CPT2 as a Convergent Node Linking Age-Associated Neuronal H3K27me3 Remodeling to Nicotinamide Mononucleotide (NMN)-Induced Expression Rescue in Metabolic Tissues.

CPT2 is identified as a potential link between age-related chromatin changes and NMN's effects on metabolism, but the study does not support broad reversal of epigenetic aging by NMN.

Summary and findings

This study examined the relationship between age-associated neuronal H3K27me3 remodeling and the expression of nicotinamide mononucleotide (NMN)-responsive genes in metabolic tissues. The analysis identified 23 genes shared between aging H3K27me3 targets and NMN-rescue genes, with CPT2 being highlighted as a significant candidate. No broad reversal of neuronal epigenetic aging by NMN was supported by the findings.

Abstract

Age-related decline in mitochondrial function and disruption of epigenetic regulation are two closely connected features of biological aging. In neurons, age-associated remodeling of repressive H3K27me3 chromatin may constrain genes needed for metabolic, synaptic, and stress-adaptive maintenance. In parallel, nicotinamide mononucleotide (NMN), an NAD+ precursor, has been reported to mitigate age-associated physiological and transcriptional changes in peripheral metabolic tissues. However, direct links between neuronal epigenetic aging programs and NMN-responsive transcriptional rescue remain unclear. Here, we performed a secondary integrative analysis of two public datasets: GSE190102, focused on age-associated neuronal H3K27me3 targets mapped through an activity-by-contact-style region-gene framework, and GSE85718, a long-term NMN transcriptomic dataset from skeletal muscle, liver, and white adipose tissue in mice. The analysis identified 23 genes shared between 21,155 aging H3K27me3-associated targets and 35 robust NMN-rescue genes. Because the aging target set was extremely broad, gene-level overlap was not statistically persuasive, and pathway-level convergence was absent. Under repressive-mark direction logic, 14 of the 23 shared genes were concordant, meaning that the NMN expression effect opposed the expected consequence of age-associated H3K27me3 remodeling. Objectives were to quantify overlap between neuronal age-associated H3K27me3 targets and robust NMN-responsive genes in peripheral metabolic tissues, classify shared genes by directional concordance under repressive chromatin logic, and identify high-priority mechanistic candidates. The analysis supports limited global convergence and nominates CPT2 as the leading convergent node for targeted validation. CPT2 emerged as the leading candidate. It showed age-associated H3K27me3 gain, a large K27me3 log-fold change of +3.504, NMN-induced expression increase in old animals, a positive NMN interaction coefficient of +0.201, and membership in the mitochondrial fatty-acid oxidation pathway. Within the downstream shared-gene mitochondrial analysis, CPT2 was the only mitochondrial-core gene, with nominal enrichment only. These findings do not support a broad reversal of neuronal epigenetic aging by NMN. Instead, they identify CPT2 as a biologically coherent and experimentally tractable candidate linking age-related repressive chromatin remodeling to NMN-responsive mitochondrial metabolism.

Key findings

• Not reported in abstract.

Limitations

• Not reported in abstract.

Elsewhere in the NAD+ (Nicotinamide Adenine Dinucleotide) corpus