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

Rahul Rai, Asish K. Ghosh, Mesut Eren, Alexander R. Mackie, Daniel C. Levine, So Youn Kim, Jonathan Cedernaes, Veronica Ramirez, Daniele Procissi, Layton H. Smith, Teresa K. Woodruff, Joseph Bass, Douglas E. Vaughan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

35 Scopus citations


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. Rai et al. identify an anti-aging role of the endogenous apelinergic axis. They show that the apelin-apelin receptor axis is downregulated with age and that its absence accelerates the onset and progression of aging. Additionally, restoration of apelin extends the murine healthspan.

Original languageEnglish (US)
Pages (from-to)1471-1480
Number of pages10
JournalCell Reports
Issue number6
StatePublished - Nov 7 2017


  • aging
  • apelin
  • APJ
  • aplnr
  • senescence

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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