Downregulation of the Apelinergic Axis Accelerates Aging, whereas Its Systemic Restoration Improves the Mammalian Healthspan

Abstract

SUMMARY Aging drives the occurrence of numerous diseases, including cardiovascular disease (CVD). Recent studies indicate that blood from young mice reduces age-associated pathologies. However, the “anti-aging” factors in juvenile circulation remain poorly identified. Here, we characterize the role of the apelinergic axis in mammalian aging and identify apelin as an anti-aging factor. The expression of apelin (apln) and its receptor (aplnr) exhibits an age-dependent decline in multiple organs. Reduced apln signaling perturbs organismal homeostasis; mice harboring genetic deficiency of aplnr or apln exhibit enhanced cardiovascular, renal, and reproductive aging. Genetic or pharmacological abrogation of apln signaling also induces cellular senescence mediated, in part, by the activation of senescence-promoting transcription factors. Conversely, restoration of apln in 15-month-old wild-type mice reduces cardiac hypertrophy and exercise-induced hypertensive response. Additionally, apln-restored mice exhibit enhanced vigor and rejuvenated behavioral and circadian phenotypes. Hence, a declining apelinergic axis promotes aging, whereas its restoration extends the murine healthspan.

Understanding muscle regenerative decline with aging: new approaches to bring back youthfulness to aged stem cells

“…Another important circulatory factor affecting satellite cell function in sarcopenic muscles is the exercise‐induced myokine apelin . Apelin levels decrease with age, and studies in mice show that this has important consequences for healthspan . A recent study revealed an association between apelin signaling and the beneficial effects of exercise, and also identified a positive effect on the regenerative capacity of aged muscle stem cells .…”

Endothelial cell–cardiomyocyte crosstalk in heart development and disease

“…For instance, ageing is known to be associated with both EC and CM dysfunction, resulting in heart hypertrophy and stiffness. During ageing, expression of both APLN and its APJ receptor are decreased and APLN infusion in 15-month-old mice reduces cardiac hypertrophy (Rai et al 2017). On the other hand, ET-1 increases in aged hearts, although its pathogenic role in determining cardiac stiffness seems to be related to its effect on cardiac fibroblasts rather than CMs (Wang et al 2015).…”

Apelin and stem cells: the role played in the cardiovascular system and energy metabolism

“…Apelin signaling down‐regulation is correlated with age‐related diseases and accelerates them. Administration of apelin can ameliorate these disorders (Rai et al, ). Oxidative stress can lead to aging‐associated diseases (Liguori et al, ).…”

“…Oxidative stress can lead to aging‐associated diseases (Liguori et al, ). Apelin raises the activity of antioxidant enzymes (Than et al, ), indicating this peptide acts as an anti‐aging factor (Rai et al, ). Apelin also decreases the reactive oxygen species (ROS) generation and pro‐oxidant enzyme expression in adipocytes, regulates glucose metabolism, and improves insulin resistance.…”