The worm in humans
Caenorhabditis elegans has a lifespan of 20 days. The worm is as small as a comma and consists of only 959 cells. Caenorhabditis elegans is very different from Homo sapiens who might, at least in Germany, live for as long as 79 years or more. Nevertheless, the tiny worm is the most important model organism for researchers into ageing who use it to study the development of age-related diseases and the ageing process itself.
But how can such a simple organism be used to investigate the complex issue of human ageing? “The answer is very simple; the worms have many similarities to humans,” said Prof. Dr. Ralf Baumeister, molecular geneticist and bioinformatician at the University of Freiburg. He has been working on Caenorhabditis elegans for more than 15 years. Millions of C. elegans specimens can be found in just one handful of soil and its suitability for scientific research was discovered in the 1960s. Two teams of researchers received Nobel prizes for work involving C. elegans. It would have been impossible for Sydney Brenner, Robert Horvitz and John Sulston in 2002, and Craig Mello and Andrew Fire in 2006, to win their Nobel Prizes without the findings obtained from work with C. elegans.
Unbeatable model organism
The C. elegans genome was sequenced in 1998. “Since then it has become known that about half of all human genes have their counterpart in the worm,” said Baumeister. In addition, almost all mechanisms and pathways that lead to diseases in humans are also found in the nematodes. The worm is also an excellent research model for several other reasons. “Since C. elegans is so small, it can easily be kept and bred in the laboratory,” said Baumeister. There are no ethical problems. The major advantage of C. elegans is that is possible to easily and specifically manipulate its genome. “In 20,000 parallel experiments, we can clearly see the effects of genes,” said Baumeister, clearly showing his enthusiasm. And since the worm only has a lifespan of three weeks, the results of life-prolonging experiments are easier to achieve than with rodents that can live as long as three years.
As early as the 1930s, researchers discovered that rats lived longer when given a low calorie diet. But it was another sixty years before the scientists learnt in the 1990s that no longer eating ample meals leads to an increase in life expectancy, at least in animals. The hormone insulin and its receptor that mediates hormonal action play a central role in the ageing process. In 1993 in San Francisco, Cynthia Kenyon was the first to show that changes in the insulin receptor doubled the lifespan of C. elegans. In 2004, Baumeister also made a spectacular discovery. He found an “ageing gene” that was controlled by insulin. The Freiburg researchers modified the gene so that it lost its susceptibility to insulin. As a result the worm lived for as long as 40 days and in combination with another mutation, for as long as 80 days.
Stress caused by free radicals
Insulin helps to control the amount of glucose dissolved in the blood; glucose is transported into the cells and turned into energy. Unfortunately, this process also creates substances that damage the organism: aggressive oxygen molecules, so-called free radicals that cause oxidative stress in the tissue. “These by-products of the energy metabolism can be compared with exhaust gas. They interfere with the activity and survival of cells,” said Baumeister describing the effect of free radicals in the body.
Abundance entails a vicious circle: the more calories in a meal, the more insulin is required. This drives the metabolism, which leads to the generation of more and more damaging oxygen molecules. The more active insulin in the body, the more mechanisms that would be able to repair the damage caused by the aggressive oxygen radicals are suppressed. Insulin and its signalling pathway not only regulate the metabolism, but also control the stress response in the body. Already the first “ageing gene” discovered by Baumeister’s research group, has turned out to be key in recognising metabolic stress and in initiating protective measures, at least as long as enough insulin is available. In cooperation with scientists from the Harvard Medical School, the researchers from Freiburg have discovered another insulin-controlled switch that controls a whole genetic network, which protects the cells against their own “exhaust gases” and is thus able to prolong the lifespan. The fact that this switch governs completely different survival mechanisms than those previously associated with the hormone is regarded as a scientific sensation. However, it is no surprise that this switch was discovered in C. elegans.
Like a spider’s web – pulling on one thread moves all the threads
Unfortunately, it is not enough to simply switch on or off these central genes in order to halt the ageing process. A complex genetic programme, of which about 150 genes are known, regulates the life expectancy of humans. “It is like a spider’s web. Pulling on one thread moves virtually all the other threads,” said Baumeister describing the complex interaction of the genes. The Freiburg researchers are investigating the specifics of this complicated network at the Centre for Biosystems Analysis (ZBSA) using systems biology methods. They are sure that hunger activates an insulin-independent protection programme in the body.
On the other hand, high insulin activity switches off these repair mechanisms in order to save energy. Although modern humans often have different plans, the human body is still programmed to use its energy – as much as possible – for reproduction. This is done at the expense of the body’s own repair mechanisms that are only activated in real emergencies. After the reproductive age, evolution no longer foresees the need to invest in expensive maintenance measures, for example the correction of genetic errors. Then, ageing progresses rapidly. In this respect, humans are no different from worms.
Increased life expectancy – a good side effect
Is it therefore possible to prevent ageing by leading an ascetic life? Is permanent fasting the key to eternal and healthy life? “This is not that easy,” said Baumeister. Although C. elegans might tolerate long periods of starvation, the majority of human stomachs would probably revolt against low calorie food with 30 per cent fewer calories than normal. Since humans do not generally like to live such a meagre life, scientists are looking for chemical substances that are able to maintain the efficiency of our repair system in the second half of life.
Resveratrol seems to be an excellent candidate. The substance is naturally found in red wine and, as tests with mice have shown, is able to delay the ageing process. However, far larger amounts are required than are contained in a bottle of Pinot Noir or Merlot. “The necessary daily dose of resveratrol requires people to drink about 800 litres of red wine,” said Baumeister. He also warns against resveratrol tablets that are sold through the Internet and which are not approved as drugs. However, the pharmaceutical industry attaches great importance to resveratrol as the example of GlaxoSmithKline has recently shown.
GlaxoSmithKline invested 720 million dollars in the small American company Sirtis which has only developed two drugs. However, the two drugs are based on chemically modified resveratrol and contain far higher concentrations of the substance than a glass or two of wine. The companies now hope that the drugs will eventually be promising candidates for the treatment of age-related diseases such as diabetes, cancer, cardiac diseases and Alzheimer’s. The fact that they prolong life will then be listed on the package leaflet under “desired side effects”.
New tasks for the worm
Baumeister is hoping to discover the secret of ageing using systems biology methods. He hopes to describe the entire network of genes and their interaction with each other. He also hopes that this will provide him with insights into the coupling of ageing to many age-related diseases in order to be able to positively interfere with this network sometime in the future. And of course, the major player in these experiments is once again Caenorhabditis elegans. The small worm will be at the centre of an important task at the University of Freiburg: it will make an important contribution to breaking down the borders between research disciplines. Successful work in the field of systems biology requires close interdisciplinary cooperation.