Combining Vitamin E-functionalized CHOcolate With Physical Exercise to Reduce the risK Of Protein Energy Malnutrition in Pre-dementia AGEd People

BACKGROUND Older adults are particularly vulnerable to undernutrition, a state resulting from defective food intake or uptake (nutrient deficiencies) leading to altered body composition and weight loss. Muscle wasting is a major drawback of this condition and a symptom of protein-energy malnutrition (PEM) and metabolic reprogramming of tissues that increase the ageing process. These changes sustain insulin resistance and impaired mitochondrial metabolism of critical organs and tissues, including skeletal muscle. Prevention of undernutrition is critical. Undernutrition correlates with an accelerated and general decline in health conditions (worsening both physical and cognitive/mental aspects), thus increasing the risk of frailty and finally accelerating physical and cognitive decline. Under these circumstances, the majority of people experience a significant loss of locomotor function, with a significant decline in quality of life, and a high risk of falls which often represents the terminal event in life. These factors can lower the frailty threshold for the oldest-old, with the consequent loss of adaptability, which is an essential feature of successful ageing. This process of deteriorating mobility is multifactorial and also includes decline in cognitive function, increased bone fragility, and reduced joint flexibility.

Strong evidence suggests that ageing and cognitive decline are associated with dysregulation of the hypothalamic-pituitary-adrenal axis (HPA axis), with a clear increase in cortisol levels. The effects of hypercortisolism are far-reaching, affecting the skeletal muscle widely, thus leading to significant sarcopenia and fragility. It is well known that HPA axis activity is impaired in Alzheimer's disease (AD) patients. This dysregulation induces an increase in cortisol levels. High levels of cortisol, one of the most catabolic hormones, also lead to noticeable sarcopenia. Mechanistic aspects include antagonistic effects on the insulin axis (secondary insulin resistance) and consequent metabolic reprogramming of tissues to gluconeogenesis sustained by non-carbohydrate precursors that include amino acids derived from the proteolytic degradation of muscle proteins. Comorbidity in frail people can further sustain the secretion and metabolic effects of cortisol, especially undernutrition and PEM. Some of us previously showed that cortisol levels are significantly higher in patients with AD and severity of the behavioural symptoms, and more importantly, changes in body mass, significantly correlated with cortisol levels. Therefore, cortisol levels, which are not regularly evaluated in AD patients, would help predict patients at risk of weight loss.

Moreover, recent findings revealed a significant decrease in cortisol levels in response to chronic physical activity in healthy individuals and patients with dementia. Physical activity treatment (PT) is a non-pharmacological treatment with great potential to attenuate the cognitive decline in healthy elderly. In patients with Mild Cognitive Impairment (MCI) it was observed that 6 months of PT significantly ameliorates BMI, 6' Walking Test (6MWT), systolic and diastolic blood pressure, glucose, cholesterol, and triglycerides. Importantly, PT may preferably be undertaken as high aerobic intensity (85-95% of maximal heart rate) intervals (HIT), as this yields superior effects on the cardiovascular system compared with PT of moderate or low intensity. HIT has successfully been applied in older individuals (8,9), and in frail populations such as patients with heart failure.

Along with physical activity, macro and micronutrients, are reported to interact with the activity of HPA-axis and to help reducing cortisol levels. Chocolate polyphenols appear to have significant effects with impact on both mental well-being and metabo-inflammatory symptoms of chronic exposure to such stress hormone (3,11-13). Cocoa-derived flavonoids can lower the levels of the active hormone cortisol. Mechanistically, these natural molecules inhibit 11β-hydroxysteroid dehydrogenase (11β-HSD) type 1, an enzyme involved in reducing cortisone to the active form cortisol. The intake of these and many other micronutrients and homeostatic factors decrease with aging due to general worsening of quantity and quality of food intake. Together with micronutrients, protein intake is a critical aspect and a major risk factor for PEM and frailty. Nutritional supplementation for frail people has been shown to slow their functional decline, improving both muscle mass and strength, particularly if this is combined with physical activity. It is now established that nutritional recommendations, including adequate protein and micronutrient intake, are important for a better quality of life in the elderly, which is common management approach of older people who are frail or at risk for developing frailty.

Vitamin E is a fat-soluble essential micronutrient with unique properties as antioxidant and cell protection factor. It is present in cellular membranes of all tissues to scavenge peroxyl radicals formed by free radical attack on polyunsaturated fatty acids. This function is particularly important to prevent mitochondrial damage and the uncontrolled release of free radicals from these organelles in the muscle. Its intake and function as cell protection factor and immune system modulator can be compromised in the elderly (20); moreover, preclinical and human experimental studies show that vitamin E positively influences myoblast proliferation, differentiation, survival, membrane repair, mitochondrial efficiency, muscle mass, muscle contractile properties, and exercise capacity. Furthermore, recent studies on the human metabolism of vitamin E demonstrated that the biotransformation of this vitamin in human tissues forms bioavailable long-chain metabolites with a role as tissue detoxification (PXR and PPAR-gamma agonist activity) and anti-inflammatory (LOX-5 inhibition) mediators. Therefore, for multiple reasons, vitamin E supplementation in the diet as a measure to support physical training in preventing age-associated PEM is worth investigating.