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.

The nucleolus, the largest membraneless organelle in the cell, is a biomolecular condensate that houses ribosomal DNA (rDNA), facilitates ribosomal subunit assembly, and serves as a dynamic reservoir for numerous unrelated proteins. Aging across eukaryotic species is accompanied by nucleolar expansion, raising the question of whether it is a correlate of aging or a driver of cellular aging. Recent studies suggest that nucleolar expansion may drive aging and this may result from age-associated changes in the biophysical properties of the nucleolus. Emerging evidence points to age-driven biophysical changes in the nucleolar condensate, including shifts in size, dynamics, and viscoelasticity, which may occur gradually or through transitions from a liquid-like state to denser gel-like, and in some contexts amyloid-like, assemblies. These transitions remodel two core condensate properties: compartmentalization and partitioning, with consequences for ribosome biogenesis and rDNA stability. Here, we review recent literature on age-driven changes in nucleolar condensation and discuss how these changes may influence nucleolar function and longevity.

Reproductive aging progressively impairs fertility and contributes to broader systemic decline. Stress granules (SGs), transient membraneless ribonucleoprotein assemblies formed during cellular stress, have recently emerged as important regulators of gonadal homeostasis. Their function is highly context dependent: properly resolved SGs promote cellular adaptation and survival, whereas persistent SGs disrupt proteostasis and trigger cell death pathways. In the testis, transient SGs protect germ cells under stress; however, persistent SG accumulation activates necroptosis through the ZBP1-RIPK3 axis, a pathway implicated in human non-obstructive azoospermia and testicular aging. In the ovary, defective autophagic clearance leads to pathological SG persistence in granulosa cells, while several SG-associated proteins are indispensable for normal oogenesis. Together, these findings indicate that dysregulated SG dynamics, particularly impaired clearance, represent a convergent mechanism linking cellular stress responses to reproductive decline. Despite these advances, critical gaps remain. The cell-type-specific regulation of SG assembly and disassembly within the gonad is not fully defined, and the molecular mechanisms by which persistent SGs drive tissue-level aging require clarification. Addressing these questions will refine our understanding of reproductive aging and its mechanistic connection to proteostatic imbalance.

Major depressive disorder (MDD) is a risk factor for many aging-related medical conditions as well as cognitive decline and mortality. These and other types of observations indicate a premature aging phenotype associated with the conditions mentioned above. Recent studies have started to elucidate the mechanisms underlying the link between MDD and premature aging, pointing towards novel treatments of this phenotype. In this review, we first present evidence linking MDD to a premature aging phenotype and its association with abnormalities in multiple hallmarks of biological aging. Next, we discuss implications for treatment in MDD, including the potential geroprotective effects of antidepressant treatment as well as the conceptualization of biological aging processes as targets for novel gerotherapeutic interventions. Finally, we highlight the importance of integrating mental health assessment into both research and clinical settings to fulfill the promises of the new medical discipline of Geromedicine in preventing age-related decline and extending healthspan in the aging population.

The decline in brown adipose tissue (BAT) activity is a hallmark of aging and is believed to contribute significantly to the loss of cold tolerance and the increased propensity for obesity with age. Paradoxically, unlike in many other tissues and organs, available evidence suggests that macroautophagy increases in BAT with aging. This aligns with observations of a negative correlation between thermogenic activity and macroautophagy in response to environmental factors such as ambient temperature, with evidence showing that macroautophagy is suppressed in thermogenically active BAT under cold conditions, and conversely, increased in warmer environments. Moreover, the activation of macroautophagy, particularly mitophagy, has been shown to be essential for the “whitening” process, whereby brown or beige adipose tissue loses its thermogenic phenotype and adopts characteristics of energy-storing white adipose tissue. In contrast, recent findings suggest that chaperone-mediated autophagy (CMA) is directly associated with BAT thermogenesis. In male mice, CMA tends to decline with age in BAT, and pharmacological activation of CMA can restore thermogenic activity. This may be due to a specific role of CMA in degrading thermogenesis-inhibiting factors that accumulate in aging BAT because of diminished CMA activity. Given the critical role of BAT in metabolic health, especially during aging, autophagic processes, and their potential druggability, emerge as a promising strategy to preserve thermogenic capacity and improve metabolic health in the elderly.

Age-related macular degeneration (AMD), primarily driven by dysfunction of the retinal pigment epithelium (RPE), is the leading cause of irreversible blindness in the elderly. As the central hub for photoreceptor support, nutrient transport, and waste clearance, the RPE is particularly vulnerable to age-related stressors that disrupt proteostasis and mitochondrial quality control. Autophagy and mitophagy are essential regulators of RPE and retinal longevity, ensuring the turnover of damaged proteins and organelles while maintaining energy homeostasis. In AMD, these pathways become compromised, contributing to lipofuscin accumulation, oxidative stress, inflammation, and progressive cell death. This review examines the physiological roles of autophagy and mitophagy in retinal homeostasis, their dysregulation in AMD, and emerging therapeutic approaches aimed at restoring these protective processes. Targeting autophagy and mitophagy is a promising strategy to preserve vision and delay the progression of AMD.

Skin diseases affect nearly one quarter of the global population, with prevalence rising sharply among older adults. By 2050, the number of individuals over 60 years will double, making age-related dermatological conditions an increasing public health concern. A central process underlying aging is cellular senescence, a stable form of growth arrest induced by diverse stressors, including DNA damage, telomere attrition, and oncogenic signaling. Senescent keratinocytes, fibroblasts, melanocytes, and immune cells accumulate in the skin with age and secrete a pro-inflammatory senescence-associated secretory phenotype (SASP) that actively shapes the cutaneous immune landscape. Although senescence can promote tissue repair and tumour suppression, the persistence of senescent cells drives inflammation, impairs immunity function, and contributes to pathology, a concept now termed senopathy. In this review, we first examine the crosstalk between senescent stromal and immune cells in human skin. Then we discuss how SASP from senescent fibroblasts inhibits the function of resident T cell, while senescent T cells adopt a paradoxical state, hyperfunctional yet non-proliferative, that can accelerate tissue damage. We further highlight the immune evasion strategies which enable senescent cells to persist and drive inflammaging. Insights from patients with Familial Melanoma Syndrome (germline CDKN2A mutations) illustrate how defective senescence pathways across multiple cell types impair cutaneous immunosurveillance and increase melanoma risk. Finally, we explore evidence for stromal- and immune-mediated cutaneous senopathies, including psoriasis, lupus, vitiligo, and leishmaniasis, where senescent cells actively drive the diseases’ progression. Based on the analysis, we propose that the skin represents a powerful and accessible model for investigating the interplay between senescent immune and non-immune cells across the lifespan, with therapeutic implications for aging and age-related pathologies.

With increasing chronological age, the vascular system gradually loses its functional integrity, a process known as vascular aging. This decline is a major contributor to arterial and venous thromboembolic disorders, which represent one of the leading causes of mortality and morbidity among aged individuals. However, the precise biological mechanisms linking systemic aging to thrombotic susceptibility remain poorly understood, hindering the development of effective preventive and therapeutic strategies for age-related thrombotic diseases. Aging, as a fundamental determinant of vascular health, shifts the balance between prothrombotic and antithrombotic mechanisms through cumulative molecular and cellular alterations across vascular cells, red blood cells, platelets, and immune cells. These interconnected hallmarks collectively disrupt endothelial homeostasis, enhance platelet reactivity, and impair coagulation and fibrinolytic pathways. Emerging factors, including clonal hematopoiesis of indeterminate potential and environmental exposures, further exacerbate the thrombotic risk in older populations. Clinically, thrombosis management in the elderly requires careful calibration between protection against ischemia and bleeding risk, as age-associated changes are known to affect the safety and efficacy of antiplatelet and anticoagulant therapies. The development of geroscience-guided interventions, alongside optimized antithrombotic strategies, will be essential to reduce the thrombotic burden and improve outcomes in the aging population.

The Hippocratic Oath enshrines the ethical imperative primum non nocere -“first, do no harm”- thereby guiding medicine practice toward the meticulous avoidance of interventions that may compromise patients’ physiological integrity and overall well-being. Following this principle, benzodiazepines were initially introduced as safer alternatives to barbiturates and have since become one of the most commonly prescribed drug classes for the long-term management of neuropsychiatric disorders in older adults with progressive health deterioration. However, emerging evidence implicates the endogenous benzodiazepine-like peptide, acyl-CoA binding protein/diazepam-binding inhibitor, in the orchestration of maladaptive stress responses. These responses are associated with accelerated pathological aging and increased risks of a spectrum of age-associated morbidities, including metabolic syndrome, cardiovascular diseases, cancers, and immune dysfunction. Corroborating these mechanistic insights, retrospective observational studies have consistently reported significant correlations between long-term benzodiazepine use and elevated risks of cardiovascular mortality, dementia, cancer incidence, impaired responsiveness to immunotherapy, and heightened vulnerability to severe infections. Given these converging lines of evidence, we strongly advocate for the cautious reduction of benzodiazepine prescriptions in elderly patients. Whenever clinically feasible, these agents should be replaced by alternative psychotropic compounds with more favorable risk-benefit profiles, in alignment with contemporary standards of geriatric pharmacotherapy and the ethical imperative to minimize iatrogenic harm.

Significant progress in clinical care has extended human life expectancy to unprecedented levels. However, this trend has been parallelled by a rise in years lived with poor health, posing profound challenges not only to individual quality of life, but also to substantial medical and socioeconomic burdens at the population level. This underscores the urgent need for strategies that extend healthspan alongside lifespan. In this regard, nicotinamide adenine dinucleotide (NAD⁺) has emerged as a central metabolic cofactor and signaling molecule that regulates processes fundamental to health and longevity, including energy metabolism, mitochondrial function, inflammation, and DNA repair. Importantly, intracellular NAD⁺ levels decline with age across multiple tissues and organ systems, and restoring NAD⁺ content has been shown to reinstate cellular and physiological function in various model systems. Among the strategies to augment NAD⁺, supplementation with its precursors, namely nicotinic acid/niacin, nicotinamide, nicotinamide riboside, and nicotinamide mononucleotide, represents the most practical and extensively studied approach. Over the past two decades, preclinical research and an increasing number of clinical trials have investigated the therapeutic potential of these precursors in preventing or reversing age-associated decline and pathologies. In this review, we synthesize recent clinical advances, critically evaluate the promise and limitations of NAD⁺ precursor supplementation, and discuss future directions for leveraging NAD⁺ metabolism to improve healthspan in a rapidly aging global population.

The biology of aging is increasingly understood through geroscience frameworks integrating molecular, cellular, physiological, and social hallmarks. Recently, we introduced psychosocial factors including mental illness as an important hallmark of aging. Indeed, exposome-centered approaches reveal complex interactions among socioeconomic, environmental, behavioral, and genomic factors. Precision Geromedicine aims to target all these determinants in a holistic fashion to improve aging trajectories and extend healthspan.

In recent years, the terms “gerosuppressors” and “gerogenes” have been introduced to describe factors that respectively delay or accelerate aging. These factors are present across various cell types. Specific proteins, such as tau predominantly expressed in neurons, may act as neuron-specific gerosuppressors or gerogenes. Tau exhibits a dual role influenced by its post-translational modifications, particularly phosphorylation. In this review, we discuss relevant examples of tau isoforms that demonstrate both roles, underscoring its dual influence on neuronal aging.