Physical activity is well-established as an important protective factor against degenerative conditions and a promoter of tissue growth and renewal. The discovery of FNDC5 as the precursor of irisin in 2012 sparked significant interest in its potential as a diagnostic biomarker and a therapeutic agent for various diseases. Clinical studies have examined the correlation between plasma irisin levels and pathological conditions using a range of assays, but the lack of reliable measurements for endogenous irisin has led to uncertainty about its prognostic/diagnostic potential as an exercise surrogate. Animal and tissue-engineering models have shown the protective effects of irisin treatment in reversing functional impairment and potentially permanent damage, but dosage ambiguities remain unresolved. This review provides a comprehensive examination of the clinical and basic studies of irisin in the context of degenerative conditions and explores its potential as a therapeutic approach in the physiological processes involved in tissue repair/regeneration.

Brain-derived neurotrophic factor (BDNF) is a key molecule in promoting neurogenesis, dendritic and synaptic health, and neuronal survival, plasticity, and excitability, all of which are disrupted in neurological and cognitive disorders such as Alzheimer’s disease (AD). Extracellular aggregates of amyloid-β (Aβ) in the form of plaques and intracellular aggregates of hyperphosphorylated tau protein have been identified as major pathological insults in AD brain, along with immune dysfunction, oxidative stress, and other toxic stressors. Although aggregated Aβ and tau lead to decreased brain BDNF expression, early losses in BDNF prior to plaque and tangle formation may be due to other insults such as oxidative stress and contribute to early synaptic dysfunction. Physical exercise, on the other hand, protects synaptic and neuronal structure and function, with increased BDNF as a major mediator of exercise-induced enhancements in cognitive function. Here, we review recent literature on mechanisms behind exercise induced BDNF upregulation and its effects on improving learning and memory and on Alzheimer’s disease pathology. Mechanisms include elevations in peripheral BDNF-inducing hormones such as osteocalcin, FNDC5/irisin, and lactate. The fundamental mechanisms of how exercise impacts BDNF and cognition are unclear but are a prerequisite to developing new biomarkers and therapies to delay or prevent cognitive decline.