13 Things That Don't Make Sense (17 page)

The tantalizing thing is, we know how to stop cells from dying. Cancer cells contain an enzyme called
telomerase
that restores the telomeres to their full length on each division. It is this that enables them to go into the runaway replication
that causes tumors to grow so fast. We could avoid the shortening of our telomeres if our cells could produce telomerase.
And they can.

In early 1998 a group of researchers led by Andrea Bodnar of the Geron Corporation in Menlo Park, California, announced they
had put a gene that activates telomerase into normal human cells, and the cells had lived twice as long as untreated cells—and
they were still going strong at the time of publication in
Science
. The cells looked good; they had the characteristics of young cells. The activated telomeres meant they had avoided the curse
of replicative senescence; they were, to all intents and purposes, immortal.

The only problem is, you don’t want immortal cells in your body because they would most likely grow into tumors. Telomere
shortening might hasten our rate of aging, but it can also protect us from cancer. It’s a tradeoff. That is also true of another
form of programmed cell death:
apoptosis
.

Apoptosis occurs in response to chemical signals. Viral infection, cellular damage, or just stress on the organism can stimulate
these signals, which take the form of hormones, growth factors, and even nitrogen monoxide. All of them can tell a cell to
die: enzymes called
caspases
start to break the cell down; the cell, effectively, eats itself. Apoptosis is an essential part of development—without it,
your hand would not have separated fingers, for example—but when it goes wrong and allows cells to live forever, it also plays
a role in the onset of cancer.

What we want to achieve in the fight against cancer is so much more complicated than simply having cells that live forever.
Somewhere in here, though, is a tantalizing secret. “Perhaps,” said the authors of a
Nature
review on cancer and aging in August 2007,“somewhere within the curse of the cancer cell’s immortality there might also lie
the secret of how we might understand and extend our own lifespan.” Not that we should hold our breath for a cure; when it
comes to understanding the roots of cancer and aging, “most of the fundamental questions remain unanswered,” the authors admit.

SO
we are left with two viable but contradictory theories. In the one camp, aging is controlled by a genetic switch that can
only have arisen through some reproductive trade-off. In the other camp—Hayflick’s camp—aging is simply the result of accumulated
defects. Cells grow old and die because of copying errors and cell shutdown. It’s not about reproduction or genes; it’s about
time.

Who’s right? If we go by the scientific data, neither camp. There is evidence that contradicts both theories.

First, there is a fruit fly problem. When Michael Rose of the University of California, Irvine, began to breed long-lived
fruit flies in 1980, their fertility declined. Things were looking good for antagonistic pleiotropy: long life came at a reproductive
cost. But then, as the life span got even longer, the fertility began to rise—above the fertility of the normal, unenhanced
flies. The flies were living 81 percent longer than the control group and were 20 percent more fertile. It’s not the only
time such an anomaly has been seen; Ken Spitze of the University of Miami bred fleas with increased life span and increased
fertility. It shouldn’t happen.

An additional problem for the theory comes from the observations of what caloric restriction—Cynthia Kenyon’s diet of choice—achieves.
Caloric restriction is thought to lower the metabolic rate and slow the production of cell-damaging chemicals known as
free radicals.
It certainly seems to lengthen life span—at least in mice, fish, worms, yeast, and rats. But the vulnerability to senescence
that can be controlled through caloric restriction doesn’t appear to have come about through antagonistic pleiotropy; controlling
your calorie intake and thus lengthening your life span doesn’t have the effect on fertility that it should. In experiments,
female mice shut down their reproductive capability at 40 percent caloric restriction, but their longevity continues to rise
if the restriction is continued up to starvation levels. Since resources are not being expended on reproduction beyond the
40 percent restriction mark, the extra longevity can only be coming from somewhere else.

Then there is the genetic switch problem. In research like Kenyon’s, with
C. elegans
, single genes have been switched on or off to control aging. As her group point out in a 2003 paper in
Science
, in many cases there is simply no cost to this—not in health and not in fertility. Pleiotropy appears to be there—if you
go so far as to remove the worms’ reproductive systems, it makes them live another four times longer—but it is not a primary
cause of senescence.

There’s no recourse to the “grandmother gene” benefit either. While in higher animals such as birds and mammals a long postreproductive
life would help in rearing the next generation, there’s no need for it in the roundworm. They do not nurture their grandchildren,
cooperate in groups, gather food for their young, or have to teach them how to fly. And yet
C. elegans
has a decent life span after reproduction. As the mathematician Joshua Mitteldorf puts it, “resources are being squandered
on a useless life extension.”

Mitteldorf, seeing the tensions between theory and experiment, became fascinated by the evolutionary biology of death. In
2004 he laid out all the evidence he could find in a paper published in
Evolutionary Ecology Research
. His conclusion was that there was no conclusion; the evolutionary origin of senescence remains a fundamental, unsolved problem.

Among the evidence, there is certainly no good news for the Hayflick camp, he says. If senescence were due to the accumulation
of mutations over a life span, the older you take fruit flies and breed them for early mortality, the easier it should be
to effect a change; damaging mutations should be there in spades. But the opposite is true. The older the flies are, the harder
it is to breed for early death in the next generation. What’s more, such a stubborn refusal to change is usually an indicator
of a finely tuned mechanism that has been selected for by evolution. Death, here, is a program, and one that has been optimized.

Then there is the
mortality plateau
, which defeats all comers. The disposable soma camp says an organism won’t repair itself after reproduction, so will be in
continuous decline. The mutation accumulation theory expects the same result to occur by default (reproduction has nothing
to do with it). The antagonistic pleiotropy theory is no different; the negative effects of the genes that gave advantage
earlier in life will kick in one by one as the clock ticks onward. But culture a population of fruit flies, and the fraction
that die per day only increases with their age until a certain point. After that, the fraction that die per day stays flat.
That doesn’t fit with any theory.

In other words, there’s no good explanation for death. But if Mitteldorf has laid out the case against the popular theories
of senescence with aplomb, what is he offering us in their place? The sheer, wanton perversity of group selection: species
dying specifically to make room for the younger generation. Aging, Mittledorf says, evolved for its own sake, not as a by-product
of better reproduction.

No one’s buying that argument, though, because, as Mittledorf puts it himself, it “casts a shadow on a great body of evolutionary
theory.” He is right—and there is something familiar about this shadow. We are staring at the biological version of dark matter:
a series of anomalous observations, complete with a possible explanation that opens up one can of worms too many. A seemingly
good explanation would force us to rethink an ancient and vital part of the theory. Darwin’s theory of natural selection,
which
can not
work via group selection, is the biological version of Newton’s universal law of gravitation. Does it need a tweak? It seems
it might. Will the majority accept the tweak that has been suggested? Certainly not.

At the moment, we seem to be in the “ignore it” phase of this anomaly. The researchers looking into genetic switches for senescence
have enough on their plates with finding the elixir of life. The other camp, those who think the former are selling (or at
least researching) snake oil, have convinced themselves there is no anomaly. In April 2007 Hayflick published a paper under
the title “Biological Aging Is No Longer an Unsolved Problem.” Sweeping aside the ranks of senescence researchers who have
exposed strikingly effective genetic pathways, Hayflick announced that the random accumulation of mutations is responsible
for aging and death. If Cynthia Kenyon can make her worms live longer, that’s because she is activating genetic switches that
guard against certain diseases that would normally finish off a worm within a fortnight. She is mitigating against disease—admittedly,
disease that is associated with old age—but she is not solving the problem of aging. Put simply, Hayflick and his followers
believe the worms live longer because they are made stronger. And that’s not the same as destroying time’s power over biological
molecules.

Kenyon and the other advocates of a genetic route to holding back the years don’t agree and are aggressively pursuing their
research. There are senescence switches, they say; find them, and flick them, and we can live forever. If only we could harvest
the genetics of the long-lived species, the Blanding’s turtle, say, or the Bowhead whale, which has an estimated life span
of over two hundred years, we might find even more clues to immortality. But there are technical difficulties with doing this;
culturing their cells is difficult, and there are legal issues with keeping and using such animals in research. And so it
seems that the arguments about death will, like the Blanding’s turtle, go on and on.

THERE
is one clue that might take us forward. Cynthia Kenyon’s studies of genetics tell us that aging is regulated by the same biochemical
pathways in yeast, flies, worms, and mammals. If the mutations arose through random chance in the various species, each would
have a different mechanism. But they don’t; everything ages the same way. The reason is obvious, according to William R. Clark,
a senescence researcher at the University of California, Los Angeles: senescence must have evolved in a common ancestor of
today’s species. Death, Clark believes, arose with the first eukaryotes, the organisms whose large and complex cells contain
a nucleus that holds heritable information.

The story begins about 3 billion years ago, when the prokaryotes, the bacteria, and archaea, ruled the Earth. At some point
these organisms evolved the ability to use light to split water into its constituent parts: the protons and electrons of hydrogen
atoms, and oxygen. The protons and electrons made photosynthesis happen, giving the bacteria a very useful commodity: energy.
The oxygen was released, an unwanted by-product of the process.

Most of the oxygen was absorbed by the green, iron-rich oceans of the era, creating heavy red particles of iron oxide that
settled on the seafloor (a floor that has since been lifted out of the water by geologic shifts, the exposed red bands of
rock giving us clues to this ancient past). When the iron was all used up, oxygen began to leak into the atmosphere above
the oceans. As the concentration of oxygen in the air rose, it brought on the
oxygen catastrophe.

Oxygen is highly toxic. When it breaks up, as it can in sunlight, the oxygen radicals formed can wreak havoc on biological
cells. Around 2.4 billion years ago, the buildup of oxygen in the atmosphere eventually led to a mass extinction of the prokaryotes.
They were, in effect, victims of their own innovation. Only those organisms living deep in the ocean, at a safe distance from
strong sunlight, survived, evolving strategies such as aerobic respiration to cope with an oxygen-rich environment.

In fact, they did more than cope; they developed sophisticated and highly efficient means of turning oxygen into ATP, the
fuel for all biological cells. It was such a successful innovation that it was soon pirated; as the eukaryotes emerged, they
engulfed the energy-generating bacteria and put them to work. It was a doubly beneficial takeover because the bacteria had
also evolved protection against the corrosive nature of oxygen, something that the eukaryotes took as part of the package.

There was just one problem for the eukaryotes: they had installed oxygen radical generators in the hearts of their cells.
The mitochondria in our cells are the fossil remnants of the original ATP-generating bacteria, and though they allow us to
generate energy, they also produce damaging oxygen radicals. There is, as they say, no such thing as a free lunch.

The problem, it seems, was big enough to require a truly innovative solution: sex. Or that’s what Clark thinks. We still don’t
know exactly why sex evolved, but he is right; it may well have been provoked by the evolution of death. Sexual reproduction’s
process of gene swapping and shuffling allows DNA correction and repair, giving the descendant a potentially advantageous
new set of genes. That is certainly beneficial in the context of the trade-off already going on between energy production
and cell damage.

The only problem is, sex may have then encouraged more death mechanisms to evolve. If you have a new set of genes, you don’t
want the old, damaged ones getting in the way; if there is a means of removing the old set, it would prove useful. And such
means exist. We know that in the group of aquatic organisms known as ciliates, a process of
apoptotic nuclear destruction
removes old DNA from the nucleus to make room for the new genetic combinations. It is a death mechanism, and it makes sense
that it was positively selected for.