Aging of the inceptive cellular population: the relationship between stem cells and aging

Abstract

The average life expectancy worldwide has about doubled and the global population has increased six fold over the past century. With improving health care in the developed world there is a proportional augmentation in the treatment necessary for elderly patients occasioning the call for increased research in the area of aging and age-related diseases. The manifestation of this research has been focalized on the causative cellular processes and molecular mechanisms involved. Here we will discuss the efforts of this research in the area of stem cells, delving into the regulatory mechanisms and how their de-regulation could be attributed to aging and age-related diseases.

Keywords: stem cells; senescence; cell cycle; apoptosis; aging; differentiation.

Figure 1.. Cell cycle in somatic cells vs. ESCs.

(a) Cell cycle regulation in somatic cells: mitogen signaling through MAPK pathway activates cyclin D - CDK4/6 kinase activity hypophosphorylating Rb family member proteins. Hypophosphorylated Rb family member proteins bind to E2F transcription factors blocking the transcription of E2F-regulated genes. To surpass the R point cyclin E - CDK2 kinase activity is activated hyperphosphorylating Rb family member proteins. Hyperphosphorylated Rb family member proteins are unable to interact with E2F factors, allowing them to activate transcription of genes necessary in the progression of cell cycle. (b) Cell cycle regulation in ESCs as is currently understood. Mitogen signaling through MAPK pathways seems to be irrelevant in the progression of cell cycle. There is cell cycle-independent expression of cyclin E - CDK2 maintaining the hyperphosphorylated levels of Rb family member proteins. This results in cell cycle-independent expression of E2F-regulated genes. Cyclin B - CDC2 is the only CDK activity that appears to be regulated by the cell cycle. ESCs have shortened gap phases and an elongated S phase of the cell cycle, with an apparent lack in the R point for G1-S transition.

Figure 2.. Pathways associated with aging in ASCs.

Bmi-1, Cbx7 (PRC1), Hmga2 are proteins that have been shown to increase in expression levels in aging ASCs along with corresponding inhibition of the INK4a/ARF locus leading to a progression into senescence and apoptosis. Rb2/p130 also shows an increase in senescent MSCs, this could be a result of HDAC1 - Rb2/p130 complex repressing E2F target gene transcription and initiating the senescence pathway.