Multi-organ Responses to CHronic Physical Activity and INactivity

Life expectancy has been increasing for the last 150 years, but the maintenance of health has not kept pace with increased lifespan, and on average, UK adults spend the last decade of life in poor-health, with major consequences for society and the individual.

Persistent physical inactivity is thought to be a key contributing factor to the risk of poor health and functional decline occurring in middle-aged and older adults. It is therefore concerning that most middle-aged adults spend \>8hrs/day being sedentary, with average step count of 3000-4000 steps/day.

To be able to holistically assess the effectiveness of future strategies to address age-related decline in health, and devise public health messages to help individuals reach older age in better health, it is essential that the complex physiological effects that activity and inactivity have across biological systems are characterised.

The goal of this intervention study is to compare the impact of physical activity and inactivity on body functioning. Twenty moderately active participants will decrease their physical activity for six months to match the average amount carried out by middle-aged people in the UK. They will then undertake 3-months of reconditioning training to restore their fitness. In addition, twenty sedentary participants will increase their physical activity to UK recommended levels for six months.

Before and at points during the intervention period, participants will be asked to make some measurements at home and attend the University of Nottingham to have multiple assessments made. These include;

* fitness, muscle strength and function tests,
* completion of questionnaires and computer-based brain puzzles
* having muscle and fat tissue biopsies and blood samples taken.
* The study also involves having MRI scans.

This 5-year study will commence in January 2024, with participant recruitment starting in March 2024 and finishing in May 2027.

This is a parallel design study comparing the impact of physical activity and inactivity on the way the body functions, to understand the mechanisms (including the inter-relationship between tissues and organs) by which lifestyle behaviours may effect health and wellbeing in later life. In particular, the mechanisms by which inactivity results in long term poor health is not well understood, and has rarely been studied in an integrated way in people. However, initial research indicates that the physiology of being inactive is not simply the reverse of being active. To enable effective treatments and public health advice to be devised so that more adults reach old age in better health, and maintain a good quality of life for a greater proportion of their older age, it is important that the impact of physical inactivity on the way the body functions is better understood. Therefore, twenty participants who are moderately, but not highly active will be asked to decrease their physical activity for six months to match the average exercise levels of middle-aged people in the United Kingdom (UK). This will require them to increase their daily sitting time to 7 hours a day and reduce their step count to \<4500 steps per day. At the end of the 6-months they will undertake 3-months of supervised reconditioning training to restore their fitness.

In addition, twenty participants who currently have low physical activity levels will be asked to increase their physical activity to UK recommended levels by attending the Medical School at Queen's Medical Centre, Nottingham, three times a week for six months to undertake a supervised exercise program.

Before and during the 6-month period (at weeks 6, 12, 18 and 24) participants will be asked to make some measurements at home (physical activity levels, dietary intake) and attend the University of Nottingham over 4 days to have multiple assessments made. These include: height; weight; body composition (body fat and lean tissue); blood pressure; fitness, muscle strength and function; sleep quality, quality of life and wellbeing (questionnaires). The rate of muscle protein breakdown and muscle protein synthesis, blood sugar regulation, and biochemistry of the blood, fat tissue and muscles will be assessed, and to enable this muscle and fat tissue biopsies will be collected and blood samples taken. The study also involves having MRI scans to study the structure and function of the brain and heart, and to determine liver and muscle fat content.

Eligibility Criteria:
Inclusion Criteria:

* Group 1 ('non-sedentary') self-reporting \<6 sedentary hrs/day, not actively involved in exercise training or a regular physical activity regimen (\>8,000\<10,000 steps/day).
* Group 2 ('sedentary') self-reporting ≥8 waking hrs/day in sedentary activities and/or ≤5,000 steps/day.
* Aged 55-65y.
* Overweight (BMI 25-29.9 kg/m2).
* Waist circumference ≥94cm (males) and ≥80cm (females).
* Willing to alter physical activity levels as instructed for 6 months
* Without neurological or psychiatric diseases, motor or cognitive restrictions
* Ability to give informed consent

Exclusion Criteria:

* Regular medication use that could interfere with measures
* A history, or evidence, of chronic cardiovascular, metabolic, musculoskeletal, renal or respiratory diseases.
* Experiencing 'long-COVID', inflammatory bowel disease or malignancy.
* Uncontrolled hypertension. Stage 1 hypertension (BP ≤160/100mmHg) with no other signs of cardiovascular disease, and blood pressure (BP) managed by routine medication will not be an exclusion.
* People employed in jobs that would preclude reducing step count and night-shift workers.
* Females who are pre/peri-menopausal or on hormone replacement therapy (due to effect of oestrogen fluctuations on primary outcomes and the longitudinal study design).
* Contraindications for MRI.
* Allergy or sensitivity to local anaesthesia, or dressing adhesive