Fibronectin type III domain-containing protein 5/irisin in extracellular vesicles is reduced in older individuals

The progressive accumulation of physiological stress as we age, known as allostatic load, is linked to an increased risk of dementia. Fostering brain resilience through physical exercise can counteract allostatic load and improve adaptation to age-related brain alterations. Fibronectin type III domain-containing protein 5 (FNDC5)/irisin is a neuroprotective exercise-linked hormone found in extracellular vesicles (EV-FNDC5/irisin). Here, we sought to analyse EV-FNDC5/irisin in ageing as a promising biomarker of brain resilience. We measured exercise-associated factors, including EV-FNDC5/irisin, brain-derived neurotrophic factor (BDNF), and cathepsin B in the serum of 31 young (18-28 years) and 19 older subjects (65-79 years). Levels of FNDC5/irisin in serum-derived EVs are markedly reduced in older subjects compared to young (P = 0.004). We report a reduction in nanoparticles isolated from the serum of older participants (P = 0.009). While EV-FNDC5/irisin positively correlates with BDNF in young subjects (Spearman r = 0.40, P = 0.038), this correlation is absent in elderly subjects (Spearman r = -0.25, P = 0.34). This study provides initial evidence that EV-FNDC5/irisin is reduced in older individuals and loses correlation with BDNF. Our identification of peripheral, exercise-linked factors associated with age may inform biomarker discovery and interventions to promote brain resilience.