The Conglomerate Theory of Female Reproductive Aging

Female reproductive aging exemplifies accelerated, system-specific decline, with the ovary undergoing the earliest and most pronounced functional deterioration of any organ system. Traditional explanations centered on follicular depletion and oocyte aneuploidy fail to account for the interdependent biochemical pathways driving reproductive senescence. This paper extends the Conglomerate Theory of Aging to female reproductive biology, presenting a unified, systems-level framework in which reactive species-initiated processes— metal bioaccumulation, advanced glycation end product (AGE) formation, advanced lipoxidation end product (ALE) accumulation, and the emergence of metal-AGE/ALE hybrid complexes— interact as mutually reinforcing elements of a single damage network. Within this framework, bioaccumulated metals, AGEs, and ALEs function as interdependent drivers of molecular damage. Metal-catalyzed redox activity amplifies the production of reactive oxygen, nitrogen, and carbonyl species, fostering environments conducive to AGE and ALE formation, while AGEs and ALEs independently propagate redox cycling and inflammation through RAGE-mediated and mitochondrial feedback. These processes collectively erode ovarian cellular integrity, induce mitochondrial and enzymatic dysfunction, accelerate follicular depletion, and disrupt hypothalamic-pituitary-ovarian axis regulation. The model highlights the therapeutic potential of multi-target approaches addressing concurrent pathways of damage amplification. Candidate strategies include glutathione restoration with GlyNAC, selective metal chelation, carbonyl-stress inhibition via compounds such as carnosine, and γ-tocopherol for nitrosative stress. Priorities for future research include biomarker discovery and integrative clinical trials using multiomics platforms to track and modulate these overlapping mechanisms. By framing reproductive aging as a network of self-reinforcing oxidative, glycoxidative, and lipoxidative processes, the Conglomerate Theory of Female Reproductive Aging offers a cohesive biochemical explanation for reproductive decline and identifies convergent intervention points to sustain fertility and extend reproductive longevity.