Aging differentially affects disease risks of various organs1. The endocrine organs undergo significant changes along aging. Clinical reports showed increased prevalence of thyroid disorders with age, especially hypothyroidism2. Primary hypothyroidism includes congenital, autoimmune, and iatrogenic causes, which can occur throughout the lifespan. But those with unknown aetiology increase dramatically (~5 fold) in the elderly (≥75 years old)3,4. In thyrocytes, accumulated thyroglobulin requires efficient protein folding in the endoplasmic reticulum (ER)5,6. When ER experiences protein folding defects, it activates the unfolded protein response (UPR), which determines the life-or-death cell fate. The most fundamental mediator in UPR signaling is inositol-requiring enzyme-1 alpha (IRE-1α)7. This study reports, for the first time, a highly conserved gene, Cellular retinoic acid binding protein 1 (Crabp1), critical to thyrocyte function in aging. CRABP1 acts by modulating clustering and activation of IRE-1α, thereby reducing thyrocyte ER stress.
