Hypothesis

Puberty-associated estradiol signaling via estrogen receptor α (ERα) accelerates the age-related rewiring of type I interferon (IFN-I) signaling from a STAT1-driven antiviral state to a STAT3-dominant inflammatory program in monocytes, CD4+ T cells, and B cells, thereby establishing an early set point for inflammaging that differs between sexes.

Rationale

The et al. findings show a monotonic increase in STAT3-phosphorylation and a concomitant decline in STAT1-phosphorylation across the lifespan, correlating with elevated IL-6, TNF, and exhaustion markers [1]. Estradiol is known to modulate JAK/STAT signaling: low-dose estrogen can enhance STAT3 phosphorylation through membrane-initiated signaling, while high-dose or chronic exposure can induce SOCS3 expression that preferentially suppresses STAT1. Estradiol levels rise sharply at puberty, and ERα is highly expressed in myeloid and lymphoid cells. If ERα signaling potentiates STAT3 activation, then the STAT1-to-STAT3 shift could begin earlier in females, contributing to the observed female-predominance of certain autoimmune conditions and earlier inflammaging.

Testable Predictions

1. Longitudinal human cohort – Measure pSTAT1 and pSTAT3 in sorted monocytes, CD4+ T cells, and B cells from individuals aged 8-22 years (pre-, peri-, and post-puberty) alongside serum estradiol. We predict that the ratio pSTAT3/pSTAT1 will increase sharply coinciding with the pubertal estradiol surge, and that this shift will be more pronounced in females than males [1].
2. ERα blockade in peripubertal mice – Treat mice with the selective ERα antagonist MPP from postnatal day 25 to 45. Flow cytometry for pSTAT1/pSTAT3 in splenic immune subsets should show a blunted STAT3 increase compared with vehicle-treated controls, while basal IFN-α levels remain unchanged.
3. Synergy with STING – In ERα-competent monocytes, transfection with cytosolic DNA (cGAMP) will produce a supra-additive increase in pSTAT3 and downstream ISGs (e.g., CXCL10) only when estradiol is present, indicating that chronic STING activation and ERα signaling cooperate to lock in the STAT3-dominant state [2].
4. Rescue by SOCS3 knock-down – If estradiol accelerates STAT3 dominance via SOCS3-mediated STAT1 inhibition, then siRNA-mediated SOCS3 knockdown in human monocytes should restore STAT1 phosphorylation despite high estradiol, reducing IL-6 and TNF secretion after IFN-α stimulation.

Implications

If confirmed, this hypothesis would reposition puberty as a critical developmental checkpoint that programs the inflammaging trajectory, explain sex differences in immune aging, and suggest that timed ERα modulation (e.g., selective estrogen receptor modulators) could delay the STAT1-to-STAT3 shift, preserving IFN-I antiviral competence and reducing inflammaging.

Falsifiability

Failure to observe a pubertal-linked increase in the pSTAT3/pSTAT1 ratio in females, or lack of effect of ERα antagonism on STAT3 dynamics in mice, would falsify the core claim that estrogen-ERα signaling drives the early STAT1-to-STAT3 switch.