The midbrain dopamine system is integral to movement, reward, and motivation, and its dysfunction underlies a range of brain disorders. Age is a primary risk factor for many of these disorders, yet systematic analysis of how the dopamine system changes during healthy aging remains relatively understudied. In this review, we first examine the impact of healthy aging on the dopamine system across sexes and species, including flies, mice, rats, and humans. We next consider the neuroadaptive mechanisms that sustain dopamine neuron function with age. Finally, we contrast the molecular mechanisms of age-related neurodegenerative diseases with those of healthy aging, exploring the possibility that loss of neuroadaptive reserve drives dopamine neurodegeneration. Elucidating these neuroadaptive mechanisms could offer a path toward preserving dopamine neuron function across the lifespan and potentially preventing age-related neurodegeneration.

Perceptions of ageing, which are often negative and focused on dependency, are open to scrutiny and can be challenged. The concept of healthy ageing, promoted by the World Health Organisation, emphasises the maintenance of functional abilities as well as prevention. The patient is viewed as an active participant in their own ageing process, in line with an approach based on empowerment. From this perspective, interprofessional support-particularly that provided by advanced practice nurses-plays a central role in the management of frailty. A specialisation in gerontology would therefore help to better address the challenges of ageing.

A testament to longevity, old age is a time of great vulnerability. An ageing and ailing body often weakens the immune system and leaves a person susceptible to illness. Ageing therefore presents a challenge for the medical profession, which addresses it through a specialised branch of medicine: geriatrics. In this field of medicine for older people, which focuses on health and quality of life, the medical profession has both positive and negative legal obligations aimed at protecting dignity.

Dignity is a concept frequently invoked in bioethics, both in the literature and in practice. However, those who use the term rarely describe or define it, despite the word's multiple meanings. This article explores its various meanings, highlighting the relational context in which it is situated, whether it is attributed or intrinsic. The discussion focuses on the impact of AI-powered assistive robots, designed to combat isolation and loneliness, as well as on relationality and dignity in the broadest sense.

Hypertension is highly prevalent among adults aged 45 years and older in India, yet limited evidence exists on the combined associations of waist circumference (WC) and body mass index (BMI) with hypertension. This study examined their independent and joint associations with hypertension using Wave 1 (2017-18) of the Longitudinal Ageing Study in India (LASI) among 59,658 adults aged 45 years and older. Hypertension was defined as measured blood pressure ≥140/90 mmHg. Multivariable logistic regression assessed associations across combined WC-BMI categories. Overall hypertension prevalence was 31.3%. Individuals with normal BMI but large WC had higher odds of hypertension (adjusted odds ratio [AOR] = 1.37; 95% confidence interval [CI]: 1.19-1.58). Obese individuals with large WC had the highest odds (AOR = 1.77; 95% CI: 1.45-2.17). Both central and general obesity were independently associated with hypertension. Routine WC assessment alongside BMI may improve identification of high-risk individuals in India's middle-aged and older population.

Sphingolipids are intrinsic components of cell membranes that are transported to lysosomes for degradation into ceramide, which is used in the Golgi to synthesize new sphingolipids. Although sphingolipid metabolism is very complicated, the degradation pathway is relatively simple and converts the sphingolipids to ceramide and sphingosine. Polymorphisms in the genes for enzymes in this pathway are associated with various lysosomal storage disorders, and one of the enzymes, glucosylceramidase (GCase1), is associated with Parkinson's disease and Lewy-body dementia as well as Gaucher disease. We construct a mathematical model of the sphingolipid degradation pathway and show that over a wide range of Vmax values of GCase1, the pathway exhibits bi-stability, two steady states with hysteresis between them. In addition, it is known that the formation of synuclein fibrils from monomers and oligomers is influenced by the degradation pathway and, in turn, inhibits GCase1. We show that there are two steady states, one with low fibril production and one with high fibril production, with hysteresis. The fact that there are two steady states with hysteresis presents both challenges and opportunities for drug discovery and dosing. Our work has implications for aging, since it is known that the expression level of the gene for GCase1 declines with age.

Neuroimaging-derived brain age has emerged as an intuitive marker of brain health and cognitive longevity. The difference between brain age and chronological age, termed brain-predicted age difference (brain-PAD), quantifies deviation from normative brain ageing and may help evaluate whether interventions could attenuate brain ageing trajectories. This review synthesizes the methodological foundations of brain age estimation, factors linked to brain-PAD across healthy ageing and disease, evidence from clinical interventions, and emerging translational applications in clinical trials. Across non-clinical and clinical populations, older-appearing brains are associated with poorer cognitive and physical function, greater physiological burden, higher mortality risk, cardiometabolic vulnerability, and a range of neurological and psychiatric disorders. Evidence from interventions remains limited and heterogeneous. Exercise provides the clearest proof-of-concept that brain-PAD is potentially modifiable, whereas dietary interventions and multidomain lifestyle programmes have produced suggestive but preliminary evidence; cognitive, sleep, and mind-body interventions have yielded sparse or mixed findings. In clinical settings, brain-PAD shows promise for predicting disease conversion, disability progression, and treatment response, and may support trial stratification, enrichment and monitoring. Evidence that medication, neuromodulation, or other interventions reliably normalize brain-PAD, however, remains inconsistent. We argue that brain-PAD is a useful but biologically nonspecific, model-derived biomarker. Its interpretation critically depends on pipeline choice, harmonization, age-bias correction, and longitudinal validity. For now, brain-PAD is best regarded as a complementary biomarker and exploratory outcome rather than a validated surrogate endpoint. Future progress will require standardized methods, validation in representative populations and prespecified longitudinal cohorts that links brain-age changes to meaningful clinical outcomes.

Immune aging comprises heterogeneous changes in hematopoietic output, immune-cell function, inflammatory regulation, and tissue-specific immune states. In parallel, the gut microbiome undergoes ecological and functional remodeling across the bacteriome, mycobiome, virome, and archaeome, but these changes do not define a single "aged microbiome" and vary with host health, frailty, diet, medication exposure, and environmental context. Here, we examine how multikingdom gut microbiome remodeling intersects with distinct trajectories of immune aging. Rather than treating dysbiosis as a uniform upstream cause of immunosenescence, we organize the evidence around four interconnected processes: microbial signal generation, tissue access and compartmentalization, host sensing, and cell-specific interpretation. Age-associated changes in microbial metabolites and immunostimulatory products can influence epithelial barrier function, inflammatory signaling, immunometabolism, hematopoiesis, and lymphoid and myeloid cell states, but evidence strength varies substantially across pathways and microbial kingdoms. Causal support is most developed for selected bacteriome-associated mechanisms in experimental models, whereas aging-specific mechanistic evidence for the mycobiome, virome, and archaeome remains comparatively limited. Importantly, this relationship is reciprocal, because intrinsic immune and tissue aging can also reshape microbial ecology and functional capacity. We therefore view the gut microbiome as a dynamic and potentially modifiable component of immune aging rather than an autonomous driver of immunosenescence. This perspective shifts the translational focus from restoring a youthful microbiome toward targeting microbiome-associated functions and host-response pathways linked to specific immune-aging phenotypes.

Population ageing has increased the burden of cardiovascular disease, cognitive decline and frailty in older adults. These conditions are often studied separately, yet increasing evidence suggests that the ageing heart, vasculature and brain are biologically interconnected. Using a hybrid design that combines a systematic literature search with narrative synthesis, this review summarizes current knowledge on heart-brain co-ageing, with emphasis on phenotypic heterogeneity, molecular mechanisms and translational interventions. Heart-brain co-ageing is characterized by partially coupled but non-synchronous ageing trajectories of cardiac, vascular and brain function. Major clinical phenotypes include vascular-dominant ageing, cardiac-output-related brain vulnerability, arrhythmia-associated thromboinflammatory injury, frailty-cognitive decline and metabolic-inflammatory co-ageing. These phenotypes differ in risk profiles, dominant mechanisms and potential biomarkers. Candidate shared mechanisms include cellular senescence, chronic low-grade inflammation, mitochondrial dysfunction, oxidative stress, endothelial impairment, blood-brain barrier disruption, epigenetic remodelling, telomere attrition, non-coding ribonucleic acid regulation, Klotho signalling, nicotinamide adenine dinucleotide metabolism and microbiome-derived metabolic signalling. Advances in multimodal imaging, circulating biomarkers, biological ageing clocks and multi-omics profiling provide new opportunities for risk stratification, although clinical standardization remains limited. Heart-brain co-ageing should not be regarded as the simple coexistence of cardiovascular and neurological diseases, but as a dynamic multi-organ ageing process shaped by shared biological drivers, interorgan interactions and organ-specific vulnerability, and we propose it as a testable conceptual framework with explicit operational criteria that distinguish coupled from parallel organ ageing. Future research should integrate longitudinal phenotyping, mechanism-based biomarkers and stratified clinical trials to develop precision interventions that preserve both cardiovascular and brain health in older adults.

Acute ozone (O3) exposure poses significant health risks to the elderly, yet its molecular mechanisms remain poorly defined. Here, we established an aged murine model (16-month C57BL/6J male mice) subjected to ozone (1.0 ppm, 6 h) and integrated lung histopathology, respiratory function, serum/lung metabolomics, and gut microbiota analysis at 7 days after exposure to explore underlying metabolic- microbiota response and possible mechanisms. Our data demonstrated that acute exposure to ozone triggered transient ventilatory dysfunction and residual histological alterations, including alveoli destruction and inflammation. In parallel, metabolic disturbances in pulmonary amino acid biosynthesis/metabolism and serum glycerophospholipid metabolism occurred, predominantly affecting autophagy and ferroptosis. Crucially, the potential involvement of the gut-lung axis was supported by ozone-induced gut microbiota dysbiosis (e.g., depletion of Muribaculaceae, Parasutterella) and its strong correlations with lung damage and metabolic disorders. Mechanistically, our data indicated that ozone activated HIF-1α signaling, contributing to lipid peroxidation and ferroptosis. Overall, these data suggested that HIF-1α-associated ferroptosis, along with systemic metabolic perturbations and gut microbiota alterations, may serve as a regulator for ozone-induced pulmonary injury in aging populations.

The microstructural and micromechanical properties of the arterial extracellular matrix (ECM) are central to vascular cell behavior but are disrupted by disease and aging. Elastin and fibrillar collagens provide essential cues, yet the effects of disease-associated ECM remodeling on smooth muscle function remain poorly defined. Here, we imaged fibrillar ECM components across layers of healthy and hypertensive arteries in a large animal model and quantified their stiffness with submicron and piconewton resolution. These animal-derived data guided the fabrication of artery-mimetic hydrogels using image-derived 3D projection micro-stereolithography (µSTL) and thiol-ene clickable bioinks. The resulting hydrogels replicated fibril features down to 2 µm with emulated curvatures and tunable stiffness spanning physiological to pathological ranges (1-35 kPa). Systematic optimization of printing parameters, including light intensity, exposure time, monomer concentration, crosslinker type, optical configurations, and hydrogel swelling solutions, ensured high-fidelity structural replication. Vascular smooth muscle cells cultured on these hydrogels revealed that diseased ECM conditions promoted hypertrophy, impaired contractility, and reduced calcium responsiveness. Quantitative PCR showed reduced expression of contractile markers (MYH11, SMTN) and marked upregulation of PTK2 (focal adhesion kinase) on hypertensive-mimetic matrices, implicating focal adhesion-dependent mechanotransduction in this response. This image-guided biofabrication platform enables precise engineering of vascular microenvironments for mechanistic studies of remodeling, therapeutic testing, and modeling of complex vascular disease states. STATEMENT OF SIGNIFICANCE: Arterial extracellular matrix stiffens and reorganizes in hypertension, yet in vitro models rarely reproduce these micron-scale changes. We measured layer-specific stiffness and fibrillar architecture in arteries from normotensive and hypertensive steers, a large animal model with fattening-induced hypertension. These data were directly translated into projection micro-stereolithography of thiol-ene hydrogels. The resulting matrices, high-fidelity 3D hydrogel prints, reproduced fibrillar features down to 2 µm with emulated curvatures and tunable stiffness spanning 1-35 kPa. Vascular smooth muscle cells cultured on hypertensive-mimetic matrices exhibited hypertrophic morphology, reduced calcium responsiveness and agonist-induced contractility, altered contractile-marker expression, and increased PTK2 expression, linking disease-associated matrix remodeling to altered mechanotransduction. This measurement-to-fabrication workflow provides a physiologically informed platform for mechanistic studies of vascular remodeling and evaluation of therapeutic responses.