Examining the impact of inactivity and diet on muscle health with age in C. elegans

Intuitively we know that lack of physical activity makes us feel both mentally and physically worse. We also appreciate that as we get older we become less active and less healthy. Surprisingly, the World Health Organization has found that inactivity does indeed cause poorer health and that, in fact, it is the fourth leading cause of death worldwide. Despite the importance of inactivity on poor health, the majority of research on how inactivity causes poor health has been conducted in astronauts (e.g. less than 900 individuals worldwide since the 1960s!). Currently allot of research is conducted on the impact of activity on health with the assumption that the mechanisms that promote health in response to activity are the same ones that promote lack of health with inactivity. However, loss of muscle in response to spaceflight or confinement to bed is rapid and large (>7% loss in 7 days, a dramatic decrease in 1 week) whereas increase in muscle in response to exercise is much slower (nobody gets fit in just 1 week at the sports centre). Thus, research into how inactivity causes poor health is needed and needed quickly. In order to gain this knowledge faster, we propose to study how inactivity causes poor health in a tiny worm and later to test if the same mechanisms act in people. This may seem far fetched but we have already shown that the muscles of this tiny worm respond to spaceflight much the same way astronauts muscles do, with many changes in the molecules that cause much to be strong and make energy declining rapidly in both the worm and in astronauts. Our past spaceflight work has suggested that decreased signal from nerve to muscle occurs in spaceflown worms and similar changes are seen in people confined to bed. Therefore we will systematically decrease signal from nerve to muscle in worms and determine the impact upon health and particularly muscle health decline with age. We will specifically ask: i) Does it matter when you are inactive (e.g. child vs. adult) in terms of the impact on health and muscle health decline with age; ii) Do repeated episodes of inactivity during adulthood (e.g. working at a desk, hospitalization, etc) have additive negative impacts on health and muscle decline with age; and iii) Can diet which produces increased health (e.g. longer life) protect against the impact of inactivity? The results of these experiments will allow us to begin to understand the molecules that control these processes and, in the future, possibly design new drugs. Equally importantly, the results from these experiments will provide a framework for testing if the findings from the worm also hold true in people but in a faster and cheaper way than starting with studying people (much as we used animals to prove spaceflight was safe before sending astronauts).

Inactivity is now recognized as the fourth leading cause of death, worldwide, by the WHO. Despite this, little research on how inactivity causes poor health is conducted. The majority is conducted on astronauts or in spaceflight analogues such as head-down tilt best rest or hindlimb immobilization where a loss of >7% of muscle mass can be observed in just 7 days. Rather, most research focuses on how activity improves health which is good for promoting health but unhelpful for: i) understanding how inactivity causes poor health given that exercise cannot increase muscle mass but >7% in just 7 days (e.g. activity and inactivity do not act by directly opposite mechanisms); ii) countering the negative consequences of inactivity (e.g. different mechanisms require different therapeutic strategies); iii) understanding risk stratification of inactive individuals (e.g. repeated office work vs. repeated hospitalization vs. the impact of age on the office worker or hospitalized). In response the the Highlight notice "New approaches to ageing research." We propose the bold new ideas that: 1) Allot of what we think of a ageing is actually inactivity (for example spaceflight is thought to be "accelerated ageing") and 2) A new model for studying inactivity's impact on health and muscle decline with age is needed. He we propose to conduct classical human physiology studies of the impact of inactivity and diet across the life-course on health and muscle decline with age but to do so in the genetic model organism C. elegans. While this idea seems radical (e.g. few people study physiology in C. elegans and few people study molecular mechanisms discovered in C. elegans in humans, the proposal is in keeping with the highlight notice's desire for more C. elegans work that is directly relevant to human health decline with age. Moreover, we hypothesize the C. elegans response to inactivity involves the same molecular changes that have been reported in human bed rest subjects and with age.

In addition to the academic beneficiaries we believe this work will benefit the staff working on the project, the wider public, the commercial private sector, international government space agencies, and charities. The PDRA on this project will benefit in three ways. First, he will gain experience with techniques not previously employed. Second, he will gain experience running a different type of project than he currently has experience with. Lastly, he will develop a unique model, worldwide, that he can use to start an independent career. All of these types of professional development will aid in his ability to seek further employment, with the management experience being the most transferable skill he will continue to develop. These impacts will be felt within the first year and fully realized in three years, with the anticipation that the PDRA will apply for independent funding in that time frame. The wider public will benefit from this work in the form of new diagnostics, treatments, and ultimately decreased public healthcare expenditure. The model and future mechanism which we identify as regulating health and muscle decline with age in response to inactivity can immediately be researched by ourselves or others for potential new diagnostics and/or therapeutics/therapeutic strategies. Successful therapeutics should reduce the public healthcare expenditure on inactivity and sarcopenia. Additionally all sectors of the UK may also benefit from increased productivity as the result of decreased loss of work days due to health problems, should this new model for studying inactivity prove to be more broadly relevant than just to ageing muscle. As this is basic research, these impacts will most likely not be felt for at least 15-20 years. The commercial private sector will benefit in much the same way that the academic beneficiaries will, specifically by having new targets for the development of diagnostics and therapeutics. These impacts will be felt within the first three years as we present and publish our results. International government space agencies may also benefit much the same as the academics and commercial sector as they too will have novel targets for diagnostics and therapeutics for the muscle loss seen in astronauts, cosmonauts, and taikonauts. These impacts will be felt within the three years as we present and publish our results. Charities will also benefit in much the same way, particularly those charities that support increased quality of life in individuals with problems that involve loss of muscle homeostasis (for example: Research into Ageing, Cancer Research UK, The Muscular Dystrophy Campaign). In order to both increase the use of novel (e.g. invertebrate models) for human health we will endeavour to host 2 workshops on using C. elegans as a model of human (patho)physiology one at an international physiology meeting (Experimental Biology) and one at the international C. elegans meeting. These workshops as well as exposure of our novel model for studying inactivity to the spaceflight research community should help reduce the use of rodent models of inactivity as we will aim to encourage direct translation of findings from worms to human subjects.