Exerkines and Blood Flow Restriction Training in Aging: Cellular and Molecular Pathways: Narrative Review

Extended Abstract

Introduction

Population ageing is a defining demographic trend of the 21st century, directly linked to rising disability, multimorbidity, and healthcare expenditures. Among the most consequential consequences of aging is the progressive decline in skeletal muscle mass, strength, and quality—a condition now recognised clinically as sarcopenia. In older adults, particularly postmenopausal women, this process is accelerated by a convergence of biological mechanisms: chronic low‑grade inflammation (“inflammaging”), mitochondrial dysfunction, anabolic resistance to dietary protein and exercise, and altered hormonal milieus including oestrogen withdrawal. These changes not only impair mobility and increase fall risk but also compromise metabolic health and independence.

Conventional high‑load resistance training remains the gold standard non‑pharmacological intervention to counteract sarcopenia. However, many older individuals face barriers such as joint pain (osteoarthritis), cardiovascular limitations, fear of injury, and poor adherence. This gap has fuelled interest in low‑load alternatives that can mimic the molecular benefits of heavy exercise without excessive mechanical stress. One such strategy is blood flow restriction (BFR) training, which combines low‑intensity exercise (typically 20–40% of one‑repetition maximum) with partial vascular occlusion using a pneumatic cuff. This creates a unique microenvironment of local hypoxia and metabolic stress—characterised by lactate accumulation, hydrogen ion buildup, and depletion of phosphocreatine—which potently stimulates anabolic and adaptive signalling pathways.

The systemic effects of exercise are increasingly understood through the lens of “exerkines”: a heterogeneous family of signalling molecules (peptides, metabolites, lipids, extracellular vesicles, and non‑coding RNAs) released from various tissues during and after physical activity. Exerkines mediate interorgan crosstalk, linking muscle, liver, adipose tissue, bone, brain, and the cardiovascular system. In the context of ageing, the exerkine network is often dysregulated, contributing to inflammation, insulin resistance, and impaired muscle regeneration. Whether BFR training—despite its low mechanical load—can favourable remodel this network in older adults remains incompletely synthesised. This narrative review, guided by a systematic literature search, aims to provide a comprehensive overview of BFR‑induced exerkine adaptations in ageing populations, highlight underlying cell signalling pathways, and identify critical knowledge gaps for future research.

The synthesised evidence reveals that BFR training in older adults robustly modulates multiple classes of exerkines, with distinct effects on anabolic, inflammatory, metabolic, and regenerative pathways.

Myokines—muscle‑derived exerkines—show a consistent shift towards an anabolic profile. Irisin, follistatin, insulin‑like growth factor‑1 (IGF‑1), and interleukin‑15 are upregulated, whereas myostatin, a negative regulator of muscle growth, is suppressed. These changes are mechanistically linked to activation of AMP‑activated protein kinase (AMPK), the PI3K/Akt/mTORC1 axis, and the transcriptional co‑activator PGC‑1α, which together enhance protein synthesis, mitochondrial biogenesis, and fibre cross‑sectional area. Importantly, these effects occur even with loads as low as 20–30% of one‑repetition maximum, highlighting the potency of metabolic stress as an alternative to mechanical tension.

Immune‑related exerkines (cytokines and chemokines) undergo a qualitative shift. While baseline chronic inflammation in ageing is associated with elevated tumour necrosis factor‑alpha (TNF‑α) and interleukin‑6 (IL‑6), BFR training induces an acute, transient rise in IL‑6 followed by increased anti‑inflammatory mediators such as IL‑10 and IL‑1 receptor antagonist. This pattern, mediated through JAK/STAT and NF‑κB signalling, promotes lipolysis, glucose uptake, and resolution of low‑grade inflammation. The dual role of muscle‑derived IL‑6 as a metabolic hormone is thus preserved under BFR, distinguishing it from the maladaptive elevation seen in chronic disease.

Adipokines, hepatokines, and osteokines are also favourably modulated. Adiponectin rises, while leptin and resistin decrease, correlating with improved insulin sensitivity and reduced adipose tissue inflammation. The hepatokine fibroblast growth factor 21 (FGF21) increases via AMPK/PGC‑1α, supporting hepatic fatty acid oxidation and metabolic flexibility. Among osteokines, osteocalcin levels tend to increase, promoting bone–muscle crosstalk, whereas sclerostin may decrease, potentially preserving bone mineral density.

Emerging exerkine categories include metabolite‑derived molecules and extracellular vesicles (EVs). β‑aminoisobutyric acid (BAIBA), β‑hydroxybutyrate, and succinate are produced during BFR and act as endocrine‑like regulators of energy expenditure and appetite. Furthermore, BFR alters the cargo of circulating EVs, enriching specific microRNAs (e.g., miR‑21, miR‑146a, miR‑133, miR‑206). These EVs can transfer regulatory signals to distant organs—liver, brain, endothelium—potentially explaining systemic benefits such as improved cognitive function and vascular health. However, direct human evidence for these latter categories in older adults undergoing BFR remains extremely limited.

From a physiological standpoint, BFR creates local hypoxia and metabolite accumulation, activating hypoxia‑inducible factor‑1α (HIF‑1α)/vascular endothelial growth factor (VEGF) for angiogenesis, AMPK for energy sensing, and PGC‑1α for mitochondrial quality control. Clinically, studies using personalised cuff pressures (40–80% of arterial occlusion pressure) and low‑load BFR (2–3 sessions/week for 6–12 weeks) report significant improvements in muscle strength, appendicular lean mass, and functional mobility (e.g., Timed Up‑and‑Go, chair‑stand test) compared to low‑load exercise alone.

Conclusion

Low‑load resistance training combined with blood flow restriction effectively remodels the exerkine network in older adults, driving anabolic, anti‑inflammatory, metabolic, and neurotrophic signalling through pathways (AMPK, mTOR, JAK/STAT, PGC‑1α) that are otherwise blunted by ageing. This mechanistic evidence positions BFR as a feasible, low‑risk alternative for sarcopenia and frailty, particularly for individuals intolerant to high‑load exercise. Nevertheless, critical knowledge gaps persist: the dose‑response relationship between cuff pressure/training volume and exerkine secretion is poorly defined; sex‑specific responses (older men vs. postmenopausal women) remain unexplored; the functional significance of EV‑miRNA and metabolite exerkines in human ageing requires dedicated investigation; and long‑term randomised controlled trials with hard clinical endpoints (falls, hospitalisation, loss of mobility) are urgently needed. Future research should prioritise standardised BFR protocols, multi‑omics profiling, and translation of molecular findings into personalised exercise prescription for older adults.

Footnotes

Funding: This research was not financially supported by any organization.

Authors’ Contributions: The authors made equal contributions to the design and writing of all sections of the manuscript.

Conflict of Interest: The authors declare that they have no conflicts of interest.