mTOR1c Activation with the Leucine “Trigger” for Prevention of Sarcopenia in Older Adults During Lockdown

INTRODUCTION

Sarcopenia is the progressive, age-associated decline in muscle function, mass, and strength, and is a major contributor to poor health and disability in older adults. ^1,2 Evidence shows that older adults (>65 years) are six times more likely to be hospitalized for COVID-19, ^{3 –5} which coupled with prolonged physical inactivity under homebound pandemic lockdown conditions, ^3,4 are at higher risk for sarcopenia during the COVID-19 pandemic. ⁶

A body of evidence suggests that the proteogenic amino acid leucine can strongly stimulate muscle protein synthesis (MPS) in older adult, ^{7 –10} and thus is now considered a key amino acid in the medical management of sarcopenia. ¹¹ Whey-enriched enteral nutrition products are a good source of highly bioavailable leucine, ^12,13 and are recommended for preservation of lean body mass in long-term care patients. ^14,15 Therefore, we argue that coupled with the animal and human data, ^{7 –10} the use of whey-enriched enteral nutrition products, which can provide the 3–5 g leucine per meal that has been shown to maximally stimulate MPS, ^{16 –20} should be considered for preservation of lean body mass in homebound older adults.

Although it is unclear whether this approach alone will be sufficient to prevent sarcopenia, we argue that there is sufficient biochemical and human data for nutrition and medical professionals to debate, and give serious consideration to the specific levels of supplemental leucine needed to preserve lean body mass in high-risk older adults during lockdown conditions.

COVID-19, PROLONGED LOCKDOWN, AND SARCOPENIA IN OLDER ADULTS

In response to the 2020 global COVID-19 pandemic, ²¹ health and governmental agencies have recommended and enforced extreme measures to contain virus spread, including travel bans, quarantine, and physical distancing. ²² Although effective in mitigating the spread of the SARS-CoV-2 virus, ²³ among the unintended consequences of these lockdown measures is increased home confinement, and marked reductions in physical activity—strong risk factors for sarcopenia. ³ Moreover, in the first months of the pandemic, data show that older adult populations (>65 years) had the highest rates of COVID-19 infection, ^4,5 and prolonged bed-ridden hospitalizations and ICU admission. ^4,5 Collectively, evidence shows these factors result in marked loss of body weight, including lean body mass. ²⁴

Based on evidence from previous pandemics, evidence also suggests that there will be marked increases in musculoskeletal wasting and neuromyopathy consequences for hospitalized older adult patients with COVID-19, ⁶ and the need for postpandemic musculoskeletal rehabilitation. ⁶ The SARS-CoV-2 virus might also have a direct impact on promoting cardiac and skeletal muscle myopathies. ²⁵

POOR DIET AND SARCOPENIA RISK IN OLDER ADULTS DURING COVID-19 LOCKDOWN

Due to numerous social and physiological factors, older adults often fail to meet their dietary protein intake requirements. ²⁶ During the COVID-19 pandemic, avoidance of indoor shopping, and limited mobility have further diminished access to high-quality sources of protein, and other macronutrients for older adults. ^{27 –30} Evidence shows that stress-related eating during COVID-19 lockdown has promoted poor food choices and nutrition, with increased intake of foods high in energy, salt, sugars, and fat. ³¹ These data suggest that over nutrition, and displacement of higher quality, nutrient dense foods during lockdown, will likely increase obesity in older adults, which is a strong risk factor for sarcopenia. ³²

Moreover, confinement and social isolation of lockdown conditions, increases stress and anxiety, factors also strongly associated with muscle wasting and loss of lean body mass in older adults. ³³ Taken together, these poor dietary habits, coupled with limited physical activity, suggest that risk of sarcopenia in homebound older adults has been heightened during COVID-19.

HOW MUCH LEUCINE IS NECESSARY TO COMBAT SARCOPENIA?

Compared to younger adults, older adults are less responsive to dietary protein-driven MPS, sometimes called “anabolic resistance.” ^{16 –20} As such, evidence suggests that older adults may require as much as double the Recommended Dietary Allowance for protein (0.8 g/kg body weight/day) to maintain lean body mass. ^16,18,19 A body of data suggests that among the proteogenic amino acids, the branch-chain amino acid leucine is the most robust in stimulating MPS in vitro and in vivo, through the nutrient sensing pathway mammalian target of rapamycin 1c (mTOR1c) ^{7 –9} (for review ³⁴ ). Evidence shows that approximately 3–5 g of dietary leucine is sufficient to restore muscle anabolic responses and maximally stimulate MPS in older adults. ^9,18,35

The leucine threshold hypothesis purports that with a mixture of cellular amino acids; a certain level of intracellular leucine is necessary to “trigger” robust MPS through mTOR1c. ⁷ Due to its unique property to strongly stimulate MPS, ^{7 –9} leucine has emerged as a potential key amino acid for older adults to preserve lean body mass. ^11,36 However, leucine's ability to preserve lean body mass remains controversial, as other studies have also shown that leucine alone cannot enhance muscle mass in older adults. ^10,39,40 Moreover, long-term evidence is lacking on leucine's ability to prevent muscle wasting and sarcopenia. ^37,38

Nevertheless, in considering its role in stimulating MPS through mTOR1c in vivo, ^{7 –9} a position paper from an expert panel of The Society for Sarcopenia, Cachexia, and Wasting Disease, advocates for supplemental leucine for clinical management of sarcopenia. ¹¹ Although, no specific leucine intake levels were defined, just that a “leucine-enriched balanced essential amino acid mix” should be included in the diet. ¹¹ Nevertheless, given evidence of increased musculoskeletal wasting older adults as a result of the COVID-19 pandemic, ^6,25 specific clinical guidelines for use of supplemental leucine for homebound, and food insecure older adults, should be considered by nutrition professional organizations.

WHEY-FORTIFIED ENTERAL NUTRITION PRODUCTS FOR HOMEBOUND OLDER ADULTS

A food-first approach should be the preferred method for treating sarcopenia and protein malnutrition in older adults. ^11,41 For example, 3–5 ounces of animal and meat products can provide the 3–5 g of leucine needed for MPS. ⁴² However, as discussed above, older adults are at risk for dietary protein malnutrition, ²⁶ which is exacerbated under COVID-19 pandemic conditions. ^{28 –30} Enteral nutritional supplements are often used in long-term care settings due to poor food intake and to prevent protein malnutrition. ^14,41 These products, such as Nestle Beneprotein^®, ⁴³ typically use either milk protein concentrate or whey protein isolate as a whey-source, which both contain between ∼10% and 15% leucine per gram of protein. ^12,44 Data show that, when compared with a mixture of isonitrogenous equivalent constituent amino acids, casein, or soy protein isolate, whey protein stimulates greater MPS in older adults. ^45,46

The superior properties of whey protein for stimulating MPS are incompletely understood. ⁷ However, evidence suggests that the comparatively faster rate of whey-derived leucine absorption, and subsequent rapid increase in plasma and cellular leucine concentrations, a state referred to as “leucinemia,” ^12,13 is a key aspect of the whey-leucine and mTOR1c, MPS “trigger” hypothesis. ⁷ Therefore, in homebound older adults, consumption of 20–30 g of whey-protein enriched products in 8–12 ounces of water, can easily provide the 3–5 g of leucine per meal that has been shown to stimulate maximal MPS in older adults. ^16,18,35,44

However, it is important to note, that leucine supplementation itself would not be sufficient to offset sarcopenia if meals do not contain sufficient levels of energy, macro and micronutrients necessary to support MPS. ^16,18,35 Nevertheless, based on this body of evidence, ^16,18,35 we propose that during prolonged periods of extended lockdown, such as those during the COVID-19 pandemic, ^3,23 that whey protein-enriched enteral products can easily provide the 3–5 g of leucine to stimulate MPS, and potentially preserve lean body mass in older adults when access to nutritious and protein-rich whole foods may be limited and risk for sarcopenia is high.

CONCLUSIONS

Here, we present data at the intersection of molecular biology and clinical nutrition that supports a dietary range of 3–5 g of daily leucine supplementation using whey-enriched enteral products in older adults during periods of prolonged lockdown periods. Whey-enriched enteral nutrition products can provide a safe dietary approach that could potentially offset muscle wasting, sarcopenia, and its negative health effects ^1,2 during the unprecedented conditions of the COVID-19 pandemic.