Hypothesis

The selective removal of dysfunctional senescent decidual stromal cells by uterine natural killer (uNK) cells is not a static process but is tightly coupled to the maternal circadian rhythm. Sleep‑driven circadian signals prime uNK cells to execute a nightly “autopsy” that decides which stromal architectures persist into the receptive phase. When this rhythm is disrupted, the clearance program fails, allowing senescence‑resistant cells to accumulate and impair decidualization.

Mechanistic rationale

• Circadian control of uNK cytotoxicity – Core clock genes (BMAL1, CLOCK) in uNK cells regulate transcription of perforin, granzyme B, and NK‑cell activating receptors (e.g., NKp46). In mice, Bmal1 deletion in NK cells reduces cytotoxic granule exocytosis by ~40% (see circadian‑immune coupling literature).
• Melatonin as a zeitgeber – Peak melatonin secretion during the biological night enhances uNK cytotoxic activity via MT1 receptors and promotes autophagic flux in target senescent cells. Sleep loss lowers nocturnal melatonin, diminishing both NK‑cell killing efficiency and the autophagic “self‑eating” pathway that makes senescent cells susceptible to clearance.
• Senolytic checkpoint – Senescent stromal cells express elevated IL17RB, CXCL12, CXCL14, CDKN1A, and CDKN2A (3, 4). These markers also render them resistant to indiscriminate senolytics (e.g., dasatinib) but susceptible to NK‑cell–mediated clearance when the NK‑cell activation threshold is met by circadian cues.
• Clearance‑resistant escape – If the NK‑cell window is mistimed or blunted, senescent stromal cells evade removal, accumulate, and secrete a maladaptive SASP that disrupts extracellular matrix organization and progesterone responsiveness (1).

Testable predictions

1. In vivo – Female mice subjected to chronic sleep fragmentation (e.g., gentle handling during the light phase) will show:
   • Reduced uterine NK‑cell cytotoxicity toward senescent stromal cells (measured by in vivo killing of p16^INK4a^+ GFP‑labelled stromal transplants).
   • Increased endometrial p16^INK4a^, IL17RB, and CXCL12 levels.
   • Lower implantation rates despite normal ovarian hormone profiles.
2. Rescue – Timed melatonin administration (ZT14‑ZT18) or selective NK‑cell agonistic IL‑15 complexes will restore NK‑cell clearance capacity, normalize senescent stromal burden, and rescue implantation rates in sleep‑fragmented mice.
3. Ex vivo – Endometrial stromal cultures from women aged >40 yr will exhibit decreased autophagy flux (LC3‑II/I ratio) and resistance to NK‑cell–mediated lysis; co‑culture with melatonin‑treated uNK cells from young donors will restore autophagic flux and increase apoptotic clearance of senescent stromal cells.
4. Human correlation – Women with self‑reported short sleep (<6 h/night) or shift work will have higher endometrial CDKN1A/CDKN2A expression and lower uNK‑cell activation markers (CD107a^+) in mid‑secretory phase biopsies, correlating with lower fecundability.

Falsifiability

If sleep disruption fails to alter uNK‑cell cytotoxicity or senescent stromal clearance in the endometrium, or if melatonin/IL‑15 rescue does not improve implantation despite restored NK activity, the hypothesis would be refuted. Conversely, demonstration that circadian modulation of uNK‑cell function directly governs the selective removal of senescence‑marked stromal cells would support the idea that the endometrium performs a nightly “autopsy” akin to the brain’s glymphatic triage, and that sleep is a gatekeeper of reproductive longevity.