Last year researchers uncovered one of the controlling portions of the process by which the hematopoietic stem cells (HSCs) that form blood decline with age. This is a part of the age-related decline of all stem cell types: researchers who subscribe to a programmed view of aging see this a part of the program of aging, a primary cause of frailty and degeneration. Researchers who theorize that aging is a non-programmed accumulation of damage, the more mainstream view at this time, see the decline of stem cell capacity as an evolved response to rising levels of cellular and molecular damage, one that evolved in order to reduce the risk of cancer arising from the actions of damaged cells.
This difference of interpretation is important. In programmed aging world, the right thing to do given the discovery of such a mechanism is to build a therapy to adjust the levels of critical controlling proteins in order to restore a youthful mode of operation - and this is all you have to do in order to halt this part of degenerative aging. In aging-as-damage world, trying to make this change happen is a largely futile endeavor, and certainly not what should be the primary focus of the research community. Such a therapy may produce short-term benefits, as it will temporarily minimize a secondary contribution to the frailty of aging. However, since it fails to address the underlying damage that causes aging and stem cell decline, it is like revving up a worn engine. The outcome will most likely be a greatly raised risk of cancer.
In any case, here is an update on last year's research. The scientists are making progress in following the chain of proteins involved in shutting down stem cell activity in older tissues:
"Although there is a large amount of data showing that blood stem cell function declines during aging, the molecular processes that cause this remain largely unknown. This prevents rational approaches to attenuate stem cell aging. This study puts us significantly closer to that goal through novel findings that show a distinct switch in a molecular pathway is very critical to the aging process." The pathway is called the Wnt signaling pathway, a very important part of basic cell biology that regulates communications and interactions between cells in animals and people. Disruptions in the pathway have been linked to problems in tissue generation, development and a variety of diseases.
Analyzing mouse models and HSCs in laboratory cultures, the scientists observed in aging cells that a normal pattern of Wnt signaling (referred to in science as canonical) switched over to an atypical mode of activity (called non-canonical). They also noticed that the shift from canonical to non-canonical signaling was triggered by a dramatic increase in the expression of a protein in aged HSCs called Wnt5a. When the researchers decided to test this observation by intentionally increasing the expression of Wnt5 in young HSCs, the cells began to exhibit aging characteristics.
Interestingly, the dramatic increase of Wnt5a in aged HSCs activated another protein called Cdc42, which turned out to be critical to stem cell aging. Cdc42 is the same protein the scientists targeted in their 2012 study. In that study, the authors showed that pharmacologically inhibiting Cdc42 reversed the aging process and rejuvenated HSCs to be functionally younger.
The researchers decided that for the current study, they would conduct experiments to see how blocking Wnt5a would affect HSC aging. To do so, they deleted Wnt5a from the HSCs of mice. They also bred mice to lack two functioning copies of the Wnt5a gene, which in essence blocked the protein's function in the HSCs of those animals. Deleting Wnt5 from cells functionally rejuvenated the HSCs. In mice bred to lack two functioning copies of the Wnt5a gene, the animals exhibited a delayed aging process in blood forming stem cells.