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.

Aims: To identify plasma proteins associated with all-cause mortality and determine their relationships with chronic disease burden and biological aging at both the organismal and organ-specific levels, thereby providing insights into the biological mechanisms underlying healthy aging and longevity.

Methods: We conducted a prospective cohort study of 1,025 older adults from the LonGenity study, analyzing 4,265 plasma proteins. Associations between protein levels and all-cause mortality were evaluated using Cox proportional hazards regression over a mean follow-up of 8.05 years. Mortality-associated proteins were further examined for their relationships with chronic disease burden and proteome-derived measures of organismal and organ-specific biological aging. Findings were independently validated in 1,124 participants from the Baltimore Longitudinal Study of Aging (BLSA).

Results: Seventeen plasma proteins were significantly associated with all-cause mortality. Higher levels of epidermal growth factor receptor (ERBB1) and anthrax toxin receptor 2 (ANTXR2) were associated with lower mortality risk and younger biological age across multiple organ systems. Conversely, higher levels of macrophage inhibitory cytokine 1 (MIC-1) (growth differentiation factor 15 (GDF15)), human epididymis protein 4 (HE4), and insulin-like growth factor-binding protein 2 (IGFBP-2) were associated with increased mortality and older biological age across multiple organ systems. Specifically, elevated MIC-1 was associated with older organismal biological age, whereas ERBB1 was associated with younger liver biological age. These associations were independently replicated in the BLSA cohort.

Conclusion: Mortality-associated plasma proteins reflect key biological pathways involved in biological aging, physiological homeostasis, and systemic stress. These biomarkers may have potential utility for identifying individuals at increased mortality risk and advancing the development of biomarkers for healthy aging and longevity.

Hibernation is one of nature’s most remarkable examples of reversible physiological adaptation, yet its potential to inform geroscience remains underexplored. Lifespan patterns in hibernators are not fully explained by allometric scaling, as hibernators can outlive non-hibernating species of comparable body size. Hibernation is further characterized by the preservation of tissue function and integrity despite marked calorie restriction, inactivity, and hypometabolism. In this review, we examine the hibernation phenotype as a naturally evolved program of biological maintenance that may limit the accumulation of age-related molecular and cellular damage. We first discuss the relationship between hibernation, longevity, and life-history evolution before reviewing evidence that hibernation modulates multiple hallmarks of ageing through integrated regulation of metabolism, mitochondrial maintenance, proteostasis, nutrient sensing, endocrine signaling, immune function, and epigenetic remodeling. We further highlight emerging observations associating hibernation with telomere maintenance and slower epigenetic ageing, while emphasizing the key knowledge gaps that remain regarding the causal relationship between the phenotype of hibernation and slower ageing, cellular senescence, genome maintenance, and age-dependent changes in hibernation expression. Finally, we discuss how comparative biology, multi-omics approaches, and functional biomarkers of ageing throughout the different phases of hibernation (before torpor, at its onset, during torpor, and after torpor) may help identify evolutionarily conserved protective mechanisms that can be translated into novel strategies to promote healthy human ageing from a bioinspired perspective. This Review was developed following discussions initiated during the September 2025 National Science Foundation (NSF) Quantitative Approaches and Understudied Questions in the Biology of Ageing Workshop (Paris, France).

There is a growing demand from society for gerotherapeutic interventions that can extend healthspan. Yet the increasing commercialization of insufficiently validated gerotherapeutics threatens to undermine the public confidence and the responsible translation of healthy longevity research into practice. The Unlock Healthy Longevity Conference 2026 convened international experts in Singapore to exchange scientific advances in precision geromedicine, with a particular focus on nutraceuticals and repurposed drugs. Precision geromedicine is increasingly being translated into clinical settings; however, standardized frameworks for clinical evaluation, implementation, quality assurance, and oversight remain insufficiently established. This emerging paradigm emphasises the need for collaboration across multiple stakeholders to support the development of a robust, safe, scalable, and equitable ecosystem. A central theme across the sessions was the need to advance clinical human validation, translation, and the development of standards and clinical guidelines. Panel discussions converged on the importance of developing robust clinical and data infrastructures to generate reproducible evidence capable of informing real-world clinical practice and enable equitable access to healthy longevity. Presentations addressed emerging clinical biomarkers of ageing and data-driven approaches to guide gerotherapeutics, including changes in DNA methylation and skin and gut as organ-level readouts of biological ageing. Several potential candidate gerotherapeutics were discussed, including the nutraceutical compounds urolithin A and ergothioneine, and repurposed drugs such as glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors. Additional sessions explored the clinical implementation of gerotherapeutics taking into account ethical, safety, and regulatory considerations. This report summarises the key messages and research priorities presented at the conference.

Aims: Human leukocyte antigen (HLA) polymorphism influences immunity by balancing protection against pathogens with the preservation of self-tolerance. This balance has been proposed to affect longevity, and associations with HLA variants have been reported. However, studies in this field have often yielded inconsistent findings due to small sample sizes and low-resolution genotyping methods. We aimed to identify HLA alleles linked to longevity while overcoming these previous limitations.

Methods: We performed high-resolution HLA genotyping using targeted sequencing (HLA-seq) in 1,265 long-lived individuals (long-lived individuals (LLI); ≥ 94 years) from Germany and compared their HLA allele frequencies with those of a large control population of 3.4 million individuals from the German Bone Marrow Donor Registry (DKMS) using χ² (chi-square) tests.

Results: Six HLA alleles were significantly associated with longevity. Of those, two exhibited the most robust associations: A*01:01g (odds ratio (OR) = 0.87; 95% confidence interval (CI): 0.80-0.95; adj. P = 0.02) and DRB1*13:02g (OR = 1.24; 95% CI: 1.10-1.41; P = 0.01). DRB1*13:02g was replicated in the UK Biobank after Bonferroni correction, whereas A*01:01g showed directionally concordant nominal support but did not remain significant after multiple-testing correction.

Conclusion: Both DRB1*13:02g and A*01:01g have previously been implicated in dementia-related phenotypes. These observations support the hypothesis that HLA variation may influence longevity partly through pathways linked to neurodegeneration. This study provides a high-resolution (2-field) HLA dataset for a longevity cohort, which should be valuable for future investigations.

Hormesis, the biphasic dose-response by which mild stressors trigger adaptive programs that leave cells better defended, has become the standard lens through which geroscience interprets lifespan-extending interventions. However, the supporting evidence comes largely from young or middle-aged animals. This review argues that the hormetic window, i.e., the range of stimulus intensities that an organism can convert into net benefit, is set not by chronological age but by integrated adaptive reserve, which is shaped jointly by aging biology, cumulative life-history exposures, and comorbidity burden. Because stress-response pathways involving nuclear factor erythroid 2-related factor 2 (NRF2), heat shock factor 1 (HSF1), forkhead box O (FOXO), adenosine monophosphate (AMP)-activated protein kinase (AMPK), autophagy, and the telomere-associated DNA damage response are progressively attenuated, and because immune resilience governs the sensing, resolution, and repair phases of any adaptive response, the window both narrows and shifts toward lower doses. Doses clearly restorative in youth can therefore fall on the damaging side of the curve in old age, and two individuals of identical chronological age may respond very differently. We apply this framework to five paradigms: mitohormesis, caloric restriction, thermal stress, exercise, and genotoxic stress, and show that the stimulus generally retains its signal in old age while the downstream amplification machinery becomes rate-limiting. Interventions with explicitly age-dependent effects, including senolytics, nicotinamide adenine dinucleotide (NAD⁺) precursors, partial reprogramming, B-cell lymphoma-extra large (Bcl-xL) overexpression, and stem-cell-derived extracellular vesicles, are examined as complementary probes of the same principle. The review closes with implications for geriatric trial design: comprehensive geriatric assessment combined with molecular biomarkers, longitudinal monitoring of a moving window, explicit safety thresholds, and sex-disaggregated analysis.

We are entering a historic demographic transition: within decades, one-third of our lives will unfold after age 60, and functional decline typically begins ten to twenty years before disease onset. Yet aging is increasingly malleable: today’s 68-year-olds show the functional profile 62-year-olds showed in earlier cohorts, a measured gain in intrinsic capacity. This gain has not yet translated into a matching compression of morbidity, and the gap between lifespan and healthspan continues to widen. Closing it through geroscience-based prevention is both a scientific opportunity and a public health necessity. This Call to Action synthesizes contributions from 60 experts convened at the Paris Healthy Longevity Summit (May 20, 2026, French National Academy of Medicine, Paris) under the High Patronage of President Emmanuel Macron, organized around one guiding question: how to make healthy longevity accessible to the greatest number of people. Contributions were synthesized into five priority pillars and fifteen actions. Five priority pillars emerged: embedding prevention across the life course; large-scale deployment of the WHO’s ICOPE program; adapting health care professional training; investing in geroscience research and biomarker validation; and changing the cultural image of aging while reorganizing care around healthy longevity. Key recommendations include a healthy longevity check-up from age 50, systematizing ICOPE assessment at every point of contact with the population, a geroscience biomarker-validation consortium, and territorial Healthy Aging Coalitions to reduce socioeconomic gaps in healthy life expectancy. This Call to Action is addressed to public authorities, health care institutions, research funders, employers, insurers, and civil society: the evidence is converging, and stakeholders are ready to act.

Cellular senescence is increasingly recognized as a key contributor to many age-related disorders and diseases, and senotherapeutics, therapies that target senescent cells (SCs), have indicated benefits in multiple preclinical models, including models of obesity, metabolic syndrome/diabetes, and their complications. Importantly, SCs are not a uniform population. They differ by originating cell type, stimuli by which senescence was induced, time since induction of senescence, and the tissue and microenvironment in which senescent cells are located, including the composition and magnitude of the senescence-associated secretory phenotype (SASP). Recent studies have indicated that senescent cell populations comprise cells that release inflammatory SASP factors and less inflammatory senescent cells that release growth factors. Senolytics, agents that eliminate senescent cells, preferentially remove the more inflammatory senescent cells while sparing the less inflammatory senescent cells that arise during processes such as acute wound healing. In another study, senescent cell heterogeneity was investigated in adipose tissue impacted by obesity, with a focus on senescence marker expression and cell-type specificity. p16⁺ senescent endothelial cells were a key source of SASP factors within adipose tissue, but p21⁺ senescent preadipocytes and immune cells also contributed substantially to the inflammatory milieu. Identifying and selectively targeting the more pathogenic, pro-inflammatory senescent cell populations may be facilitated by single-cell-level analyses to elucidate the extent of senescent cell heterogeneity and markers of different senescent cell subpopulations. Appreciating the diversity of senescent cells may be critical, since refining senotherapies based on specific SC subtypes may lead to the development of individualized and personalized therapies, potentially improving upon existing broader-spectrum strategies.

Aims: Δ133p53α is a naturally occurring isoform of the human p53 protein that inhibits p53-mediated cellular senescence. We previously reported that transgenic expression of this senescence-inhibitory p53 isoform counteracts aging-associated pathological changes in progeria model mice (heterozygous Lmna^G609G/+). The anti-aging effect of Δ133p53α was attributed in part to reduced levels of the proinflammatory cytokine IL-6. This study aims to comprehensively profile Δ133p53α-induced changes in cytokines and chemokines.

Methods: A Luminex-based multiplex quantitative assay was performed using mouse serum samples from transgenic Δ133p53α-expressing Lmna^G609G/+ mice and non-expressing controls. Quantitative RT-PCR and RNA in situ hybridization assays were used to assess Cxcl10 expression in mouse tissues. In addition, gene expression datasets from human tissues were analyzed.

Results: In the Luminex assay, used as an exploratory screen, transgenic Δ133p53α expression was suggestively associated with reduced serum levels of not only IL-6 but also CXCL1, IL-1α, and CXCL10. We further characterized CXCL10, which has not previously been linked to progeria in mice or humans. Consistent with reduced serum CXCL10 levels, both young (15-week-old) and old (10-month-old) Δ133p53α-expressing Lmna^G609G/+ mice showed reduced Cxcl10 expression in the liver, spleen, and brain, major organs that produce CXCL10, compared with age-matched non-expressing controls. In naturally aged wild-type mice (2 years old), transgenic Δ133p53α expression also significantly repressed Cxcl10 expression in the spleen and brain. An inverse association between CXCL10 and Δ133p53α levels was observed in human spleen tissues.

Conclusion: CXCL10, a proinflammatory chemokine elevated in both accelerated and natural aging, is a potential target of the anti-inflammatory activity of Δ133p53α.

Aging is a complex biological process, which is affected by several factors, lifestyle, diet, genetic or epigenetic factors, environmental stress, and metabolisms. Among others, several reports observed increased glycolysis in senescent cells (SnCs) and individual aging, whose causal effects or biological mechanisms have been unclear. Recently, we identified phosphoglycerate mutase 1 (PGAM1)-checkpoint kinase 1 (Chk1) binding as a booster for glycolytic metabolism and cell viability in SnCs. Secretory phenotype of inflammatory factors, known as senescence associated secretory phenotype (SASP), is one of prominent properties in SnCs, which accelerates chronic inflammation and aging-relevant dysfunctions in tissues. Inhibition of PGAM1-Chk1 binding removes SnCs and suppresses SASP, alleviating organ damage and pulmonary fibrosis in vivo. Thus, PGAM1-Chk1 interaction represents a target for senolysis to preserve resilience in aging.

Alzheimer’s disease (AD) and related dementias are closely associated with alterations in microglial states. These microglial changes occur in response to amyloid-β (Aβ) accumulation and aberrant tau phosphorylation and can either protect against or exacerbate AD progression, depending on factors such as disease stage, genetic background, and environmental influences. This review focuses on recent advances in understanding the protective functions and features of microglia during the early stages of AD, while highlighting the outstanding questions regarding how these protective states deteriorate and become dysfunctional as the disease progresses. Interestingly, epidemiological studies have suggested an inverse relationship between AD and cancer incidence, and in this context, we provide a comparative analysis of microglial phenotypes in AD and cancer to speculate on how insights from anti-tumor microglia may inspire new strategies for reprogramming microglia to combat AD and related dementias.

Aims: This study aimed to characterise the natural killer (NK; CD3^-CD16⁺CD56⁺) and monocyte compartments in 54 participants by analysing absolute cell counts in relation to age, sex, cytomegalovirus (CMV) serostatus, an established marker of immune ageing, and interleukin-6 (IL-6) values, as an indicator of inflamm-ageing.

Methods: The analysis was conducted in a cohort of Sicilians (28 females and 26 males) aged 19-110 years, including 20 adults (19-64 years), 15 older adults (68-88 years), 11 long-living individuals (93-104 years), and 8 semi- and supercentenarians (105-110 years; hereafter referred to as the oldest centenarians). Multiple negative binomial regression models were used to assess the independent effects of age, sex, CMV serostatus, and IL-6 concentrations on NK and monocyte counts.

Results: Although NK cells and monocytes are generally reported to increase with age, adjustment for covariates revealed that NK cell counts showed only a non-significant age-related trend. In contrast, no statistically significant independent association with age was detected for monocytes. A statistically significant sex effect emerged, with men exhibiting higher NK cell counts than women. Monocyte counts were significantly and positively associated with IL-6 levels.

Conclusion: These findings suggest that previously reported associations of advanced age, particularly extreme longevity, with higher NK-cell and monocyte counts may not be independent of sex, in the case of NK cells, or of chronic low-grade inflammation, as reflected by IL-6 levels, in the case of monocytes. Given the observational design, these results should be interpreted as adjusted associations rather than evidence of mediation or causality.

Over decades, nomenclature in erythrocyte cell death research has been unrefined. Recently, several attempts have been made to adapt the nomenclature suggested by the Nomenclature Committee on Cell Death (NCCD) guidelines to erythrocytes. Within the framework of the standardization of terms used in erythrocyte cell death studies, erythrocyte senescence and eryptosis, a regulated cell death of erythrocytes, have been defined and the formal distinction between both events has been recently established. Differences in their physiological role have been underscored, and markers that can be used to distinguish between erythrocyte senescence and eryptosis have been identified. As a further step, we aim to dissect cellular senescence in nucleated cells and erythrocytes, identifying their hallmarks, key triggers, molecular mechanisms, immunity-related effects, as well as physiological aspects. Available evidence suggests that cellular senescence in nucleated cells can be considered an active biological program, while erythrocyte senescence rather reflects a more passive, gradual accumulation of cellular damage. Fundamental mechanism-based and physiological differences between senescence in nucleated cells and erythrocytes highlighted in this mini-review indicate that the use of the term ‘erythrocyte senescence’ should be discouraged as misleading. Instead, the term ‘erythrocyte aging’ might be more appropriate.

Somatic mutations accumulate in tissues throughout life and are increasingly being recognized as contributors to aging. While their role in cancer has been extensively characterized, their occurrence and functional impact in the cardiovascular system remain poorly understood, partly due to technical limitations in detecting low-frequency and cell-specific variants. Recent advances in single-cell sequencing have begun to unveil how somatic mutations accumulate both in vascular resident cells, including vascular smooth muscle cells, and in circulating hematopoietic cells, such as those associated with clonal hematopoiesis of indeterminate potential. Both resident vascular cells and infiltrating immune cells harboring clonally expanded somatic mutations may influence vascular pathology. This mini-review summarizes the current knowledge on somatic mutation accumulation in the vasculature, focusing on recent studies and the techniques applied for their detection. In addition, we discuss emerging evidence for the functional relevance of somatic mutations in aging and age-related vascular disease.

Cardiovascular aging is characterized by progressive loss of regulatory capacity, reduced physiological reserve, and increased vulnerability to stress and disease. Resting heart rate (RHR) and heart rate variability (HRV) provide complementary measures of cardiac automaticity and autonomic regulation, capturing important dimensions of cardiovascular aging. Comparative and epidemiological evidence demonstrates that elevated RHR and reduced HRV predict morbidity and mortality across species and human populations, reflecting cumulative physiological stress and declining regulatory function. Biological pathways associated with these autonomic phenotypes include sympathetic overactivation, parasympathetic withdrawal, neuroendocrine dysregulation, impaired baroreflex function, chronic inflammation, oxidative stress, and mitochondrial dysfunction. Clinical and mechanistic studies indicate that behavioral interventions (e.g., exercise and dietary modulation), pharmacological therapies, and neuromodulatory approaches can favorably influence RHR and HRV, although their causal effects on aging trajectories remain uncertain. Recent advances in wearable technologies and machine-learning-based phenotyping enable continuous assessment of autonomic function in both research and real-world settings. Integrating RHR and HRV into geroscience frameworks may help link autonomic regulation with fundamental aging mechanisms and cardiovascular risk. As accessible, noninvasive measures of physiological resilience and adaptability, RHR and HRV have potential value for advancing precision approaches to healthy cardiovascular aging and longevity.

Time-restricted eating (TRE), a form of intermittent fasting that limits food intake within a consistent daily window, has gained attention as a feasible strategy to promote metabolic health and align eating with circadian rhythms. Aging and obesity share overlapping pathophysiological mechanisms, including increased visceral adipose tissue (VAT), chronic inflammation, and circadian disruption, which accelerate cardiometabolic decline and multimorbidity. In this Perspective, we examine TRE within a geroscience framework, integrating evidence from human trials and preclinical models to evaluate its potential relevance for aging-related processes. We discuss how the timing of food intake influences VAT distribution and glucose regulation, with early TRE schedules showing particular promise for enhancing nocturnal glycemic control and reducing abdominal subcutaneous adipose tissue. Drawing on circadian biology and caloric restriction literature, we highlight mechanistic insights linking feeding-fasting cycles to autophagy, nutrient sensing, and longevity. We also consider emerging evidence of sex-specific responses to TRE, which may inform personalized approaches. However, most clinical studies remain short-term and focus on cardiometabolic risk markers rather than validated measures of biological aging or functional outcomes. We therefore emphasize the need to distinguish between demonstrated metabolic benefits and proposed gerotherapeutic effects, and argue that future trials should incorporate biomarkers of biological age, circadian robustness, and physiological resilience. TRE represents a low-cost, scalable, and behaviorally simple intervention that could complement existing strategies in geromedicine to extend healthspan and delay age-related decline.

Cryobiology and geroscience share complementary goals in understanding and mitigating biological damage. Cryopreservation enables the long-term storage of living cells, tissues, and organs, with direct applications in aging-related interventions requiring transplantation, cell therapies, and regenerative approaches. Advances in cryopreservation technologies may expand biobanking of viable specimens across the lifespan, thus facilitating studies of aging phenotypes, biomarker discovery, drug screening, and therapeutic development. Notably, cryoinjury and biological aging share several common molecular features, including oxidative stress, DNA damage, protein misfolding, and mitochondrial dysfunction. These parallels suggest that repurposing geroscience-informed interventions may improve preservation outcomes by enhancing cellular resistance to cryogenic stress and post-thaw recovery. Here, representative opportunities at the interface of cryobiology and geroscience are summarized, emphasizing bidirectional strategies that may advance both fields. This Perspective builds upon discussions from the 2025 Quantitative Approaches and Understudied Questions in the Biology of Aging Workshop (Paris, France).

Aims: Increased gamma-aminobutyric acid type A (GABA_A) receptor activity has been identified in hypersomnolence syndromes, but its role and regional cerebral topography of receptor occupancy in excessive daytime sleepiness (EDS) in Parkinson’s disease (PD) is unknown. Dopaminergic functions or medications may contribute to EDS. Neuroimaging shows evidence of increased brain GABAergic activity in PD. We investigated the relationship between EDS, GABA_A receptor binding, striatal dopamine and dopaminergic medication use in PD.

Methods: Six PD patients underwent [¹¹C]flumazenil GABA_A receptor and [¹¹C]dihydrotetrabenazine (DTBZ) dopaminergic positron emission tomography (PET), clinical and Epworth Sleepiness Scale (ESS) assessments.

Results: Mean ESS score was 12.7 ± 4.5. Mean levodopa equivalent dose (LED) was 1,170 ± 616 mg. There was no significant correlation between nigrostriatal [¹¹C]DTBZ PET (R = 0.138, p = 0.792) or disease duration (R = 0.209, p = 0.902) and ESS scores. In contrast, there was a significant inverse relationship between striatal GABA_A receptor activity and ESS scores (β = -0.942, p = 0.024), more prominent in the caudate head (β = -0.949, p = 0.011). Therefore, frontal cortex binding was explored. A significant inverse relationship between frontal cortical GABA_A receptor activity and ESS (R = -0.884, p = 0.042) was found. A trend toward positive association between LED and ESS (R = 0.773, p = 0.053), was weakened (β = -0.128, p = 0.738) by the addition of caudate head GABA_A receptor activity into the model (β = -1.066, p = 0.055), suggesting that the association between LED and ESS may be mediated by GABAergic changes in the striatum.

Conclusion: Increased striatal and frontal cortical GABAergic activity is a more significant determinant of daytime somnolence than dopaminergic functions in PD. Findings may augur novel inverse GABA_A receptor agonist drug therapy for EDS in PD.

Cells rely on lysosomes and autophagy to maintain homeostasis under fluctuating environmental and metabolic conditions. However, how these degradative systems are dynamically coordinated across stress, senescence, and aging remains incompletely understood. Transcription factor EB (TFEB), a member of the microphthalmia/transcription factor E (MiT/TFE) family, has emerged as a key regulator of lysosomal biogenesis and autophagy by controlling the coordinated lysosomal expression and regulation (CLEAR) gene network, integrating nutrient sensing, mitochondrial status, Ca²⁺, redox signaling, and mechanistic target of rapamycin complex 1 (mTORC1) activity. While TFEB activation promotes lysosomal and metabolic adaptation during acute stress, accumulating evidence indicates that its activity is tightly constrained in time and magnitude, and that altered TFEB dynamics critically shape cellular fate decisions. Here, we synthesize current findings showing that transient TFEB activation supports stress resilience and recovery. In contrast, persistent, insufficient, or dysregulated TFEB signaling contributes to divergent senescence trajectories and age-associated decline in proteostasis. We further discuss how defects in TFEB regulation underlie impaired autophagy–lysosome function during aging across tissues. Notably, both insufficient and excessive TFEB activity can be maladaptive. Together, this framework positions TFEB as a dynamically regulated node linking stress adaptation, senescence progression, and aging, and highlights the need for context- and tissue-specific strategies aimed at restoring TFEB responsiveness rather than constitutively enhancing its activity.

Aims: Testing the hypothesis that excess mutations induced in primary fibroblasts by a low dose of N-ethyl-N-nitrosourea (ENU) are inversely correlated with species-specific maximum life span.

Aims: Testing the hypothesis that excess mutations induced in primary fibroblasts by a low dose of N-ethyl-N-nitrosourea (ENU) are inversely correlated with species-specific maximum life span.

Methods: To measure excess mutations induced by ENU we treated primary cells of 10 mammalian species, greatly differing in life span. We treated all cells with a low dose, non-toxic dose of ENU (20 ug/ml). We then extracted DNA from all treated and untreated cells and quantified somatic mutation burden by single-molecule sequencing. We measured excessive mutations by calculating the ΔSNVs and we analyzed this across species with linear regression.

Results: The average values for ΔSNV were found to range from 0.773 in mice to 0.367 in whale, resulting in a modest inverse correlation with species-specific maximum life span (R² = 0.2067, P < 0.001).

Conclusion: We conclude that DNA repair accuracy, the main determinant of genome sequence integrity, modestly correlates with life span suggesting that longer lived species have better repair capacities compared to shorter-lived species, which is in keeping with genome instability being a primary hallmark of aging and highlights its important role for longevity.

Autophagy is a conserved cellular clearance pathway that supports homeostasis by removing damaged or superfluous intracellular components. Within microglia, autophagy is emerging as a regulator of key processes that modify neurodegeneration, including phagocytosis, cytokine secretion, and senescence. Many studies that have examined the effect of disrupted autophagy on microglial functions have used genetic knockouts of the machinery required to conjugate microtubule-associated light chain 3 (LC3) to the autophagic membrane. However, much of this molecular machinery is also required for a set of distinct but related pathways known as the conjugation of ATG8s to single membranes (CASM). CASM includes processes of particular importance in microglia, such as LC3-associated phagocytosis and LC3-associated endocytosis. It is thus not clear which of the effects of the disruption of LC3 conjugation in microglia are attributable to the loss of autophagy or the loss of CASM function. In this review, we describe the mechanisms of autophagy and CASM and highlight the effects of the loss of these pathways on key microglial processes relevant to brain ageing and neurodegenerative diseases. We discuss recent literature that has revealed the effects of ageing and neurodegeneration on microglial autophagy, and the effects of microglial autophagy and/or CASM disruption on key microglial functions such as phagocytosis, cytokine secretion, and senescence. Finally, we discuss the potential therapeutic implications of these findings for neurodegeneration and highlight key unanswered questions for future research.

Accumulating evidence has indicated that the normal tissue adjacent to tumor (NAT) is distinct from both healthy and tumor tissues. It is suggested that the crosstalk between NAT and tumor tissues helps shape the tumor microenvironment and promotes cancer progression, but the molecular and cellular evidence for this crosstalk is scarce. In this perspective, we propose that NAT tissue constitutes a unique “peritumoral microenvironment (Peri-TME)” mostly conditioned by the tumor. Furthermore, cellular senescence is identified as a key characteristic of Peri-TME, which accelerates tumor growth, as illustrated in our recent studies in colorectal cancer (CRC). Finally, strategies to target the senescent Peri-TME may represent an effective means to disrupt the vicious interaction between Peri-TME and Tumor and enhance therapeutic efficacy.

Aging is a heterogeneous, multi-system process driven by the interplay between accumulating molecular damage and the progressive erosion of resilience. While damage accumulates in a ubiquitous and homogeneous fashion, resilience is finite and unequally distributed across physiological systems and individuals, yielding distinct biological trajectories that diverge early in life, giving rise to the individual-specific decline in physiological function and the manifestation of a diverse spectrum of organ-specific diseases, and converge only when multisystem dysregulation overwhelms compensatory capacity. Early deviations in mitochondrial function, proteostasis, inflammation, and metabolic regulation often remain clinically silent, detectable only through gerodiagnostics, longitudinal, sensitive biomarkers of aging. Yet most biomarkers were developed to detect disease rather than quantify aging biology, and their mechanistic specificity declines with advancing multimorbidity. Precision geromedicine therefore requires the integration of gerodiagnostics that capture system-level resilience and stress responsiveness with measures of functional reserve, behavior, physiology, and the exposome, enabling the identification of individualized aging trajectories and the biological pathways that drive them. This combined approach clarifies causal pathways, enables earlier detection of vulnerability and supports individualized gerointerventions that modify aging trajectories rather than specifically but narrowly focusing on individual age-related diseases.

Autophagy is a fundamental catabolic process that is critical for maintaining cellular homeostasis and protein quality control in the central nervous system (CNS). While neuronal autophagy has been extensively characterized, growing evidence highlights the indispensable roles of glial autophagy, specifically in astrocytes, oligodendrocytes and microglia, in CNS physiology and pathology. These glial populations employ the autophagic machinery to regulate distinct but interconnected functions: astrocytes manage metabolic support and glutamate homeostasis; oligodendrocytes rely on autophagic flux for differentiation and myelin maintenance; and microglia employ specific pathways, such as LC3-associated phagocytosis, to orchestrate immune surveillance and inflammasome regulation. Impairment of glial autophagy has been implicated in non-cell-autonomous neurodegeneration, leading to excitotoxicity, myelin damage, the emergence of senescence-associated secretory phenotypes, and persistent neuroinflammation. Dysregulation of autophagic pathways during ageing has also been implicated in the pathogenesis of multiple neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. In this review we summarize the cell-type-specific molecular mechanisms of autophagy in glia, and delineate their role in the clearance of pathogenic aggregates such as β-amyloid, α-synuclein, and mutant huntingtin. A deeper understanding of the spatiotemporal dynamics of glial autophagy and associated intercellular crosstalk is essential to fully elucidate the complex etiology of age-associated neurodegenerative conditions.