The contributory role of vascular health in age-related anabolic resistance

Abstract

Sarcopenia, or the age-related loss of skeletal muscle mass and function, is an increasingly prevalent condition that contributes to reduced quality of life, morbidity, and mortality in older adults. Older adults display blunted anabolic responses to otherwise anabolic stimuli-a phenomenon that has been termed anabolic resistance (AR)-which is likely a casual factor in sarcopenia development. AR is multifaceted, but historically much of the mechanistic focus has been on signalling impairments, and less focus has been placed on the role of the vasculature in postprandial protein kinetics. The vascular endothelium plays an indispensable role in regulating vascular tone and blood flow, and age-related impairments in vascular health may impede nutrient-stimulated vasodilation and subsequently the ability to deliver nutrients (e.g. amino acids) to skeletal muscle. Although the majority of data has been obtained studying younger adults, the relatively limited data on the effect of blood flow on protein kinetics in older adults suggest that vasodilatory function, especially of the microvasculature, strongly influences the muscle protein synthetic response to amino acid feedings. In this narrative review, we examine evidence of AR in older adults following amino acid and mixed meal consumption, examine the evidence linking vascular dysfunction and insulin resistance to age-related AR, review the influence of nitric oxide and endothelin-1 on age-related vascular dysfunction as it relates to AR, briefly review the potential causal role of arterial stiffness in promoting skeletal muscle microvascular dysfunction and AR, and provide a brief overview and future considerations for research examining age-related AR.

Keywords: Ageing; Anabolic resistance; Blood flow; Insulin; Muscle protein synthesis; Vasodilation.

Figure 1

During the ageing process, there are gradual impairments in vascular function, anabolic signalling, arterial compliance, and insulin sensitivity. These impairments may ultimately lead and/or contribute to anabolic resistance, or a reduced ability to mount a muscle protein synthetic response to anabolic stimuli. Over time, anabolic resistance promotes sarcopenia, or the age‐related loss in muscle mass and function, resulting in a loss of functional ability and independence in older adults.

Figure 2

The impact of meal consumption in an older (left) and younger adult (right). In the older adult, there is an increased tendency for insulin to stimulate endothelin‐1 (ET‐1) release from the vascular endothelium, rather than nitric oxide (NO) as typically observed in healthy younger adults. Additionally, shear stress subsequent to an increase in blood flow stimulates the glycocalyx to release NO from the vascular endothelium in younger adults, whereas this effect is significantly reduced with ageing. Glucagon‐like peptide‐1 (GLP‐1) also stimulates vasodilation through NO‐dependent and NO‐independent mechanisms in a postprandial state. Finally, the NO that is produced in older adults is more likely to be scavenged by overproduced and/or unregulated reactive oxygen species (ROS) (i.e. oxidative stress). Consequently, meal consumption in younger adults is ultimately more likely to cause a robust vasodilatory response, thus enhancing the anabolic potential of meal consumption via greater nutrient delivery to skeletal muscle, when compared with older adults.

Figure 3

Ageing is associated with alterations in the vascular smooth muscle cells, loss of elastin, and increased collagen deposition in the large elastic arteries. Carotid–femoral pulse wave velocity is measured by dividing the distance (d) between a point on the carotid and femoral artery by the time it takes (Δt) for a pulse wave to travel from the carotid to femoral tonometry points in m/s. In younger adults, there are multiple points of impedance mismatch that reflect portions of the pulsatile energy back towards the heart, buffering the pulsatile energy travelling along the vessel, slowing the overall speed of the pulse wave, and protecting the microcirculation. In older adults, there is a more distal point of wave reflection due to stiffening of the elastic arteries, resulting in faster pulse wave transit times and excessive transmission of pulsatile energy into the microcirculation.

Figure 4

The postprandial skeletal muscle protein synthetic (MPS) response is dependent on amino acid delivery, which is the product of amino acid availability (e.g. concentrations) and blood flow (e.g. perfusion). In healthy younger adults, submaximal doses of essential amino acids (EAAs) are able to optimally stimulate MPS, whereby increasing to a maximal dose of EAAs does not result in further increases in MPS. In older healthy adults, submaximal doses of EAAs are often not able to optimally stimulate MPS, but when maximal doses are given, these individuals are often able to saturate the MPS response. In older sarcopenic adults, neither submaximal nor maximal doses of EAAs are able to optimally stimulate MPS. We propose that a rate‐limiting factor for older adults consuming submaximal and older sarcopenic adults consuming maximal EAA doses to be an inability of the meal consumption to promote adequate skeletal muscle perfusion, resulting in high circulating amino acid concentrations in these populations, but poor delivery and consequently impaired increases in MPS.