Further studies of the modulation of the physiological maturation and ageing process - a comparative study of voluntary exercise and food restriction in the rat

The elderly part of the population increases both in numbers and age, which results in an increased prevalence of chronic degenerative diseases in the population as a whole. Maintenance of lifelong physical fitness and avoidance of overweight are important preventive strategies against especially cardiovascular diseases, colon cancer, diabetes mellitus, and diseases of the musculo-skeletal system. An active life-style also increases life expectancy of the individual (or mean lifespan of the population). Results from studies on ageing animals agree with these findings from population studies. We showed in a previous study on rats that life-long exercise in a treadmill kept the bodyweight lower, reduced the decline of spontaneous activity, reduced the speed of various biomarkers of ageing, and preserved certain key cells in the brain. The mechanisms behind the beneficial effects of physical activity and avoidance of overweight are, however, largely unknown. In an on-going study (P 12474-MED from the Austrian Science Fund) we study the effects of life-long physical exercise and food restriction (avoidance of overweight in the rat) on the physiological ageing processes in the rat from the age of five to that of 23 months (18 months). Outbred male rats are used, which enables the study of changes in various parameters during the maturation and ageing processes within a reasonably short period of time. Since rats with free access to food grow obese with ageing, food restriction will be used as a model for avoidance of overweight. Parameters for spontaneous activity and body composition are studied repeatedly (longitudinally) during the 18 months. We now have in vivo data from the first six months showing that the relative and absolute amounts of fat are reduced for the rats training voluntarily in running wheels compared to the those pair fed with them. Further that the body weight is correlated inversely with the amount of running in wheels. Training in treadmill, on the other hand, was milder and less effective. It should, however, be noted that the same amount of treadmill training in our previous study showed pronounced beneficial effects after 18 months of training. Finally, that the weight gain of sedentary rats with ad libitum access to food not only increased the amount of fat but also the size and fat free mass of the body. It can, therefore, be anticipated that the results after 18 months of training (when the animals are 23 months old) will be more pronounced than in our previous studies. It is, therefore, important to analyse also the time points of 15 and 19 months in order to establish a time axis for the development of these changes as proposed in this application. The animals will be sacrificed at the ages of 15 and 19 months. As in the on-going study the nervous and the immune systems will be studied together with a number of other organs and tissues with emphasis on degenerative and malignant processes. Further, biomarkers of ageing will be evaluated. The results will be integrated into a multivariate model, which also takes the time factor into account, in order to evaluate to what extent exercise retards the ageing processes and overweight accelerates them. Whether exercise and lean body composition act differently on the ageing processes will also be analysed. Further, tissues from these animals will be stored in a tissue bank for later studies of questions arising from the analyses in this study.

The background was - as was for the previous project FWF P12474-MED - that physical inactivity and overweight cause major health problems today. The degree of physical fitness has not improved in recent years, but overweight has become more frequent. A moderate increase of physical activity would reduce several major illnesses and promote health The key question is whether the mechanisms that improve health and life expectancy by physical exercise share properties with those of restrained caloric intake. The previous project showed in an animal model (male Sprague- Dawley rats) that lifelong voluntary physical exercise as well as mild food restriction has beneficial effects (at the age of 23 months). This project was designed to analyse how these beneficial effects develop during the lifespan. The groups were: (1) voluntary exercise in running wheels, (2) food restricted to the extent that they kept the same body weight as the animals running in wheels, (3) forced exercise on a treadmill, (4) no exercise and no food restriction, (5) same as "4" but with four animals in each cage. These animals were investigated at the ages of 15 and 19 months together with a 5 month old baseline group. The previous project had shown that voluntary exercise and moderate food restriction enhanced survival especially at the highest ages. This project showed the same pattern. The animals in the sedentary groups gained most in body weight. Voluntary running in wheels was more effective than forced running in a treadmill to keep the body weight low. The same was true for the accumulation of fat. Of the animals in the groups with no exercise and free access to food those kept four in each cage gained more in both body weight and fat compared to those housed individually in cages. A reliable biomarker for ageing (thermal stability of collagen) indicated that both voluntary exercise and mild food restriction retarded ageing throughout the adult lifespan, while forced exercise in a treadmill had a less pronounced effect. The most obese group underwent the most pronounced ageing according to this biomarker of ageing. Analysis of immunological parameters showed that voluntary running in wheels modulates the effects of ageing on the immune system somewhat more effectively than food restriction and pronouncedly more than forced exercise. Animals in this model are prone to develop degenerative lesions in a number of organs, especially the kidneys. Both voluntary exercise and mild food restriction mitigated significantly the development of these lesions, while the effect of forced exercise in a treadmill only had a minor effect. The overweight group, developed the most severe lesions. The conclusions are that lifelong voluntary exercise as well as mild food restriction retard several aspects of the ageing process and prevent the development of degenerative processes in the body.