ReviewJournal of neuroendocrinology2026
The aging paradox of Cushing's syndrome: Stress without clear senescence?
Review in Journal of neuroendocrinology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Abstract
Cushing's syndrome (CS), characterized by chronic endogenous hypercortisolism and disruption of the normal circadian cortisol rhythm, represents a unique human model for investigating the interplay between stress endocrinology and biological aging. Glucocorticoid excess drives multiple convergent aging pathways: it suppresses telomerase activity and may accelerate telomere attrition, induces durable epigenetic remodeling, including hypomethylation of stress-responsive genes such as FKBP5, TET-mediated DNA hydroxymethylation changes, and broad dysregulation of circadian clock loci, and promotes telomere-independent senescence through mitochondrial dysfunction, oxidative stress, and cytokine-driven inflammation. These observations underpin a proposed dual-pathway model of glucocorticoid-accelerated aging, in which direct telomerase suppression and indirect epigenomic remodeling converge on common hallmarks of cellular senescence. However, clinical evidence remains heterogeneous and inconclusive: studies of leukocyte telomere length in CS report discrepant results attributable to assay platform differences, failure to correct for glucocorticoid-induced lymphopenia, small sample sizes, and predominant reliance on cross-sectional designs. Epigenetic clocks capable of quantifying biological age acceleration, particularly second-generation tools such as GrimAge and DunedinPACE, have not yet been applied to CS cohorts, representing a critical evidence gap. Furthermore, virtually all molecular aging measurements in CS have been performed in peripheral blood, leaving the causal chain from glucocorticoid excess to organ-level aging and excess mortality empirically unproven. Rather than a definitive null result, this paradox reveals that CS is an underexplored natural experiment: the syndrome's defined onset, quantifiable cortisol exposure, and surgically curable course offer a unique before-after design for testing whether stress-induced endocrine disruption genuinely accelerates biological aging through telomere and epigenetic mechanisms.
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