Abstract
To investigate aging mechanisms in murine hematopoietic stem cells (HSCs), a microarray analysis was performed on sorted Lin-cKit+ Sca-1+ cells of young and old mice of two strains: long-lived C57B6L/6 (B6) and short-lived DBA/2 (D2). Following analysis by two-way ANOVA with a FDR of 5%, the data was organized using gene ontology software. The following age-related transcriptional changes were found to be of significance: increases in 20S (α and β) and 26S proteasome subunits, ribosomal proteins, mitochondrial enzymatic proteins, and carbohydrate metabolism, and a decrease in ubiquitination proteins. In general, B6 changes were more dramatic than those of D2. These data are surprisingly consistent with well-established theories of aging in post-mitotic cells, most commonly neurons, where the function of the proteasome decreases while the number of proteasome subunits increases in a compensatory manner to maintain protein turnover. Eventually, the proteasome can become over-loaded and the lysosomal pathway must assume the load of additional protein degradation. It is common for protein aggregates, lysosomal dysfunction, and damaged mitochondria to be observed in neurons with inhibited proteasome function. Our data are consistent with the initial steps in this theory, but the later, dysfunctional consequences of proteasome inhibition have not yet been observed in HSCs. It is interesting that this pattern would be present in stem cells, since they are responsible for self-renewal and differentiation throughout the lifetime of the organism. It is possible that the lack of protein aggregates or dysfunctional mitochondria is actually due to dilution by cell division, especially considering that the proteasome is responsible for degradation of many cell cycle proteins and that genes involved in energy production were up regulated. Therefore, it is possible that HSCs show similar aging trends with regard to the proteasome but do not have the same cellular consequences as post-mitotic cells. It is also interesting that B6 and D2 showed the same aging trends but B6 appears better able to compensate for proteasome alterations. For example, B6 increases the beta catalytic subunits of the 20S proteasome core more so than its short-lived counterpart. Additionally, B6 are known to have more HSCs in old age than D2, which is consistent with more cells being able to either compensate for decreased proteasome function or to increase cell cycle to dilute out any deleterious effects of proteasome inhibition. These data suggest that HSCs share common aging trends with other cell types; however, they are able to maintain “healthy aging” more effectively than post-mitotic cells, especially in the case of B6. It is tempting to speculate that the longevity of D2 mice could be limited by its alterations in proteasome function and its decreased ability to compensate other cellular responses in order to maintain homeostasis.
Author notes
Corresponding author
