Exerkine fibronectin type-III domain-containing protein 5/irisin-enriched extracellular vesicles delay vascular ageing by increasing SIRT6 stability

Eur Heart J. 2022 Nov 14;43(43):4579-4595. doi: 10.1093/eurheartj/ehac431.


Aims: Exercise confers protection against cardiovascular ageing, but the mechanisms remain largely unknown. This study sought to investigate the role of fibronectin type-III domain-containing protein 5 (FNDC5)/irisin, an exercise-associated hormone, in vascular ageing. Moreover, the existence of FNDC5/irisin in circulating extracellular vesicles (EVs) and their biological functions was explored.

Methods and results: FNDC5/irisin was reduced in natural ageing, senescence, and angiotensin II (Ang II)-treated conditions. The deletion of FNDC5 shortened lifespan in mice. Additionally, FNDC5 deficiency aggravated vascular stiffness, senescence, oxidative stress, inflammation, and endothelial dysfunction in 24-month-old naturally aged and Ang II-treated mice. Conversely, treatment of recombinant irisin alleviated Ang II-induced vascular stiffness and senescence in mice and vascular smooth muscle cells. FNDC5 was triggered by exercise, while FNDC5 knockout abrogated exercise-induced protection against Ang II-induced vascular stiffness and senescence. Intriguingly, FNDC5 was detected in human and mouse blood-derived EVs, and exercise-induced FNDC5/irisin-enriched EVs showed potent anti-stiffness and anti-senescence effects in vivo and in vitro. Adeno-associated virus-mediated rescue of FNDC5 specifically in muscle but not liver in FNDC5 knockout mice, promoted the release of FNDC5/irisin-enriched EVs into circulation in response to exercise, which ameliorated vascular stiffness, senescence, and inflammation. Mechanistically, irisin activated DnaJb3/Hsp40 chaperone system to stabilize SIRT6 protein in an Hsp70-dependent manner. Finally, plasma irisin concentrations were positively associated with exercise time but negatively associated with arterial stiffness in a proof-of-concept human study.

Conclusion: FNDC5/irisin-enriched EVs contribute to exercise-induced protection against vascular ageing. These findings indicate that the exerkine FNDC5/irisin may be a potential target for ageing-related vascular comorbidities.

Keywords: Exercise; Extracellular vesicles; FNDC5; SIRT6; Senescence; Vascular ageing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aging
  • Angiotensin II / pharmacology
  • Animals
  • Child, Preschool
  • Extracellular Vesicles*
  • Fibronectins / metabolism
  • HSP40 Heat-Shock Proteins / metabolism
  • Humans
  • Inflammation / metabolism
  • Mice
  • Mice, Knockout
  • Muscle, Skeletal / metabolism
  • Sirtuins*
  • Transcription Factors / metabolism


  • Fibronectins
  • Transcription Factors
  • Angiotensin II
  • Sirtuins
  • SIRT6 protein, human
  • FNDC5 protein, human
  • DNAJB3 protein, human
  • HSP40 Heat-Shock Proteins
  • Sirt6 protein, mouse
  • FNDC5 protein, mouse