The acid test
Why do some yeast cells grow old whereas others do not?
Dr Chris Smith spoke to Kiersten Henderson from the Fred Hutchinson Cancer Research Center about how aging occurs...
Chris - An interesting feature of many cell types is that they can divide asymmetrically, meaning that the mother and daughter cells are different, and the same can apply to aging with a progressively senescing mother cell repeatedly giving rise to youthful offspring, but how? Kiersten Henderson has been looking yeast to find out.
Kiersten - We're interested in understanding how cells age and we're doing that using a microbe, which is a model organism called budding yeast. And we simply began by asking what happens to cells as they age, and we did that by looking at the functions of different compartments or organelles inside the cell during aging, and we noticed that the function of a particular compartment, called the vacuole, declines with age. So, normally what happens in the vacuole, it stores ions and amino acids - so, things that could potentially be harmful to the cell but are necessary to cells, and also proteins are degraded there, they are unwanted. And we noticed that vacuole function declines pretty early in aging, and we wanted to figure out how it is that that occurs.
Chris - How did you do that? How were you investigating what those vacuoles were doing and why they deteriorate, or for want of a better phrase, "Clap out," as the organism ages? And what is aging in the context of a yeast?
Kiersten - Well, aging in a yeast is defined, and this happens to our cells, human cells also, they only undergo a certain number of divisions and then they stop dividing, and they take on characteristics of age. They just don't look as healthy. A really interesting feature, though, of budding yeast is that aging is asymmetric between the original cell and the daughter cell that it produces. We were able to use that observation to ask, because we expect that the factors that are causing aging will also be asymmetric between mother cells and their daughter cells. And we found, when we looked at the vacuole, yes, it's function declines during aging but the function is regained in daughter cells, so, they're born young even though the mother cell is aging. They're rejuvenated. So, we wanted to see what was it that was causing this decline in vacuole function but the rejuvenation of vacuole function in daughter cells. And we started by looking for proteins that were retained in mother cells during aging, so it just weren't passed on to daughter cells, and we found, one in particular, the protein at the membrane of cells and it's job is to regulate the acidity of cells.
Chris - It's fascinating to think that an aged mother can have a pristine cellular offspring, or daughter, isn't it? And it's interesting that the yeast knows in inverted comas "how to partition," so that you get a pristine daughter and an aged mother. What are the chemicals that are contributing to the aging, the ones you've discovered that are these membrane proteins? What do they actually do, and why are they partitioned asymmetrically in that way do you think?
Kiersten - Well, we don't know why they're partitioned asymmetrically, but right now, one of them in particular that we find initiates aging and affects the function of the vacuole. It's job is to regulate the acidity inside the cell, so it moves protons, which are acid equivalents outside of the cell and that protein that's on mother cells is very, very low on newborn daughter cells as they emerge from the mother cell as they are being formed. That actually allows the pH or the acidity inside the newborn daughter cell to be normal again. The amount of acidity in a mother cell is actually declining with age but it becomes normal again when daughter cells are born, and that actually allows for normal function of organelles inside, like the vacuole inside daughter cells.
Chris - Do you think this is cause or effect? In other words, are you seeing something which is a consequence of the aging process, or do you think this is something that's causal of the aging process?
Kiersten - Our goal was to identify factors that actually cause aging, so we're able to modulate the amounts of this particular protein at the membrane and actually affect lifespan. So, if we decreased the amount and make the inside of the cell more acidic and allow for a more normal function of organelles, like the vacuole, this actually extends lifespan.
Chris - So, why don't all cells then just do that themselves? Why don't they evolve to perpetuate themselves and therefore not age as fast or is that indeed, what does happen in say, cancer cells which have an indefinite lifespan potentially?
Kiersten - So, there's definitely a trade-off for this function. It's an essential function for young cells, so they have to be able to do this to grow properly, so they can't simply reduce function. So, there's definitely a trade-off because there needs to be less function to get a longer lifespan but it causes aging ultimately.
Chris - And of course, the killer question that everyone is dying for me to ask. Have you found the fountain of youth? Is there a way to reverse this process, or to minimise the aging process on the basis of what you found, at least, in yeasts that we could potentially extrapolate to our own cells and slow down aging?
Kiersten - Well, everyone who discusses my work with me likes to joke that proton pump inhibitors, which change the acidity inside cells, could potentially extend lifespan, but we really don't know yet how that would affect things.
Chris - So, maybe I'll put myself on Omeprazole, just in case. That was Kiersten Henderson from the Fred Hutchinson Cancer Research Institute.