RATS and mice are the most widely used animals in biomedical research. They are hugely important in the early stages of drug testing, before clinical trials in humans can begin.
Unfortunately, laboratory rats and mice are not up to the job. They are kept under conditions that give them little opportunity for exercise, and at the same time they have access to as much food as they can eat. As a result they are overfed, unfit and obese.
Such 鈥渃ouch-potato鈥� animals develop a range of health problems, including insulin resistance, diabetes, high blood pressure, impaired brain function, increased oxidative stress and inflammation. They also have elevated levels of glucose, triglycerides and 鈥渂ad鈥� cholesterol in their blood, and are more susceptible to cancer, neurodegenerative disease and kidney disease. Unsurprisingly, they die prematurely.
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Obesity is especially problematic. Rodents kept under normal lab conditions gain weight throughout their adult lives. Up to 50 per cent of the body weight of a typical middle-aged laboratory rodent is fat. Some strains of lab rat attain a body weight in excess of 1 kilogram, nearly double that of a healthy rat.
Surprisingly, very few scientists who use rats and mice in their research are mindful of the fact that their animals are so unhealthy. They ought to be. The widespread use of sedentary, obese animals may be leading to spurious experimental results. Drugs shown to be effective in couch-potato rodents may prove ineffective 鈥� or have side effects 鈥� in fit and healthy subjects, while promising drugs may be thrown out before ever being tested properly because they don鈥檛 work in couch-potato animals.
鈥淭he widespread use of sedentary, obese lab animals may be leading to spurious results鈥�
Consider cancer research. We know that some carcinogens are more potent in overweight animals and that couch-potato rodents have an elevated risk of developing tumours. In addition, many types of tumour grow more rapidly in animals with unlimited access to food, and certain aspects of metastasis 鈥� the process by which tumours spread to new sites in the body 鈥� appear to differ between obese and slender mice. Experimental cancer drugs might therefore act differently in couch-potato individuals than in their slender counterparts.
More than 500 phase II clinical trials of cancer drugs have been carried out in human patients. The majority of these drugs worked in animal studies but failed once they progressed into human clinical trials (). It is reasonable to suggest that some of them failed because they were tested in couch-potato rodents.
For example, angiogenesis 鈥� the development of new blood vessels to feed growing tumours 鈥� appears to play a far more prominent role in tumour growth in obese individuals than it does in thin ones. This may mean that anti-angiogenic drugs that work in fat mice may have little effect on slender ones.
Admittedly, the risk of several types of cancers is increased in people who are overweight and sedentary. But many cancers strike otherwise healthy people at any age. It is therefore important to know whether potential cancer therapies that are effective in couch-potato animals are equally effective in fitter ones.
Similar arguments apply to neurodegenerative conditions such as Alzheimer鈥檚, Parkinson鈥檚 and Huntington鈥檚. Drugs for these are generally tested in mice that have been genetically modified to mimic the disease in humans. Alzheimer鈥檚 mice, for example, have been modified to develop progressive degeneration in brain regions involved in learning and memory.
These mice are also housed in obesogenic conditions, and their unhealthy lifestyles may be contributing to their neurodegeneration. In Alzheimer鈥檚 mice, the disease progresses more slowly when the animals鈥� diet is restricted, and progresses faster in animals with diabetes. Diet and exercise also delay onset and slow disease progression in mouse models of Parkinson鈥檚 and Huntington鈥檚 diseases. So when drugs work in these animal models, it may be because they target the effects of a sedentary, gluttonous lifestyle, not the underlying disease. In normal animals, they may not work as well, if at all.
The failure of several different stroke drugs in human trials, despite their clear effectiveness in animal models, might be due to the fact that the animal testing was done on couch-potato mice. Similar arguments can be applied to cardiovascular and renal disease, in which metabolic status impacts the disease processes.
Over-reliance on couch-potato lab animals is a critical but under-appreciated issue in biomedical research. Even though an increasing number of people in industrialised countries lead a couch-potato lifestyle, it is unlikely that results from trials with unhealthy animals apply to the majority of humans.
Ideally, drugs and other medical interventions should be tested in both couch-potato and healthy animals. It is not difficult or expensive to keep lab rats in better conditions. Simply reducing their food intake and providing running wheels results in dramatic reductions in body weight and body fat, and extends lifespan by up to 40 per cent. In addition to better informing the development of biomedical interventions, comparisons of couch-potato and fit animals will also reveal new mechanisms by which diet and exercise affect basic biology and the development of disease.
Many patients suffering from cancer, cardiovascular disorders and neurodegenerative disease are otherwise fit and trim. Treatments for fit humans should be tested in fit animals.
