Pentadecanoic acid as a potential endogenous mTOR modulator for age-related female infertility: Mechanistic insights,...

Age-related female infertility is a major reproductive health challenge that accelerates sharply after the age of 34, primarily due to declining oocyte quality, increased chromosomal abnormalities, and impaired embryonic developmental competence. Emerging evidence identifies chronic hyperactivation of the mechanistic target of rapamycin (mTOR) signalling pathway as a central molecular driver of ovarian aging, promoting excessive ribosome biogenesis, impaired proteostasis, suppressed autophagy, mitochondrial dysfunction, and oxidative stress within oocytes and surrounding cumulus cells. Although rapamycin, the prototypical mTOR inhibitor, has demonstrated promising effects in improving ovarian function and in vitro fertilization outcomes, its teratogenic potential, immunosuppressive properties, metabolic side effects, and prolonged pre-conception washout requirements limit its clinical applicability in fertility management. This review synthesises current evidence on the role of mTOR in ovarian aging and is complemented by an original molecular docking analysis performed by the authors to evaluate the interaction between pentadecanoic acid and the mTOR kinase domain, an endogenous odd-chain saturated fatty acid, as a potential fertility-safe mTOR modulator. A comprehensive review of the literature was conducted using PubMed and related databases, encompassing pentadecanoic acid biochemistry, molecular mechanisms, mTOR signalling architecture, ovarian aging biology, rapamycin pharmacology, and molecular docking studies. Available evidence indicates that pentadecanoic acid activates AMP-activated protein kinase (AMPK), modulates PPAR-α/δ signalling, supports cellular antioxidant defence, and collectively attenuates anabolic mTOR activity while promoting autophagic recycling and metabolic homeostasis. Molecular docking analysis against the mTOR kinase domain (PDB ID: 4JSV) demonstrated that pentadecanoic acid binds within the active site with a binding energy of -4.4 kcal/mol through interactions with key hydrophobic residues, including Leu1936, Ile1939, Tyr2144, Val2227, and Gly2142, whereas rapamycin exhibited a stronger affinity (-10.1 kcal/mol). Unlike rapamycin, pentadecanoic acid is endogenously produced, compatible with pregnancy, and requires no washout period. Collectively, these findings position pentadecanoic acid as a promising endogenous mTOR modulator with potential therapeutic relevance for age-related female infertility, warranting further mechanistic investigations and well-designed human clinical trials.