Cell Polarity and Aging - A Unifying Theory

I just read this fascinating theory that was fully explained in a review that appeared in the latest issue of Cell. This theory connects the origin of cell polarity with aging and it suggests that the centrosome may carry genetic information. Today I'll focus on the first deep connection polarity and aging. Later this week, I'll write about how the centrosome fits in.

What is polarity?

It is the mechanism by which the cell reorganizes its internal structure so that it now has two different sides. These two sides could by "front" and "back" or "up" and "down". So that if you are a crawling cell it dictates which part of your body is driving migration (the leading edge) and which part is retracting (the tail). It also forces your organelles to reposition them selves with respect to the two sides. Thus in a crawling fibroblast,

1) the nucleus is repositioned from a random position to a location between the microtubule organizing center (MTOC) and the back of the cell
2) an actin meshwork is formed just beneath the leading edge and is swept back towards the cell body
3) vessicles are transported from the golgi, which lies at the MTOC, to the plasma membrane right at the leading edge
4) actin based contraction is activated near the rear of the cell
...

But polarity is not only for crawling cells. If you are a cell that lines the gut wall, cell polarity signals dictate which part of the cell is facing the inside of the gut, where food is being digested, and which part if facing the blood system, where all the metabolites from digestion must end up. If you are a neuron it dictates which cell extensions (or neurites) become dendrites, where incoming impulses from your neighbors are collected, and which neurite becomes your axon, where outgoing impulses are sent. In each case, the polarization mechanism aligns all of the insides of the cell to accomplish any one of these tasks.

It turns out that the molecules that determine cell polarity are conserved throughout eukaryotes. Three core proteins in this signalling cascade are
1) the G-protein known as Cdc42
2) the molecular motor dynein and its associated complex dynactin
3) actin polymerizing protein proteins, the formin family members and the Arp2/3 complex.

In animals a fourth set of important players are the Par proteins.

The question becomes why would such a diverse set of cells, including yeast and plasmodium (that unicellular pathogen that causes malaria) care so much whether they have a front and a rear? These unicellular cells don't crawl, they don't form part of a larger organ such as the gut, they don't have neurons. So why?

Part of the answer is that in certain circumstances they do need to organize themselves in response to extra-cellular cues. Yeast of different mating types tend to fuse together, just like our egg and sperm do, in order to recombine the two genomes. So one yeast will "shmoo" towards it's mate. The shmoo tip can be thought of the the front of the cell and the rest is the cell's rear. Likewise when plasmodium invades a red blood cell it uses the same proteins to polarize towards the host. In all cases Cdc42 like proteins mark the site of polarity, actin is polymerized right at that site and swept back towards the rear, the nucleus is positioned between the MTOC and the "front". All eukaryotic cells seem to do the exact same thing.

Although most of these proteins are not conserved in bacteria, most bacteria do polarize as well, and they tend to use similar strategies to accomplish this task.

But if you dig deep down and observe why most yeast and bacteria polarize, you realize that there's another curious event coupled to polarization, and it has to do with cell division and aging.

Let's pretend you are a unicellular organism - what would be the best strategy to ensure the long-term multi-generational survival of your lineage?

Over your short life you've done a lot of good. You duplicated your DNA into two, you've made lots of macromolecules like ribosomes and some metabolites such as lipids and amino acids. But you have also accumulated lots of harmful crap, such as damaged proteins, aggregated insoluble crap, and mutations in your genome. Now much of the garbage can be destroyed and recycled, but some of it is ... well you're just stuck with it. What is the best course of action? And remember you have to out compete your neighbors.

One approach is to distribute everything equally amongst your two offspring. Everyone gets a copy of the DNA genome, everyone gets metabolites, everyone gets the crap. Lets say you make 10 arbitrary units of crap in your lifetime. That means that you'll give half of the crap (5 units each) to each new cell. Then over time the next generation will probably make as much crap as you did, about 10 units each, so that by the time they divide each cell has 15 units of crap and their offspring will start off 7.5 units of nastiness. As you can plainly see, with each generation the crap builds up and everyone is unhappy.

A second approach is to give all the crap to one of the two new cells and keep the other one pristine. Lets call these two cells the crap cell and the pristine cell. What's the result of this second strategy? Using our crap metric from above, the first cell accumulates 10 units of garbage over its lifetime and then gives it all to one offspring, the crap cell, and none to the other offspring, the pristine cell. Those cells then grow and by the time they divide each second generation cells have made 10 units of additional crap each. The crap cell has 20 units the pristine cell 10. The two cells divide and dump all their garbage on one of their offsprings. One cell starts with 20 units of crap, one cell with 10 units and two cells are again crap free. The end result of this strategy? Part of your descendents will become more and more decrepit as they fill up with crap, while others remain pristine.

If the two strategies described above were to meet and compete, then you could easily pick out the winners of such a contest. The pristine cells, unburdened with garbage, grow faster and are more resistant to stress then either their crappy siblings or the fleet of cells that divide their crap equally. Yes the best strategy under certain circumstances is to pump all your resources into a winner and thus create at the same time a natural born looser in the process. And in fact this second strategy is exactly what budding yeast do.

But in order to create unequal offspring, budding yeast use the polarity pathway.

How?

Take one cell. Then use the cell polarization machinery to chose a front and a back. Then divide. The rear becomes a crap cell (aka the mother cell) while the front becomes its pristine sibling (aka the daughter cell). The crap cell inherits all the agregates, the old macromolecules that might have some damage, and the old cell body.

But for the pristine cell, everything is new. Its cell body is a newly sprouted bud that emerges from the site of polarization. A "polarisome" complex at the tip of the bud helps produce long actin cables that stretch all the way into the mother cell body. Motor proteins use these tracks to deliver new material into the bud. Microtubules that emanate from the nucleus are captured by the polarisome and are then used to drag the pristine cell's share of the genetic material into the bud. Mitochondria and endoplasmic reticulum are also actively transported into the bud. There is one catch, the actin and microtubule tracks must cross the bud neck. To enter into the pristine cell proteins and organelles must pass through this highly guarded constriction. Crap, old macromolecules, such as nuclear pore complexes, and damaged DNA are barred from entering into the bud. Nothing is left to chance.

In fact any risky behaviors, such as DNA rearrangements that promote mating type switching, are confined to the crap cell - you don't want the pristine bud to undertake such potentially hazardous tasks.

From these asymmetric cell divisions there is always one lineage of cells, a long line of "mother cells", that inherits crap generation after generation. This lineage becomes more and more decrepit and after about 30-40 generation, the poor mother cell lineage can no longer sustain itself and eventually enter into a state of non-replication (i.e. senescence). Accumulating all this crap takes a toll.

But is this connection between polarity and senescence extends beyond the world of yeast. Everything I above happens more-or-less in our stem cells. It turns out that the determinants of stemness are dictated by the same polarity signals that promotes the production of a daughter bud and a mother cell in yeast.

Think about it. When a stem cell divides, one offspring retains stemness, the other cell can either be a stem cell as well or become a cell that activates a genetic program that allows it to differentiate. In the second scenario you have an asymmetric cell division. It turns out that the SAME POLARITY PROTEINS ARE USED TO GENERATE THESE TWO UNEQUAL CELLS. Just replace the bud with the stem cell, to be kept in pristine condition, and the mother with the differentiating cell, an entity with limited proliferation potential. In fact if you look at polarity in other systems, such as asymmetric cell division in worms, you'll note the the polarity signaling cascade (Cdc42, Par proteins, etc) are involved in determining which cell gives rise to the germ cells (i.e. the ultimate stem cells to be kept pristine from generation to generation) and the rest of the body (i.e. the crap-filled cell , the mother).

So there you have it - a deep connection between polarity and aging.

(If I have time, I'll post something with regards to how the centrosome fits into all of this.)

Ref:
Ian G. Macara and Stavroula Mili
Polarity and Differential Inheritance--Universal Attributes of Life?
Cell (08) 135:801-812