Genetic and environmental rejuvenation of aging stem cells

The Buck Institute for Research on Aging held a symposium on Stem Cell Research and Aging March 1-2, 2012 in Novato, California. A range of levels of talks were given by scientists in the field to an audience of approximately 100 people. Three of the overall themes included a focus on the commonality of systemic cellular processes in development, aging, and rejuvenation, the importance of intervention in middle age when pre-clinical conditions are already in effect (for example, synapse loss, and over/under-expressed transcriptional profiles), and some of the challenges encountered thus-far in human stem cell clinical trials. The stage of the research is still more focused on characterization in a variety of model organisms rather than translational intervention for humans. Two of the most interesting areas of presentation were epigenetics and neurodegenerative disease.

Epigenetics
Since a good definition distinguishing young and old cells is not yet available, it was suggested that a cell’s epigenetic state and transcriptional network could be used to determine cell age and measure the impact of rejuvenation interventions. The stem cell environment is a critical factor to stem cell health and operation, and it has been found that aging can be reversed by altering the stem cell environment. One technique uses heterochronic parabiosis (pairing older and younger cells together), where each cell takes on the expression profiles of other. Genes that are downregulated in aging are reexpressed when exposed to younger cells, and stem cells put in an old environment take cues and act old (e.g.; have different expression profiles and lose lineage fidelity). Other rejuvenation techniques involve manipulating the transcriptional network, the networks of small RNAs that regulate the stability of the stem cell niche, and function appropriately in younger cells but not in older cells. However, in addition to heterochronic parabiosis, muscle stem cells may be rejuvenated through transcriptional interventions such as overexpressing the protein upd, activating the notch gene, inhibiting the Wnt gene or the TGF-beta gene, and stimulating proteins secreted by embryonic stem cells. The good news is that given the right genetic and environmental clues, aging cell states may be reversed.

Neurodegenerative disease
Regarding neurodegenerative disease, there is a new understanding of human cortical neurogenesis; that it occurs in the outer sub-ventricular zone (OSVZ) as opposed to the ventricular region, which also may explain how so many cortical columns are generated. The results of a four-year NINDS-sponsored clinical trial injecting fetal brain stem cells into aged patients with Parkinson’s disease were discussed; that the outcome and side effects were discouraging. This type of trial might fare better in patients who did not already have the movement disorder dyskinesia and with an improved understanding of the biological mechanisms of the disease, and better cellular delivery methods. Also regarding Parkinson’s disease, synapse loss is already beginning in middle age; for example there may be a 60% synapse loss before the disease is detected. Pacemaker neurons degenerate synapses and then synapse loss degenerates soma (the cell body of neurons).