The most rapidly growing population segment is represented by those over 60 years of age (World Health Organization 2014). Within the next 30 years, this group of people is expected to represent 22% of the general population. In the United States, the number of Americans aged 65 and older is projected to nearly double from 52 million in 2018 to 95 million by 2060 or slightly more than 23% of the total population (U.S. Census Bureau 2019).
Within this senior population, there is a continual involuntary loss of skeletal muscle mass known as sarcopenia (Thomas 2007). This primarily age-related process is defined by loss of skeletal muscle mass and function and decrements in physical activity, endocrine function, and protein metabolism. Starvation and cachexia, along with aging, represent the dominant pathologic contributors of involuntary weight and skeletal muscle loss. Descriptors associated with these contributors include involuntary weight loss (≥5% over 6–12 months) and malnutrition (weight loss, reduced food intake and nutrient absorption, inflammation due to acute and chronic disease, and overall reduction in functional status).
“Normal” skeletal muscle mass and muscle strength decline is a continual, involuntary process that begins after peaking in the 20s to 40s. At this point, the skeletal muscle mass decreases approximately 0.5% to 1% per year, whereas the annual muscle strength loss is 2.5% to 4% (Mitchell et al. 2012). During this process, there are significant muscle composition changes, reflecting changes in contractile and non-contractile tissue (Yamada 2018).
Cachexia, which may affect as many as 9 million patients globally, is seen in the late stages of almost every major chronic illness (i.e., cancers and HIV); it affects 16%–42% of people with heart failure, 30% of those with chronic obstructive pulmonary disease, and up to 60% of people with kidney disease (Lok 2015). Interestingly, for many years it was overlooked, as clinicians and investigators focused their attention on the primary illness instead.
Cachexia is an integral component of involuntary weight loss in the setting of disease-associated wasting. It is further defined as an inflammatory-associated wasting of protein, particularly skeletal muscle, and loss of energy stores. Cytokines, hormones (such as leptin and insulin), several interleukins, and growth factors, elicited in disease and as principal mediators of inflammation, may in effect tilt our physiology toward catabolic breakdown of tissue in order to mobilize critical nutrients for the central nervous system and aspects of immune function.
Despite cachexia’s impact on mortality and data strongly suggesting that it hinders treatment responses and patients’ ability to tolerate treatment, those who study involuntary weight loss say it has not received the attention it deserves. No consistently effective therapies have been developed to prevent or hamper its progression. Even for patients who are able to eat—appetite suppression or anorexia is a common cachexia symptom— efforts to improve nutrition often offer little respite (National Cancer Institute 2011). It is interesting to speculate that under-reporting of cachexia as a “contributing cause of death” has perennially affected the primacy placed on research and funding of this enormously pervasive process.
There is limited evidence that suggests that when hospitalized older patients are supplemented with essential amino acids, there may be improved muscle function, particularly among those assigned to bed rest (Ferrando et al. 2010). Even among healthy individuals who volunteered for 10 days of bed rest, there was a significant decline in muscle protein synthesis, particularly in the lower extremities (Kortebein et al. 2007). Importantly, even among younger healthy individuals who volunteered for 7 days of bed rest, there was a decline in whole-body protein, which could be mitigated through a dietary protein intake of 1 g/kg bw. Some research suggests that the current RDA for protein (0.8 g/kg bw) may not be adequate to maintain skeletal muscle mass among older individuals and certainly not adequate for those restricted to bed rest (Campbell et al. 2001).
Arginine supplementation (3 g) with an essential amino acid cocktail (EAA, 15 g) administered orally among older and younger subjects improved muscle microvascular perfusion without apparent impacting of myofibrillar protein synthesis (Mitchell et al. 2016). A similar study conducted earlier indicated EAA supplementation (8 g) appears to improve microvascular responses without affecting protein synthesis (Phillips et al. 2015). On the other hand, a 2-week supplementation with leucine (4g/meal x 3 meals/ day) appeared to improve protein synthesis among those consuming a low-protein meal (Casperson et al. 2012).
In searches for mechanisms associated with age-related sarcopenia, several groups of investigators recently reported that variations in the peptide apelin or its receptor gene expression contribute to antiinflammatory pathways in myofibers and affect mitochondriogenesis in human subjects and rodent models (Vinel et al. 2018; Vinel et al. 2019). Important to renal function, especially among the elderly population where glomerular filtration rate (GFR) typically declines, these data suggest apelin, which is a peptide induced by exercise and expressed in blood vessels, stomach, muscle, adipose tissue, heart, lung, and select regions of the brain, is critical in maintaining or enhancing muscle function. This foundational observation is supported by critical studies among apelindeficient rodents where loss of lean tissue mass is reflected in detected hypoplasia and atrophy of an array of muscle fibers, and reduced muscle strength when compared to muscle in control animals.
In a critical sarcopenia study across ethnicities (China, Japan, Singapore, United Kingdom, Jamaica), among nearly 120 older men, there appeared to be consistent transcriptional dysfunctions in skeletal muscle (Migliavacca et al. 2019). These dysfunctions, associated with low or altered signaling through ERRα and PGC-1α in sarcopenic muscle, contribute to our understanding of mechanisms that drive this relentless component of aging.
As we wrestle with understanding and managing the various forms of involuntary weight loss, we must acknowledge that it is a complex and multidimensional spectrum, both in terms of etiology and in approaches to slowing its progression in health and disease. As we acknowledge that there is much to learn and do, we also must not forget that in normal circumstances, good nutrition with adequate high-quality protein in conjunction with regular weight-bearing and graded aerobic exercise, such as walking, can at least help slow the progression of sarcopenia and keep us all functioning to maintain good muscle health (Gray-Donald et al. 2014; Marzetti et al. 2017).