Background
Age-related loss in muscle mass, strength and function, which has been termed sarcopenia, has been linked to a range of common chronic diseases, including an increased risk for falls and fractures [
1‐
3]. Although there is no single cause of sarcopenia, physical inactivity, inadequate nutrition and age-related reductions in circulating sex steroids, growth factors and vitamin D, and concomitant increases in pro-inflammatory cytokines such as interleukin-6 (IL-6), C-reactive protein (CRP) and tumor necrosis factor-alpha (TNF-α), have all been implicated [
2,
4]. There is also strong evidence that dementia and related cognitive deficits in older people, particularly deficits in executive function such as the ability to concentrate, to attend selectively, multi-task and to plan and strategize, are associated with both risk factors for falls [e.g., postural instability, impaired gait, reduced ability to perform activities of daily living (ADL)] as well as future falls [
5]. Other studies have also reported that low muscle mass and strength and muscle loss are associated with cognitive impairment [
6‐
8] and brain atrophy [
9]. Thus, identifying interventions that can optimize muscle mass, strength and function, and improve cognitive function are likely to provide the greatest benefits in terms of ensuring that older adults can live independently and relatively disease and disability free into old age.
Progressive resistance training (PRT) is promoted as one of the few lifestyle approaches that can significantly increase muscle strength, mass and size, but there remains considerable heterogeneity in the skeletal muscle responses to PRT in older adults [
10,
11]. For muscle hypertrophy to occur there must be a net increase in muscle protein balance, that is, muscle protein synthesis (MPS) must exceed muscle protein breakdown (MPB). PRT can stimulate MPS above resting levels, but MPB also rises such that net protein balance remains negative in the fasted state [
12]. While the provision of protein (amino acids) post-exercise can overcome this imbalance and result in a net positive protein balance, the anabolic sensitivity of skeletal muscle to protein appears to be blunted with ageing [
12]. As a result, it has been suggested that older adults require a higher dose of protein to maximise MPS and promote muscle hypertrophy in response to PRT [
12,
13]. Although the optimal dose of protein needed to enhance the anabolic response to PRT in older adults is not known, there is some evidence that a daily protein intake >1.2 to 1.5 g/kg body weight or 20–40 g of high quality protein ingested following PRT can promote MPS and muscle hypertrophy [
13‐
16]. While most previous studies have focused on the effects of milk (whey and casein) and soy protein, red meat is another rich source of protein that contains complete and balanced proportions of all eight essential amino acids, and has been shown to promote MPS at rest and following PRT in older adults and the elderly [
17‐
20]. For instance, it has been shown that ingestion of a 113 g (moderate) serving of beef (30 g protein) produced a 50 % increase in MPS [
18], with no further gains following the ingestion of a larger 340 g serving (90 g protein) [
20]. In a recent 4-month randomised controlled trial (RCT) in women aged 60 years and over, we found that ingestion of two ~80 g servings of cooked lean red meat on most days of the week enhanced the effects of PRT on muscle mass, strength and serum insulin-like growth factor-1 (IGF-1) and reduced inflammation [serum IL-6]; there were no adverse effects on blood pressure, lipids or kidney function [
15]. Despite these positive findings, promoting daily consumption of red meat is not consistent with the current Australian Dietary Guidelines [
21]. Thus further research is needed to determine whether less frequent consumption (e.g., an intake consistent with current dietary guidelines of no more than 455 g per week of cooked lean red meat) is equally effective when consumed in combination with exercise.
In addition to preserving muscle health in older people, recent attention has focused on identifying strategies to attenuate age-related cognitive declines as this has been identified as a key risk factor associated with falls and disability in the elderly [
22], and precedes the development of dementia and Alzheimer’s disease [
23]. Globally the prevalence of dementia is estimated to increase from around 35 million people in 2010 to around 115 million people by 2050, with many more people having some degree of cognitive impairment [
24]. Currently there are no disease modifying pharmacological treatments to cure or delay the progression to dementia. However, regular exercise, including aerobic training, PRT or the combination, has been recognised as promising strategies that can induce a cascade of molecular and cellular processes which may improve brain function, structure and/or neural connectivity via several pathways, including the release of various growth and neurotrophic factors, and cognitive function, particularly measures of executive functioning and processing speed [
25‐
29]. However, not all studies have reported beneficial effects of exercise on measures of cognition, which may relate to differences in the study populations, study duration, training dose (duration, intensity and/or frequency) and/or the dietary habits of individuals.
Previous research has shown that certain dietary patterns or nutrients can have a positive effect on neuronal plasticity and cognitive function among older adults [
30‐
33]. Although the data from randomised controlled trials is limited, a number of reviews have highlighted that the findings from epidemiologic studies tend to support a protective role of omega-3 fatty acids, B-vitamins or antioxidants and the Mediterranean diet [
30,
32,
33]. There is also emerging evidence that dietary protein and its constituent amino acids are associated with cognitive function in older adults [
34‐
36]. In a population-based, prospective study (median follow-up 3.7 years) in 937 elderly aged 70–89 years who were cognitively normal at baseline, a higher dietary protein intake was associated with a 21 % reduced risk of mild cognitive impairment or dementia, independent of potential confounders [
37]. While there are few intervention trials which have examined the effects of dietary protein or protein supplementation on cognition, a study in healthy young men demonstrated that a high-protein meat diet for 3 weeks improved cognitive function (reaction time for demanding tasks) [
38]. Moreover, an Australian study reported that women habitually consuming less than the recommended intake of red meat were twofold more likely to experience depressive or anxiety disorders than those consuming the recommended amount [
39]. Given that red meat contains other nutrients in addition to protein such as iron, zinc, several B vitamins, omega-3 fatty acids and possibly vitamin D which have all been linked to cognitive function, we hypothesise that combining a diet rich in red meat with PRT will be more effective for enhancing cognitive function and neural plasticity in older adults than PRT alone.
There are several lines of evidence to support our hypothesis. One of the proposed mechanisms by which exercise may improve cognition and neural plasticity as well as muscle health is via an increase in circulating IGF-1 and serum brain-derived neurotrophic factor (BDNF) and/or a reduction in systemic inflammation [
40,
41]. It is well known that IGF-1 is central to muscle growth, but it has also been shown to have neuroprotective actions by promoting neuronal growth, survival and differentiation [
40,
42]. IGF-1 has also been shown to augment BDNF concentrations, which is a neurotrophin that functions to support the growth and maintenance of neuronal circuits as we age [
40]. Indeed, a number of human studies have reported a link between circulating BDNF concentrations and cognition [
43,
44], and there is evidence that BDNF stimulates neurons to survive longer and branch and connect in new ways (synaptic plasticity) to promote memory and learning [
40,
45] as well as executive function and processing speed [
44,
46]. Finally, increased inflammation has also been linked to muscle loss and cognitive impairment, and associated with an increased risk of dementia [
47,
48]. Building upon our previous 4-month randomised controlled trial in elderly women which showed that PRT combined with increased consumption of lean red meat on most days of the week resulted in a greater increase in serum IGF-1 and a reduction in circulating IL-6 levels compared to PRT alone, together with existing research which has shown that dietary protein and exercise can stimulate an increase in serum BDNF, we hypothesise that combining these approaches will be more effective at improving cognitive performance in older adults than exercise alone. In addition, by measuring changes in cortical plasticity using Transcranial Magnetic Stimulation (TMS), a painless and non-invasive technique that allows an assessment of neuroplasticity through cortical excitability and inhibition (eg. responsiveness of the entire neural pathway from the motor cortex to the muscle), this study will provide new data on the role of PRT combined with increased dietary protein on neural plasticity in the elderly.
The primary aim of this 24-week randomised controlled trial with a 24-week follow-up in community-dwelling older adults is to examine the effects of a multi-modal exercise program involving PRT combined with a protein-enriched diet achieved through lean red meat consumed three days per week (on training days) on skeletal muscle mass, size and strength, and cognitive function. The secondary aims of the study are to:
1.
Evaluate the effects of the intervention on physical functioning, neural plasticity (corticospinal excitability and inhibition and voluntary activation), various growth and neurotrophic factors and systemic inflammatory markers associated with muscle and cognitive health, and health-related quality of life;
2.
Explore whether any intervention related changes in cognitive function are modulated by body composition, neurotrophic markers, inflammatory cytokines, circulating growth factors, bioavailable zinc and cardiovascular risk factors;
3.
Determine if the 24-week supervised and structured exercise and protein intervention can lead to long-term behavioural changes with regard to maintaining participation in exercise and/or consuming a diet rich in red meat in older adults.
Discussion
This community-based RCT will be the first to evaluate whether a multi-modal exercise program incorporating PRT in combination with increased dietary protein achieved through the consumption of two ~80 g servings of cooked lean red meat on each of the three training days is a safe and effective strategy to enhance muscle mass, size and strength and cognitive function in community-dwelling older adults. In addition, this study will determine whether such an intervention translates into long-term behavioural changes with regard to adopting a healthier lifestyle that incorporates regular participation in PRT and consumption of a diet high in protein (red meat). This is important because age-related muscle wasting and a decline in cognitive function have both been implicated in the development and progression of many chronic diseases, including falls and dementia. From a public health perspective, if the intervention proves to be effective, the pragmatic nature of the intervention, with the exercise conducted within local community-based health and fitness centres and dietary protein increased through the use of lean red meat at an intake equivalent to the current Australian dietary guidelines of 3–4 serves per week, should ensure that the program can be easily implemented and adopted and is applicable in real life.
Another strength of the study is that our secondary outcomes will provide a unique opportunity to: 1) evaluate the effects of the intervention on neural plasticity, and 2) identify potential biological determinants of exercise and protein-induced changes in cognitive function (and skeletal muscle health) in older adults. Specifically, this study will be one of the first to determine whether combining exercise with increased dietary protein (lean red meat) can have a positive effect on a range of neurobiological markers, including various circulating growth and neurotrophic factors (e.g., IGF-1, BDNF, VEGF) and systemic inflammatory cytokines in older adults, and whether any changes in these biological determinants in response to the intervention are associated with any changes in cognitive function and neural plasticity.
In summary, we believe that the findings from this study will form the basis for more targeted nutrition and exercise guidelines for the management and prevention of age-related changes in muscle and neural health as well as cognitive function in older people. We anticipate that the findings from this study will provide direct evidence that the current guidelines to consume no more than 455 g of lean red meat is a safe, acceptable and effective dose and source of protein that can have beneficial effects on improving multiple health outcomes when combined with regular exercise. In addition, we expect that the results will also show that there are no adverse effect of this approach on cardiovascular-related health outcomes or kidney function. This is important because there are some concerns that a high red meat diet is associated with a number of adverse health outcomes, including an increased risk of heart disease, type 2 diabetes and certain cancers.
Competing interests
RMD, JG, MP, DK, KE, SOC and CAN have no competing interests.
Authors’ contributions
RMD originated the idea for the study and will supervise the project. RMD, DK, KE and CAN were co-investigators of the successful funding proposal. JG will act as trial coordinator along with MP and they will be responsible for the data acquisition with assistance from SOC and DK. RMD and JG wrote the manuscript and JMP, DK, KE, SOC and CAN reviewed draft versions. All authors have read and approved the final version.