Background. Early childhood experiences have long-lasting effects on subsequent mental and physical health, education, and employment. The measurement of these effects relies on insensitive behavioral signs, subjective assessments by adult observers, neuroimaging or neurophysiological studies, or retrospective epidemiologic outcomes. Despite intensive research, the underlying mechanisms of these long-term changes in development and health status remain unknown. Methods. We analyzed scalp hair from healthy children and their mothers using an unbiased proteomics platform combining tandem mass spectrometry, ultra-performance liquid chromatography, and collision-induced dissociation to reveal commonly observed hair proteins with a spectral count of 3 or higher. Results. We observed 1368 non-structural hair proteins in children and 1438 non-structural hair proteins in mothers, with 1288 proteins showing individual variability. Mothers showed higher numbers of peptide spectral matches and hair proteins compared to children, with important age-related differences between mothers and children. Age-related differences were also observed in children, with differential protein expression patterns between younger (2 years and below) and older children (3–5 years). We observed greater similarity in hair protein patterns between mothers and their biological children compared with mothers and unrelated children. The top 5% of proteins driving population variability represented biological pathways associated with brain development, immune signaling, and stress response regulation. Conclusions. Non-structural proteins observed in scalp hair include promising biomarkers to investigate the long-term developmental changes and health status associated with early childhood experiences.

One-carbon metabolism influences gene expression by providing methyl units for DNA, RNA, and histone methylation. Robust methylation requires rapid hydrolysis of the methylation by-product S- adenosylhomocysteine (SAH) by S- adenosylhomocysteinase (Ahcy). Here, we show Ahcy is a redox-sensitive enzyme that is inhibited by oxidation of a conserved cysteine, C195, in vitro and in vivo . Transient oxidation of Ahcy is neuroprotective in a Drosophila light stress model where it results in rapid gene expression changes and protects against retinal degeneration. Thus, redox sensing by the one-carbon metabolic enzyme Ahcy enables rapid changes in gene expression in response to changes in redox homeostasis.