The findings are early and involve laboratory manipulation of mouse cells, so it remains to be seen what direct application they may have for humans. Still, the study expands what is known about the basic molecular and cellular mechanisms of aging a necessary step to one day designing rational approaches to aiding a healthy aging process.
One reason the research team focused on Cdc42 is that previous studies have reported elevated activity of the protein in various tissue types of older mice which have a natural life span of around two years. Also, elevated expression of Cdc42 has been found in immune system white blood cells in older humans.
In the current study, researchers found elevated activity of Cdc42 in the HSCs of older mice. They also were able to induce premature aging of HSCs in mice by genetically increasing Cdc42 activity in the cells. The aged cells lost structural organization and polarity, resulting in improper placement and spacing of components inside the cells. This disorganization contributed to the cells' decreased functional efficiency.
The researchers then analyzed HSCs from older mice to see if inhibition of Cdc42 would reverse the aging process. They used a specific dose (5uM) of a pharmacologic inhibitor of Cdc42, CASIN, to reduce the protein's activity in the cells processing them for 16 hours ex vivo in laboratory cultures. This improved structural organization, increased polarity and restored functionality in the older cells to levels found in young cells.
To test the rejuvenated cells, the researchers used a process known as serial competitive transplantation. This included extracting HSCs from young (2-4 months) and aged (20-26 months) mice and processing them in laboratory cultures. Young and rejuvenated cells were then engrafted into recipient mice. This allowed scientists to compare how well young and rejuvenated aged HSCs started to repop
|Contact: Nick Miller|
Cincinnati Children's Hospital Medical Center