Hypothesis: Perivascular Fibroblast-Derived Wnt5a Maintains Zona Reticularis Progenitor Niche and Its Age‑Dependent Loss Drives DHEAS Decline

Core proposition With advancing age, perivascular fibroblasts in the adrenal cortex reduce secretion of Wnt5a, a non‑canonical Wnt ligand that sustains zona reticularis (ZR) progenitor proliferation and steroidogenic enzyme expression. This decline uncouples ZR homeostasis from corticotropin (ACTH) signaling, leading to selective atrophy of the ZR while the zona fasciculata (ZF) remains ACTH‑responsive, thereby producing the observed cortisol/DHEAS dissociation.

Mechanistic chain

1. In young adults, perivascular fibroblasts adjacent to the ZR capsule release Wnt5a, which binds ROR2 receptors on ZR progenitor cells, activating β‑catenin‑independent pathways that upregulate CYP17A1 and SULT2A1, the key enzymes for DHEAS synthesis (4).
2. Wnt5a also promotes angiocrine factors (e.g., VEGF‑A) that preserve the microvascular network surrounding the ZR, preventing centripetal rarefaction (6).
3. With age, chronic low‑grade inflammation and elevated glucocorticoids induce fibroblast senescence (↑p16^INK4a^, ↓Wnt5a transcription) (1).
4. Reduced Wnt5a diminishes progenitor proliferation, accelerates ZR atrophy, and lowers DHEAS output, while ACTH‑driven cortisol production in the ZF persists or increases due to preserved ACTH receptor density and 11β‑HSD1 activity.
5. The resulting rise in cortisol/DHEAS ratio weakens hippocampal glucocorticoid receptor‑mediated negative feedback, flattening the diurnal rhythm and attenuating the cortisol awakening response (CAR) (2).

Testable predictions

• Prediction 1: Immunohistochemical staining of human adrenal biopsies will show a significant inverse correlation between perivascular fibroblast Wnt5a expression and zona reticularis thickness across ages (r < –0.5, p < 0.01).
• Prediction 2: Ex vivo adrenal explants from older donors treated with recombinant Wnt5a will exhibit increased CYP17A1 mRNA and DHEAS secretion (≥30% rise vs. vehicle) without altering F‑ACTH‑stimulated cortisol.
• Prediction 3: In aged mice, fibroblast‑specific Wnt5a overexpression (using Pdgfrb‑CreERT2;Rosa26‑Wnt5a) will preserve ZR volume, maintain DHEAS levels, and lower the cortisol/DHEAS ratio compared with littermate controls.
• Prediction 4: Pharmacologic inhibition of Wnt5a in young adult mice will recapitulate the aging phenotype: reduced ZR progenitor Ki‑67+, decreased DHEAS, and elevated cortisol/DHEAS ratio within 2 weeks.

Falsifiability If any of the above experiments fail to show the predicted direction of change (e.g., Wnt5a supplementation does not raise DHEAS or fibroblast Wnt5a levels do not correlate with ZR morphology), the hypothesis would be refuted, indicating that perivascular fibroblast Wnt5a is not a primary driver of age‑related ZR atrophy.

Implications Confirming this mechanism would reposition DHEAS decline as a fibroblast‑mediated paracrine failure rather than solely a cell‑intrinsic adrenal senescence, opening therapeutic avenues such as targeted Wnt5a delivery or senolytics to restore the adrenal niche and normalize the cortisol/DHEAS ratio, potentially mitigating cognitive and metabolic sequelae of adrenal aging.