Exerkines, Neurodegeneration, and Ketogenic Metabolic Therapy: A clinically grounded approach to brain health
Exercise has long been recommended for brain health, yet growing clinical and translational research now explains why movement exerts neuroprotective effects. Central to this understanding are exerkines—exercise-induced signaling molecules that communicate between skeletal muscle, the immune system, metabolic organs, and the brain. Rather than acting solely through mechanical or cardiovascular pathways, exercise functions as a systemic metabolic and neuroendocrine therapy.
A 2026 clinical review by Hye Soo Chung and Kyung Mook Choi in Diabetes & Metabolism Journal synthesizes evidence showing that exerkines play a critical role in improving insulin sensitivity, reducing systemic and neuroinflammation, enhancing mitochondrial function, and supporting neuroplasticity. These mechanisms directly target pathways implicated in neurodegenerative diseases, which consistently feature cerebral glucose hypometabolism, mitochondrial dysfunction, oxidative stress, and chronic inflammatory signaling.
Among the most relevant exerkines for brain health is brain-derived neurotrophic factor (BDNF), a key regulator of synaptic plasticity, learning, memory, and mood. BDNF levels are reduced in Alzheimer’s disease, Parkinson’s disease, depression, and insulin resistance, yet increase reliably in response to aerobic exercise and lactate signaling. Lactate itself, once considered metabolic waste, is now recognized as both a neuronal fuel and a signaling molecule that crosses the blood–brain barrier and stimulates BDNF expression. Additional exercise-responsive factors, including irisin, fibroblast growth factor-21 (FGF-21), and acute muscle-derived IL-6, further contribute to mitochondrial biogenesis, metabolic flexibility, and anti-inflammatory regulation.
Clinically, these findings support structured exercise as a targeted intervention for neurodegeneration rather than a nonspecific lifestyle recommendation. Regular aerobic activity at moderate intensity, resistance training to preserve muscle and insulin sensitivity, and tolerable lactate-producing efforts collectively create a biochemical environment that supports neuronal resilience and repair. Importantly, consistency and metabolic signaling appear more influential than intensity alone.
When combined with Ketogenic Metabolic Therapy (KMT), the neuroprotective effects of exercise-derived exerkines may be amplified. Ketogenic therapy shifts the brain’s fuel source from glucose to ketones, which remain accessible in states of cerebral glucose hypometabolism. Ketones also function as signaling molecules, reducing neuroinflammatory pathways, improving mitochondrial efficiency, lowering glutamate excitotoxicity, and supporting inhibitory neurotransmission. Exercise and ketogenic therapy converge on shared metabolic targets—insulin regulation, inflammation reduction, and mitochondrial optimization—creating a synergistic framework supported by emerging clinical data.
Neurodegeneration is increasingly understood not as an isolated neurological condition, but as a metabolic and inflammatory process expressed in the brain. Addressing movement-derived signaling and metabolic fuel availability together allows clinicians to intervene upstream, targeting mechanisms rather than symptoms.
At Katallage Wellness, we integrate clinically informed exercise strategies with metabolic nutrition and ketogenic therapies to support brain health, cognitive resilience, and long-term neurological function.