Hypothesis

We propose that a gonad‑derived signal, analogous to GDF11 but acting specifically on the lysosomal transcription factor TFEB, actively suppresses TFEB nuclear translocation during early adulthood to prioritize lysosomal biogenesis for vitellogenesis and oocyte maturation. This suppression reduces autophagic flux, conserving nucleotides and amino acids for reproduction. After the reproductive window, the signal wanes, allowing TFEB to resume its homeostatic role, but the preceding period of low autophagy causes irreversible damage that manifests as aging. Thus, autophagy decline is not a passive by‑product of damage but an antagonistically pleiotropic program that trades early‑life fecundity for late‑life survival.

Mechanistic Basis

• Early‑life gonadotropins (LH/FSH) stimulate somatic gonads to secrete a peptide we term Repro‑Lysin (RL). RL binds a membrane receptor on peripheral tissues, activating the MAPK‑ERK pathway, which phosphorylates TFEB at serine‑122, promoting its binding to 14‑3‑3 proteins and cytoplasmic retention.
• Cytoplasmic TFEB fails to activate CLEAR network genes (ATG5, ATG7, BECN1, lysosomal proteases), lowering autophagosome formation and lysosomal acidification.
• The same RL‑ERK axis also up‑regulates MITF and TFE3, diverting lysosomal resources toward melanin and yolk protein deposition, directly supporting oocyte vitellogenesis.
• When gonadal output declines post‑reproduction, RL levels fall, ERK activity diminishes, TFEB is dephosphorylated by calcineurin, translocates to the nucleus, and restores CLEAR expression—but the earlier autophagic deficit has already allowed accumulation of damaged mitochondria and protein aggregates, driving senescence.
• This mechanism mirrors the trl-1 phase‑switch in C. elegans [1] and the apoB trade‑off in humans [2], positioning TFEB as a node where reproductive signaling directly modulates the autophagy‑longevity axis.

Testable Predictions

1. Manipulation of RL – Neutralizing RL with antibodies in young adult mice will increase TFEB nuclear localization, raise LC3‑II/I ratios, and extend median lifespan without reducing litter size; conversely, exogenous RL in aged mice will suppress TFEB and accelerate frailty.
2. Genetic uncoupling – Knock‑in of a TFEB S122A mutant (non‑phosphorylatable) should render TFEB constitutively nuclear, leading to elevated basal autophagy, normal early‑life fertility, and significant lifespan extension, confirming that the phosphorylation site mediates the trade‑off.
3. Population genetics – In human cohorts, polymorphisms in the RL receptor gene that reduce signaling should correlate with higher autophagic flux markers in blood, later age at menopause, and increased survival past 85 years, whereas gain‑of‑function variants associate with earlier reproductive peak and earlier mortality.
4. Group‑selection test – In socially structured insect models (e.g., Nasonia vitripennis), RNAi knockdown of the RL ortholog in older workers should delay autophagy decline, increase individual longevity, but reduce colony productivity under fluctuating environments, supporting a lineage‑level benefit.

Potential Challenges

• If RL neutralization extends lifespan without fertility cost, the antagonistic pleiotropy premise weakens, suggesting autophagy decline may be non‑adaptive damage.
• Compensatory pathways (TFE3, MITF) could mask phenotypes; double‑knockout studies may be required.
• RL may have pleiotropic effects beyond TFEB (e.g., on IGF‑1 signaling); tissue‑specific rescue experiments will be needed to isolate the lysosomal arm.