Function Promoting Therapies Come of Age

Sarcopenia, the age-associated loss in skeletal muscle mass and function, is a key underlying biological substrate for the observed declines in movement behavior, decreased physiological capacity, reduced functional performance, and increased disability and mortality observed with advancing age (1). The origins of sarcopenia are multifactorial but are driven by multiple environmental influences (decreased dietary protein intake, vitamin D status, reduced levels of physical activity) along with factors related to primary biological aging (increased pro-inflammatory cytokines, decrease pro-myogenic anabolic hormones, altered motor unit behavior) (2,3). Over the past 30 years, observational evidence has accumulated illustrating the association between proximal deficits in muscle mass and function and more distal outcomes related to mobility and activities of daily living among older persons living in the community. Therapeutic modalities that specifically target age-associated deficits in skeletal muscle function have been proposed as potential “function promoting therapies.” In this issue of the Journal, a series of papers report on results from rigorously designed randomized controlled TRIALS evaluating the efficacy of a number of purported “function promoting therapies” in older adults with a wide range of levels of physical functioning and comorbidities on changes in muscle function and mobility.

Evidence from observational cohort studies have generally shown that loss of lean mass with advancing age is, in part, mediated by reduced dietary consumption of protein. Houston et al. reported from the Health, Aging, and Body Composition (Health ABC) study that 3-year loss of lean mass was associated with average dietary protein intake which persisted even when adjusted for daily energy intake and change in body mass (4). Analysis from two additional cohorts have confirmed these findings and suggested a relationship between protein intake and the development of the frailty syndrome (5,6). In this issue of the Journal, Hruby et al. reported a significant association between dietary protein intake and a lower risk of loss of functional integrity, a composite self-report index consisting of 17 measures of function: 5 measures of activities of daily living (dressing, bathing, eating, transferring, and toileting); 3 Rosow-Breslau measures (heavy work, walk up and down flight of stairs, and walk a half mile without help); and 9 Nagi measures (pulling/pushing large objects, stooping, reaching below shoulder, reaching above shoulder, writing or fingering small objects, standing for long periods, sitting for long periods, lifting or carrying <10 and >10 lbs) (7). Sex-stratified analysis in their study revealed that this relationship was driven by a significant relationship between higher dietary protein intake and lower risk of loss of functional integrity in women alone which may be a result of sex differences in body composition. Despite these studies, more recently, an analysis of 5-year change in muscle cross-sectional area by computed tomography (CT) scans failed to find a relationship with both the total and source (animal vs plant) of protein intake in older adults in the Health ABC study (8).

Markofski et al. present the results of a randomized trial that examined the effects of daily essential amino acid supplements (15 g/d) compared to placebo with or without a structured program of aerobic exercise training using a 4 × 4 factorial design (9). They found that aerobic exercise training increased maximal aerobic capacity and habitual walking speed and that aerobic exercise training in combination with the essential amino acid supplement further increased muscle strength and skeletal muscle protein synthesis in healthy older community-dwelling older adults (65–82 years). Despite the additive effects of aerobic exercise training plus essential amino acid supplementation on increases in skeletal muscle protein synthesis, there were no significant differences in the change in lean mass across all of the intervention groups. These data suggest that the combination of aerobic exercise training plus daily amino acid supplement may optimize improvements in muscle strength in response to aerobic exercise training and also enhance the exercise-induced increase in skeletal muscle protein synthesis without increasing mass per se. Further highlighting the impact of high-quality protein supplementation on the modulation of changes in lean mass, Arentson-Lantz examined the impact of a diet augmented with high-quality whey protein on changes in lean mass and muscle strength during 7 days of bed rest and 5 days of rehabilitation (10). Participants were randomized to an isocaloric mixed diet or a diet enriched with whey protein with equivalent total protein intakes. The whey protein-enriched diet partially prevented the loss in leg lean mass during bed rest and enhanced recovery of muscle strength during rehabilitation. Both of these studies highlight the role that specific amino acids such as leucine play the modulation of lean body mass and muscle function. Interestingly, neither study was able to show a positive effect with respect to changes in physical functioning which may be a result of the general good health of the study populations or the impact of the relatively small samples sizes in both studies. Future work is needed to confirm the findings and evaluate the impact of supplemental amino acids on physical functioning in older adults. Supporting these findings, Tieland et al. reported significant improvements in muscle size with 30 g of high-quality protein compared to placebo plus resistance exercise, but no differences in the change in muscle strength or physical function (11). In contrast, they also examined a similar protein supplementation regimen alone with no exercise in frail elderly subjects and observed significant improvements in physical performance with no change in muscle size or cross-sectional area (12). A recent report showed that provision of a daily nutritional supplement containing 20 g of whey protein in combination with a moderate intensity exercise program increased high-density muscle cross-sectional area and reduced intermuscular fat accumulations in older men and women with mobility limitations (13). Interestingly, a more recent study by Bhasin et al. examined the interaction between topical testosterone therapy and a high versus low protein diet in older men with usual protein intakes less than or equal to 0.8 g/kg/d using a 2 × 2 factorial design and found that increasing dietary protein intake to 1.3 g/kg/d for 6 months did not further increase lean body mass over and above the increases observed with testosterone therapy alone (14).

While most but not all observational studies have shown a relationship between low dietary protein intake and accelerated lean mass loss and poorer physical functioning, the randomized trials have been mixed with respect to increasing lean mass with supplemental protein. However, in studies where supplemental protein has been provided to older adults in combination with some form of exercise training, a significant increase in muscle cross-sectional area or lean mass has been observed. Clearly, there is a need for additional well-designed randomized trials aimed at identifying the appropriate quantity, quality, and timing of dietary protein intake and potential synergies with exercise training in diverse populations of older adults.

Chronic low-grade inflammation and biomarkers of oxidative stress have been associated with muscle weakness, poor mobility, and disability (15). In a multicenter randomized pilot trial, Pahor et al. examined the effect of losartan (50–100 mg/d), fish oil (1.4–2.8 g/d), placebo, or combined losartan plus fish oil on changes in inflammatory burden and gait speed in older adults (N = 290, age ≥ 70 years) with baseline mobility limitations and chronic low-grade inflammation (16). Neither losartan, nor fish oil, nor their combination had any effect on lowering inflammation, as measured by circulating interleukin-6, or mobility, as measured as gait speed during the 400-m walk test. In contrast, Munguia report on the positive effects of flavonoid-enriched coco on cardiometabolic outcomes, oxidative stress, and inflammatory burden (17). This study showed that a natural cocoa powder supplement (179 mg of flavonoids) reduced markers of cardiometabolic health, oxidative stress, and inflammation (glucose, triglyceride, malondialdehyde, and interleukin-6) and improved performance-based measures of physical functioning.

Finally, Deer et al. report of a Phase I randomized trial examining evidence-based “pragmatic” interventions in older adults following acute hospitalization (18). Based on the existing evidence-base for the efficacy of exercise training, dietary protein supplementation, and testosterone therapy, the investigators randomized 100 hospitalized older adults who were randomized and upon discharge received either 20 g of whey protein per day, isocaloric placebo, placebo plus structured rehabilitation, whey protein plus rehabilitation, or testosterone enanthate (single intramuscular injection [100 mg in women and 200 mg in men)]. Participants were followed for 4 weeks and readmission rates were found to be highest in the placebo group and lowest in the group receiving a single dose of testosterone enanthate. Importantly, this study highlights the feasibility of conducting carefully controlled trials of evidence-based function promoting therapies in hospitalized older patients upon discharge. The establishment of the efficacy of these therapies in this population at high risk for falls, fractures, readmission, and other bad outcomes may lead to the successful translation of these therapies into standard clinical care of older adults and should serve as a model for how these therapies can be effectively evaluated.

With the current interest in the development of therapeutic targets aimed at restoring mobility and improving physical functioning in older adults, the studies published in this issue of the Journal illustrate the ability to successfully recruit, enroll, and retain older adults in clinical trials. We remain in very early days in the identification of appropriate therapeutic targets in skeletal muscle and in agreement for a standardized set of outcomes to evaluate efficacy in this area. However, as you can see from these excellent papers, there is much consistency regarding participant selection and the uniformity of outcomes chosen. Indeed, clinical trials of “function promoting therapies” in older adults are finally coming of age.

Funding

This work was supported by the U.S. Department of Agriculture (USDA), under agreement no. 58-1950-4-003 and the Boston Claude D. Pepper Center Older American Independence Center supported by the National Institute on Aging (1P30AG031679). Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the view of the USDA.

Conflict of Interest

R.A.F. reports grants from National Institutes of Health (National Institute on Aging) and the USDA; grants, personal fees, and other from Axcella Health, other from Inside Tracker, grants and personal fees from Biophytis, grants and personal fees from Astellas, personal fees from Cytokinetics, personal fees from Amazentis, grants and personal fees from Nestle’, and personal fees from Glaxo Smith Kline, outside the submitted work.