Combating hypothalamic ageing through exercise

It is popularly accepted that the way to a long life is through regular exercise, good sleeping habits and a healthy diet. Indeed, regular exercise is beneficial for the brain and body and can help us lose fat, repair the brain, stimulate the production of new brain cells, improve our problem solving abilities, and strengthen our body clock. A key to having good sleep and dietary habits is to make sure that we maintain regular bed-times and meal times. Daily regularity in sleeping and feeding arises because our body clock, which tells us when to awaken and when to eat, is matched to the 24h changes in daylight. Unfortunately, as we age, both our body clock and our synchronization to the external world can weaken, resulting in disruptions in sleep-wake cycle, eating and impaired problem-solving abilities. In people leading sedentary lifestyles, such disruptions worsen and the ageing process is sped up, leading to premature death. This is called 'unhealthy ageing' and recently we have found similar effects in sedentary mice. Maintaining mice in social groups but without a means to exercise, results in these animals becoming obese in old age. They also have poor control of their eating and resting habits and weakened body clocks. Remarkably, when provided with an exercise wheel, these mice choose to vigorously run in the wheel and, within 6 weeks, they lose 8% of their body weight. This suggests that negative aspects of a sedentary lifestyle may be corrected by exercise in old age. Unfortunately, we do not understand how this change in lifestyle affects the activity of brain cells that control the body clock and food consumption. We also lack knowledge of how exercise may regulate body fat levels in old animals and we do not know if brain repair, new brain cell production and problem-solving performance in these mice are affected by exercise in old age. Further, we do not know if adopting an active lifestyle in young or middle adulthood can prevent subsequent age-related obesity, body clock disruption, and decline in decision-making. Whether regular exercise can slow-down the ageing process in animals with body clocks weakened through loss of a key signaling chemical is also not known.

In this research, we aim to study how providing mice with the opportunity to voluntarily exercise in a wheel at different stages of life thwarts the ageing process. We anticipate that the younger the animals are when they begin exercising, the more effectively the abnormal ageing process will be lessened. It is possible that even after spending half their life in a sedentary state that animals will show a significant improvement in their brain and body functions following the opportunity to exercise. Animals with weakened or completely dysfunctional body clocks are potentially prone to accelerated ageing and we will explore whether exercise is an effective intervention in these animals. It is also possible that regular exercise will stimulate the ageing brain to produce new cells and improve problem-solving capabilities. Through this research project, we will establish new ways of restoring brain and body rhythms to promote good health and longevity.

As we grow older, our physiology and behaviour deteriorate. This is compounded by a sedentary lifestyle, poor diet, and low quality sleep. This 'unhealthy ageing' is associated with increased risk of obesity, cardiovascular and metabolic disease, impaired brain function, and poorly coordinated body clock rhythms. Indeed, aged mice maintained in a sedentary state become obese and have impairments in their daily metabolic profile as well as their body clock and the rhythms it regulates. Inflammation of the brain, including the hypothalamus (the brain's main circadian and homeostatic regulatory centre) and the hippocampus (a major site for learning and memory) occurs in obesity and unhealthy ageing. In this proposal, we aim to evaluate the utility of voluntary exercise in a running-wheel in countering effects of unhealthy ageing. Through evaluating circadian rhythms, metabolic and inflammatory markers, performance on cognitive tasks as well as molecular and neuronal activity in the hypothalamus, we will determine how providing running-wheels at different points in the lifespan can counter unhealthy ageing associated with a sedentary lifestyle. We will establish whether this voluntary exercise stimulates the production on new brain cells in the hypothalamus and hippocampus. We will also test the effectiveness of exercise to promote healthy ageing in animals with genetically weakened body clocks. Our proposed work programme will be the first to simultaneously assess the effectiveness of voluntary physical exercise on hypothalamic molecular and neuronal activity, brain cellular plasticity, cognition, and metabolic activity as well as body composition profile in unhealthy ageing.

The research questions posed within this proposal are of major interest to ACADEMIC GROUPINGS in biological and biomedical sciences, gerontologists, veterinarians, and animal behaviour specialists. The circadian clock is hot topic as evidenced by the recent award of the Nobel Prize for Medicine to Hall, Rosbash, and Young for their landmark work on the molecular circadian clock. The academic community will benefit from elucidation of the effectiveness of scheduled voluntary exercise to counter obesity and the short- and long-term effects of sedentary lifestyle of rodents in the animal care facility. Further, neurophysiologists and neuroendrocrinologists interested in how hypothalamic cellular activity is altered by unhealthy ageing as well as by exercise. Understanding how exercise improves body weight regulation, brain health, and the body clock presents clear implications to human health and welfare. As such, research findings will impact greatly on the HEALTH CARE COMMUNITY. For example, CL actively engages with Alzheimer's sufferers at the Sunrise Centre in Hale Barns and will present the work of this project to them, their caregivers, and their families. We will disseminate findings by publishing primary papers and reviews in high impact journals, and presenting work at national and international meetings. We anticipate that the proposed work will produce 2-3 high-quality primary research papers.

Our findings will be of interest to the GENERAL PUBLIC due to the prevalence of obesity and unhealthy ageing in our modern society. At its most basic, the work will engage sections of the population who wish to learn about their health and human physiology. This work also has realistic potential to inform the general public about how exercise habits can improve general health, ameliorate some aspects of ageing, and extend healthy ageing. Research findings will be delivered to the general public through public engagement activities (e.g. brain awareness week), as well as through mass media. For example, our articles in the scientific literature have been reported in national and international newspapers, on local radio, and on the intranet.

The proposed research is of interest to ANIMAL INSTRUMENTATION MANUFACTURERS due to direct implications for home cage designs and the incorporation of provision for small rodents to have the opportunity to physically exercise. Currently all main manufacturers of EU approved home cages do not have running-wheels (or other provision for exercise) incorporated into their designs, but this needs to be rectified. Since exercise can counter effects of obesity and unhealthy ageing on brain and body health, this is important and relevant work. Similarly, the Home Office will be interested since they currently do not legislate for the provision of exercising devices in home cages and our research may influence such legislation of the Animal Act. In the context of "building partnerships to enhance take-up and impact, thereby contributing to the economic competitiveness of the United Kingdom", we will engage with cage manufacturers to facilitate research findings being taken-up by and impacting upon industrial beneficiaries. JG has already co-authored work revealing how a new well-ventilated design of cage for rats improved their cognitive performance (Lyst et al., 2010). Manchester has taken a strong proactive role in developing links with major biomedical companies, enhancing public communication of science, as well as identification and development of commercialization opportunities. Dedicated members of staff are employed within the Faculty to assist in these areas.

Benefits of this research to the UK ECONOMY are neither immediate nor guaranteed, but eating disorders, obesity, cardiovascular disease, diabetes and unhealthy ageing are, and will continue to be, a massive burden on the NHS. Thus, the future economic benefits of this work potentially substantial.