X-Message-Number: 15160
From: "Mark Plus" <>
Subject: "Gerontological Incertitude"
Date: Fri, 22 Dec 2000 08:28:02 -0800



The biology of growing old

Gerontological incertitude
Dec 21st 2000
From The Economist print edition

Why do people grow old? Recent research has revealed something of what 
happens in ageing, and how it happens. But why? That s another story

THE human race has spent millennia celebrating, damning and defying old age. 
But understanding it, from a scientific standpoint, has long proved elusive. 
Why does the body alter so dramatically with time? In the past decade, new 
tools and fresh ideas have started to give researchers a grip on the  what  
of ageing the complex changes that go on within the body s cells over time. 
They even have some inkling as to the  how  of ageing, the biochemical 
processes which may trigger these cellular phenomena. But why the body 
should become more prone to these pressures in the first place is much 
debated. Ageing is one of nature s almost universal phenomena virtually all 
multicellular creatures, if given a chance, will go through the process but 
still one of its most mysterious.

A distinct process
Non-scientists tend to think of  ageing  as a continuous, lifelong process, 
a series of changes from childhood, or indeed conception, onwards. Most 
biologists have a different view. They see the period of ageing as one 
distinct from that of early development. First come the minutes, months or 
years that a body may spend to put its growing house in order by forming 
cells into organs and systems. Next comes its reproductive phase. Only 
thereafter, say biologists, does the systematic increase in molecular 
disorder set in which, with its effects, amounts to ageing.

They didn t know why. Nor do we yet

Those effects are plain to see: slowing-down and a growing susceptibility to 
disease. It is as if the processes that helped to build the body, and keep 
it in line, turn against it. Joints stiffen as their molecular mesh of 
collagen tightens, the same process that helped to strengthen them in early 
life. Most cells have already stopped dividing in the run-up to 
reproduction. That is a useful check, then, on disruptive disorders like 
cancer; but it means that, as ageing organs start to break down, and new 
cells are needed to replace the old, these are not available.

This might seem an odd design flaw to have slipped past natural selection. 
But then evolution is all about optimising the passage of genes from one 
generation to the next. That means, for example, that traits which are 
advantageous in early life are favoured, even though they may cause later 
harm. To borrow a comparison from Leonard Hayflick, a cell biologist at the 
University of California, San Francisco (UCSF), the body is rather like one 
of the Mars fly-by probes, but engineered to reproduce, not reconnoitre. 
Once the body s mission is accomplished, nature, like NASA, has little 
interest in what happens next. The reproductive lifespans of members of a 
given species are probably thus optimised to match the time an individual of 
that species might expect to survive before being cut down by accident, 
predation or disease. Physiological resources go into reproduction, not 
prolonging life thereafter.

Humanity, however, has increasingly mastered such threats, raising its life 
expectancy to the point that most members of the species live well beyond 
their reproductive period of life. Our old age, says Dr Hayflick, is an 
artefact of civilisation.

Molecular mayhem
Senescence then, according to this hypothesis, is not some self-destruct 
mechanism, encoded by a specific  ageing  gene, which is suddenly switched 
on at a certain point in an organism s life, in order, say, to keep 
population levels in check. But genes do play a role in the process. Studies 
that have been made of elderly identical and fraternal twins, for instance, 
suggest that roughly 35% of man s longevity is due to genetic factors, the 
rest being attributable to a wide variety of environmental factors such as 

Believe in that, you'll believe anything

How the genes concerned contribute to the human ageing process is, as yet, 
unknown. But one of the great leaps forward in ageing research in the past 
decade has been the discovery in experimental animals of genes that 
influence their lifespan. Laboratories around the world are now filled with 
preternaturally youthful, or prematurely old, yeast, worms, fruit flies and 
mice created through genetic engineering. This tinkering has revealed a 
number of biochemical pathways which are involved in the ageing process in 
such animals.

For example, among roundworms (C. elegans, as scientists know the creature), 
those that have had one of their genes called daf-2 tweaked in the 
laboratory live twice as long as counterparts that have not. They are also 
friskier in their old age. The gene in question is known to encode a protein 
involved in a hormonal system which, among other things, helps cells resist 
 oxidative stress  the onslaught of some nasty molecules known as  free 
radicals . Similarly, the lifespan of mice can be lengthened by almost a 
third through genetic tinkering that blocks their production of a protein 
called p66shc, and so makes them better able to resist oxidative damage.

Free radicals are produced continuously as cells go about their daily 
business, and are churned out en masse when cells come under stress. But the 
body has a suite of powerful enzymes which act as molecular police to keep 
these radicals in check. When they do get out of control, free radicals can 
cause the sort of damage characteristic of ageing cells, including broken 
DNA and misformed proteins.

One of the most persuasive links between oxidative damage and ageing is the 
injury that free radicals do to telomeres. Telomeres are the bits of DNA 
that are found at the end of chromosomes. Many cells spend their lives 
dividing, and with each division their telomeres become a little shorter. 
Eventually the cells reach their  Hayflick limit , discovered by Dr Hayflick 
in the 1960s, at which point they stop dividing, go quiet for a while and 
then die. The telomere, we now know, acts as a sort of molecular clock, 
allowing a cell to keep track of divisions and hence of its lifespan. But 
some cells, such as cancerous ones, keep going on and on. They produce an 
enzyme called telomerase that keeps their telomeres up to scratch as free 
radicals break them down. So the cells never reach their Hayflick limit.

Calvin Harley and his researchers at Geron, a biotechnology firm at Menlo 
Park, California, are trying to genetically engineer bits of telomerase into 
cells that have stopped dividing, to get them to restart the process and 
reset their clocks. The firm is careful to point out that this is not a 
wholesale anti-ageing therapy, but rather (it hopes) a new way of tackling 
degenerative diseases that may afflict both young and old, such as diabetes, 
in which certain cells have ceased to function. Geron hopes one day to find 
drugs that might directly stimulate telomerase production in humans.

It's called life, little one

Meanwhile, millions of people will go on dosing themselves with 
 anti-oxidants  such as vitamin A, in the hope of keeping age at bay. 
Largely in vain: compounds like these are absorbed and distributed through 
the body in such a way that they have little impact on individual cells.

What does appear to work, at least in mice and monkeys, is to reduce their 
caloric intake by at least a third. This seems to boost their lifespan by up 
to 50%, and make them less liable to neurological disorders. But how? Work 
by Mark Mattson and his colleagues at the National Institute on Ageing in 
Baltimore, Maryland, suggests that cutting back on the calories reduces the 
production of free radicals. One can hardly set out to starve humans, but 
the researchers are working on small molecules that might be able to mimic 
the effect: they are studying rats to see if one promising compound, 
2-deoxy-D-glucose, will lengthen the animals  lifespan.

Hope and experience
There is great hope amongst biologists that new science will fulfil the 
age-old dream of prolonging youth. Cynthia Kenyon, a worm specialist at 
UCSF, is optimistic that genetic experiments in other organisms can point 
the way to the underlying determinants of ageing, not just in flying or 
furry creatures but in humans as well. She is one of a new wave of 
developmental biologists who have rejuvenated the sluggish field of ageing 
research. Their new tools and fresh ideas, taken from the worlds of 
molecular biology and genomics, give them confidence that  ageing is a 
disease that can be cured, or at least postponed. 

Dr Hayflick, today the grand old man of gerontology, is less sanguine. He 
reckons that the genetic pathways so far revealed in experimental organisms 
may tell us about processes in early development, whose pleasing side-effect 
is longer life, but not so much about what happens in the body as it 
approaches the end of its lifespan. Nor is that insight likely to come 
quickly, he says, given the way current biomedical research focuses on the 
symptoms of old age, such as stroke or heart disease, rather than the 
fundamental processes going on in cells that make them more vulnerable to 
such mishaps in the first place. Ageing is not a disease to be remedied, 
says Dr Hayflick, and those who strive to stave it off are disturbing a 
process as natural as the development of a child. Like any other walk of 
life, gerontology too has its generation gap.

Get your FREE download of MSN Explorer at http://explorer.msn.com

Rate This Message: http://www.cryonet.org/cgi-bin/rate.cgi?msg=15160