https://www.cell.com/cell-metabolism/fulltext/S1550-4131(26)00187-7
My view: More glucose → More ROS.
chatGPT:
Summary
This is a review article arguing that chronic glucocorticoid signalling — cortisol in humans, corticosterone in rodents — can act as a systemic accelerator of aging-like pathology, while acute pulsatile glucocorticoid signalling remains adaptive. The central distinction is not simply “high cortisol is bad”, but that persistent, flattened or pharmacologically prolonged glucocorticoid exposure disrupts the normal circadian/ultradian signalling pattern. The authors frame glucocorticoids as short-term survival hormones that “buy time” acutely but may “steal time” chronically.
The paper links chronic glucocorticoid exposure to multiple aging phenotypes: insulin resistance, visceral adiposity, fatty liver, sarcopenia, osteoporosis, impaired immune surveillance, neurocognitive decline, cardiovascular remodelling, poor wound healing, cataracts, and sleep/circadian disruption. Figure 1 on page 2 summarizes this model visually: stress, circadian disruption and chronic inflammation activate the HPA axis, causing prolonged cortisol exposure, which then alters nutrient sensing, suppresses autophagy, impairs mitochondria and promotes senescence, leading to metabolic, skeletal, immune, cardiovascular and neurodegenerative disease.
A major mechanistic thread is the GC–ACBP/DBI axis. ACBP/DBI, also called acyl-CoA-binding protein or diazepam-binding inhibitor, is presented as a stress-induced, autophagy-inhibitory mediator. The authors argue that glucocorticoids induce hepatic ACBP/DBI secretion, which then systemically suppresses autophagy and contributes to metabolic and immune consequences of glucocorticoid excess. In mouse models of Cushing-like glucocorticoid exposure, ACBP/DBI knockout or neutralisation reportedly prevents many features including hyperphagia, dyslipidaemia, insulin resistance, visceral adiposity, steatosis, sarcopenia, osteoporosis and depression.
The paper also maps chronic glucocorticoids onto the “hallmarks of aging”: genomic instability, telomere attrition, epigenetic alterations, proteostasis loss, disabled macroautophagy, deregulated nutrient sensing, mitochondrial dysfunction, senescence, stem-cell exhaustion, extracellular matrix remodelling, altered intercellular communication, chronic inflammation, dysbiosis and psychosocial isolation. Figure 3 on page 7 is the key visual synthesis, showing glucocorticoids as a multi-level driver of these aging hallmarks.
Claimed novelty
The most novel part is not the idea that chronic cortisol is harmful; that is well established from Cushing syndrome, steroid therapy, stress biology and metabolic disease. The novelty is the aging-framework synthesis: the paper explicitly positions chronic glucocorticoid signalling as a context-dependent gerogenic pathway, connecting endocrine stress biology to modern hallmarks-of-aging theory.
The second novelty is the emphasis on ACBP/DBI as a central mediator. The authors go beyond saying that glucocorticoids cause metabolic and immune side effects; they propose a specific intermediary pathway in which glucocorticoids stimulate hepatic ACBP/DBI secretion, ACBP/DBI suppresses autophagy and modulates GABA-A receptor signalling, and this mediates many chronic glucocorticoid phenotypes. Figure 4 on page 10 lays out this model, including the claim that anti-inflammatory glucocorticoid effects are relatively ACBP/DBI-independent, whereas metabolic and immunosuppressive effects are ACBP/DBI-dependent.
A third useful novelty is the paper’s focus on temporal structure. The authors stress that acute glucocorticoid pulses are not intrinsically pathological; rather, loss of pulsatility and circadian architecture is a major problem. This is important because it reframes treatment questions: the goal may not be simply “less cortisol”, but restoration of appropriate rhythmic cortisol signalling.
Critique
The paper is strong as a conceptual review, but its causal case is uneven. The authors themselves acknowledge that much of the mechanistic evidence comes from preclinical models, whereas much human evidence is associative. That matters because chronic stress, poor sleep, obesity, inflammation, depression, frailty and illness all influence each other. Elevated cortisol may be a driver in some contexts, a compensatory response in others, or simply a marker of systemic dysregulation.
The ACBP/DBI section is exciting but perhaps over-centralised. The mouse evidence sounds powerful, especially where liver-specific ACBP/DBI deletion or antibody neutralisation blocks Cushing-like phenotypes, but this does not yet prove that ACBP/DBI is the dominant mediator of glucocorticoid-driven aging in humans. Aging is slow, tissue-specific and heterogeneous; a 4–6 week hydrocortisone model in mice may capture steroid toxicity better than organismal aging.
The review also risks conflating several different states: overt Cushing syndrome, mild autonomous cortisol secretion, exogenous steroid therapy, obesity-associated tissue cortisol regeneration, circadian disruption, psychosocial stress and normal aging. These may share mechanisms, but their dose, timing, tissue distribution and reversibility differ substantially. For example, pharmacological dexamethasone exposure is not equivalent to slightly flattened diurnal cortisol in an older person.
Another weakness is that the paper is more detailed on harm pathways than on quantitative thresholds. It does not clearly answer practical questions such as: how much flattening of cortisol rhythm is clinically meaningful, what exposure duration matters, which tissues are most vulnerable, or what biomarkers best identify a person in a glucocorticoid-driven pro-aging state.
Finally, from your acetylation/splicing perspective, the paper is relevant but incomplete. It discusses epigenetic alterations, chromatin reconfiguration, histone acetylation redistribution and transcriptional memory, but it does not deeply explore whether chronic glucocorticoids impair nuclear acetyl-CoA availability, long-gene transcription, spliceosome dynamics or RNA splicing fidelity. That could be an important missing mechanistic bridge, especially because glucocorticoids affect metabolism, mitochondria, autophagy and chromatin simultaneously.
Bottom line
This is a persuasive and useful review. Its strongest contribution is to frame chronic, flattened glucocorticoid signalling as a stress-to-aging conversion mechanism, with ACBP/DBI as a candidate mediator linking cortisol to autophagy suppression, metabolic dysfunction and immune impairment. Its main limitation is that the human causal evidence is still indirect, and the ACBP/DBI model needs longitudinal human validation before it can be treated as a central aging mechanism rather than a powerful steroid-toxicity pathway.