Stress granules: Emerging regulators of reproductive aging

Reproductive aging progressively impairs fertility and contributes to broader systemic decline. Stress granules (SGs), transient membraneless ribonucleoprotein assemblies formed during cellular stress, have recently emerged as important regulators of gonadal homeostasis. Their function is highly context dependent: properly resolved SGs promote cellular adaptation and survival, whereas persistent SGs disrupt proteostasis and trigger cell death pathways. In the testis, transient SGs protect germ cells under stress; however, persistent SG accumulation activates necroptosis through the ZBP1-RIPK3 axis, a pathway implicated in human non-obstructive azoospermia and testicular aging. In the ovary, defective autophagic clearance leads to pathological SG persistence in granulosa cells, while several SG-associated proteins are indispensable for normal oogenesis. Together, these findings indicate that dysregulated SG dynamics, particularly impaired clearance, represent a convergent mechanism linking cellular stress responses to reproductive decline. Despite these advances, critical gaps remain. The cell-type-specific regulation of SG assembly and disassembly within the gonad is not fully defined, and the molecular mechanisms by which persistent SGs drive tissue-level aging require clarification. Addressing these questions will refine our understanding of reproductive aging and its mechanistic connection to proteostatic imbalance.