Hypothesis: Circadian control of NAD+ biosynthesis gates the transition from physiological to pathological decidual senescence. In young endometrium, BMAL1‑CLOCK drives rhythmic expression of NAMPT, sustaining NAD+ levels that activate SIRT1. SIRT1 deacetylates p53 and FOXO1, promoting autophagic clearance of transiently senescent decidual cells and preserving the stromal microenvironment needed for implantation. With age, declining BMAL1 dampens NAMPT oscillations, NAD+ falls, SIRT1 activity wanes, and p16^INK4a^‑positive senescent cells accumulate beyond the physiological threshold. Their SASP (IL‑6, TNF‑α) further suppresses BMAL1 transcription via NF‑κB, creating a feed‑forward loop that locks the endometrium in a pro‑inflammatory, senescence‑rich state. Restoring NAD+ rhythm—either by timed supplementation of NAD+ precursors (e.g., nicotinamide riboside) aligned to the active phase or by pharmacological BMAL1 agonists—should re‑engage SIRT1‑mediated senolysis, reduce pathological senescence, and rescue decidualization capacity.

Predictions: (1) In aged wild‑type mice, timed NR administration (ZT0‑ZT4) will increase endometrial NAMPT and NAD+ levels, elevate SIRT1 activity, and halve the proportion of p16^INK4a^+ stromal cells compared with ad‑libitum NR. BMAL1 knockout mice show infertility and hormone deficits physiological decidual senescence markers excessive decidual senescence in RPL age‑related p16^INK4a^ accumulation (2) Conditional stromal‑cell Bmal1 knockout mice will fail to show this rescue, confirming BMAL1 dependence. BMAL1 knockout mice show infertility and hormone deficits (3) Treated aged mice will exhibit improved decidual markers (PRL, IGFBP‑1) and increased litter size, whereas senolytic treatment alone will not improve outcomes without concurrent circadian NAD+ restoration. peri‑menopausal stromal decidualization deficit CLOCK‑BMAL1 controls estradiol/progesterone for decidualization (4) In human endometrial biopsies from recurrent‑implantation‑failure patients, ex‑vivo culture with NR plus a circadian dexamethasone pulse will reduce SA‑β‑Gal positivity and increase progesterone‑responsive gene expression relative to untreated controls. RIF endometrial epithelial and signaling defects implantation failure-associated stromal senescence and stem cell loss

Falsification: If timed NAD+ boosting does not lower senescent cell burden or improve decidualization in aged mice, or if Bmal1 loss does not abolish the effect, the hypothesis is refuted. Likewise, if human endometrial cultures show no senescence reduction despite NAD+ rhythm restoration, the proposed mechanistic link between circadian NAD+ flux and decidual senescence would be invalid.