The POI-Accelerated Aging Paradox: A Multi-Omics Approach to Characterizing Systemic Sequelae in Premature Ovarian Insufficiency
DOI:
https://doi.org/10.64229/f57a9b93Keywords:
Premature ovarian insufficiency, Primary ovarian insufficiency, Accelerated aging, Proteomics, Metabolomics, Inflammation, SASP, Systems biologyAbstract
Background: Premature ovarian insufficiency is estimated to affect nearly 3-4% of women globally and is increasingly recognized as a condition associated with premature biological aging involving cardiovascular, skeletal, and neurocognitive systems, including elevated cardiovascular, skeletal, and neurocognitive risks. Whether premature ovarian insufficiency (POI) represents a unique aging phenotype or simply early natural menopause remains unknown. Methods: This is a cross-sectional study which compared 75 women with idiopathic POI (age 25-39 years), 75 age-matched eumenorrheic controls, and 75 women with natural menopause (age 50-55 years). Participants underwent comprehensive clinical assessment and fasting blood collection. Proteomic profiling (Olink® Explore 3072), untargeted metabolomics (UHPLC-MS/MS), and high-sensitivity inflammatory markers (hs-CRP, IL-6, TNF-α, GlycA) were measured. Proteomic age acceleration was calculated using a validated 28-protein aging clock. Results: POI patients demonstrated a striking multi-omics signature of accelerated aging. Compared to controls, 847 proteins were differentially expressed, with marked upregulation of senescence-associated secretory phenotype (SASP) proteins. SASP levels in POI closely approximated natural menopause. Metabolomic profiling revealed 246 differentially abundant metabolites, characterized by branched-chain amino acid accumulation (leucine FC=2.1) and altered glycerophospholipid metabolism. Inflammatory markers were markedly elevated in POI versus controls (hs-CRP: 2.84 vs. 1.02 mg/L, p<0.001) and comparable to natural menopause. Proteomic age acceleration revealed that POI patients had a predicted biological age of 44.8 years versus chronological age 32.4 years__an acceleration of 12.4 years. Conclusions: POI is associated with a systemic accelerated aging phenotype that qualitatively parallels natural menopause but occurs prematurely, with proteomic age acceleration of approximately 12 years. These findings support earlier initiation of preventive screenings and suggest that targeting inflammatory and metabolic pathways may offer therapeutic benefits.
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