Pinpointing beta adrenergic receptor in ageing pathophysiology: victim or executioner? Evidence from crime scenes

Abstract

G protein-coupled receptors (GPCRs) play a key role in cellular communication, allowing human cells to sense external cues or to talk each other through hormones or neurotransmitters. Research in this field has been recently awarded with the Nobel Prize in chemistry to Robert J. Lefkowitz and Brian K. Kobilka, for their pioneering work on beta adrenergic receptors (βARs), a prototype GPCR. Such receptors, and β2AR in particular, which is extensively distributed throughout the body, are involved in a number of pathophysiological processes. Moreover, a large amount of studies has demonstrated their participation in ageing process. Reciprocally, age-related changes in regulation of receptor responses have been observed in numerous tissues and include modifications of βAR responses. Impaired sympathetic nervous system function has been indeed evoked as at least a partial explanation for several modifications that occur with ageing. This article represents an updated presentation of the current knowledge in the field, summarizing in a systematic way the major findings of research on ageing in several organs and tissues (crime scenes) expressing βARs: heart, vessels, skeletal muscle, respiratory system, brain, immune system, pancreatic islets, liver, kidney and bone.

Hypothalamic Sirt1 protects terminal Schwann cells and neuromuscular junctions from age‐related morphological changes

“…Impaired sympathetic neural function is associated with several age‐related systemic changes (Santulli & Iaccarino, 2013), and systemic physiological improvements seen in BRASTO mice result from sympathetic stimulation (Satoh et al., 2013). In addition, the sympathetic nervous system is present within skeletal muscle of young adult mice (Khan et al., 2016; Rudolf et al., 2013) and may modify muscle contraction, perfusion, and metabolism (Rudolf et al., 2013).…”

“…Another sympathetic receptor that mediates responses to catecholamines, the β2‐AR, is found extensively throughout the body. While all three β‐adrenergic receptor types are present in skeletal muscle, there is a 10‐fold increased proportion of the β2 isoform in skeletal muscle (Santulli & Iaccarino, 2013). An age‐related decline in responsiveness to β2‐ARs has been proposed (Ford, Dachman, Blaschke & Hoffman, 1995), and β2 receptor agonists have reversed age‐related muscle weakness and wasting in rats (Ryall, Plant, Gregorevic, Sillence & Lynch, 2004).…”

“…Aging is associated with progressive skeletal muscle mass decline, muscle fiber denervation, and motor unit loss and remodeling (Santulli & Iaccarino, 2013). With age, degenerative changes may affect not only muscle and nerve, but also the interface between the two, the neuromuscular junction (NMJ).…”

Long-term α1B-adrenergic receptor activation shortens lifespan, while α1A-adrenergic receptor stimulation prolongs lifespan in association with decreased cancer incidence

“…β 2 ARs promote aging and reduced lifespan mostly due to adverse effects on cardiac and pulmonary functions and its age-related impairment to regulate insulin secretion (Gao et al 2003;Santulli et al 2012;Santulli and Iaccarino 2013). However, it could also be due to polymorphisms in the receptor.…”

Effects of olmesartan therapy on the expression of lung adrenoceptors in rats with chronic heart failure

“…The SNS would be activated in CHF and the elevated catecholamine could down-regulate β-AR by activating β-adrenergic receptor kinase and phosphorylating β-AR. 23 Therefore, the down-regulation of β 1 -AR may be a compensatory reaction to high levels of catecholamine in CHF.…”