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<p>Spontaneous preterm birth (sPTB) is a leading cause of neonatal mortality and long-term morbidity worldwide, affecting approximately 15&#xa0;million infants annually. Despite advances in obstetric care, its incidence has remained largely unchanged, reflecting an incomplete understanding of the biological mechanisms governing the timing of parturition. While infection and inflammation have traditionally dominated etiological models, these alone do not fully explain the heterogeneity in disease onset, progression, and outcomes. Emerging evidence suggests that sPTB may represent a state of accelerated gestational aging, in which cellular stress pathways prematurely activate labour mechanisms that are normally tightly regulated at term. This narrative review synthesizes current evidence linking mitochondrial dysfunction, oxidative stress, and cellular senescence to the pathogenesis of sPTB. Across gestational tissues, including the placenta, fetal membranes, decidua, cervix, and myometrium, molecular stress induces shifts characterized by impaired mitochondrial oxidative phosphorylation, increased reactive oxygen species generation, and activation of senescence-associated pathways. Beyond reflecting cellular injury, these processes actively propagate inflammatory signalling, extracellular matrix remodelling, and endocrine activation that collectively promote premature labour. We further integrate underexplored mechanistic pathways, including mitochondrial dynamics and mitophagy, ferroptosis, nicotinamide adenine dinucleotide (NAD⁺) metabolism, inflammasome activation, extracellular vesicle signalling, and deoxyribonucleic acid (DNA) damage responses. These interconnected pathways interact through damage-associated molecular patterns (DAMPs), cytokines, and extracellular vesicles to coordinate pathological crosstalk across the maternal-fetal interface. Emerging multi-marker biomarker strategies and targeted therapeutic approaches, including mitochondrial antioxidants, senolytic agents, and inflammasome inhibitors, are also discussed within this framework. Mitochondrial dysfunction and cellular senescence represent central biological axes linking molecular stress with premature activation of labour pathways in sPTB. Conceptualizing sPTB as accelerated gestational aging provides a unifying framework for integrating diverse mechanistic pathways, refining risk stratification, and guiding the development of targeted, precision-based interventions to reduce the global burden of prematurity.</p>

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Mitochondrial dysfunction and cellular senescence drive accelerated gestational aging in spontaneous preterm birth: a narrative review

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月8日

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  • Gagana Hanumaiah,
  • Thejesh Srinivas,
  • Akhila Vasudeva

摘要

Spontaneous preterm birth (sPTB) is a leading cause of neonatal mortality and long-term morbidity worldwide, affecting approximately 15 million infants annually. Despite advances in obstetric care, its incidence has remained largely unchanged, reflecting an incomplete understanding of the biological mechanisms governing the timing of parturition. While infection and inflammation have traditionally dominated etiological models, these alone do not fully explain the heterogeneity in disease onset, progression, and outcomes. Emerging evidence suggests that sPTB may represent a state of accelerated gestational aging, in which cellular stress pathways prematurely activate labour mechanisms that are normally tightly regulated at term. This narrative review synthesizes current evidence linking mitochondrial dysfunction, oxidative stress, and cellular senescence to the pathogenesis of sPTB. Across gestational tissues, including the placenta, fetal membranes, decidua, cervix, and myometrium, molecular stress induces shifts characterized by impaired mitochondrial oxidative phosphorylation, increased reactive oxygen species generation, and activation of senescence-associated pathways. Beyond reflecting cellular injury, these processes actively propagate inflammatory signalling, extracellular matrix remodelling, and endocrine activation that collectively promote premature labour. We further integrate underexplored mechanistic pathways, including mitochondrial dynamics and mitophagy, ferroptosis, nicotinamide adenine dinucleotide (NAD⁺) metabolism, inflammasome activation, extracellular vesicle signalling, and deoxyribonucleic acid (DNA) damage responses. These interconnected pathways interact through damage-associated molecular patterns (DAMPs), cytokines, and extracellular vesicles to coordinate pathological crosstalk across the maternal-fetal interface. Emerging multi-marker biomarker strategies and targeted therapeutic approaches, including mitochondrial antioxidants, senolytic agents, and inflammasome inhibitors, are also discussed within this framework. Mitochondrial dysfunction and cellular senescence represent central biological axes linking molecular stress with premature activation of labour pathways in sPTB. Conceptualizing sPTB as accelerated gestational aging provides a unifying framework for integrating diverse mechanistic pathways, refining risk stratification, and guiding the development of targeted, precision-based interventions to reduce the global burden of prematurity.