Is Nuclear DNA Damage Responsible for Stem Cell Aging?
Researchers here cast doubt on nuclear DNA damage as a primary cause of decline in the stem cell population that is responsible for creating immune cells and blood cells. All cell populations accumulate random mutations in nuclear DNA over the course of aging. It is well proven that this causes a rise in cancer risk, though as noted in the paper here that isn't a simple linear relationship. The consensus position is that this damage also contributes to degenerative aging in the form of increased disarray in cell operations, but there is no solid evidence to demonstrate that this is in fact so, nor to show the degree to which it is a cause of aging in comparison to other forms of damage. There are opposing viewpoints from those who suggest that nuclear DNA damage isn't in fact significant in aging beyond the matter of cancer, at least over the present human life span.
The mammalian blood system consists of many distinct types of differentiated cells with specialized functions like erythrocytes, platelets, T-and B-lymphocytes, myeloid cells, mast cells, natural killer cells and dendritic cells. Many of these mature blood cells are short-lived and need thus to be replaced at a rate of more than one million cells per second in the adult human. This continuous replenishment depends on the activity of hematopoietic progenitor cells (HPCs) and ultimately hematopoietic stem cells (HSCs).
HSCs numbers and HSCs potential are controlled via complex regulatory mechanisms involving tight molecular and cellular control of quiescence, self-renewal, differentiation, apoptosis, and localization as well as cell architecture. Under steady state conditions, HSCs are a largely quiescent, slowly cycling cell population, where only 8% of cells enter the cell cycle per day. However, in response to stress, HSCs exit quiescence and expand and differentiate. The mostly quiescent status of HSCs is thought to be a protective mechanism against endogenous stress caused by reactive oxygen species and DNA replication. In contrary to a common assumption that cell loss is tightly associated with aging, the number of phenotypic HSCs actually increases in both mouse and humans. In the aged bone marrow, there are two- to ten-fold more HSCs present when compared to young. Aged HSCs show under stress, like for example in serial transplantation assays, a diminished regenerative potential as consequence of a lower long-term self-renewal capacity. Aging-associated changes can be attributed at least in part to aging of HSCs. Aged HSCs are deficient in their ability to support erythropoiesis and show a markedly decreased output of cells from the lymphoid lineage, whereas the myeloid lineage output is maintained or even increased compared to young HSCs.
A controversially discussed cell-intrinsic factor driving HSC aging is DNA damage. HSCs are responsible for maintaining tissue homeostasis throughout a lifetime. It is therefore critical for HSCs to maintain their genomic integrity to reduce the risk of either BM failure or transformation. The paradigm of the DNA damage theory of stem cell aging states that aging-associated changes in the DNA repair system in HSCs, together with changes in cell cycle regulation due to increased DNA damage with age, are thought to result in elevated DNA mutations, which then causally contribute to the decrease in HSCs function with age. However, genetic engineering of mutations in most of the genes linked to DNA damage response so far did not result in the "aging-characteristic" initial expansion of the number of phenotypic HSCs, rendering a central role for these genes and the pathways they represent with respect to physiological aging of the hematopoietic system not likely.
Data confirms a mild 2-3 fold aging-associated increase in the mutation frequency in hematopoiesis, the increase though is linear and not exponential with respect to age, rendering a cause-consequence relationship to the exponential increase of leukemia upon aging unlikely. Modeling of aging of HSCs populations based on evolutionary theories also demonstrates that accumulation of genetic changes within HSCs are not sufficient to alter selectivity and fitness of HSCs, and identified non-cell autonomous mechanisms, aka changes in the stem cell niche, as the major selective driving force for aging-associated leukemia. Such conclusions are also supported by the observation that while a 22-fold increase in the mutational load initiated cancer, a modest 2-3 fold increase in mutational load did not result in leukemia initiation. Finally, novel data from our laboratory demonstrated that the quality of the DNA damage response in HSCs does not change upon aging.
Since the accumulation of DNA mutations in HSCs upon aging might not be directly linked to the functional decline of HSCs with age and an aging-associated exponential increase in the incidence of leukemia, what other mechanisms might contribute to these phenotypes? It could already be shown that aging of the HSCs niche and environment plays an important role in selecting and expanding normal and pre-leukemic HSC and HPC clones upon aging. Thus the concept of adaptive landscapes has been recently developed. In this concept, the niche environment of HSCs changes upon aging, influencing the functionality of HSCs. The mutations acquired over time might not influence the HSC per se. In addition to extrinsic factors also intrinsic alterations that are not mutations in DNA might ultimately contribute to HSCs aging. We have recently reported that HSCs change their polarity upon aging, both in the cytoplasm and the nucleus. It might thus be possible that also changes in the general architecture of the cell might contribute to HSC aging. Changes in the 3D arrangement of epigenetic marks and structural proteins might influence for example cell divisions in a way that reduces potential in daughter stem cells, contributing to intrinsic HSC aging. In summary, multiple mechanisms might contribute to aging of HSCs, and ultimately depend on the interplay between cell extrinsic and cell intrinsic factors.