Fasting Affects the Immune System via the Brain

This mechanism also affected mTOR.

A new study has found that the immune remodeling associated with fasting is significantly influenced by neuronal activity. These findings could be important in the context of fasting mimicking, metabolic disorders, and cancer ^[1].

Fasting and the Immune System

Decades after the emergence of the modern field of geroscience, caloric restriction continues to be lauded as one of the most effective interventions for health and longevity. Fasting, as a subset of caloric restriction, offers numerous benefits ^[2]. However, despite its potential advantages, there are numerous caveats, and the practice should be undertaken with caution. For instance, several studies have recently indicated that intermittent fasting may be associated with an increased risk of cardiovascular mortality ^[3].

Fasting has a profound effect on the immune system: it is known to lower inflammation and reduce the circulation of pro-inflammatory monocytes—cells that can infiltrate tissues to become macrophages or dendritic cells, crucial components of the innate immune system. However, the specific mechanisms behind this immune reorganization remain inadequately understood.

Mind Over Body

Researchers at the University of Manchester conducted a study to elucidate whether the regulation of immune response during fasting is due to direct sensing of nutrient levels by the immune system or if it necessitates signaling from the brain. Their investigation revealed intriguing results regarding the role of hypothalamic neurons in this process.

Hunger and satiety are regulated by two distinct subsets of neurons in the hypothalamus. The first subset, known as Agouti-related peptide (AgRP) neurons, promotes feelings of hunger; the second, pro-opiomelanocortin (POMC) neurons, signals satiety.

In their experiments, researchers genetically engineered mice to allow for the transient activation of these two groups of neurons. Activation of AgRP neurons in non-fasted mice resulted in decreased levels of circulating pro-inflammatory monocytes, replicating the effects typically seen after a 20-hour fast. Notably, this occurred without any observed drop in blood glucose levels.

Conversely, when fasted mice were re-fed, concurrent artificial activation of AgRP neurons inhibited the increase in monocytes that was expected during the re-feeding phase, despite the restoration of normal blood glucose levels. This suggests that the perception of hunger—driven by AgRP neuron activity—can override systemic nutrient signals in regulating monocyte levels.

In another part of the study, the researchers activated POMC neurons in fasted mice, which countered the fasting effects by increasing monocyte levels even without food present. Dr. Giuseppe D’Agostino, the lead senior researcher, noted, “Our perceptions can shape our bodies in ways we don’t always notice... this study underscores the significant role the brain plays in regulating the immune system.”

The mTOR Connection

Activating AgRP neurons also mimicked fasting by reducing the levels of CCL2, a cytokine that recruits monocytes from the bone marrow into circulation. The addition of exogenous CCL2 partially counteracted this effect.

Given that the liver is known to regulate CCL2 levels, researchers investigated its role in this process. They found that key genes usually upregulated in the liver during fasting were not activated by AgRP neuron stimulation. However, the researchers observed a decrease in hepatic mTOR activity, a protein recognized as a potent longevity regulator in various animal models ^[4].

Blocking mTOR inhibition in the liver diminished the impact of AgRP neuron activation on CCL2 levels and monocyte numbers. The study suggests a “fly-by-wire” mechanism where neuronal control directly modulates immune responses via central nervous system signaling, independent of local nutrient availability.

Lead author Dr. Cavalcanti de Albuquerque indicated that understanding how the brain exerts control over immune cells could have vital implications for treating conditions related to infections, inflammation, metabolic issues, and psychiatric disorders.

Implications and Future Directions

The ramifications of this study extend beyond understanding fasting. They highlight the profound interconnectedness of the brain and the immune system. Future research may focus on:

• Exploring how neuronal signaling can be leveraged to induce similar immune benefits without fasting.
• Investigating therapeutic interventions for immune-related conditions that could harness the brain's regulatory capabilities.
• Studying the differential impacts of various caloric restriction strategies on immune function and longevity.

The study underscores the importance of maintaining a healthy connection between mental and physical health, offering new avenues for understanding the role of fasting and nutritional strategies in health optimization.

Literature Cited

• [1] Hunter, J., et al. (2025). Brain sensing of metabolic state regulates circulating monocytes. Science Immunology.
• [2] Waziry, R., et al. (2023). Effect of long-term caloric restriction on DNA methylation measures of biological aging in healthy adults from the CALERIE trial. Nature Aging, 3(3), 248-257.
• [3] Sebastian, S. A., et al. (2024). Intermittent fasting and cardiovascular disease: A scoping review of the evidence. Disease-a-Month, 101778.
• [4] Miller, R. A., et al. (2014). Rapamycin‐mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. Aging Cell, 13(3), 468-477.