ReviewNutrients with anabolic/anticatabolic, antioxidant, and anti-inflammatory properties: Targeting the biological mechanisms of aging to support musculoskeletal health
Introduction
Musculoskeletal aging is characterized by the progressive loss of tissue and organ function which, if persists, may lead to the onset of several age-related pathologies such as sarcopenia, osteosarcopenia, and physical frailty (Kirk et al., 2020a). These pathologies are considered the “modern-day geriatric giants” given their increasing prevalence in an aging society (Morley, 2017) and the adverse outcomes attributed including mobility disability, falls, fractures, and even premature death (Bhasin et al., 2020; Cruz-Jentoft et al., 2019; Dent et al., 2019; Kirk et al., 2020b). With poor musculoskeletal health, chronic pain may also occur and require medications such as analgesics or corticosteroids to alleviate symptoms but in turn, accelerate musculoskeletal pathologies by contributing to muscle and bone loss (Klein, 2015).
Recognizing the socioeconomic burdening associated with aging, the National Institutes of Health set up the geroscience initiative to understand the genetic, molecular, and cellular, alterations that occur during senescence (Kennedy et al., 2014). Among the biological mechanisms of aging, changes in protein metabolism (favoring proteolysis), macromolecular damage (driven by oxidative stress), and chronic low-grade inflammation (also known as “inflammaging”), contribute to the structural and functional decline of the musculoskeletal system. Protein metabolism of skeletal muscle and bone declines by around 10% per decade, shifting the balance in favor of catabolism over time (Kirk et al., 2020a). Age-related increases in free radicals, a hallmark of aging, drive oxidative stress resulting in cellular damage and eventually apoptosis (El Assar et al., 2020; Liguori et al., 2018; Luo et al., 2020). Along this causal pathway, free radical damage is closely linked to inflammaging contributing to cellular dysfunction. Such changes may translate into an older person losing between 25 and 40% of bone structure at the femoral neck and distal radius and around 50% of total lean (muscle) mass by age 80 (Chen et al., 2013; Janssen et al., 2000). These morphological alterations begin incipiently from mid-life and, if no intervention is initiated, an octogenarian may be at high risk of poor health outcomes.
As musculoskeletal tissue is dependent on metabolically active nutrients such as amino acids, vitamins, and minerals, which act as key signaling molecules for gene expression of proteins and enzymes, nutritional status is an important modifiable risk factor for sarcopenia, osteosarcopenia, and physical frailty. However, during aging, nutritional deficits become prevalent due to diminished appetite, swallowing difficulties (dysphagia), poor dentition, impaired taste and smell, as well as food insecurity and malabsorption (JafariNasabian et al., 2017; Kirk et al., 2021). To confound this issue, nutritional requirements to maintain normal physiological and biochemical processes increase with age due to increased levels of proteolysis, oxidative stress, and inflammaging, as mentioned above. Therefore, provision of nutrients with anabolic/anticatabolic, antioxidant, and anti-inflammatory properties represents a feasible avenue to target the biological mechanisms of aging implicated in musculoskeletal pathologies (Fig. 1).
To date, several reviews have highlighted the potential role of nutritional interventions in respect to their effects on individual tissues or organs (Gielen et al., 2021), with little work focusing on the pillars of aging as described by the geroscience initiative. Thus, this article aimed to identify nutrients that stimulate anabolic signaling, promote cellular antioxidant defense, and downregulate pro-inflammatory pathways to maintain musculoskeletal health (Fig. 2) and reduce chronic pain, with a focus on recent work from pre-clinical and clinical studies of older persons.
Section snippets
Mechanisms of action: anabolic muscle resistance and anti-inflammatory properties
Proteins, which are made up of amino acids (AA) and peptide bonds, support muscle architecture and contractile filaments needed for force production, as well as making up around 50% of the bone matrix in the form of collagen and non-collagen proteins. Thus, proteins and their constituent AA serve a fundamental, biological purpose for musculoskeletal health. For its role in pain control, adequate protein ingestion is needed for endorphins' (a group of endogenous opioid neuropeptides) synthesis
Mechanisms of action: antioxidant and anti-inflammatory properties
Tryptophan is an EAA required for the production of several bioactive compounds that have important physiological roles (Cervenka et al., 2017). It can be found in protein foods including milk, dairy products and peanuts (Perna et al., 2020). Higher circulating tryptophan levels predicted a trend towards lower subsequent hip BMD decline and osteoporotic fracture risk in older community-dwelling persons (mean age: 72 y) (Su et al., 2019). Although a study of dietary tryptophan intake showed no
Combined nutritional interventions
Multi nutrient supplementation has become an area of investigation as the age-related deterioration of the musculoskeletal system has been recognized as complex, with several biological mechanisms involved (depicted in Fig. 1). This concept is also supported by protein-rich “whole-food” approaches which include a variety of non-protein derived nutrients that may facilitate muscle remodeling in disuse-induced muscle atrophy commonly found in physically frail older persons. In this approach, the
Conclusions
Intakes of anabolic/anticatabolic nutrients such as protein (1.2–1.5 g/kg/day), leucine (2–3 g/meal) or HMB (1.5 g/meal) may attenuate age-related muscle and bone loss. Maintaining sufficient plasma concentrations of vitamin D (>20 or 30 ng/mL) may support the beneficial effects of protein by promoting anabolism and attenuating inflammaging. Improving nutritional status with micronutrients (B12, folate, vitamin K2) that decline with aging should also be considered. Finally, further RCTs are
Sponsor's role
None.
CRediT authorship contribution statement
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published.
Declaration of competing interest
Prof. Duque has served as a member of Advisory Boards at TSI Pharmaceuticals, Lilly, Abbott, TSI, and Amgen Australia and is a member of the board of speakers for Amgen, Abbott, Lilly, Sanofi, and Novartis Australia. Dr. Kirk is supported by a research grant from TSI Pharmaceuticals which manufacture vitamin D and HMB supplements. Dr. Kositsawat has no conflict of interest to declare.
Acknowledgments
We would like to thank Ms. Kathleen Crea for her help with the literature search and Ms. Marissa Gauthier for her assistance with reference management.
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