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Nicotinamide Mononucleotide alleviates aging defects of Hutchinson-Gilford progeria syndrome

ABSTRACT: Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare genetic disorder characterized by mutations in the LMNA gene, resulting in progerin accumulation and accelerated aging, with limited therapeutic options currently available. This study demonstrates the significant therapeutic potential of nicotinamide mononucleotide (NMN) in alleviating HGPS phenotypes at both cellular and organismal levels. Using patient-derived induced pluripotent stem cell-mesenchymal stem cells (iPSC-MSCs), we demonstrated that enhancing NAD+ biosynthesis through NMN supplementation effectively restored mitochondrial function, reduced DNA damage and inflammatory markers, and mitigated oxidative stress. Furthermore, in G608G transgenic mouse models receiving NMN administration over four months, we observed significant improvements in fertility and gonadal function, enhanced cardiovascular parameters, ameliorated skin pathology, and extended lifespan. These comprehensive findings establish NMN supplementation as a promising therapeutic strategy for HGPS and potentially other aging-related disorders.

ORGANISM(S): Homo sapiens

PROVIDER: GSE295355 | GEO | 2025/08/01

REPOSITORIES: GEO

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Recapitulation of human premature aging by using iPSCs from Hutchinson-Gilford progeria syndrome

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Project description:Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disease that is frequently caused by a de novo point mutation at position 1824 in LMNA. This mutation activates a cryptic splice donor site in exon 11, and leads to an in-frame deletion within the prelamin A mRNA and the production of a dominant negative lamin A protein, known as progerin. Here we show that HGPS cells experience genome-wide alterations in patterns of H3K27me3 deposition, changes in the associations of genomic loci with nuclear lamin A/C, and, at late passages, genome-wide loss of spatial compartmentalization of active and inactive chromatin domains that characterizes chromosome folding in normal cells. We further demonstrate that the H3K27me3 changes associate with gene expression alterations in HGPS cells. Our results support a model that the accumulation of progerin in the nuclear lamina leads to altered H3K27me3 marks in heterochromatin, possibly through the down-regulation of EZH2, and disrupts heterochromatin-lamina interactions. These changes may then lead to the genomic disorganization and changes in transcriptional regulation we observe in HGPS fibroblasts. ChIP-Seq was performed for H3K27me3 and lamin A/C in the human genome in three primary fibroblast cell lines: an HGPS patient (HGPS), normal cells from the father of the HGPS patient (Father), and age-matched normal cells (Age Control). Two biological replicates were performed.

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