Grażyna Gromadzka

Aging is the strongest risk factor for chronic diseases such as cardiovascular diseases, cancer, diabetes, and neurodegenerative disorders. Advances in geroscience indicate that pharmacological modulation of conserved molecular pathways may extend healthspan and delay multimorbidity. A structured narrative review of the PubMed, Scopus, and Web of Science literature published between January 2010 and May 2026 was conducted, with seminal earlier studies retained where relevant. The review focused on molecular pathways implicated in aging, pharmacological interventions targeting these pathways, and their preclinical and clinical evaluation. Particular emphasis was placed on translational evidence, including human biomarker studies and randomized clinical trials, and on the distinction between biomarker modulation and clinically meaningful outcomes. Repurposed drugs such as metformin and rapamycin have among the most extensive preclinical and translational evidence, although clinical evidence for broadly applicable geroprotection remains limited. Statins, SGLT2 inhibitors, GLP-1 receptor agonists, and menopausal hormone therapy have established disease-specific or cardiometabolic benefits that may have indirect relevance to geroprotection, but direct effects on biological aging and healthspan remain unproven. Other candidates, including senolytics, NAD⁺ precursors, taurine, and epigenetic reprogramming approaches, are at different stages of translational development, with evidence ranging from promising preclinical findings to early human studies. Across interventions, a substantial gap remains between mechanistic plausibility and clinically validated geroprotection. Geroprotective pharmacology represents a promising but incompletely validated approach to extending healthspan. Major uncertainties include the absence of universally accepted biomarkers and clinical endpoints of biological aging, heterogeneity in treatment response, optimal timing and duration of interventions, and long-term safety. Future research should prioritize adequately powered randomized clinical trials integrating standardized measures of biological aging with clinically meaningful outcomes, alongside biomarker-guided patient selection, appropriate treatment timing, and careful assessment of long-term safety. The future of geroprotective medicine will depend not only on identifying additional pharmacological targets, but on demonstrating that their modulation produces durable and clinically meaningful benefits in humans.

Glutathione is an abundant intracellular low-molecular-weight thiol that contributes importantly to cellular redox homeostasis. Besides its well-established role in the antioxidant defense of the cell, glutathione regulates mitochondrial function, metabolism of toxicants, protein thiol oxidation/reduction, redox signaling, and immunity. Disturbances in glutathione metabolism have been shown to play a role in various diseases; however, it has become clear that changes in glutathione metabolism are a part of a complex, multifactorial process. In this review, we summarize current knowledge of the molecular mechanisms governing glutathione synthesis, recycling, compartmentalization, and biological functions, with particular emphasis on redox signaling, the nuclear factor erythroid 2-related factor 2/Kelch-like ECH-associated protein 1 (Nrf2/Keap1) pathway, and reversible protein S-glutathionylation. We further examine how disturbances in glutathione homeostasis interact with mitochondrial dysfunction, chronic inflammation, metabolic stress, and impaired cellular signaling in Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, multiple sclerosis, Wilson’s disease, type 2 diabetes, and nonalcoholic fatty liver disease. We also evaluate current translational interventions targeting restoration of glutathione balance through glutathione supplementation, precursor supplementation, pharmacological modulation of endogenous antioxidant mechanisms, dietary interventions, and changes in lifestyle. Despite the fact that many interventions have been promising at the mechanistic and experimental level, there are still insufficient clinical data because of the problems associated with glutathione availability, tissue specificity, disease variability, and a lack of sufficiently powered clinical trials. The conclusion of this review is that glutathione should not be viewed as a universal therapeutic target; instead, glutathione should be perceived as an important factor contributing to cellular resilience and able to help other disease-specific interventions. Future progress in glutathione-based interventions will likely depend on integrating redox biomarkers, patient stratification, and precision medicine strategies to identify individuals most likely to benefit from targeted modulation of glutathione homeostasis.

Wilson’s disease (WD) is an autosomal recessive disorder of copper metabolism caused by ATP7B mutations, characterized by hepatic copper accumulation and multisystem involvement. Several rare inherited and acquired conditions can closely mimic WD, posing diagnostic challenges and the risk of inappropriate therapy. By examining neuroimaging patterns and distinguishing between diagnostic criteria, this narrative review provides a comprehensive synthesis of WD-mimicking disorders, emphasizing their molecular mechanisms, clinical phenotypes, and biochemical features. WD-mimicking disorders encompass ATP7A-related neurodegenerations (Menkes disease, occipital horn syndrome, X-linked distal hereditary motor neuropathy), MEDNIK syndrome, Huppke–Brendel syndrome, aceruloplasminemia, congenital disorders of glycosylation, primary familial intrahepatic cholestasis type 3, and acquired copper deficiency syndromes. Mechanisms include systemic copper deficiency, impaired intracellular trafficking, defective ceruloplasmin biosynthesis, secondary hepatic copper accumulation, and abnormal glycosylation. Clinical features range from neurodevelopmental delay, movement disorders, and hepatic dysfunction to dermatologic, hematologic, and connective-tissue abnormalities. Biochemical profiles may overlap with WD, particularly low serum ceruloplasmin and total copper, altered urinary copper excretion, and elevated hepatic copper in some disorders. Neuroimaging and genetic testing provide critical discriminative value. Management is largely supportive, with disease-specific therapies available in selected conditions, such as subcutaneous copper in Menkes disease or monosaccharide supplementation in certain congenital disorders of glycosylation subtypes. Accurate differentiation between WD and WD-mimicking disorders requires careful integration of clinical, biochemical, imaging, and molecular data. Recognition of distinctive features and understanding underlying pathophysiology are essential to avoid misdiagnosis and inappropriate anti-copper therapy, optimize management, and improve patient outcomes.

Prostate cancer (PCa) progression is critically driven by androgen receptor (AR) signaling, which integrates hormonal cues with metabolic programs supporting tumor growth, survival, and therapy resistance. Emerging evidence suggests that intermittent fasting (IF) and related dietary interventions—such as time-restricted eating (TRE), alternate-day fasting (ADF), and fasting-mimicking diet (FMD)—modulate systemic metabolism, including reductions in insulin and insulin-like growth factor 1 (IGF-1), and induce intracellular nutrient stress that can influence AR activity, splice variant expression (e.g., AR-V7), and downstream metabolic pathways. This systematic literature review (Scopus, PubMed, Web of Science; publications up to December 2025; search terms: “prostate cancer,” “androgen receptor,” “AR splice variants,” “intermittent fasting,” “fasting mimicking diet”, “metabolism,” “therapy resistance”) summarizes preclinical and clinical studies addressing the impact of IF on AR signaling, lipogenesis, mitochondrial function, redox homeostasis, and therapy response. Preclinical studies indicate that IF can reduce AR expression, impair nuclear translocation, modulate AR splice variants such as AR-V7 via nutrient-sensitive splicing mechanisms, and enhance sensitivity to androgen deprivation therapy and AR-targeted agents. Mechanistically, IF-induced metabolic stress engages AMP-activated protein kinase (AMPK), mechanistic target of rapamycin (mTOR), and sirtuin pathways, alters lipid and mitochondrial metabolism, and transiently increases reactive oxygen species (ROS), creating vulnerabilities in prostate tumor cells. Translational evidence suggests potential benefits of integrating IF with standard therapy, but effects may depend on fasting regimen, caloric intake, macronutrient composition, and patient metabolic context, including risk of lean mass loss. This review highlights the metabolic crosstalk between IF and AR signaling and emphasizes the need for future clinical studies incorporating biomarker-guided approaches and body composition monitoring to fully exploit this intersection for improved therapeutic outcomes in prostate cancer.

Aging is a multifactorial process marked by a progressive decline in physiological function and increased vulnerability to diseases such as neurodegeneration, cancer, cardiovascular disorders, and infections. A central feature of aging is inflammaging, a state of chronic low-grade inflammation driven by cellular senescence, mitochondrial dysfunction, and oxidative stress. Recently, two regulated forms of non-apoptotic cell death—ferroptosis and cuproptosis—have emerged as critical mechanisms linking redox imbalance, mitochondrial stress, and disrupted metal homeostasis to age-related pathology. Ferroptosis, an iron-dependent process characterized by lipid peroxidation and impaired glutathione peroxidase 4 (GPX4) activity, and cuproptosis, a copper-dependent mechanism associated with protein lipoylation stress, both intersect with aging-related changes in mitochondrial and metabolic function. Importantly, these two forms of cell death should not be viewed as entirely separate pathways but rather as interconnected axes within a broader metal–redox–metabolic network. Disturbances in copper or iron homeostasis, glutathione (GSH)/GPX4 dysfunction, mitochondrial and iron-sulfur (Fe–S) cluster compromise, and enhanced lipid peroxidation may converge to lower cellular survival thresholds, thereby exacerbating oxidative damage, immune dysfunction, and tissue degeneration and ultimately fueling aging and inflammaging. This review offers a unique integrated perspective that situates ferroptosis and cuproptosis within a unified framework of aging biology, emphasizing their roles in age-related diseases and the therapeutic potential of targeting these pathways through nutritional, pharmacological, and lifestyle interventions.

Background: Intermittent fasting (IF) is emerging as a promising non-pharmacological intervention in oncology, with the potential to modulate key biological processes including metabolic reprogramming, inflammation, autophagy, and immune function, particularly through the PI3K/AKT/mTOR pathway. However, translating IF into clinical practice requires robust tools to monitor its biological impact and therapeutic effectiveness. Objective: This narrative review aims to present and critically evaluate current diagnostic and monitoring strategies that can support the safe and effective integration of IF into oncological care. Methods: A comprehensive literature search was conducted across PubMed/Medline, Science Direct, Scopus, Wiley Online Library, and Google Scholar using a combination of free-text and MeSH terms related to intermittent fasting, oncology, biomarkers, immunophenotyping, metabolic pathways, gut microbiome, and diagnostic imaging. Results: Two principal categories of monitoring objectives were identified. The first—mechanistic monitoring—focuses on elucidating IF-induced biological effects, including modulation of insulin/IGF-1 signaling, oxidative stress reduction, autophagy activation, immune reprogramming, and microbiome alterations. Advanced research tools such as single-cell RNA sequencing, proteomics, metabolomics, and circulating tumor DNA (ctDNA) assays offer high-resolution insights but currently remain limited to preclinical or translational settings due to cost and complexity. The second—clinical response monitoring—assesses IF’s impact on treatment outcomes, including chemotherapy and immunotherapy response, toxicity reduction, tumor dynamics, and maintenance of nutritional and functional status. This requires clinically validated, accessible, and interpretable diagnostic tools. Conclusions: A dual-layered monitoring framework that integrates both mechanistic insights and clinical applicability is essential for the personalized implementation of IF in oncology. Although preliminary findings are promising, large-scale randomized trials with standardized protocols are necessary to confirm the efficacy, safety, and feasibility of IF in routine oncological care. The integration of IF with modern diagnostics may ultimately contribute to a more individualized, biologically informed cancer treatment paradigm.

Wilson’s disease (WD) is an autosomal recessive disorder of copper metabolism caused by mutations in the ATP7B gene. While hepatic manifestations are frequent, psychiatric symptoms occur in up to 30% of patients and may precede neurological signs. This study was the first to assess the relationship between oxidative stress, selected genetic polymorphisms, and psychiatric symptoms in WD. A total of 464 patients under the care of the Institute of Psychiatry and Neurology in Warsaw were studied. Genotyping for GPX1 (rs1050450), SOD2 (rs4880), and CAT (rs1001179) was performed, along with biochemical analyses of copper metabolism, oxidative DNA, lipid and protein damage, and systemic antioxidant capacity. Among the most important observations are the following: the homozygous GPX1 rs1050450 TT and SOD2 rs4880 CC genotypes were associated with the lowest prevalence of psychiatric symptoms. The CAT rs1001179 TT genotype was linked to a delayed onset of psychiatric symptoms by 6.0–8.5 years. Patients with or without psychiatric symptoms did not differ significantly in saliva 8-OHdG, total antioxidant capacity, serum glutathione (GSH), catalase, and MnSOD; however, patients reporting psychiatric symptoms had significantly higher prostaglandin F2α 8-epimer (8-iso-PGF2α) concentrations and tended to have lower serum glutathione peroxidase (Gpx) concentrations compared to those without such symptoms. Our data firstly provide consistent evidence that oxidative stress balance associated with copper overload in the CNS may be associated with CNS damage and the development of psychiatric symptoms of WD. In particular, our findings of increased oxidative lipid damage together with decreased Gpx activity indirectly suggest that damage to neuronal membrane lipids, which may be potentially related to abnormalities in GSH metabolism, may have an etiological role in CNS damage and related symptoms.

Complex regional pain syndrome (CRPS) is an idiopathic, highly debilitating chronic disorder with persistent regional pain accompanied by a combination of sensory, motor, and autonomic abnormalities. It is not only difficult to treat but also difficult to study. This scoping review aimed to identify the key clinical and molecular challenges encountered in CRPS research and to examine the assessment tools currently employed. A comprehensive search was conducted across PubMed/Medline, Science Direct, Scopus, Wiley Online Library, and Google Scholar using a combination of free text and MeSH terms related to CRPS, clinical and molecular aspects, neuroinflammation, biomarkers, and research challenges. We analyzed 55 original clinical research papers on CRPS and 17 studies of immunological/biochemical/molecular aspects of CRPS. A significant degree of heterogeneity was observed in the methodologies employed across the reviewed studies. The most frequently reported challenges included difficulties in participant recruitment and controlling confounding factors (reported in 62% of studies), such as the heterogeneity of the patient population, the influence of pain coping strategies and psychological factors, and the impact of sociocultural factors (reported in 62% of studies). Research into diagnostic and prognostic markers for CRPS also faces numerous challenges. Recruiting participants is difficult due to the rarity of the condition, resulting in small sample sizes for studies. In vitro models often fail to replicate the complexity of in vivo inflammation, limiting their applicability. Findings from early CRPS stages may not generalize to chronic CRPS because of differing pathophysiological mechanisms and symptom profiles. Additional obstacles include the disorder’s heterogeneity, difficulties in controlling confounding factors, variability in treatment approaches, and the lack of standardized tools and baseline comparisons. These issues hinder the development of reliable biomarkers and evidence-based treatments. Due to these difficulties, the exact cause of CRPS is still not fully understood, making it difficult to develop effective, specific treatments and conduct targeted research.

Wilson’s disease (WD) is an autosomal recessive disorder of copper metabolism. The genetic defect in WD affects the ATP7B gene, which encodes the ATP7B transmembrane protein, which is essential for maintaining normal copper homeostasis in the body. It is primarily expressed in the liver and acts by incorporating copper into ceruloplasmin (Cp), the major copper transport protein in the blood. In conditions of excess copper, ATP7B transports it to bile for excretion. Mutations in ATP7B lead to impaired ATP7B function, resulting in copper accumulation in hepatocytes leading to their damage. The toxic “free”—unbound to Cp—copper released from hepatocytes then accumulates in various organs, contributing to their damage and clinical manifestations of WD, including hepatic, neurological, hematological, renal, musculoskeletal, ophthalmological, psychiatric, and other effects. While most clinical manifestations of WD correspond to identifiable organic or cellular damage, the pathophysiology underlying its psychiatric manifestations remains less clearly understood. A search for relevant articles was conducted in PubMed/Medline, Science Direct, Scopus, Willy Online Library, and Google Scholar, combining free text and MeSH terms using a wide range of synonyms and related terms, including “Wilson’s disease”, “hepatolenticular degeneration”, “psychiatric manifestations”, “molecular mechanisms”, “pathomechanism”, and others, as well as their combinations. Psychiatric symptoms of WD include cognitive disorders, personality and behavioral disorders, mood disorders, psychosis, and other mental disorders. They are not strictly related to the location of brain damage, therefore, the question arises whether these symptoms are caused by WD or are simply a coincidence or a reaction to the diagnosis of a genetic disease. Hypotheses regarding the etiology of psychiatric symptoms of WD suggest a variety of molecular mechanisms, including copper-induced CNS toxicity, oxidative stress, mitochondrial dysfunction, mitophagy, cuproptosis, ferroptosis, dysregulation of neurotransmission, deficiencies of neurotrophic factors, or immune dysregulation. New studies on the expression of noncoding RNA in WD are beginning to shed light on potential molecular pathways involved in psychiatric symptomatology. However, current evidence is still insufficient to definitively establish the cause of psychiatric symptoms in WD. It is possible that the etiology of psychiatric symptoms varies among individuals, with multiple biological and psychological mechanisms contributing to them simultaneously. Future studies with larger samples and comprehensive analyses are necessary to elucidate the mechanisms underlying the psychiatric manifestations of WD and to optimize diagnostics and therapeutic approaches.

Alpha-synuclein (α-syn) is a 140-amino-acid, intrinsically disordered, soluble protein that is abundantly present in the brain. It plays a crucial role in maintaining cellular structures and organelle functions, particularly in supporting synaptic plasticity and regulating neurotransmitter turnover. However, for reasons not yet fully understood, α-syn can lose its physiological role and begin to aggregate. This altered α-syn disrupts dopaminergic transmission and causes both presynaptic and postsynaptic dysfunction, ultimately leading to cell death. A group of neurodegenerative diseases known as α-synucleinopathies is characterized by the intracellular accumulation of α-syn deposits in specific neuronal and glial cells within certain brain regions. In addition to Parkinson’s disease (PD), these conditions include dementia with Lewy bodies (DLBs), multiple system atrophy (MSA), pure autonomic failure (PAF), and REM sleep behavior disorder (RBD). Given that these disorders are associated with α-syn-related neuroinflammation—and considering that SARS-CoV-2 infection has been shown to affect the nervous system, with COVID-19 patients experiencing neurological symptoms—it has been proposed that COVID-19 may contribute to neurodegeneration in PD and other α-synucleinopathies by promoting α-syn misfolding and aggregation. In this review, we focus on whether SARS-CoV-2 could act as an environmental trigger that facilitates the onset or progression of α-synucleinopathies. Specifically, we present new evidence on the potential role of SARS-CoV-2 in modulating α-syn function and discuss the causal relationship between SARS-CoV-2 infection and the development of parkinsonism-like symptoms.