Hallmark Of Aging Research Articles

The hallmarks of aging as a conceptual framework for health and longevity research.

The inexorability of the aging process has sparked the curiosity of human beings since ancient times. However, despite this interest and the extraordinary scientific advances in the field, the complexity of the process has hampered its comprehension. In this context, The Hallmarks of Aging were defined in 2013 with the aim of establishing an organized, systematic and integrative view of this topic, which would serve as a conceptual framework for aging research. Ten years later and promoted by the progress in the area, an updated version included three new hallmarks while maintaining the original scope. The aim of this review is to determine to what extent The Hallmarks of Aging achieved the purpose that gave rise to them. For this aim, we have reviewed the literature citing any of the two versions of The Hallmarks of Aging and conclude that they have served as a conceptual framework not only for aging research but also for related areas of knowledge. Finally, this review discusses the new candidates to become part of the Hallmarks list, analyzing the evidence that supports whether they should or should not be incorporated.

Dietary intake of micronized avian eggshell membrane in aged mice reduces circulating inflammatory markers, increases microbiota diversity, and attenuates skeletal muscle aging.

Avian eggshell membrane (ESM) is a complex extracellular matrix comprising collagens, glycoproteins, proteoglycans, and hyaluronic acid. We have previously demonstrated that ESM possesses anti-inflammatory properties in vitro and regulates wound healing processes in vivo. The present study aimed to investigate if oral intake of micronized ESM could attenuate skeletal muscle aging associated with beneficial alterations in gut microbiota profile and reduced inflammation. Elderly male C57BL/6 mice were fed an AIN93G diet supplemented with 0, 0.1, 1, or 8% ESM. Young mice were used as reference. The digestibility of ESM was investigated using the static in vitro digestion model INFOGEST for older people and adults, and the gut microbiota profile was analyzed in mice. In addition, we performed a small-scale pre-clinical human study with healthy home-dwelling elderly (>70 years) who received capsules with a placebo or 500 mg ESM every day for 4 weeks and studied the effect on circulating inflammatory markers. Intake of ESM in elderly mice impacted and attenuated several well-known hallmarks of aging, such as a reduction in the number of skeletal muscle fibers, the appearance of centronucleated fibers, a decrease in type IIa/IIx fiber type proportion, reduced gene expression of satellite cell markers Sdc3 and Pax7 and increased gene expression of the muscle atrophy marker Fbxo32. Similarly, a transition toward the phenotypic characteristics of young mice was observed for several proteins involved in cellular processes and metabolism. The digestibility of ESM was poor, especially for the elderly condition. Furthermore, our experiments showed that mice fed with 8% ESM had increased gut microbiota diversity and altered microbiota composition compared with the other groups. ESM in the diet also lowered the expression of the inflammation marker TNFA in mice and in vitro in THP-1 macrophages. In the human study, intake of ESM capsules significantly reduced the inflammatory marker CRP. Altogether, our results suggest that ESM, a natural extracellular biomaterial, may be attractive as a nutraceutical candidate with a possible effect on skeletal muscle aging possibly through its immunomodulating effect or gut microbiota.

Emerging roles of mitochondrial functions and epigenetic changes in the modulation of stem cell fate.

Mitochondria serve as essential organelles that play a key role in regulating stem cell fate. Mitochondrial dysfunction and stem cell exhaustion are two of the nine distinct hallmarks of aging. Emerging research suggests that epigenetic modification of mitochondria-encoded genes and the regulation of epigenetics by mitochondrial metabolites have an impact on stem cell aging or differentiation. Here, we review how key mitochondrial metabolites and behaviors regulate stem cell fate through an epigenetic approach. Gaining insight into how mitochondria regulate stem cell fate will help us manufacture and preserve clinical-grade stem cells under strict quality control standards, contributing to the development of aging-associated organ dysfunction and disease.

The Association of Skeletal Muscle Energetics With Recurrent Falls in Older Adults Within the Study of Muscle, Mobility and Aging.

Falls in the older population are a major public health concern. While many physiological and environmental factors have been associated with fall risk, muscle mitochondrial energetics has not yet been investigated. In this analysis, 835 Study of Muscle, Mobility and Aging (SOMMA) participants aged 70-94 were surveyed for number of falls (total), recurrent falls (2+), and fall-related injuries over the past 12 months at baseline and again after 1 year. Skeletal muscle energetics were assessed at baseline in vivo using 31P Magnetic Resonance Spectroscopy for the maximal rate of adenosine triphosphate recovery (ATPmax)after an acute bout of exercise, and ex vivo by High-Resolution Respirometry for the maximal rate of complex I and II supported oxygen consumption (MaxOXPHOS) in permeabilized muscle fibers from the vastus lateralis. At least 1 fall was reported in 28.7% of SOMMA participants in the first year of the study, with 12% of older adults reporting recurrent falls (2+). Individuals who experienced recurrent falls had a slower 400-m walk gait speed (1.0±0.2 vs 1.1±0.2, p < .001), reported fewer alcoholic drinks per week in the past year (2.4±4.3 vs 2.8±4.4, p = .054), and took a significantly greater number of medication in the 30 days before their baseline visit (5.6±4.4 vs 4.2±3.4, p < .05). A history of falls was reported in 63% of individuals who experienced recurrent falls in the first year of the study compared to 22.8% who experienced 1 or fewer falls. MaxOXPHOS was significantly lower in those who reported recurrent falls (p = .008) compared to those with 1 or fewer falls, but there was no significant difference in ATPmax (p = .369). Neither muscle energetics measure was significantly associated with total number of falls or injurious falls, but recurrent falls were significantly higher with lower MaxOXPHOS (risk ratio = 1.33, 95% confidence interval = 1.02-1.73, p = .033). However, covariates accounted for the increased risk. Mitochondrial energetics were largely unrelated to fall risk in older adults when accounting for variables, suggesting that the complex etiology of falls may not be related to a single "hallmark of aging" biological pathway.

Simultaneous assessment of mitochondrial DNA copy number and nuclear epigenetic age towards predictive models of development and aging

ObjectiveMitochondrial dysfunction and nuclear epigenetic alterations, two hallmarks of aging, are associated with aberrant development and complex disease risk. Here, we report a method for the simultaneous assessment of mitochondrial DNA copy number (mtDNA-CN) and DNA methylation age (DNAm age) from the same DNA extraction using quantitative polymerase chain reaction (qPCR) and array data, respectively.ResultWe present methods for the concurrent estimation of mtDNA-CN and DNAm age from the same DNA samples. This includes qPCR to estimate mtDNA-CN, representing the number of circular mitochondrial genomes in a cell, and DNA methylation microarray data to estimate the epigenetic age of an individual. Further, we provide a method for the combination of these metrics into a shared metric termed ‘mtEpiAge’. This approach provides a valuable tool for exploring the interplay between mitochondrial dysfunction and nuclear epigenetic alterations, and their associations with disease and aging.

Augmented mitochondrial apoptotic signaling impairs C2C12 myoblast differentiation following cellular aging through sequential passaging.

Aging is associated with the steady decline of several cellular processes. The loss of skeletal muscle mass, termed sarcopenia, is one of the major hallmarks of aging. Aged skeletal muscle exhibits a robust reduction in its regenerative capacity due to dysfunction (i.e., senescence, lack of self-renewal, and impaired differentiation) of resident muscle stem cells, called satellite cells. To replicate aging in vitro, immortalized skeletal muscle cells (myoblasts) can be treated with various agents to mimic age-related dysfunction; however, these come with their own set of limitations. In the present study, we used sequential passaging of mouse myoblasts to mimic impaired differentiation that is observed in aged skeletal muscle. Further, we investigated mitochondrial apoptotic mechanisms to better understand the impaired differentiation in these "aged" cells. Our data shows that sequential passaging (>20 passages) of myoblasts is accompanied with significant reductions in differentiation and elevated cell death. Furthermore, high-passage (HP) myoblasts exhibit greater mitochondrial-mediated apoptotic signaling through mitochondrial BAX translocation, CYCS and AIFM1 release, and caspase-9 activation. Finally, we show that inhibition of mitochondrial outer membrane permeability partly recovered differentiation in HP myoblasts. Together, our findings suggests that mitochondrial apoptotic signaling is a contributing factor to the diminished differentiation that is observed in aged myoblasts.

Nuclear Phosphoproteome Reveals Prolyl Isomerase PIN1 as a Modulator of Oncogene-Induced Senescence

Mammalian cells possess intrinsic mechanisms to prevent tumorigenesis upon deleterious mutations, including oncogene-induced senescence (OIS). The molecular mechanisms underlying OIS are, however, complex and remain to be fully characterized. In this study, we analyzed the changes in the nuclear proteome and phosphoproteome of human lung fibroblast IMR90 cells during the progression of OIS induced by oncogenic RASG12V activation. We found that most of the differentially regulated phosphosites during OIS contained prolyl isomerase PIN1 target motifs, suggesting PIN1 is a key regulator of several promyelocytic leukemia nuclear body proteins, specifically regulating several proteins upon oncogenic Ras activation. We showed that PIN1 knockdown promotes cell proliferation, while diminishing the senescence phenotype and hallmarks of senescence, including p21, p16, and p53 with concomitant accumulation of the protein PML and the dysregulation of promyelocytic leukemia nuclear body formation. Collectively, our data demonstrate that PIN1 plays an important role as a tumor suppressor in response to oncogenic ER:RasG12V activation.

Electro-metabolic signaling.

Precise matching of energy substrate delivery to local metabolic needs is essential for the health and function of all tissues. Here, we outline a mechanistic framework for understanding this critical process, which we refer to as electro-metabolic signaling (EMS). All tissues exhibit changes in metabolism over varying spatiotemporal scales and have widely varying energetic needs and reserves. We propose that across tissues, common signatures of elevated metabolism or increases in energy substrate usage that exceed key local thresholds rapidly engage mechanisms that generate hyperpolarizing electrical signals in capillaries that then relax contractile elements throughout the vasculature to quickly adjust blood flow to meet changing needs. The attendant increase in energy substrate delivery serves to meet local metabolic requirements and thus avoids a mismatch in supply and demand and prevents metabolic stress. We discuss in detail key examples of EMS that our laboratories have discovered in the brain and the heart, and we outline potential further EMS mechanisms operating in tissues such as skeletal muscle, pancreas, and kidney. We suggest that the energy imbalance evoked by EMS uncoupling may be central to cellular dysfunction from which the hallmarks of aging and metabolic diseases emerge and may lead to generalized organ failure states-such as diverse flavors of heart failure and dementia. Understanding and manipulating EMS may be key to preventing or reversing these dysfunctions.

Nurturing longevity through natural compounds: Where do we stand, and where do we go?

AbstractThe revolution in aging research through the past decade has driven the progress in interventions that promote longevity. Dissection of the “old” hallmarks of aging has provided solid data for the definition of at least three “new” ones, opening avenues for the development of novel hallmark‐targeted pro‐longevity approaches. The quest for geroprotectors is of enormous interest with the ultimate goal of finding the alchemical stone that induces healthy aging and increases lifespan, pushing the limits of human longevity or even uncovering the absence of such limits. Several of the well‐appreciated geroprotectors that are recognized as longevity promoters are of natural origin such as metformin, resveratrol, aspirin, and spermidine. As the search for pharmacological modulators of healthspan and lifespan continues, numerous studies are focusing on the potential of plant secondary metabolites. The current review attempts to critically assess the available interventions and the breakthrough discoveries in the field of longevity research over the past decade. Correspondingly, novel approaches targeting the hallmarks of aging have been outlined, and the future goals in longevity research have been enlightened. Special emphasis has been placed on the potential of plant‐derived compounds as pro‐longevity agents.

Derailed protein turnover in the aging mammalian brain

Efficient protein turnover is essential for cellular homeostasis and organ function. Loss of proteostasis is a hallmark of aging culminating in severe dysfunction of protein turnover. To investigate protein turnover dynamics as a function of age, we performed continuous in vivo metabolic stable isotope labeling in mice along the aging continuum. First, we discovered that the brain proteome uniquely undergoes dynamic turnover fluctuations during aging compared to heart and liver tissue. Second, trends in protein turnover in the brain proteome during aging showed sex-specific differences that were tightly tied to cellular compartments. Next, parallel analyses of the insoluble proteome revealed that several cellular compartments experience hampered turnover, in part due to misfolding. Finally, we found that age-associated fluctuations in proteasome activity were associated with the turnover of core proteolytic subunits, which was recapitulated by pharmacological suppression of proteasome activity. Taken together, our study provides a proteome-wide atlas of protein turnover across the aging continuum and reveals a link between the turnover of individual proteasome subunits and the age-associated decline in proteasome activity.

Partial loss of Sorting Nexin 27 resembles age- and Down syndrome-associated T cell dysfunctions

BackgroundSorting Nexin 27 (SNX27)-retromer complex facilitates cargo recycling from endosomes to the plasma membrane. SNX27 downregulation in neurons, as the result of Trisomy 21 (T21), has been linked with cognitive deficits due to impairment of AMPA and NMDA receptor recycling. Studies in human T cell lines likewise demonstrated that SNX27 regulates the correct delivery of cargoes to the immune synapse limiting the activation of pro-inflammatory pathways. Nevertheless, the physiological consequences of partial SNX27 loss in T cell homeostasis are still unclear.ResultsIn this study, we have explored the consequences of T cell specific partial SNX27 downregulation in mice. T cells with partial SNX27 deficiency show a marked deficit in the CD4+ T cell pool, a hallmark of aging in mice and humans, and a well-characterized comorbidity of individuals with Down syndrome (DS). When analyzed ex vivo, CD4+ T cells with partial SNX27 deletion demonstrate enhanced proliferation but diminished IL-2 production. In contrast, the CD8+ population show enhanced expression of pro-inflammatory cytokines and lytic enzymes.ConclusionsThis mouse model supports the relevance of SNX27 in the organization of the immune synapse, previously described in cell lines, as well as in the control of T cell homeostasis. Individuals with DS experiment an acceleration of the aging process, which particularly affects the immune and central nervous systems. Thus, we hypothesize that reduced SNX27 expression in DS could contribute to the dysregulation of these systems and further research in SNX27 will shed light on the molecular factors underlying the phenotypes observed in people with DS and its contribution to aging.

Putrescine Upregulates Melanogenesis Through Modulation of MITF Transcription Factor in B16F1 Mouse Melanoma Cells.

Ageing is a biochemical, metabolic and genetic physiological phenomenon. The suppression of melanin biosynthesis, evident in the greying of the hair, is a hallmark of ageing resulting from translation failure, reduced enzyme activity and cellular senescence. Putrescine, the smallest member of the polyamine family and an organic chemical, is present in living mammalian cells and plays a crucial role in regulating skin melanogenesis. Therefore, the purpose of this study is to explore the effect of putrescine on the signalling pathways of melanogenesis in melanoma cells. Melanin production capacity of putrescine was analysed using a tyrosinase activity assay. To assess the cell viability of B16F1 cells exposed to putrescine, a tetrazolium dye MTT assay was performed. The effect of putrescine on melanin synthesis in the presence of H2O2 was evaluated using various in vitro assays in B16F1 cells. The effect of putrescine on melanin production in B16F1 cells was determined using a specific melanin production assay. Gene expression was analysed using real-time polymerase chain reaction (RT-PCR). Furthermore, the effect of putrescine on the expression of proteins related to melanin production in the cells treated with H2O2 was analysed by immunofluorescence and Western blot analysis. Putrescine increased tyrosinase activity and showed no cytotoxicity in B16F1 cells. In addition, putrescine effectively scavenged H2O2, as shown by the reduction of intracellular H2O2 amounts in 2',7'-dichlorofluorescin diacetate analysis, and promoted melanin production in living cells. The stimulation of melanogenesis by putrescine was attributed to the increased expression of Mitf, Tyr, Trp-1 and Trp-2 genes. Immunofluorescence assays revealed that putrescine enhanced the expression of proteins associated with melanogenesis and upregulated TYR, TRP-1 and TRP-2 via the microphthalmia-associated transcription factor (MITF) and increased the expression of methionine sulfoxide reductases A (MSRA) and B (MSRB) in the cells treated with H2O2, effectively promoting melanogenesis. These results suggest that putrescine can be used to stimulate melanin synthesis. This is the first study to investigate the effect of putrescine on the signalling pathways of melanogenesis in B16F1 melanoma cells. The results confirm that putrescine can promote melanogenesis through the expression of TYR, TRP-1 and TRP-2 via the MITF in cells treated with H2O2. Putrescine can be used exclusively as a cosmetic product to prevent premature greying of hair.

Development of a specific fluorescent probe to detect advanced glycation end products (AGEs).

Advanced glycation end products (AGEs) play a pivotal role in the aging process, regarded as a hallmark of aging. Despite their significance, the absence of adequate monitoring tools has hindered the exploration of the relationship between AGEs and aging. Here, we present a novel AGE-selective probe, AGO, for the first time. AGO exhibited superior sensitivity in detecting AGEs compared to the conventional method of measuring autofluorescence from AGEs. Furthermore, we validated AGO's ability to detect AGEs based on kinetics, demonstrating a preference for ribose-derived AGEs. Lastly, AGO effectively visualized glycation products in a collagen-based mimicking model of glycation. We anticipate that this study will enhance the molecular tool sets available for comprehending the physiological processes of AGEs during aging.

Innate immunity in peripheral tissues is differentially impaired under normal and endotoxic conditions in aging.

Chronic low-grade inflammation is a hallmark of aging, aka "inflammaging", which is linked to a wide range of age-associated diseases. Immune dysfunction increases disease susceptibility, and increases morbidity and mortality of aging. Innate immune cells, including monocytes, macrophages and neutrophils, are the first responders of host defense and the key mediators of various metabolic and inflammatory insults. Currently, the understanding of innate immune programming in aging is largely fragmented. Here we investigated the phenotypic and functional properties of innate immune cells in various peripheral tissues of young and aged mice under normal and endotoxic conditions. Under the steady state, aged mice showed elevated pro-inflammatory monocytes/macrophages in peripheral blood, adipose tissue, liver, and colon. Under lipopolysaccharide (LPS)-induced inflammatory state, the innate immune cells of aged mice showed a different response to LPS stimulus than that of young mice. LPS-induced immune responses displayed differential profiles in different tissues and cell types. In the peripheral blood, when responding to LPS, the aged mice showed higher neutrophils, but lower pro-inflammatory monocytes than that in young mice. In the peritoneal fluid, while young mice exhibited significantly elevated pro-inflammatory neutrophils and macrophages in response to LPS, aged mice exhibited decreased pro-inflammatory neutrophils and variable cytokine responses in macrophages. In the adipose tissue, LPS induced less infiltrated neutrophils but more infiltrated macrophages in old mice than young mice. In the liver, aged mice showed a more robust increase of pro-inflammatory macrophages compared to that in young mice under LPS stimulation. In colon, macrophages showed relatively mild response to LPS in both young and old mice. We have further tested bone-marrow derived macrophages (BMDM) from young and aged mice, we found that BMDM from aged mice have impaired polarization, displaying higher expression of pro-inflammatory markers than those from young mice. These data collectively suggest that innate immunity in peripheral tissues is impaired in aging, and the dysregulation of immunity is tissue- and cell-dependent. Our findings in the rodent model underscore the complexity of aging immunity. Further investigation is needed to determine whether the immune profile observed in aged mice is applicable in age-associated diseases in humans.

Aging, Cellular Senescence, and Glaucoma.

Aging is one of the most serious risk factors for glaucoma, and according to age-standardized prevalence, glaucoma is the second leading cause of legal blindness worldwide. Cellular senescence is a hallmark of aging that is defined by a stable exit from the cell cycle in response to cellular damage and stress. The potential mechanisms underlying glaucomatous cellular senescence include oxidative stress, DNA damage, mitochondrial dysfunction, defective autophagy/mitophagy, and epigenetic modifications. These phenotypes interact and generate a sufficiently stable network to maintain the cell senescent state. Senescent trabecular meshwork (TM) cells, retinal ganglion cells (RGCs) and vascular endothelial cells reportedly accumulate with age and stress and may contribute to glaucoma pathologies. Therapies targeting the suppression or elimination of senescent cells have been found to ameliorate RGC death and improve vision in glaucoma models, suggesting the pivotal role of cellular senescence in the pathophysiology of glaucoma. In this review, we explore the biological links between aging and glaucoma, specifically delving into cellular senescence. Moreover, we summarize the current data on cellular senescence in key target cells associated with the development and clinical phenotypes of glaucoma. Finally, we discuss the therapeutic potential of targeting cellular senescence for the management of glaucoma.

Molecules with Pre-Clinical Evidence of Targeting Aging in Multi-species Models for Consideration in Companion Animal Medicine

Aging is the most significant risk factor for chronic disease in humans and animals. There are hallmarks of aging which are characteristics that manifest normally during aging and that can be experimentally aggravated and ameliorated. Although age is not formally recognized as a disease by the FDA or the National Institute on Aging, identifying these hallmarks of characteristic molecular, cellular, and organ-ismal functions and causes of aging allows for the consideration of aging as a disease process. This enables practitioners to more precisely treat and prevent specific aspects of aging as done with traditional disease. Anti-aging research has progressed at an exponential rate in the past 2 decades, providing insights to targets within each of these hallmarks that can allow intervention via lifestyle modifications, nutraceuticals, and pharmaceutical agents. The nutraceutical and pharmaceutical compounds selected for this review have shown the potential to either delay or prevent onset of aging-related morbidity or mortality in multiple laboratory species, with evidence for safety in the relatively few published pharmacokinetic and toxicity trials in companion animals. For clinical inclusion of such interventions into companion animal medicine, more well-designed studies and the development of monitoring protocols to measure healthspan index would be helpful to adequately assess efficacy of such interventions.

Fecal Microbiota Transfer from Young Mice Reverts Vascular Aging Hallmarks and Metabolic Impairments in Aged Mice.

As a major risk factor for cardiometabolic diseases, aging refers to a gradual decline in physiological function, characterized with 12 conspicuous hallmarks, like telomere attrition, chronic inflammation, and dysbiosis. Common vascular aging hallmarks include endothelial dysfunction, telomere dysfunction, and vascular inflammation. In this study, we sought to test the hypothesis that young-derived gut microbiota retards vascular aging hallmarks and metabolic impairments in aged hosts. We also aimed to study the therapeutic efficacy of young microbiota in hosts of different ages. Fecal microbiota transplantation (FMT) from young to aged or middle-aged C57BL/6 mice was conducted for 6 consecutive weeks after antibiotic pretreatment. Endothelium-dependent relaxations (EDRs) in mouse arteries were determined by wire myography. Inflammation and AMPK/SIRT1 signaling in mouse aortas and intestines were studied by biochemical assays. The telomere function of aortas and intestines, in terms of telomerase reverse transcriptase expression, telomerase activity, and relative telomere length, were also studied. FMT significantly reverted vascular dysfunction and metabolic impairments in middle-aged mice than in aged mice. Besides, FMT significantly reverted inflammation and telomere dysfunction in aortas and intestines of middle-aged mice. Improved intestinal barrier function and activated AMPK/SIRT1 signaling potentially underlie benefits of FMT. The findings imply gut-vascular connection as potential target against age-associated cardiometabolic disorders, highlight crosstalk among aging hallmarks, and suggest a critical timepoint for efficacy of anti-aging interventions.

High-throughput assessment of cellular senescence.

Cellular senescence is a molecular process that is activated in response to a large variety of distinct stress signals. Mechanistically, cellular senescence is characterized by an arrest in cell cycle accompanied by phenotypic adaptations and physiological alterations including changes in the secretory profile of senescent cells termed the senescence-associated secretory phenotype (SASP). Here we describe a detailed, automation- compatible method for the detection of senescence-associated beta galactosidase (SA-β-gal) activity as a hallmark of cellular senescence using a conventional fluorescent microscope equipped with a transmitted light module. Moreover, we outline a protocol for the automated analysis of cellular senescence using convolutional neural networks (CNNs) and mathematical morphology. In sum, we provide a toolset for the high throughput assessment of cellular senescence based on light microscopy and automated image analysis.

MitomiRs: The Role of Mitochondrial miRNAs in Regulating Radiation-Induced Cellular Senescence

The problem of human exposure to ionizing radiation has attracted increasing attention in various scientific fields. Recently, a substantial amount of data has been collected on the age-related risks associated with radiation exposure, which has enabled researchers to uncover the relationship between ionizing radiation and cellular senescence. This has led to the search for cellular targets of radiation, with mitochondria being one of the identified targets. Ionizing radiation causes mitochondrial dysfunction and the emergence of a characteristic age-related phenotype in cells, including increased ROS production, SASP development, changes in the epigenetic profile, and genomic instability. Mitochondrial dysfunction is often underestimated as a crucial hallmark of cellular senescence, and its underlying mechanisms are extensive and complex. In particular, mitochondrial miRNAs (mitomiRs) that regulate mitochondrial gene expression, and consequently, the function and dynamics of the organelles themselves, are of particular interest. Considering that mitomiRs are highly sensitive to even minor disturbances arising from irradiation, resulting in significant changes in their expression, they may serve as promising biomarkers of radiation exposure. In this review, we examine the evidence supporting the key role of mitomiRs in radiation-induced cellular senescence and integrate the latest knowledge on the underlying molecular mechanisms of this interaction.

Arterial Stiffness and Heart Failure With Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is prevalent and associated with a poor prognosis, imposing a significant burden on society. Arterial stiffness is increasingly recognized as a crucial factor in the pathophysiology of HFpEF, affecting diagnosis, management, and prognosis. As a hallmark of vascular aging, arterial stiffness contributes to increased afterload on the left ventricle (LV), leading to diastolic dysfunction, a key feature of HFpEF. Elevated arterial stiffness is linked with common cardiovascular risk factors in HFpEF, such as hypertension, diabetes and obesity, exacerbating the progression of disease. Studies have demonstrated that patients with HFpEF exhibit significantly higher levels of arterial stiffness compared to those without HFpEF, highlighting the value of arterial stiffness measurements as both diagnostic and prognostic tools. Moreover, interventions aimed at reducing arterial stiffness, whether through pharmacological therapies or lifestyle modifications, have shown potential in improving LV diastolic function and patient outcomes. Despite these advancements, the precise mechanisms by which arterial stiffness contributes to HFpEF are still not fully understood, necessitating the need for further research.