Brain aging represents a critical risk factor for neurodegenerative diseases and cognitive decline, yet the measurement of biological brain age remains challenging. Brain aging clocks, which quantify the discrepancy between predicted brain age and chronological age, have emerged as powerful tools for assessing brain health and predicting disease outcomes. Recent advances have transformed these clocks from simple global metrics to sophisticated, multi-modal approaches that capture regional heterogeneity, measure the pace of aging, and achieve cellular resolution. This review examines the methodological evolution of brain aging clocks, including the development of regional brain age gradients, pace-of-aging measurements, and multi-modal integration strategies. We then explore the cellular and molecular mechanisms underlying accelerated brain aging, with particular emphasis on cellular senescence, cell-type-specific aging patterns, vascular dysfunction and blood-brain barrier breakdown, mitochondrial decline, proteostasis failure, synaptic loss, and the accumulation of senescent cells in neurodegenerative conditions. Epigenetic clocks and emerging plasma biomarkers (neurofilament light, GFAP, phosphorylated tau), particularly DNA methylation-based approaches, are discussed in the context of their relationship with neuroimaging markers and cognitive outcomes. Clinical applications are reviewed, including the prediction of neurodegenerative disease, the impact of socioeconomic and geographic disparities on brain aging, and emerging senotherapeutic interventions. Finally, we address current challenges in biomarker standardization, the need for longitudinal validation, and future directions toward precision aging medicine. Together, these advances position brain aging clocks as essential tools for understanding neural aging mechanisms and developing targeted interventions to promote healthy brain aging. SIGNIFICANCE STATEMENT: As populations age globally, predicting who will develop dementia or cognitive decline before symptoms appear has become a critical medical challenge. Brain aging clocks - tools that measure whether a person's brain appears biologically older or younger than their chronological age - offer a promising solution. This review explains how these tools have advanced from simple brain scans to sophisticated methods that detect aging at the level of individual cell types, and how "zombie cells" called senescent cells drive accelerated brain aging. We also show that brain aging may be slowed through lifestyle changes and emerging drugs, though robust human efficacy trials are ongoing. These insights open new paths toward earlier diagnosis and personalized treatments for Alzheimer's disease and other brain disorders.
Pericarpium Citri Reticulatae 'Chachiensis' (PCRC), a renowned traditional Chinese medicine, exhibits enhanced efficacy following prolonged aging, yet the underlying mechanisms remain poorly understood. This study employed metabolomics and microbiomics to analyze multi-source PCRC, elucidating the dynamic changes in non-volatile chemicals and microbial communities over a 7-year aging period. In the metabolomic analysis, a total of 306 differential metabolites were identified as potential indicators of aging, among which seven metabolites exhibited a consistent time-dependent increase in relative content over the seven-year period. Microbiomic analysis revealed that Bacillus and Xeromyces were significantly enriched in 7-year-aged PCRC and consistently dominated the microbial community throughout the aging. Spearman correlation analysis indicated a potential association between dominant microorganisms and aging time-dependent metabolites, suggesting that their interaction was a critical component of the PCRC aging process. These findings provide novel insights into PCRC aging mechanisms and establish a theoretical foundation for quality assessment and aging time classification.
Klotho, an anti-aging protein, controls the insulin-like growth factor-1 (IGF-1) and suppresses inflammation implicated in senescence. We previously reported that glycyrrhizin (GL), a medicinal ingredient of licorice root, significantly attenuates inflammatory responses by inhibiting high-mobility group box 1 (HMGB1). In this study, we investigated whether GL is effective in suppressing the decline in Klotho levels and aging-induced frailty. After oral administration of GL three times a week for 12 months, the following effects were observed: reductions in the increases in blood fats, steatoses, obesity, and kidney aging; maintenance of activity level and rotarod test performance. Furthermore, we found beneficial effects of GL on the blood levels of functional proteins; upregulation of anti-aging factors, IGF-1 and Klotho; decrease in cystatin-C, an indicator of declining kidney function; and decreases in IL-6 and TNF-α, inflammatory cytokines. GL also seemed to increase superoxide dismutase 2, an antioxidant enzyme, in the liver and kidneys. As GL can inhibit HMGB1, it may attenuate this inflammatory amplification loop, reducing the systemic senescence-associated secretory phenotype and thus mitigating multiple aging phenotypes by maintaining Klotho levels.
Aging-related neurological disorders, including stroke, Alzheimer's disease (AD), Parkinson's disease (PD), epilepsy, and various neuroinflammatory conditions, affect over three billion individuals worldwide and constitute leading causes of morbidity, disability, and socioeconomic burdens. Aging contributes not only to the increased incidence of these disorders but also to their progression through interconnected mechanisms, including endothelial dysfunction, oxidative stress, chronic inflammation, mitochondrial dysfunction, cellular senescence, metabolic imbalance, and gut microbiota dysbiosis. These processes collectively impair neuronal survival, synaptic plasticity, and cognitive and motor functions. Traditional Chinese medicine (TCM), with its characteristic multi-component and multi-target therapeutic strategies, has emerged as a promising approach to counteract age-associated neurological decline. Accumulating preclinical studies suggest that TCM interventions may exert neuroprotective, anti-inflammatory, and antioxidant effects, modulate autophagy, restore metabolic homeostasis, and potentially delay cellular senescence. However, high-quality clinical evidence on safety and efficacy remains limited. This review summarizes current insights into the molecular interplay between aging and neurological disorders and highlights the therapeutic potential of TCM in targeting hallmarks of aging, providing perspectives for integrative prevention and treatment strategies for neurodegenerative and neurovascular diseases.
Aging is characterized by a decline in function of intestinal stem cells (ISCs), but the extent to which this is shaped by systemic factors is unclear. Here we show that the ISC aging phenotype can be propagated from old to young mice utilizing heterochronic parabiosis, and implicate a role for inflammation in these effects, as anti-inflammatory drugs, including TNF antibodies, restored function. Parabiotic rescue experiments demonstrate that TNFR1 knockout protected young ISCs from the old environment. In young organoids, TNF downregulated crypt budding, while impairing mitochondrial pathways and fatty acid oxidation (FAO). However, aged ISC function was enhanced by boosting mitochondrial fusion, whereas FAO in aged crypts was improved by countering inflammation with salicylate treatment. Thus, these data identify the old environment through the progeronic factor TNF, as a driver of ISC aging phenotypes through intestinal epithelial cell TNF receptor 1 signaling to downregulate FAO, proliferation and regenerative capacity in these cells.
This review aims to summarize recent advances in the mechanistic understanding of senile osteoporosis, with particular focus on the interconnected roles of cellular senescence, metabolic dysfunction, and systemic homeostatic imbalance in age-related skeletal degeneration. Emerging evidence indicates that senile osteoporosis is not driven solely by age-related hormonal decline, but by a complex network of biological processes involving senescence of bone marrow mesenchymal stem cells, accumulation of the senescence-associated secretory phenotype, mitochondrial dysfunction, oxidative stress, chronic low-grade inflammation, and disturbances in glucose and lipid metabolism. These alterations disrupt bone remodeling through key signaling pathways, including RANKL/OPG, Wnt/β-catenin, AMPK/SIRT1, NF-κB, and PI3K/Akt/mTOR. Together, these mechanisms impair osteogenesis, enhance osteoclastogenesis, deteriorate bone microarchitecture, and increase skeletal fragility. This broader pathophysiological framework may explain why conventional antiresorptive therapies, although effective in reducing bone resorption, often fail to fully restore the structural and functional deficits of the aging skeleton. Senile osteoporosis should be viewed as a systemic aging-related disorder involving both deterioration of the local bone microenvironment and whole-body metabolic dysregulation. Current evidence-based pharmacological treatments, including bisphosphonates, denosumab, teriparatide, abaloparatide, and romosozumab, remain central to fracture prevention and bone mass preservation. However, these interventions do not fully reverse the biological processes of skeletal aging. Emerging strategies targeting cellular senescence, the senescence-associated secretory phenotype, mitochondrial dysfunction, oxidative stress, nutrient-sensing pathways, and gut microbiota are under active investigation and may complement established therapies in the future. A clearer distinction between approved anti-osteoporotic drugs and experimental geroscience-based interventions is essential for translating mechanistic insights into clinically meaningful treatment strategies.
Salvia cadmica, an Anatolian endemic species traditionally used for wound healing and inflammation, has been scarcely investigated for its anti-aging potential. In this study, the aqueous-ethanol extract of S. cadmica was evaluated for its antioxidant, cytoprotective, and anti-senescence effects using in vitro and in silico approaches. LC-ESI-MS/MS analysis identified rosmarinic acid (3447 µg/g), luteolin 7-glucoside (767 µg/g), and luteolin (586 µg/g) as major constituents. The extract exhibited strong antioxidant capacity, particularly in the phosphomolybdenum assay (713.51 mg TEs/g), and showed notable radical scavenging activity in ABTS (140.00 mg TEs/g) and DPPH (99.20 mg TEs/g) assays. In H2O2-induced senescent human dermal fibroblasts (HDFa), pre-treatment with the extract significantly reduced senescence-associated β-galactosidase positivity from 97.15% to 49.12% and improved cell viability. The extract downregulated MMP1 and MMP3 mRNA expression (0.51- and 0.66-fold, respectively) while markedly upregulating COL1A1 expression (7.48-fold). Molecular docking and MM/GBSA analyses revealed that luteolin 7-glucoside showed high binding affinities toward MMP1 and MMP3 (ΔGdocking = -9.06 and -9.86 kcal/mol; ΔGMM/GBSA = -37.21 and -50.22 kcal/mol, respectively). In silico ADMET predictions supported a favorable dermal safety profile. Overall, S. cadmica represents a promising natural source of bioactive compounds with antioxidant and anti-aging potential relevant to skin aging prevention.
This study aimed to investigate the protective effects of Naematelia aurantialba ethanol extract (NAAE) against skin photoaging. Furthermore, we sought to elucidate the underlying repair mechanisms and related pathways. The results indicated that NAAE treatment significantly enhanced cell viability and proliferation under UV stress, while exerting potent antioxidant effects by effectively reducing intracellular reactive oxygen species (ROS) accumulation and mitigating oxidative damage. Furthermore, NAAE accelerated the migration capacity of damaged cells and promoted skin repair. In animal models, NAAE inhibited UV-induced skin injuries in a concentration-dependent manner and facilitated tissue regeneration. Further investigations revealed that NAAE exerted photoprotective effects by modulating several key metabolic pathways and biological processes, including fatty acid metabolism and nuclear receptor activity. Moreover, NAAE positively influenced the skin microbiota by reducing the abundance of harmful bacteria and promoting the proliferation of beneficial bacteria, potentially enhancing skin barrier function through the cross-system mechanism of the "gut-skin axis." This study provides a theoretical basis for the use of NAAE in preventing and repairing skin photoaging and offers new insights for the development of natural plant-derived skincare products.
Skin photoaging, predominantly caused by chronic ultraviolet B (UVB) exposure, is characterized by oxidative stress, collagen degradation, and disruption of the skin barrier. Deer placenta polypeptides (DPP) are rich in bioactive amino acids (AAs); however, their antioxidant and dermo-protective effects remain insufficiently elucidated, and their topical application is limited by enzymatic instability and poor transdermal permeability. To overcome these limitations, we developed a liposome-hydrogel composite delivery system to enhance the stability, skin penetration, and bioactivity of DPP. DPP obtained via enzymatic hydrolysis exhibited a favorable AA profile, free radical-scavenging activity, and a low molecular weight distribution (3-14 kDa). DPP-loaded liposomes (DPP-LIP) demonstrated high encapsulation efficiency, uniform nanosize, and effective preservation of bioactivity. Incorporation of DPP-LIP into a sodium alginate (SA) hydrogel yielded a composite formulation (DPP-LIP-SA) with sustained-release properties and a 2.7-fold enhancement in transdermal permeation. In a UVB-induced photoaging mouse model, topical administration of DPP-LIP-SA markedly alleviated oxidative stress, inflammatory responses, DNA damage, and extracellular matrix degradation. Mechanistically, DPP-LIP-SA treatment activated the Nrf2/HO-1 antioxidant pathway, inhibited TLR4/MyD88/NF-κB-mediated inflammatory signaling, reduced reactive oxygen species accumulation and lipid peroxidation, and restored extracellular matrix homeostasis by promoting collagen synthesis while suppressing MMP-mediated collagen degradation. Collectively, these findings identify DPP as a potent bioactive peptide resource with intrinsic antioxidant and reparative properties and demonstrate that integration of nanocarriers with hydrogel matrices substantially enhances dermal bioavailability. This composite delivery platform shows strong potential as a peptide-based topical strategy for preventing and treating skin photoaging.
Accurate predictions of complex clinical drug-drug interactions (DDIs), arising from dual induction and time-dependent inhibition (TDI) of CYP3A4, has remained challenging with conventional in vitro and static/dynamic modeling approaches. In this work, we aimed to anticipate the hepatic DDI effects of 6 CYP3A4 precipitant drugs using a liver-chip coupled to microfluidic perfusion, which enabled simulating clinically relevant pharmacokinetic (PK) time-concentration profiles. Midazolam clearance was measured in the liver-chip to determine the CYP3A4-mediated DDI net effect following exposure to precipitants under either dynamic or constant concentration conditions. For direct comparison, hepatic DDI reference values were generated based on clinical DDI studies by physiologically based PK modeling. Under microfluidic perfusion, CYP3A4 activity in the liver-chip was retained for 3 days and inducible by rifampicin. Although most precipitant drugs induced CYP3A4 mRNA levels, CYP3A4 activity net effects showed either induction or inhibition, in line with clinical observations. Compared with a mechanistic static net effect model and physiologically based PK simulations, liver-chip predictions showed closer alignment and higher accuracy relative to hepatic reference values. Although constant exposures offered the strongest quantitative performance, the ability to apply dynamic PK profiles represents a distinctive feature of this platform. Collectively, these findings position the human liver-chip as a novel translational platform for predicting complex hepatic CYP3A4 DDIs arising from dual TDI and induction in a single, holistic in vitro model. This approach aligns with the broader global regulatory shift toward human-relevant new approach methodologies. SIGNIFICANCE STATEMENT: Complex CYP3A4-mediated drug-drug interactions (DDIs), driven by concurrent time-dependent inhibition and induction, remain difficult to anticipate using conventional in vitro and modeling frameworks. This study establishes a human liver-chip model capable of capturing dual CYP3A4 inhibition and induction within a single experiment, and evaluates how clinical exposure regimes shape the quantitative prediction of hepatic DDI effects. Relative to modeling approaches, this platform demonstrates superior accuracy against hepatic DDI references, supporting more translational DDI risk assessments.
Falls are a major tipping point in older adults, heralding functional decline and increased healthcare utilisation. Falls-risk-increasing drugs (FRIDs) are a key risk factor for falls, but their influence on outcomes when prescribed after a fall is under-examined. This study examined the association between an index fall requiring medical attention and subsequent 2-year risk of falls and fractures, evaluating how FRID use modifies this relationship. We analysed data from Waves 5 and 6 of The Irish Longitudinal Study on Ageing, including participants ≥ 70 years with 2-year follow-up. FRIDs were identified from medication lists using STOPPFall. Regression models were used to assess the association between index falls and falls/fracture outcomes during follow-up: Falls, falls requiring medical attention, emergency department visits due to falls, and fractures. Two-way interactions were used to assess how FRID use modified this association. Of 1717 participants, 14% reported a fall requiring medical attention at baseline; 38% were prescribed ≥ 1 FRID. Index falls were associated with increased future falls (OR 2.65), falls requiring medical attention (OR 3.82), ED attendance due to a fall (OR 2.93), and fractures (OR 2.46) over 2 years (all p < 0.01). Combined exposure to both a fall and FRIDs further amplified risk, with odds ratios ranging from 3.77 to 4.36 across outcomes. A fall requiring medical attention is a strong predictor of future falls burden, and FRID use significantly amplifies this risk. These findings highlight the need for targeted medication review within comprehensive geriatric assessment for older people with falls.
Aging and inflammation reduce bone marrow B cell output. While myeloid bias among multi-potent progenitors is one cause, how the developmental cascade of B-committed progenitors is affected remains less well characterized. Here, we identify dynamic modulation of the inflammation response factor NF-κB as a hallmark of healthy lymphopoiesis, but it is diminished in aged B-lymphopenic mice. Indeed, genetic dysregulation of NF-κB dynamics results in severe B-lymphopenia. Model-aided analysis of in vivo progenitor populations and ex vivo experimental time courses reveals that accelerated differentiation of pro-B cells results in skipping critical proliferative phases. Single-cell transcriptomics confirmed premature cell-state transitions, characterized by inappropriate activation of NF-κB target genes that cause wholesale increases in protein synthesis rates. This imbalanced proteostasis leaves little spare energetic capacity to support population expansion, leading to premature differentiation. Our findings indicate that developmental NF-κB dynamics safeguard B lymphopoiesis, thereby identifying a mechanistic cause of age-associated humoral immune deficiency.
Pituitary tumors (PT) constitute the second most frequent intracranial tumor. A subset of PT can behave aggressively despite multimodal treatment. Hallmarks such as cellular senescence, epithelial-mesenchymal transition (EMT), and stemness have been implicated in tumor progression, but their role in PT pathogenesis remains is unclear. We performed spatial transcriptomics (ST) in dopamine agonist resistant prolactin secreting PT, as well as single nucleus RNAseq (snRNAseq) in growth hormone secreting and non-functioning of gonadotropic differentiation PT to describe the senescence, proliferative and stemness landscapes. Bioinformatic analyses included clustering, senescence scoring (SenePy), cell cycle inference (ccAFv2), differentiation potential (CytoTRACE2), and EMT signature evaluation. Primary tumor cell cultures were established to validate senescence (β-galactosidase activity) and to assess the senolytic effect of dasatinib. All PT included in the study were transcriptomically heterogeneous, showing between three and ten transcriptional clusters. Senescence analysis reveals two main clusters regardless of PT lineage: One with a high and the other one with low senescence score. Most spots contain terminally differentiated cells at phase G1/G0 of the cell cycle. Distinct alteration in different signaling pathways were found in clusters with low senescence score: PI3K-cascade-FGFR1 and inositol phosphate metabolism among prolactin secreting tumors, phosphatidyl inositol signaling system and serine/threonine kinase activity the in GH-secreting PT, sphingolipid signaling pathway and serine/threonine kinase alterations among non-functioning of gonadotropic differentiation PT. Dasatinib treatment of primary cell cultures of pituitary tumors of different lineages showed significant dose-dependent cell death, accompanied by caspase-3/7 activation and morphological changes consistent with apoptosis. Our data show that PT may contain senescent and terminally differentiated cells without any EMT evidence, and dasatinib could represent an alternative for therapy resistant PT.
Anti-aging foods not only benefit elderly individuals but also drive the development of safe and effective natural drugs. Here, we report that the addition of total flavonoids of litchi seed (TFL) delays replicative senescence and stress-induced senescence. TFL alleviates the senescence-associated secretory phenotype (SASP) and reduces the degree of DNA damage caused by bleomycin (BLM). TFL also counteracts stress-induced pulmonary senescence and fibrosis. TFL reduces the protein level of p21 in mouse lung and alleviates pulmonary fibrosis. Transcriptome profiling further reveals that TFL plays a key role in its anti-aging mechanism by inhibiting the SASP. Mechanistically, TFL suppresses p65 protein expression, thereby inhibiting IL-1α and IL-1β and delaying cellular senescence. Gut microbiome analysis reveals that the abundance and functions of the mouse gut microbiome change after BLM exposure and that TFL treatment reverses these changes. Overall, we provide a theoretical basis for the future application of TFL as a potential anti-aging product.
Endothelial cells (ECs) serve as crucial components of blood vessels and are vital for preserving vascular health in humans. The aging of these cells significantly accelerates vascular aging. Factors released by aging ECs serve as key initiators of arterial dysfunction and various cardiometabolic diseases. As a result, the targeted removal of aging ECs from injured tissues could reduce these issues and potentially improve lifespan. In this research, we explored the therapeutic capabilities of chimeric antigen receptor (CAR)-T cells designed to focus on senescent cells as potential senolytic agents. We identified GPNMB, a transmembrane glycoprotein, as a protein characterized by extensive expression during cellular senescence. Our findings demonstrate that CAR-T cells specifically targeting GPNMB can efficiently remove senescent cells in vitro. In addition to this, the engineered CAR-T cells significantly clear replicative and doxorubicin (Dox)-induced senescent human umbilical vein ECs (HUVECs). Notably, these CAR-T cells successfully eradicated senescent HUVECs within a Matrigel matrix implanted subcutaneously in mice, thereby creating a simulated in vivo environment that mimics physiological conditions. The findings emphasize the possibilities of CAR-T cells in treating EC senescence.
The proportion of older adults with frailty undergoing total hip arthroplasty (THA) has increased significantly against the backdrop of the rapidly aging population. However, the benefits of ciprofol in this population have not been widely investigated. We conducted a single-center, prospective, double-blind, randomized controlled trial. From October 2024 to July 2025, this study was conducted at a large, university-affiliated tertiary care hospital. After obtaining ethical approval, 78 older adults with frailty undergoing hip arthroplasty scheduled for elective laparoscopic surgery were enrolled. Using a randomized numerical table method, they were classified into either the ciprofol group (Group A) or the propofol group (Group B), with 39 patients in each group. Cardiac output (CO) and the mean arterial pressure (MAP) were recorded at eight intraoperative time points from T0 to T7, in addition to the use of intraoperative vasoactive drugs, postoperative awakening time, extubation time, postoperative complications, and length of hospitalization. At T2 (preintubation) and T3 (immediately postintubation), MAP and CO in the ciprofol group were significantly higher than those in the propofol group (P < 0.05). Furthermore, the use of intraoperative vasoactive drugs was significantly lower in Group A. No significant differences were observed between these groups in postoperative awakening time, extubation time, the length of hospitalization, and complications. Ciprofol shows comparable efficacy as propofol for the induction and maintenance of anesthesia during THA in older adults with frailty. Furthermore, ciprofol yields a better perioperative hemodynamic profile and causes fewer adverse effects.
N6-methyladenosine (m6A) is the most abundant internal epitranscriptomic modification in eukaryotic mRNA. It dynamically regulates RNA splicing, transport, stability, and translation efficiency through the "Writers-Erasers-Readers" system, thereby playing a broad role in gene expression regulation. Skeletal muscle, a key metabolic and locomotor organ, undergoes precise m6A-mediated regulation during development, regeneration, homeostasis, and aging. In this review, we systematically summarize the composition and function of the m6A modification system, with a focus on its critical roles in skeletal muscle physiology, including satellite cell fate determination, myofiber differentiation and fusion, and energy homeostasis. Furthermore, we dissect the molecular mechanisms by which m6A network dysregulation contributes to skeletal muscle diseases such as sarcopenia, muscular dystrophy, muscle atrophy, metabolic myopathies, and fibrosis. The therapeutic potential of small-molecule drugs and intervention strategies targeting the m6A pathway is also discussed. This work provides a new epitranscriptomic perspective for the precise diagnosis and targeted therapy of skeletal muscle diseases.
Caffeine, a safe methylxanthine, has been widely used for the treatment of skin diseases such as cellulite, hair loss, aging, and psoriasis. However, its skin penetration is low. Transcutol is a biocompatible, nonvolatile permeation enhancer which solubilize large number of drugs and does not change the integrity of the skin structure. In this study, the skin permeability of synthetic and natural caffeine gels was compared by ex vivo experiments. Furthermore, Transcutol P was used as a permeation enhancer, and its impact on skin permeation enhancement was determined. The skin penetration of caffeine from the formulation containing coffee extract, a type of natural caffeine, is higher than that of the formulation containing pure synthetic caffeine. This effect is likely due to the presence of coffee, which can act as a skin permeation enhancer. Additionally, the use of Transcutol P in a formulation containing coffee extract at a concentration of 2.5% caused the highest amount of flux. Therefore, the formulation of gel containing natural caffeine along with 2.5% Transcutol is optimal and can be used for further studies. It can be concluded that the addition of 2.5% Transcutol P in the formulation containing coffee extract resulted in the highest skin permeation.
Accumulating evidence highlights the pivotal role of ferroptosis in diverse cardiovascular diseases (CVDs) such as atherosclerosis, aortic aneurysm, aortic dissection, vascular aging, calcific aortic valve disease, myocardial ischemia reperfusion injury, cardiomyopathy, and heart failure. Studies on the molecular mechanism of ferroptosis have revealed potential targets for the treatment of CVDs, and a large number of studies have reported evidence of drug-mediated ferroptosis and iron metabolism mechanisms intervening in CVDs. This review delves into the latest molecular characteristics of ferroptosis, associated biological processes, and regulatory pathways. Notably, various compounds like iron chelators (e.g., deferoxamine, deferiprone), chloroiodohydroxyquin and its derivatives, antioxidants (e.g., vitamin E, lipoic acid, selenium), Ferrostatin-1 (Fer-1), etc., have demonstrated efficacy in animal studies against CVDs, offering cardiovascular protection. In summary, this review outlines the role of ferroptosis in CVDs, the regulatory effects of relevant drugs (including natural products) on ferroptosis within cardiovascular contexts, aiming to provide valuable insights for CVDs management and the development of novel therapeutics.
Nonsteroidal anti-inflammatory drugs (NSAIDs) have traditionally been central to pharmacological pain management in Japan, but population aging and increased use of mechanism-based analgesics may be changing prescribing patterns. We compared oral analgesic prescribing between fiscal year (FY) 2014 and FY2022 using nationwide claims-based open data, focusing on age and sex differences. We analyzed aggregated prescription volumes from the 1st and 9th editions of the National Database of Health Insurance Claims and Specific Health Checkups of Japan Open Data for FY2014 (April 2014-March 2015) and FY2022 (April 2022-March 2023). Analgesics were grouped as acetaminophen, NSAIDs, cyclooxygenase-2 selective inhibitors, weak opioids, duloxetine, neuropathic pain medications, and neurotropin. We calculated population-based prescription volume rates (per 1,000 population) using official population estimates and summarized patterns by sex and age group (<20, 20-64, ≥65 years). We also calculated within-age-group composition (percent share). Poisson regression with log(population) offset estimated incidence rate ratios (IRRs) comparing FY2022 versus FY2014 using robust standard errors; NSAID IRRs were further examined by age-sex strata. Total prescription volume increased from 3.69 × 109 in FY2014 to 6.09 × 109 in FY2022. Rates per 1,000 population increased in all age groups, with the largest absolute increase among adults aged ≥65 years. NSAIDs remained the most frequently prescribed class by rate in adults aged 20-64 years, but composition shifted away from NSAIDs toward acetaminophen and neuropathic pain medications, most notably in older adults. Overall IRR was 1.55, with large increases for acetaminophen (2.51), neuropathic pain medications (2.14), duloxetine (2.29), and weak opioids (1.88), while NSAIDs changed modestly (1.15). NSAID rates decreased in older female strata (IRR <1 from ages 70-74 years). Oral analgesic prescribing in Japan increased substantially between FY2014 and FY2022, alongside age-specific shifts away from NSAIDs toward acetaminophen and neuropathic pain medications, particularly among older adults.