Aging in Microbes

Aging is very old.

Long before there were plants and animals, aging was fully-developed in one-celled eukaryotes and before that in bacteria.  This seems strange–almost paradoxical.  In fact, for a long while, biologists would have said for aging to exist in bacteria was somewhere beetween “impossible” and “meaningless.”

In 1957, George Williams published what has since become the standard, accepted theory of why aging exists and how it arose.  In a seminal article, he listed eight numbered predictions of the theory, six of which have not fared very well.  But the prediction that met the most direct and flagrant contradiction was the one he probably felt was the surest bet: “There should, therefore, be no senescence of protozoan clones.”

 

With and Without Sex

The rules of the evolutionary game are different in sexual and asexual communities, and consequences for the strategies by which the game is played are dramatic.  In a sexual community you can be pretty sure that if you succeed in mating and your offspring survive, then your genes have a future.  Some of them will continue on, and others will be out-competed, and some of them will succumb to genetic drift and disappear.  Successful individuals will pass a lot of their genes into the future, and unsuccessful individuals will leave only a few.  Conversely, looking back in time, you have two parents, four grandparents, eight great grandparents, etc.  By the time you get to 20 generations, that’s a million people, and probably they’re not all different.  (People marry their sixth and fifth and even fourth cousins all the time and never know it.)

But in asexual communities (this may not be obvious) it’s winner-takes-all.  If you have a stable colonty of a billion bacteria, the laws of population genetics (essentially just statistics) say that within 100 generations, descendents of all but one of that original population will have disappeared with no legacy.  Everyone alive 100 generations from now will have been descended from a single individual alive today.  Bacteria breed rapidly, and 100 generations of bacteria might be about two weeks.

 

Aging in Bacteria

Because of this winner-take-all competition, bacteria are using every trick in the book to get ahead, or even get a tiny edge.  For example, their genomes are far more compact and economical than yours and mine because the time it takes to copy the DNA can limit the speed of their reproduction.  One trick for getting ahead is asymmetric reproduction, and asymmetric reproduction was the first form of aging, the “birth of death” if you will.

Let’s say you were one of these bacteria, trying to beat the billion-to-one odds and be the one and only great-grandfather of the future.  You want to split in two, and as quickly as possible.  The quicker you divide, the quicker your odds go from 1 in a billion to 2 in a billion.  You can do a little better yet if you divide asymmetrically, giving a little boost to one of your two progeny at the expense of the other.  If the lesser twin loses, it’s no great loss–after all, losing is what you expected anyway.  But if the greater twin has a little extra juice, that could make all the difference.  This is especially true, since the better offspring of the better offspring is doubly endowed, and might have an advantage that grows from one generation to the next.

Some rod-shaped bacteria actually perform this trick.  Each new half-rod has one end that used to be an end and one end that used to be a middle.  It retains a subtle memory of its history, and if it has recently come from an end, it is stronger than if it has recently come from a middle.  In this diagram, the generations of bacteria are arrayed as though they stayed close together, strung in a line.  This is just for illustration–in fact they are living and moving separately; but they retain a memory of where in the line they belong.

Rod-bacteria-multiply

 

The bacteria whose virtual positions would have been on the ends are the strongest.  The ones in the middle become weaker and weaker, and eventually this lineage dies out.  This asymmetry in replication of bacteria is the oldest, most primitive form of senescence.

From here, it is a short step to an asymmetry that is more like parent and child.  The “mother” bacterium buds with a smaller version of herself, and again and again.  But the mother won’t keep this up forever–if she is not first killed by something external, she will age–bacterial senescence–and stop reproducing after awhile.  This is real, full-bore aging, in its earliest and most primitive instance.

 

Aging in Protists

Protists (or protoctists) are single-celled life but much larger and more complex than bacteria, the first eukaryotes.  Aging and programmed death in protists is already highly-developed, multiformed, adaptive, and plastic in response to the environment–with all the ecological functions ascribed to aging in animals and plants.  I presume that aging was fully developed in this way long before there was multi-celled life.  There are two principal forms of programmed death in protists.  One is apoptosis, and the other is cellular senescence (telomere attrition).

 

Apoptosis

Apoptosis, or cell suicide, was discovered in the 19th century, and for more than 100 years it was understood to be a multipurpose mode of eliminating cells in the body that are either diseased or merely unwanted.  Before a cell dies “unwillingly” of external causes (e.g., starvation), it goes to every extreme to keep itself alive.  All its protective machinery is engaged in high gear, and when it fails, it fails spectacularly.  The cell is in complete disarray.  Apoptosis is just the reverse.  When the cell receives a signal (either from the outside, or within) it begins an orderly process of closing down its operation, recycling its biochemical stores, and fading gentle into the that good night.  The cell slices up its own DNA, digests its own proteins, and turns itself into useful pieces that other cells might ingest.

During development of the foetus in the womb, much of the body’s shape is sculpted by subtraction (the way Michelangelo did it).  For example, fingers on the hand take shape as cells in webs between the fingers eliminate themselves via apoptosis.  More surprisingly, the brain develops via a process of selection.  Starting with a thousand times more neurons than it needs, they grow connections to one another, and those that remain poorly connected (almost all of them) die via apoptosis.  This process continues after birth, so that an adult has fewer brain cells than an infant.  It is unclear whether this should be regarded as an early form of aging or as part of ongoing brain development.

Later in life, cells that become cancerous detect that they are a danger to the body and fall on their swords, using apoptosis.  Cells that are infected with a virus similarly figure it out early and kill themselves to limit spread of the virus.

All this fits well with theory, and is easy to understand.  Somatic cells have no evolutionary future, no long-term interests of their own apart from the welfare of the body as a whole.  Since they share 100% of their genes with the germ line, they are happy to live and die as appropriate to the needs of the body.

But microbes are independent evolving units, and according to evolutionary theory they are locked in competition with one another.  A yeast cell would never voluntarily sacrifice its own chances for those of another yeast cell…or such was the thinking until 2004.

Readers of this blog are familiar with Valter Longo and his work on fasting and caloric restriction.  In the 1990s when Longo was a grad student at UCLA, he discovered that a starving colony of yeast cells adapts by pruning itself.  95% of the cells die, not of starvation, but via apoptosis.  They digest themselves and turn themselves into food for the remaining 5%.  This was so surprising and counter to evolutionary theory, that early versions of his paper were dismissed and sent back to him with a patronizing message that there must be some error.  Time and again, he returned to the lab to measure all the different biophysical and biochemical signatures of apoptosis.

It was a great education for Longo, both in the biochemistry of apoptosis, and also in the politics of science.  By the time his paper was accepted for publication in the Journal of Cell Biology, Longo was done with his PhD, done with his post-doc, and a young professor at University of Southern California.  And now, 11 more years out, there aremany known examples of apoptosis in protists, and the biology community acts as though “we always knew that.”

 

Cellular Senescense

Cellular senescence was discovered by Leonard Hayflick in the early 1960s, and, like Longo, Hayflick had to overcome a great deal of skepticism and dogma to get his work accepted.  Before Hayflick, the flawed experiments of Alexis Carrel had been accepted for half a century as proof that (even though bodies as a whole are subject to aging) cells could continue to propagate forever.  The mechanism behind the “Hayflick limit” was discovered a few years by Carol Greider and Elizabeth Blackburn.  Every time a cell divides, it loses a little DNA from the ends of its chromosomes, the telomeres.  The telomere is made of repetitive DNA, and carries no information, so it can easily be replenished.  But, curiously, the enzyme that performs the replenishing (telomerase) is locked up epigenetically in most cells most of the time, and so the cells’ telomeres are permitted to shrink until the chromosome becomes chemically unstable, and the cell dies.

The biology community discovered this phenomenon in multi-celled higher organisms, and had a ready explanation for cellular senescence.  Greider herself [1990] supplied the rationale:  cells that divide too many times are probably dividing out of control.  They are cancerous, and cellular senescence is there to put a check on their rogue adventure.  This explanation is accepted overwhelmingly today, though there was never a shred of evidence for it, and in fact cellular senescence in humans actually increases cancer risk.

But long before there was cancer, before there were plants and animals, cellular senescence and the rationing of telomerase evolved in cilliates for quite another purpose.  Ciliates (e.g. paramecia) are some of the most “advanced” protists.  Their cells are surrounded by tiny hair-like cila that they use like oars to propel themselves through the water, and do so in shockingly intelligent ways, pursuing food or fleeing from a predator or locating a mate.

In most protist communities, sex is optional.  Reproduction is via meitosis, simple cell division.  Sex is an entirely separate function, accomplished via conjugation, in which two cells of the same species sidle up to one another, merge their protoplasm, and then exchange DNA, with individual genes swapped between homologous chromosomes.  By the time that two individuals emerge from this process, they have lost their identities, so that each one is “half me and half you”.

The key to understanding cell senescence is that, in ciliates, telomerase is kept under lock and key during the process of mitosis, so the telomeres are permitted to shorten in generation after generation of clones.  But during conjugation, telomerase is freely expressed, and telomeres are restored to their full length, ready for dozens or even hundreds of cell divisions.

What is the purpose of this form of aging?  There can be but one answer:  cell senescence evolved in ciliates in order to enforce the sharing of genes.  In an asexual community, competition is cutthroat, and the winner takes all.  In a sexual community, genes are combined and recombined, diversity reigns, and evolution can follow a far more creative path.  But what’s to stop a particularly macho young stud from opting out of the sex game, reproducing fast and furious, regarding his co-conspirators only as competition and wiping them out?  All the diversity and potential of the community would be lost if this happens.  So cell senescence evolved to prevent rogue individuals from opting out of sexual sharing.

Aging in ciliates evolved for the purpose of promoting a diverse community and enhancing the evolutionary response in adapting to changing environments.  And in higher organisms, aging continues to function in these same ways.

 

The Bottom Line

The present evolutionary theory of aging was formulated in the 1950s, before any of this was known.  It was designed to apply to higher animals that age gradually.   Not even plants (which often don’t age) were considered, let alone semelparity (instant death after reproduction) or any of the topics on this page–cellular senescence and apoptosis and asymmetric division in bacteria.  Hardly anyone ever notices that the standard theory assumes implicitly that aging evolved “late” (after the Cambrian explosion) and for reasons that only apply to multi-celled.

Not only the function and mechanisms are the same, but many of the same genes that regulate aging in microbes also regulate aging in multi-celled animals and plants.  But if the currently-accepted theory of aging is correct, then aging in one-celled life forms must be completely unrelated to aging in higher organisms.  From our present vantage, this seems absurd, but that’s not the way it happened historically.

I believe that aging in one-celled and multi-celled life serves similar purposes to aging in microbes, and the purposes have to do with ecology.  One purpose is population regulation, to keep a population from outgrowing its food supply; the second is to promote diversity and evolutionary change, to keep the population adapting and innovating.

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This article originally appeared here on Josh’s blog Aging Matters.