Long-term glucocorticoid medication is indispensable for controlling inflammatory, autoimmune, allergic, neurologic and oncologic diseases, yet its cumulative toxicity resembles accelerated biological aging. We develop the concept that systemic glucocorticoids can cause iatrogenic aging by activating the acyl-CoA binding protein/diazepam-binding inhibitor (ACBP/DBI)-gamma-aminobutyric acid type A (GABAA) receptor axis. ACBP/DBI has emerged as a circulating biomarker of biological aging and age-related diseases in human cohorts, and as a driver of pathological aging in rodent models. Extracellular ACBP/DBI acts on a subset of GABAA receptors containing the gamma-2 subunit, overlapping with the benzodiazepine-sensitive receptor system. Epidemiological associations between chronic benzodiazepine exposure and dementia, cancer, cardiovascular events, infections and immune dysfunction therefore provide a pharmacological parallel to persistent ACBP/DBI signaling. Among endocrine stimuli, glucocorticoids are the strongest inducers of ACBP/DBI expression and secretion. Glucocorticoid receptor activation stimulates hepatocyte-derived ACBP/DBI release, converting endocrine stress into ACBP/DBI-mediated systemic autophagy inhibition, metabolic dysfunction and immunosuppression. In mice, genetic deletion, antibody-mediated neutralization or receptor-level interruption of ACBP/DBI signaling attenuates multiple features of glucocorticoid excess, including obesity, diabetes, dyslipidemia, sarcopenia, osteoporosis and impaired anticancer immunity. In sharp contrast, ACBP/DBI neutralization does not interfere with the anti-inflammatory action of glucocorticoids. Clinically, chronic endogenous or exogenous glucocorticoid exposure is associated with metabolic syndrome, unfavorable body-composition changes, osteoporosis, sarcopenia, cardiovascular disease, neurocognitive decline and infection susceptibility. In this Perspective, we propose that protracted systemic glucocorticoid therapy represents a paradigmatic form of iatrogenic aging that activates a stress-endocrine ACBP/DBI-GABAA receptor program. In practice, we strongly recommend avoiding chronic, high-dose glucocorticoid medications, whenever possible.

Aging is a major risk factor for chronic diseases, and reliable biomarkers are urgently needed to improve healthspan. Nuclear condensates (NCs), membraneless organelles formed via liquid-liquid phase separation (LLPS), regulate essential nuclear functions including transcription, DNA repair, and RNA processing. This review summarizes recent advances in NC biology, focusing on their dynamic changes during cellular senescence and their dysregulation in major aging-related diseases, including neurodegeneration, cancer, progeroid syndromes, and cardiovascular diseases. Canonical NCs such as nucleoli, Cajal bodies, PML-NBs, nuclear speckles, paraspeckles, and heterochromatin domains undergo structural and functional remodeling with aging, and their dysregulation, manifested as morphological alterations, aberrant phase transitions, or mislocalization of components, contributes to disease pathogenesis. We also discuss the emerging, though still largely exploratory, potential of NCs as diagnostic biomarkers, highlighting both imaging and molecular strategies for clinical translation as well as the substantial challenges that remain. Finally, we outline key unanswered questions and future directions, with an emphasis on the need for standardized methodologies, causal mechanistic studies, and validated clinical assays. Collectively, this review suggests that NCs may offer new conceptual and therapeutic angles on aging-related diseases.

How is it possible to double the lifespan of an organism already close to death? Many biological theories of aging fail to explain this phenomenon. At the Physics of Aging workshop, we used late-life lifespan extension in Caenorhabditis elegans to illustrate how a simple stochastic dynamical-systems model can naturally account for dramatic geriatric interventions. We build on a Langevin-type framework in which aging can occur in stable or unstable dynamical regimes, depending on whether slow, lifespan-determining modes are initially restoring or non-restoring. We argue that C. elegans operates in the unstable regime, a view supported independently by temporal scaling of survival curves, late-life mortality deceleration, and persistent lifespan effects following transient interventions. In the unstable regime, stochastic fluctuations are amplified over time until a failure threshold is reached as a first-passage event. The instability rate α sets the speed of this divergence, while the nonlinear feedback strength g, together with α, sets the failure boundary z_max = α/g. Auxin-induced degradation of DAF-2 in very old animals is interpreted as a late shift in dynamical parameters, and the model naturally accounts for the resulting lifespan extension without requiring reversal of accumulated structural damage. This reconciles persistent senescent pathologies with restored proteostasis and stress resilience, and suggests that altering regulatory instability, rather than reversing damage, can strongly reshape survival trajectories. More broadly, this work illustrates how low-dimensional, physics-inspired stochastic models can capture key features of aging and motivate new collaborations on late-life interventions.

During aging, modifiable lifestyle factors, such as physical activity, play an increasingly important role. Specifically, it is known that physical fitness declines relatively predictably with age and that resistance training can be a highly effective strategy for preventing this decline, both at muscular and cognitive levels. Several studies have described that one of the mechanisms mediating some of the beneficial effects of physical exercise during aging is the regulation of miRNAs, and in particular, the miR-29 family appears to play a relevant role. In this review, we analyse, firstly, the relevance of the miR-29 family in aging and, secondly, the protective effects of resistance exercise in delaying age-related dysfunction through the regulation of miR-29.