by Dr. Francis Collins
Basic scientists have long studied aging by looking inside of cells. While this research has produced many important leads, they are now starting to look outside the cell for the wealth of biochemical clues contained in the bloodstream.
To introduce you to this exciting frontier in aging research, this blog highlighted a while back the work of Tony Wyss-Coray at Stanford School of Medicine, Palo Alto, CA. He and a colleague had just received a 2013 NIH Director’s Transformative Research Award to explore the effects of exercise on the brains of mice. Their work, in fact, produced one ofScience Magazine’s Breakthrough Discoveries of 2014. Their team showed that by fusing the circulatory systems of old and young mice to create a shared blood supply, the young blood triggered new muscle and neural connections in the older mice, while also improving their memories.
As fascinating as this theoretical Fountain of Youth was, Wyss-Coray recognized a critical limitation. He had no way of knowing how factors secreted by the young mouse could actually cross the blood-brain barrier and rejuvenate neurons. To solve this unknown, Wyss-Coray recently received a 2015 NIH Director’s Pioneer Award to build a potentially game-changing tool to track the aging process in mice.
Wyss-Coray and team will develop a way to get cells to place distinctive tags on the roughly 4,000 proteins that mouse and human cells routinely secrete into the bloodstream to communicate, called the “communicome” (every large collection of biological molecules seems to be called an “ome” these days!). His earlier research shows the composition of the communicome changes dramatically with age. By getting cells to tag these proteins as they are produced, much like barcoding an overnight package, Wyss-Coray will know their tissue of origin, allowing him to figure out where they travel and how their concentrations in the bloodstream change over time. This would potentially enable him to begin answering longstanding questions such as where does aging start, what drives it, and how does the process spread to different parts of the body?
The new tool isn’t a powerful new gadget from Silicon Valley. It starts with something called bioorthogonal chemistry. Coined in 2003, the term refers to chemical reactions that don’t interfere with normal cellular processes. They involve an inert biochemical that, in this case, has been introduced into the cell.
Wyss-Coray’s inert biochemical of choice is an amino acid called pyrrolysine, which is derived from single-celled Archaebacteria. He wants to genetically modify mice to produce a molecule called a transfer RNA that specifically recognizes pyrrolysine. He’ll then feed pyrrolysine to the mice and hope the transfer RNA starts inserting it unobtrusively into proteins.
If successful—and it’s been done in worms and flies—he could take the next step and prompt cells to insert a fluorescently labeled pyrrolysine into a select number of communicome proteins as trackable tags, making it possible to see where they go. It’s still yet to be determined how he’ll image the proteins. But there are number of existing technologies that might do the trick.
If all goes well, Wyss-Coray would like first to pursue a question that has occupied neuroscience for decades: Which proteins secreted into the bloodstream actually make it to the brain? The answer would allow him to generalize their baseline levels and see how they change with age and in models of Alzheimer’s disease. Knowing what’s changed and its consequences for memory and other cognitive processes, it will be possible to add what’s needed and potentially slow or even reverse certain aspects of the aging process.