SUPPLEMENT Proceedings of the IUNS 20 th International Congress of Nutrition ( Part 2 ) Keeping Older Muscle “ Young ” through Dietary Protein and Physical Activity 1 , 2

Sarcopenia is characterized by decreases in both muscle mass and muscle function. The loss of muscle mass, which can precede decrements in muscle function, is ultimately rooted in an imbalance between the rates of muscle protein synthesis and breakdown that favors a net negative balance (i.e., synthesis < breakdown). A preponderance of evidence highlights a blunted muscle protein synthetic response to dietary protein, commonly referred to as “anabolic resistance,” as a major underlying cause of the insipid loss of muscle with age. Dietary strategies to overcome this decreased dietary amino acid sensitivity include the ingestion of leucine-enriched, rapidly digested proteins and/or greater protein ingestion in each main meal to maximally stimulate muscle anabolism. Anabolic resistance is also a hallmark of a sedentary lifestyle at any age. Given that older adults may be more likely to experience periods of reduced activity (either voluntarily or through acute illness), it is proposed that inactivity is the precipitating factor in the development of anabolic resistance and the subsequent progression from healthy aging to frailty. However, even acute bouts of activity can restore the sensitivity of older muscle to dietary protein. Provided physical activity is incorporated into the daily routine, muscle in older adults should retain its capacity for a robust anabolic response to dietary protein comparable to that in their younger peers. Therefore, through its ability to “make nutrition better,” physical activity should be viewed as a vital component to maintaining muscle mass and function with age. Adv. Nutr. 5: 599S–607S, 2014. Introduction Adequate quantity and quality of skeletal muscle mass are vital for overall health and function. In addition to its obvious role in converting chemical energy to mechanical work, skeletal muscle is a major disposal site for blood glucose and FAs and is a significant contributor to the basal metabolic rate (1). Skeletal muscle is the only appreciable “storage reservoir” for body amino acids and, as such, is called upon during periods of reduced energy and/or physiologic stress (e.g., acute inflammation). Finally, a reduced amount of lean body mass has been reported to be a predisposing factor for the risk of hospitalization and is associated with a greater length of stay (2). Therefore, the protection of this vital tissue is important to maintain overall health and a high standard of living with advancing age. Aging is associated with a gradual and insipid loss of lean body mass that, when accompanied by decrements in muscle strength and/or performance, is classically defined as sarcopenia (3). Although multiple definitions of sarcopenia exist (3–6), the transition from healthy aging to severe sarcopenia (i.e., frailty) is a progressive condition that generally occurs along a continuum but is necessarily accompanied by significant losses of muscle mass. Given that the loss of lean mass can precede that of functional limitations (3) and may represent the proverbial “canary in the coal mine” for the development of sarcopenia, a wealth of research has delved into the etiology of muscle loss with the aim of developing effective strategies to attenuate its loss or, more preferably, augment its mass. Dietary Protein Requirements Dietary protein is an essential macronutrient for the maintenance of lean body mass and overall health in individuals of all ages. Provided energy needs are met, the current RDA for older adults is not different from that for their younger counterparts, with daily intakes of 0.8 g/(kg $ d) suggested to be sufficient to meet the metabolic demand for this macronutrient (7). This amount of protein would generally be regarded as “adequate,” with daily intakes below this 0.8 g/(kg $ d) threshold categorized as “suboptimal. ” However, recent 1 Published in a supplement to Advances in Nutrition. Presented at the International Union of Nutritional Sciences (IUNS) 20th International Congress of Nutrition (ICN) held in Granada, Spain, 15–20 September 2013. The IUNS and the 20th ICN wish to thank the California Walnut Commission and Mead Johnson Nutrition for generously providing educational grants to support the publication and distribution of proceedings from the 20th ICN. The contents of this supplement are solely the responsibility of the authors and do not necessarily represent the official views of the IUNS. The supplement coordinators were Angel Gil, Ibrahim Elmadfa, and Alfredo Martinez. The supplement coordinators had no conflicts of interest to disclose. 2 Author disclosure: D. R. Moore, no conflict of interest. * To whom correspondence should be addressed. E-mail: dr.moore@utoronto.ca. ã2014 American Society for Nutrition. Adv. Nutr. 5: 599S–607S, 2014; doi:10.3945/an.113. 005405. 599S D ow naded rom http/academ ic.p.com /advances/arttract/5/5/599S/4565779 by gest on 12 M arch 2019 consensus statements and expert opinions have questioned the adequacy of current protein requirement guidelines by providing evidence that protein intakes greater than the RDA are associated with better health outcomes (e.g., muscle mass and function, bone health, immune function, etc.) in older adults (8–10). As such, the prevailing view is that protein intake should be viewed in terms of what is “optimal”; this can extend to both what is required acutely to maximally stimulate muscle protein synthesis (discussed in more detail below) and/or chronically (in terms of daily protein intake) to maximize health outcomes in the elderly (e.g., retention of muscle mass and function) (8). Metabolic Regulation of Skeletal Muscle Mass Skeletal muscle proteins are continuously being remodeled or “turned over” through the simultaneous processes of protein synthesis and breakdown. The continuous turnover of skeletal proteins ensures that a functional pool of proteins exists as old and potentially damaged proteins are targeted for degradation by the ubiquitin-proteosome system and are subsequently broken down into their constituent amino acids. These amino acids liberated through degradation can subsequently be exported from the cell to serve as substrates for the synthesis of other body proteins and/or gluconeogenesis. Alternatively, and perhaps more importantly from a muscle net balance perspective (i.e., the algebraic difference between protein synthesis and protein breakdown), amino acids from the free pool can be reutilized to synthesize new skeletal muscle proteins. Although the loss of muscle mass with aging is multifactorial in nature, it is ultimately rooted in an imbalance in the rates of protein synthesis and protein breakdown that favors a net negative protein balance. With a turnover rate of ~1–2%/d, an average older adult with ~18 kg of muscle mass could expect to break down and resynthesize ~180–360 g of muscle protein in a typical 24-h period. Given that muscle loss with age can occur at a modest ~1%/y (the equivalent of ~100 g/y or ~0.3 g/d) (11), even slight differences in the rates of protein synthesis and breakdown could translate into meaningful differences in net protein balance that, over time, could contribute to the risk of developing sarcopenia. Some studies suggest that basal rates of muscle protein synthesis may be suppressed somewhat with age (12,13), although this finding is not universal (14,15). However, accumulating evidence points to a significant role for an attenuated anabolic effect of meal feeding in the progression of muscle loss with aging (8), which is primarily manifest through a suppressed stimulation of muscle protein synthesis with dietary amino acid ingestion. Therefore, this review focuses on the role nutrition plays in stimulating muscle anabolismwith feeding and how activity, and especially inactivity, can significantly affect the sensitivity of aging muscle to dietary nutrients. The “Anabolic Resistance” of Aging Underlying physiology. Dietary protein (and subsequently amino acid) ingestion is one of the most robust physiologic stimuli to enhance muscle net protein balance, an effect that is primarily mediated by an essential amino acid–induced stimulation of muscle protein synthesis (16). Although protein ingestion stimulates muscle protein synthesis regardless of age (17), a preponderance of evidence suggests that older skeletal muscle is less efficient at assimilating dietary protein–derived amino acids into new muscle proteins (8). For example, with optimal protein or amino acid ingestion, older adults were reported to display a robust increase in muscle protein synthesis that is generally equivalent to their younger counterparts (18–20); this suggests that, under appropriate nutritional conditions, otherwise healthy older muscle for the most part retains the capacity to respond to protein intake. However, at relatively suboptimal protein intakes, older adults typically display an attenuated muscle protein synthetic response when compared with their younger peers (21). The reduced sensitivity of skeletal muscle tissue to dietary protein–derived amino acids is often referred to as “anabolic resistance. ” Although some evidence suggests that older adults may have an attenuated capacity for insulin-induced suppression of muscle protein breakdown (22), the anabolic resistance of muscle protein synthesis is believed to be the major underlying mechanism of the normal loss of muscle mass with advancing age (8). The mechanisms underpinning the anabolic resistance of muscle protein synthesis are multifactorial but are ultimately rooted in an inability to enhance mRNA translation, the rate-controlling step for protein synthesis that is primarily regulated by the mammalian target of rapamycin (mTOR) signaling pathway (23) in response to dietary amino acids. Splanchnic extraction has variably been reported to be greater in older adults (24,25), which could reduce the appearance of dietary amino acids (especially after suboptimal protein intakes) in the ci