Reinforcing the SENS rejuvenation biotechnology view of the importance of lysosomal aggregates in aging, researchers here demonstrate a link between lyososomal function and the ability of neural stem cells to support brain tissue. Lysosomes inside cells are recycling machines, packed with enzymes capable of breaking down near everything they will encounter. They are the ultimate destination for damaged proteins and other broken cellular structures. Unfortunately, lysosomes do encounter molecular waste that they cannot handle, and long-lived cells become ever more burdened by damage as their lysosomes falter and become bloated. The processes of recycling and cellular maintenance back up and run down, and the cells become dysfunctional.
The solution envisaged by the SENS Research Foundation is to build therapies capable of safely breaking down the unwanted contents of lysosomes. The most promising way forward appears to be mining the bacterial world for enzymes that might serve as a starting point. The known resilient lysosomal wastes do not accumulate in graveyards, so we know those bacteria and their useful molecular tools are out there, waiting to be discovered. The first SENS program to work along these lines successfully discovered a number of candidate enzymes that proceeded to further development, and are currently at various stages in that process.
Young, resting neural stem cells in the brains of mice store large clumps of proteins in specialized cellular trash compartments known as lysosomes. As the cells age, they become less proficient at disposing of these protein aggregates, and their ability to respond readily to "make new neurons" signals wanes. Restoring the ability of the lysosomes to function normally rejuvenates the cells' ability to activate, the researchers found. "We were surprised by this finding because resting, or quiescent, neural stem cells have been thought to be a really pristine cell type just waiting for activation. But now we've learned they have more protein aggregates than activated stem cells, and that these aggregates continue to accumulate as the cells age. If we remove these aggregates, we can improve the cells' ability to activate and make new neurons. So if one were able to restore this protein-processing function, it could be very important to bringing older, more dormant neural stem cells 'back to life.'"
Researchers isolated several populations of cells for study from the brains of both young and old mice, including resting neural stem cells, activated neural stem cells, and the neural cell progenitors that arise from activated stem cells. They found that resting stem cells expressed many lysosome-associated genes, while activated stem cells expressed genes associated with a protein complex involved in protein destruction called a proteasome. Strict control of production and disposal allows cells to maintain the necessary protein inventory to carry out needed cellular functions.
"The fact that these young, pristine resting stem cells accumulate protein aggregates makes us wonder whether they actually serve an important function, perhaps by serving as a source of nutrients or energy upon degradation." Old resting stem cells express fewer lysosome-associated genes and begin to accumulate even higher levels of protein aggregates. "It's almost as if these older cells lose the ability to store, or park, these aggregates. We found that artificially clearing them by either activating lysosomes in older cells or subjecting them to starvation conditions to limit their protein production actually restored the ability of these older resting stem cells to activate. We'd like to know whether the aggregated proteins are the same in the young and old cells. What do they do? Are they good or bad? Are they storing factors important for activation? If so, can we help elderly resting stem cells activate more quickly by harnessing these factors? Their existence in young cells suggests they may be serving an important function."