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Nothing
sounds more unscientific, more starry-eyed and unrealistic,
than the quest for immortality. But yet, as each year passes,
a greater percentage of the very down-to-earth pharmaceutical
industry is devoted to precisely this pursuit. The quest
to beat death, to halt the apparently – but not necessarily
– inevitable decline of the human mind and body with
the progress of time.
Of course, the goal of eluding death long pre-exists science.
It has taken hundreds of forms throughout history, pervading
all cultures and eras. The ancient Chinese, for instance,
had Taoist Yoga, a very complex discipline defining a life-long
series of practices that, if adhered to precisely, purportedly
resulted in physical immortality. Part of this teaching
was that, by refraining from ejaculation for his entire
life, a man could store his “essential energy”
in a space by the top of his head, until he accumulated
enough to create an eternal fetus that would grow into his
deathless self. The modern variation of such ideas is less
colorful but perhaps more likely to succeed: subtle biological
and pharmaceutical research aimed at discovering the roots
of aging, and creating chemical remedies.
The increasing number of elderly is one of the major trends
in current demography. For instance, in 1950, only one in
ten U.S. citizens was over the age of 65. Now the figure
is about one in 8; and by 2030 it may be 1 in 5. There’s
little doubt that the current human age record of 122 (Madame
Jeanne Calment, who died in 1997) will soon be overturned.
This ongoing increase in lifespan has been primarily due
to a reduction in various deadly diseases, resulting from
improved hygiene and medical care.
But one thing our success at reducing disease has taught
us is this: the real killer is not disease, but senescence.
After a certain amount of time, the body’s microscopic
parts just stop working, of their own accord, without the
interference of any germs or viruses or cancerous mutations.
This is the essential dark side of the human condition,
and the focus of current scientific work on anti-aging.
Scientists have a “short list” of biological
and biochemical factors suspected to collectively underlie
aging -- and for each of these likely culprits, there is
a pharma firm or a maverick scientist working on the cure.
It is entirely plausible that within decades – not
centuries or millennia – pharmacological science will
have made the very concept of getting old obsolete.
A
healthy body is not a constant pool of cells, but rather
a hotbed of continual cellular reproduction. There are only
a few exceptions, such as nerve cells, which do not reproduce,
but simply persist throughout an organism’s lifespan,
slowly dying off. In youth, newly formed cells outnumber
dying cells; but then from about 25 on, then, things begin
to go downhill, and the number of newly formed cells is
less than the number of cells that die. Little by little,
bit by bit, cells just stop reproducing.
The sad fact is that most types of human cells have a natural
limit to the number of cell divisions they will undergo.
This number, usually around 50 or so, is called the Hayflick
limit, named after Leonard Hayflick, the researcher who
discovered it in the mid-1960’s. Once a cell's Hayflick
limit is reached the cell becomes senescent, and eventually
it dies.
This may have the sound of inevitability about it –
but things start to sound different when one takes a look
at our one-celled cousins, such as amoebas and paramecia.
These creatures reproduce asexually, by dividing into two
equal halves – neither half sensibly classified as
“parent” or “child.” This means
that essentially, the amoebas alive today are the same ones
alive billions of years ago. These fellows qualified for
social security a rather long while ago, and yet they’re
still alive today, apparently not having aged one bit –
cells untroubled by the Hayflick limit. This nasty business
of aging seems to have come along with multicellularity
and sexual reproduction – a fascinating twist on the
“sex and death” connection that has fascinated
so many poets and artists.
Unlike in asexually-reproducing creatures, cells in multicellular
organisms fall into two categories: germ-line cells which
become sperm or egg for the next generation; and soma cells
that make up the body. The soma cells are the ones that
die, and the standard answer to “Why?” is “Why
not?” The “disposable soma theory” argues
that, in fact, our soma cells die because it’s of
no value to our DNA to have them keep living forever. Throughout
most of the history of macroscopic, sexually-reproducing
organisms, immortal organisms would not have had an evolutionary
advantage. Rather, there was an evolutionary pressure toward
organisms that could evolve faster. And if a species is
going to evolve rapidly, it’s valuable for it to have
a relatively rapid turnover from one generation to the next.
There doesn’t seem to be any single cellular “grim
reaper” process causing soma cell senescence. Rather,
it would appear that there several distinct mechanisms,
all acting in parallel and in concert.
There are junk molecules, accumulating inside and outside
of cells, simply clogging up the works. And then there are
various chemical modifications that impair the functioning
of molecular components, such as DNA, enzymes, membranes
and proteins. Of all these chemical reactions, oxidation
has attracted the most attention, and various anti-oxidant
substances are on the market as potential aging remedies.
Another major chemical culprit is “cross-linking”:
the occasional formation of unwanted bridges between protein
molecules in the DNA – bridges which cannot be broken
by the cell repair enzymes, interfering in the production
of RNA by DNA. Cross-linkages in protein and DNA can be
caused by many chemicals normally present in cells as a
result of metabolism, and also by common pollutants such
as lead and tobacco smoke.
As time passes, signalling pathways and genetic regulatory
networks within cells can be altered for the worse, due
to subtle changes in cellular chemistry. The repair mechanisms
that would normally correct such errors appear to slow down
over time. “Telomeres,” the ends of chromosomes,
seem to get shorter each time a cell divides, causing normally
suppressed genes to become activated and impair cell function.
And finally, the brain processes that regulate organism-wide
cell behavior decline over time, partly as a result of ongoing
cell death in the brain.
The really frustrating thing about all these phenomena is
that none of them are terribly different from other processes
that naturally occur within cells, and which cells seem
to know quite well how to cure and repair. It would seem
that cells have just never bothered to learn how to solve
these particular problems that arise through aging, because
there was never any big evolutionary advantage to doing
so. We may well die, not because it would be so hard to
engineer immortal cells, but because it was not evolutionarily
useful to our DNA to allow us to live forever.
Curing
old age is one kind of speculative research that modern
capitalist society seems relatively willing to fund.
For instance, Larry Ellison, the controversial 55-year-old
chief executive of Oracle, is the largest single supporter
of anti-aging research, with $20 million per year committed.
He may be the second-richest man in the world, but he’s
smart enough to realize that “you can’t take
it with you” – and he’s deploying his
wealth strategically with this in mind. He makes no bones
about his motivations. ``Death has never made any sense
to me,” he says. “How can a person be there
and then just vanish, just not be there? … Death makes
me very angry. Premature death makes me angrier still.”
Much of the funding for anti-aging research, though, comes
not from immortality-obsessed visionaries, but from stolid
biotech firms concerned with curing particular diseases.
As it turns out, most of the factors underlying aging are
also connected to various particular medical conditions.
This dual focus drives the R&D of dozens of pharma firms.
For instance, Centaur Pharmaceuticals discovers and develops
new drugs for various diseases involving ischemia and inflammation,
which its scientists believe will also have general anti-aging
properties. Geron focuses on telomere shortening and cell
death, with applications both to anti-aging and to cancer.
Human Genome Sciences works on understanding signal transduction
pathways – how they work, why they fail and how to
repair and redirect them – a quest which, if successful,
will have myriad applications.
Perhaps the most advanced work in the field is going on
at a company called Alteon Inc. Alteon has picked up a train
of research begun in the early 1900’s, regarding the
formation of complexes between sugars and the amino acids
of proteins. At first these complexes were found to cause
the toughening and discoloration of food observed during
the cooking process and after prolonged storage. It was
later determined that these same structures were part of
a new biochemical pathway in which permanent glucose structures
were formed on the surface of proteins. These structures
-- "Advanced Glycosylation Endproducts" or A.G.E.’s
-- were seen to interact with adjacent proteins to form
pathological links between proteins, called A.G.E. crosslinks.
And these crosslinks seem to play a critical role in diabetes,
as well as in the Hayflick limit of various human cells.
Alteon is currently testing medication that promises to
prevent this crosslinking from occurring.
But
even Alteon’s drugs aren’t yet on the market.
If one wants to live as long as possible, what can one do
right now?
The most promising, immediately applicable anti-aging work
has to do not with pills but with caloric restriction. There
is increasing evidence that if you eat about 70% of what
you’d ordinarily want, you’ll live a lot longer.
You need to eat a healthy diet, rich in vitamins and proteins,
but low in calories.
This has been tested extensively in various nonhuman mammals.
For instance, mice normally don’t live over 39 months,
but caloric restriction has produced mice with 56 months
lifespan. This corresponds proportionally to a 158 year-old
human. And these long-lived mice aren’t old and crusty
-- they’re oldster/youngsters, keen-minded, strong-bodied
and healthy. Studies on monkeys are currently underway,
though this naturally will take a while, due to monkeys’
relatively long lives.
Why does caloric restriction work? It increases the ability
of the body to repair damaged DNA, and it decreases the
amount of oxidative (free radical) damage in the body. It
increases the levels of repair proteins that respond to
stress, it improves glucose-insulin metabolism, and for
some reason, not fully understood, it delays age-related
immunological decline as well. Basically, many of the well-known
mechanisms of senescence set in more slowly if the body
has to process less food over its lifetime. Of course, it’s
not yet demonstrated that caloric restriction will do for
humans what it’s done for other animals, but none
of the researchers involved with the work seems to have
much doubt. The relation of this line of thinking with anti-aging
pharmacology has yet to be investigated – it may well
be there are medications that work most effectively in coordination
with a caloric restriction diet.
The caloric restriction work looks highly believable…
however I have to admit I don’t have the will to try
it out myself. I’m a fairly thin person, not a heavy
eater, but you can’t see my ribs – I enjoy eating
too much to starve myself in hopes of living longer. Anyhow,
no one’s sure how much good severe caloric restriction
would do me, if I started it out at my current ripe old
age of 35. However, if you have more willpower than I do
in this regard, and you try it out yourself and reach 150
or so, please send me an e-mail and let me know!
The
Immortality Pill is not yet available, alas. The pharma
Fountain of Youth is not yet upon us. But the first batch
of serious anti-aging medications is coming soon to a pharmacy
near you. Funded by a mixture of visionaries and pragmatists,
biochemists, geneticists and pharmacologists are going to
chip away at the problem of cell senescence, bit by bit,
gene by gene, biochemical process by biochemical process,
year after year, decade after decade. And with each new
drug and each new dietary recommendation they produce, the
average human lifespan will get longer and longer. No end
is in sight. The process of scientific advance may be too
slow to save us from dying -- but for our grandchildren,
or great-great-grandchildren, “old age” may
well be something they read about in the history books,
along with black plague and syphilis, an ailment of the
past.
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