberg, 2005), can occur and ultimately lead to cellular senescence (Hayflick, 1965; Campisi and d’Adda di Fagagna, 2007). Experimental manipulations, such as serial transplantation, clearly reveal that adult stem cells have a finite replicative lifespan that can be exhausted (Siminovitch et al., 1964; Waterstrat and Van Zant, 2009). However, as serial transplantation experiments subject stem cells to excessive rounds of cell division, it remains to be determined whether replicative aging alone is sufficient to contribute to the decline of stem cell function in long-lived mammals during normal aging(ref).”
Continuing(ref): “Adult stem cells are also susceptible to the kinds of age-related changes, namely chronological aging, that occur in nondividing cells, such as neurons and cardiomyocytes (Busuttil et al., 2007). These changes include the accumulation of damaged macromolecules, such as proteins, lipids, and nucleic acids, some of which may, in fact, aggregate and form stable, long-lived complexes that are toxic to the cell (Rajawat et al., 2009; Koga et al., 2011). Adult stem cells exhibit prolonged periods of quiescence in most mammalian tissues (Li and Clevers, 2010). Damaged macromolecules can accumulate in stem cells during this time, just as in long-lived postmitotic cells. Specific macromolecules or macromolecular aggregates may even be selectively retained in stem cells as they undergo the process of self-renewal by asymmetric cell division (Conboy et al., 2007; Knoblich, 2008). In this sense, the self-renewing progeny represent a kind of cellular continuum and only add to the risk that adult stem cells may suffer from the effects of chronological aging(ref).”
In mammals, the pools of available adult stem cells do not normally run out with aging, but aged adult stem cells may become resistant to differentiation and may not differentiate with the correct mix of end cell types
“Aging in stem cells causes changes in the fate or functionality of stem cell progeny. In some cases, such as neural stem cells (NSCs) and melanocyte stem cells (Maslov et al., 2004; Inomata et al., 2009), these changes may lead to a depletion of the stem cell pool (Fig. 2; Kuhn et al., 1996; Maslov et al., 2004). However, in most stem cell compartments, the number of stem cells does not decline significantly with age (Booth and Potten, 2000; Brack and Rando, 2007; Giangreco et al., 2008); rather, these stem cells experience a change in cell fate with age. — In young animals, stem cells divide asymmetrically to self-renew and give rise to lineage-specific differentiated progeny during tissue homeostasis or regeneration. With age, some stem cells lose their lineage specificity and give rise to nonfunctional progeny, resulting in loss of tissue integrity and decline of physiological function, even though the number of stem cells remains unaffected. Some stem cells lose the capacity for self-renewal, resulting in symmetric cell divisions giving rise to two differentiated daughters and a gradual depletion of the stem cell pool. The senescence of stem cells can also contribute to a loss of functional stem cells. The increase in malignancies with age, particularly in epithelia with high turnover rates, has been proposed to arise from within the stem cell compartment or from early progenitors(ref).”
Continuing: “Within the hematopoietic system, the ratios of differentiated progeny change with age. Hematopoietic stem cells (HSCs) from both old humans and old mice show an increased propensity to differentiate along the myeloid rather than the lymphoid lineage (Sudo et al., 2000; Rossi et al., 2005). Such lineage bias is not caused by a change in the differentiation potential of individual HSCs but rather by a preferential selection of distinct subsets of HSCs over time (Cho et al., 2008; Beerman et al., 2010; Challen et al., 2010). The differential responsiveness of these two HSC populations to TGF-β may further enhance the skewed ratio between myeloid versus lymphoid progeny in old individuals (Challen et al., 2010). Although the progeny of the aged HSCs do not include any cells that are not otherwise part of the normal repertoire of cells produced by HSCs, this lineage skewing results in a decreased number of memory B cells and naive T cells (Linton and Dorshkind, 2004; Min et al., 2004) and adversely affects immunological responses (Rink et al., 1998; Grubeck-Loebenstein et al., 2009.”
Adult stem and progenitor cells are subject to replicative senescence and express very different genes when young and old, but not due to telomere erosion
This point was made in the October 2010 blog entry Telomere lengths, Part 3: Selected current research on telomere-related signaling. “The 2009 publication Aging and Replicative Senescence Have Related Effects on Human Stem and Progenitor Cells is important in that a) it established that at least some stem cells are subject to replicative senescence, b) gene expression patterns of young and old stem cells vary drastically with age, and that c) telomere erosion does not appear to be responsible for the differences in gene expression of old and younger stem cells. The research looked at the gene-expression effects of replicative senescence on mesenchymal stromal cells (MSC) and human hematopoietic progenitor cells (HPC) and compared these to the gene-expression effects found in in-vivo aging. It found the effects to be similar, suggesting that stem and progenitor cells are subject to replicative senescence, just as other types of body cells are. Further, at least in HPCs, telomere erosion does not appear to be well-correlated with aging.”
“The same publication reports “The regenerative potential diminishes with age and this has been ascribed to functional impairments of adult stem cells. Cells in culture undergo senescence after a certain number of cell divisions whereby the cells enlarge and finally stop proliferation. This observation of replicative senescence has been extrapolated to somatic stem cells in vivo and might reflect the aging process of the whole organism. In this study we have analyzed the effect of aging on gene expression profiles of human mesenchymal stromal cells (MSC) and human hematopoietic progenitor cells (HPC). MSC were isolated from bone marrow of donors between 21 and 92 years old. 67 genes were age-induced and 60 were age-repressed. HPC were isolated from cord blood or from mobilized peripheral blood of donors between 27 and 73 years and 432 genes were age-induced and 495 were age-repressed. The overlap of age-associated differential gene expression in HPC and MSC was moderate. However, it was striking that several age-related gene expression changes in both MSC and HPC were also differentially expressed upon replicative senescence of MSC in vitro. Especially genes involved in genomic integrity and regulation of transcription were age-repressed. Although telomerase activity and telomere length varied in HPC particularly from older donors, an age-dependent decline was not significant arguing against telomere exhaustion as being causal for the aging phenotype. These studies have demonstrated that aging causes gene expression changes in human MSC and HPC that vary between the two different cell types. Changes upon aging of MSC and HPC are related to those of replicative senescence of MSC in vitro and this indicates that our stem and progenitor cells undergo a similar process also in vivo.”
Age-related behavior of adult stem cells is influenced by epigenetic factors that impact on key signaling pathways involved in cell division and differentiation
“The ability of stem cells to produce an appropriate repertoire of tissue-specific progeny is crucial for functional tissue homeostasis and regeneration. The extent to which adult stem cells and their progeny are committed to a particular lineage is determined largely by the epigenome, influencing which genes will be expressed and which will be repressed and ultimately shaping the phenotypic characteristics of the cells (Bernstein et al., 2006; Mikkelsen et al., 2007; Hemberger et al., 2009). The execution of the epigenomic program that influences the fate of stem cell progeny is modulated by environmental factors and mediated by signaling pathways that have important roles in organogenesis during development, including the Wnt, Notch, and Hedgehog pathways (Berger, 2007; Brack et al., 2008; Rittié et al., 2009; van der Flier and Clevers, 2009). With age, untimely activation of these pathways as a result of signals from the “old environment” may lead to aberrant lineage specification of stem cell progeny as has been demonstrated in tissues, such as skeletal muscle, tendon, and the hematopoietic system (Sudo et al., 2000; Taylor-Jones et al., 2002; Brack et al., 2007; Zhou et al., 2010). Accumulation of these abnormal progeny contributes to the gradual deterioration of tissue structure and function associated with aging(ref).”
Notch and MAPK are key pathways involved in cell proliferation and differentiation
I first touched on these signaling pathways in the 2009 blog post Niche, Notch and Nudge. “The grist of this post deals with both new research and a couple of complicated cell signal-transduction pathways that have been extensively studied for over 15 years now, known as Notch and MAPK. — Notch is an ancient signaling pathway that has been inherited from primitive multi-cellular organisms and has to do with signaling between cells, such as when stem cells decide to differentiate. “Because Notch often acts in concert with other signaling pathways, it is able to regulate a diverse set of biological processes in a cell-context dependent manner(ref). “ Notch protein receptors (there are 4 different ones) sit on the surfaces of cells and communicate between adjacent cells via Notch ligands. Ligand binding to a receptor alters the chemical conformation, that is the three dimensional shape of the receptor protein(ref).” Intracellular proteins transmit Notch signals into the cell’s nucleus where they can activate genes, including ones that initiate differentiation in stem cells. Notch signaling can play an important role in determining the morphology of organs. For example see this publication. Also Notch plays several important roles in stem and progenitor cell differentiation, particularly ones that maintain balance during development. “Notch signaling is a powerful means of turning adult CNS precursor cells into astrocytes(ref).” “In the developing nervous system, the balance between proliferation and differentiation is critical to generate the appropriate numbers and types of neurons and glia. Notch signaling maintains the progenitor pool throughout this process(ref).”
MAPK/ERK is another very complicated signal transduction pathway way that couples intracellular responses to the binding of growth factors to cell surface receptors. MAPK signaling is important for cell growth and differentiation, inflammation and apoptosis. A diagram showing all the ways MAPK signaling can work would fill a large wall. For example this diagram shows four different MAPK cascades. Clicking on the individual bubbles in the diagram reveal more-detailed diagrams, showing cascades such as for growth, differentiation and inflammation.
Both Notch and MAPK signaling are deeply involved in embryogenesis and stem cell differentiation. It is no surprise that there is crosstalk between the Notch and MAPK pathways. For example, this report states: “Here we show that Notch signaling activation in C2C12 cells suppresses the activity of p38 MAPK to inhibit myogenesis. Our results show that Notch specifically induces expression of MKP-1, a member of the dual-specificity MAPK phosphatase, which directly inactivates p38 to negatively regulate C2C12 myogenesis.”
The same 2009 blog entry cites a number of other publications relating Notch and MAPK signaling to stem cell differentiation.
The protein JDP2 is involved with epigenetic modifications to histones relevant to age-related changes in stem cell differentiation and cell senescence
This subject is covered in the February 2011 blog post JDP2 – linking epigenetic modifications, stem cell differentiation, cell senescence, cell stress response, and aging. “JDP2 is involved with epigenetic modifications to histones relevant to age-related changes in stem cell differentiation and cell senescence. Like the previously-discussed Smurf2 gene, JDP2 is involved in the regulation of the differentiation and proliferation of cells. Its presence or absence affects whether cells differentiate or become senescent. The new research has implications related to organismal aging and for the Programmed Epigenomic Changes theory of aging. I review some of the new publications here and relate new findings to matters I have discussed previously.”
Molecular control inhibiting differentiation, particularly the presence of P21 and adequate DNA methylation, is essential to prevent exhaustion of adult stem cell pools
This is an older finding pointed out in a May 2010 blog entry Something new about P21. “Expression of P21 is a barrier to stem cell differentiation. The 2000 publication Hematopoietic Stem Cell Quiescence Maintained by p21cip1/waf1 states “Therefore, p21 is the molecular switch governing the entry of stem cells into the cell cycle, and in its absence, increased cell cycling leads to stem cell exhaustion. Under conditions of stress, restricted cell cycling is crucial to prevent premature stem cell depletion and hematopoietic death.” In the absence of P21, hematopoietic stem cells would not remain quiescent in their niches but would instead prematurely differentiate when stress occurs exhausting the pools of those cells and interrupting the normal functioning of the stem cell supply chain leading to premature death. The 2009 paper Accelerating stem cell proliferation by down-regulation of cell cycle regulator p21 offers a consistent message. “Inhibition of the cell cycle regulator p21 results in significant acceleration of mesenchymal stem cell proliferation without promoting spontaneous cellular differentiation.” That blog entry also describes how P21 control of differentiation is a key factor in the process of limb regeneration.
Adequate DNA methylation is also implicated in maintenance of pools of undifferentiated adult stem cells. From the blog entry DNA Methyltransferases, stem cell proliferation and differentiation: “Adult stem cells, including neural progenitor cells and hematopoietic stem cells depend on DNA methylation for their survival in undifferentiated state. This methylation in turn depends critically on the actions of DNA methyltransferases. In plain language, the methyltransferases keep lineages of adult stem cells continuing in their niches throughout life instead of having all the adult cells differentiating early in life leaving no reserves of such cells.
Neurogenesis is a much-studied model of adult stem cell differentiation
Brain cell renewal depends on neurogenesis due to differentiation of neural adult stem cells mainly in the hippocampus and cell migration. The process goes on throughout life. Neurogenesis is an important special case of adult stem cell differentiation. What is known about neurogenesis some extent applies also to differentiation of other adult stem cell types. See the blog entry Age-related memory and brain functioning – focus on the hippocampus.
Neural stem cell self-renewal and proliferation can be affected by epigenetic interventions in histone H2AX
The 2009 publication Cell cycle restriction by histone H2AX limits proliferation of adult neural stem cells reports “Adult neural stem cell proliferation is dynamic and has the potential for massive self-renewal yet undergoes limited cell division in vivo. Here, we report an epigenetic mechanism regulating proliferation and self-renewal. The recruitment of the PI3K-related kinase signaling pathway and histone H2AX phosphorylation following GABAA receptor activation limits subventricular zone proliferation. As a result, NSC self-renewal and niche size is dynamic and can be directly modulated in both directions pharmacologically or by genetically targeting H2AX activation. Surprisingly, changes in proliferation have long-lasting consequences on stem cell numbers, niche size, and neuronal output. These results establish a mechanism that continuously limits proliferation and demonstrates its impact on adult neurogenesis. Such homeostatic suppression of NSC proliferation may contribute to the limited self-repair capacity of the damaged brain.”
Multiple kinds of changes may be involved in older adult stem cells affecting their differentiation capabilities
Quoting selectively from the 2011 publication Manifestations and mechanisms of stem cell aging “Among the cell-intrinsic changes that may mediate age-related changes in stem cell function are alterations at the level at the genome, the epigenome, and the proteome.
- Genome-level changes may include including single- and double-strand DNA breaks, chromosomal translocations, telomere shortening, and single base mutations (Akbari and Krokan, 2008; Wang et al., 2009). DNA repair systems have evolved to maintain genomic integrity, and it has been proposed that the intrinsic DNA repair activity and fidelity in different species may influence the rate of aging (Hart and Setlow, 1974). Mutations in proteins involved in DNA repair, such as the WRN (Werner Syndrome ATP-Dependent) helicase and the ATM (Ataxia Telangiectasia Mutated) kinase, have been associated with segmental progeroid syndromes in humans and mice that have features of accelerated aging in multiple tissues and organs (Savitsky et al., 1995; Gray et al., 1997; Kudlow et al., 2007), providing evidence for the crucial role of DNA repair machinery for normal tissue homeostasis.
- Unlike acquired DNA mutations, epigenomic changes, including DNA methylation and posttranslational modifications of histones, are dynamically maintained by a balance among chromatin-remodeling complexes and are, thus, reversible (Goldberg et al., 2007). Given the influence of cell extrinsic factors on the epigenome and the reversibility of chromatin modifications, epigenomic changes may underlie the stochastic aspects of aging (Herndon et al., 2002; Fraga et al., 2005; Kirkwood, 2005) and certain environmental influences that delay or even apparently reverse aging, such as the lifespan-extending effect of dietary restriction and the rejuvenation of aged stem cells by exposure to a young environment (Conboy et al., 2005; Dorshkind et al., 2009; Fontana et al., 2010). In yeast, lifespan extension by dietary restriction appears to require Sir2 (Lin et al., 2000), a histone deacetylase that has been shown to extend the lifespan in several model organisms (Longo and Kennedy, 2006). In Caenorhabditis elegans, members of the H3K4 methyltransferase complex affect lifespan in a germline-dependent manner (Greer et al., 2010).
- Maintenance of the intracellular proteome requires timely removal of improperly folded or damaged proteins that can otherwise impede normal cellular function (Koga et al., 2011). Autophagosomes, chaperones, lysosomes, and the ubiquitin–proteasome system are all important cellular processes and machineries that maintain protein homeostasis (Rajawat et al., 2009; Koga et al., 2011). Together, they sense and remove misfolded or aberrant proteins in cells and ensure a functional proteome. With age, the protein homeostatic machinery becomes less efficient and less effective (Rodriguez et al., 2010; Koga et al., 2011), and these functional declines would only accentuate the negative effect of proteomic changes during aging. — Age-related increases in the levels of damaged proteins have been well documented in long-lived postmitotic cells, such as neurons, cardiomyocytes, and skeletal myofibers, and in some cases, these damaged proteins form aggregates or inclusion bodies that can cause proteotoxicity to cells (Rodriguez et al., 2010.”
As pointed out in my treatise “Buildup of levels of Ink4a/P16 associated with aging slows down the rate of differentiation of adult stem cells. “Recent evidence shows that loss of Bmi-1, a polycomb transcriptional repressor of theInk4a-Arf locus, results in progressive loss of HSCs in adult mice with subsequent failure of hematopoiesis.” – “ These results show that either both p16Ink4a and p19Arf can inhibit HSC self-renewal in a serial transplant setting, or that only p16Ink4a is necessary(ref).“
Also I mention that in Victor’s blog entry P53 and Longevity, there is some discussion of the role of P53 with respect to stem cells. “There is an intimate relationship among p53, stem cell development, and epigenetic regulation of these processes, and it began to evolve in the fishes.” (ref).
Among the key factors affecting adult stem cells and their ability to differentiate are aging-related changes in the niches. As pointed out in the blog entry What every vampire already knows, “age-related loss of capability to reproduce and differentiate has to do with what is going on in the niches in which stem cells live. “Our results reveal that aged differentiated niches dominantly inhibit the expression of Oct4 in hESCs and Myf-5 in activated satellite cells, and reduce proliferation and myogenic differentiation of both embryonic and tissue-specific adult stem cells (ASCs). Therefore, despite their general neoorganogenesis potential, the ability of hESCs, and the more differentiated myogenic ASCs to contribute to tissue repair in the old will be greatly restricted due to the conserved inhibitory influence of aged differentiated niches(ref).”
Energy metabolism is critical in determining stem cell health and fate
The point is made for neural stem cells in the 2011 publication Energy metabolism in adult neural stem cell fate. “The adult mammalian brain contains a population of neural stem cells that can give rise to neurons, astrocytes, and oligodendrocytes and are thought to be involved in certain forms of memory, behavior, and brain injury repair. Neural stem cell properties, such as self-renewal and multipotency, are modulated by both cell-intrinsic and cell-extrinsic factors. Emerging evidence suggests that energy metabolism is an important regulator of neural stem cell function. Molecules and signaling pathways that sense and influence energy metabolism, including insulin/insulin-like growth factor I (IGF-1)-FoxO and insulin/IGF-1-mTOR signaling, AMP-activated protein kinase (AMPK), SIRT1, and hypoxia-inducible factors, are now implicated in neural stem cell biology. Furthermore, these signaling modules are likely to cooperate with other pathways involved in stem cell maintenance and differentiation. This review summarizes the current understanding of how cellular and systemic energy metabolism regulate neural stem cell fate. The known consequences of dietary restriction, exercise, aging, and pathologies with deregulated energy metabolism for neural stem cells and their differentiated progeny will also be discussed. A better understanding of how neural stem cells are influenced by changes in energy availability will help unravel the complex nature of neural stem cell biology in both the normal and diseased state.” Note that each of the pathways mentioned here are known to be involved in organismal aging.
The reduced functional and differentiation capabilities of older adult stem can to some extent be rejuvenated by epigenetic interventions
The 2011 publication Epigenetic regulation of aging stem cells relates “The function of adult tissue-specific stem cells declines with age, which may contribute to the physiological decline in tissue homeostasis and the increased risk of neoplasm during aging. Old stem cells can be ‘rejuvenated’ by environmental stimuli in some cases, raising the possibility that a subset of age-dependent stem cell changes is regulated by reversible mechanisms. Epigenetic regulators are good candidates for such mechanisms, as they provide a versatile checkpoint to mediate plastic changes in gene expression and have recently been found to control organismal longevity. Here, we review the importance of chromatin regulation in adult stem cell compartments. We particularly focus on the roles of chromatin-modifying complexes and transcription factors that directly impact chromatin in aging stem cells. Understanding the regulation of chromatin states in adult stem cells is likely to have important implications for identifying avenues to maintain the homeostatic balance between sustained function and neoplastic transformation of aging stem cells.”
The April 2010 blog entry DNA Methyltransferases, stem cell proliferation and differentiation reviews research of DNA methyltransferases and their key regulatory roles on the epigenetics of adult stem cells. “DNA methylation, particularly when applied to CG-rich promoter sequences, has been shown to silence gene expression in a heritable manner. DNA methylation is therefore a form of cellular memory. Because DNA methylation is not encoded in the DNA sequence itself, it is called an epigenetic modification (ref).”, I remind my readers that the 13th theory of aging covered in my treatise, Programmed Epigenomic Changes, envisages aging as a systematically articulated set of epigenomic changes including changes in DNA methylation in cells accumulated with aging. See my blog entry Homicide by DNA methylation.” – That blog entry reviews research relating to how DNA methyltransferases 1. initiate and maintain methyl marks, 2. are involved in self-renewal of embryonic stem (ES) cells, and 3. act in somatic (adult) stem cells including: hematopoietic, epithelial, neural and muscle cells. It also relates to the molecular factors that keep stem cells from differentiating and the role of methyltransferases once those cells start differentiating.
Addressing adult stem cell aging may be a fruitful approach to addressing human aging
The 2011 publication Emerging models and paradigms for stem cell ageing reports “The interesting overlap between the biology of ageing and the biology of stem cells has been reviewed extensively3, 5, 6, 7, 8. To the extent that stem cell ageing is itself an important factor in organismal ageing, it may be possible to develop therapeutic approaches to age-related diseases based on interventions to delay, prevent or even reverse stem cell ageing. Therefore, understanding the basic properties of stem cells as they age, and the mechanisms that promote or prevent stem cell ageing, have significant implications for regenerative medicine and the goal of extending ‘healthspan’.”
Dental pulp niches appear to be important both for dental health and possibly also for health and longevity.
The 2011 publication Dental pulp stem cells, niches, and notch signaling in tooth injury reports “Stem cells guarantee tissue repair and regeneration throughout life. The decision between cell self-renewal and differentiation is influenced by a specialized microenvironment called the ‘stem cell niche’. In the tooth, stem cell niches are formed at specific anatomic locations of the dental pulp. The microenvironment of these niches regulates how dental pulp stem cell populations participate in tissue maintenance, repair, and regeneration. Signaling molecules such as Notch proteins are important regulators of stem cell function, with various capacities to induce proliferation or differentiation. Dental injuries often lead to odontoblast apoptosis, which triggers activation of dental pulp stem cells followed by their proliferation, migration, and differentiation into odontoblast-like cells, which elaborate a reparative dentin. Better knowledge of the regulation of dental pulp stem cells within their niches in pathological conditions will aid in the development of novel treatments for dental tissue repair and regeneration.” See also the blog entry Dental Pulp Stem Cells – the big needle vs the tooth fairy.
Targeting adult cancer stem cells is a form of therapy being actively researched.
This is a subject I have discussed before in the blog entries, and is not something I will get into further in this blog entry. Recent relevant publications include:
Additional relevant publications include: