X-Message-Number: 15160 From: "Mark Plus" <> Subject: "Gerontological Incertitude" Date: Fri, 22 Dec 2000 08:28:02 -0800 From: http://www.economist.com/science/displayStory.cfm?Story_ID=457321 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 diet. 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