June 05, 2014
In A World Out of Time by Larry Niven, people live forever by teleporting the unfolded protein aggregates associated with aging out of their cells. Turns out that our very clever yeast Saccharomyces cerevisiae can do the same thing and it doesn’t need a machine.
Instead of teleporting the aggregates away, yeast saddles the mother cell with them when it buds. The daughter has now regained her youth and the mother is left to struggle with old age.
In a new study in Science, Hill and coworkers show that the yeast metacaspase gene MCA1 is critical in this process. But it doesn’t look like it is involved in segregating these bundles to the mother cell. Instead, it appears to help clear away many of the bundles left in the daughter. If it were in Niven’s original story, Mca1p might be a little nanobot that chewed up any aggregates the teleporter missed.
This all makes sense given caspases’ role in multicellular beasts. There, these executioner proteases chew up cellular proteins during apoptosis, the process of programmed cell death that is a critically important part of development and growth.
Although apoptosis has been observed in yeast and Mca1p is involved in the process, it has always been a bit of a mystery why a single-celled organism needs a mechanism for suicide. This study now suggests that yeast’s only caspase, Mca1p, has a role as a healer as well as an executioner. It saves the daughter by degrading and proteolytically clearing away the aggregated bundles clogging up her cell.
Scientists already knew that HSP104 was a key player in making sure that aggregates stayed with mom. Hill and coworkers used this fact and performed a genetic interaction screen using HSP104 to identify MCA1 as required to keep protein aggregates out of the daughter in response to a heat shock. Follow up work confirmed this result by showing that overexpressing MCA1 led to more efficient segregation of aggregates and that deleting it led to poor segregation of aggregates.
Digging deeper, these authors found that this poor segregation was because Mca1p was not eliminating aggregates in the daughter, as opposed to affecting the segregation itself. They also showed that the protease activity of Mca1p was needed for this effect.
In the final set of experiments we’ll discuss, the authors looked to see what effect MCA1 has on the life span of a yeast cell. They saw little effect of deleting MCA1 unless a second gene was also deleted: YDJ1, which encodes an HSP40 co-chaperone. The double deletion mutant yeast were able to divide fewer times before petering out. Consistent with this, overexpressing MCA1 led to increased life span and this effect was enhanced in the absence of YDJ1.
Finally, cells lived for a shorter time if just the active site of the Mca1p protease was compromised in a ydj1 deletion background. This again confirms that proteolysis is key to MCA1’s effects on aging.
So yeast attains eternal youth by both dumping its age-related aggregates on its mother and by using Mca1p to destroy any aggregates that managed to get into the daughter. The daughter gets a reset until she builds up too many aggregates, in which case she gets saddled with them.
Yeast may be showing us another way to live a longer life. If we can specifically degrade our aggregates without causing our cells to commit mass suicide, maybe we can extend our lives. And we don’t even need fancy teleporting machinery; we just need to adapt the molecular machinery yeast is born with. Feel free to use this idea for a new science fiction story!
by D. Barry Starr, Ph.D., Director of Outreach Activities, Stanford Genetics
Categories: Research Spotlight
Tags: ageing, caspase, protein aggregates, Saccharomyces cerevisiae