Academy

Methionine Cycle and Longevity Signaling

Overview: The methionine cycle (Met-C) is a fundamental metabolic pathway that recycles homocysteine to methionine using vitamin B12–dependent enzymes. This cycle produces S-adenosylmethionine (SAM), which donates methyl groups for key methylation reactions on DNA, RNA, proteins, and lipids. Proper function of Met-C is essential for cellular homeostasis, stress responses, and lifespan regulation.

Key Components

• Methionine Synthase (METR-1): Converts homocysteine to methionine using methyl-tetrahydrofolate and vitamin B12.
• S-Adenosylmethionine (SAM): The primary methyl donor in cells, regulating epigenetic marks and metabolic processes.
• S-Adenosylhomocysteine (SAH): Product of methylation reactions, hydrolyzed to homocysteine, completing the cycle.

Vitamin B12’s Role

Vitamin B12 acts as a cofactor for methionine synthase. Adequate dietary or microbial B12 ensures sufficient Met-C flux, supporting SAM synthesis. Deficiency or excess B12 can disrupt methylation balance, affecting gene expression, stress tolerance, and aging.

Neuronal Met-C and Serotonin

In Caenorhabditis elegans, the Met-C in ADF serotonergic neurons directly influences serotonin production:

1. High B12 diet enhances METR-1 activity in ADF neurons.
2. Increased flux raises SAM levels, driving up tph-1 expression, the rate-limiting enzyme for serotonin synthesis.
3. More serotonin is released, linking metabolism to behavior and longevity signaling.

Neuron-Gut Signaling Axis

Serotonin triggers a multi-step cascade:

• MOD-1 Activation: Serotonin binds MOD-1 chloride channels on downstream interneurons.
• FLR-2 Release: Interneurons secrete the FLR-2 glycoprotein hormone/neuropeptide.
• FSHR-1 Engagement: FLR-2 activates FSHR-1 GPCRs on intestinal cells.
• TIR-1 Phase Transition: FSHR-1 signaling induces TIR-1/SARM1 oligomerization.
• p38-MAPK Activation: Oligomerized TIR-1 activates NSY-1/SEK-1/PMK-1, driving cytoprotective gene expression and lifespan extension.

Implications for Longevity Science

This neuron-gut signaling model reveals how dietary metabolites, metabolism, and neurotransmission coordinate to regulate organismal aging. Understanding Met-C’s role in neurons opens avenues for targeted interventions and microbiota-based therapies to modulate healthspan.