Adrenal Aging: Region-Specific Vulnerability and Proteostatic Decline - Mechanisms, Biomarkers, and Translational Opportunities

The adrenal gland integrates stress, metabolic, immune, and circadian signals to safeguard organismal homeostasis, yet its aging biology has been comparatively overlooked. Converging evidence from recent primate single-nucleus atlases, functional perturbations in human adrenal cells, human pathology, and multi-organ proteome aging resources reveals a coherent mechanistic picture: adrenal aging is region-specific, substrate-limited, and constrained by proteostasis, characterized by decline of dehydroepiandrosterone sulfate (DHEA-S) and aldosterone, while preserved cortisol output on average with diurnal flattening and higher prevalence of autonomous cortisol secretion with ageing. These endocrine trajectories implicate heightened vulnerability of the zona reticularis (ZR) and zona glomerulosa (ZG) versus the zona fasciculata (ZF). At the cellular level, ZR cells exhibit senescence, immune activation, and lipid metabolic disruption, including downregulation of androgen sulfation. Broad reduction of LDLR across cortex limits cholesterol import reduces DHEA-S, linking substrate scarcity to endocrine decline. Proteostatic lesions including aggresomes, amyloid, and lipofuscin accumulate across zones, aligning adrenal changes with systems-level proteome aging and vascular susceptibility. Key pathological correlates like ZR thinning, accumulation of aldosterone-producing cell clusters (APCCs), and higher prevalence of adrenal tumors underscore an age-biased remodeling of zonal identity and control hierarchies. Developmental and sex-dimorphic programs, including WNT/FRZB signaling and extracellular matrix remodeling, likely preconfigure later-life vulnerability. In this perspective, we synthesize these advances into a mechanistic model connecting centripetal differentiation, cholesterol trafficking, proteostasis collapse, inflammaging, and vascular aging to endocrine dysfunction and highlight biomarker strategies to index "adrenal age". We also outline near-term clinical deployment opportunities in older adults with adrenal incidentalomas or frailty using combined hormonal and plasma proteomic readouts, supported by human multi-organ proteomic evidence of proteostasis and vascular aging, aiming to restore cholesterol handling, reinforce proteostasis, and modulate senescence and niche signals.