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Arterial stiffness is an emerging indicator of cardiovascular risk, but its causal relationship with a variety of age-related diseases is unclear. The objective is to assess the causal relationship between arterial stiffness index (ASI) and age-related diseases by Mendelian randomization (MR) analysis. We obtained instrumental variables associated with age-related diseases from genome-wide association studies (GWAS) of 484,598 European individuals, and data for ASI were obtained from the UK Biobank GWAS of 127,127 participants. We used the inverse variance-weighted as the primary analysis method. In addition, several sensitivity analyses including MR-Egger, weighted-median (WM), Mendelian randomization pleiotropy residual sum and outlier, and Cochran's Q test were performed to test the robustness of the results. Reverse MR analysis was also performed to assess reverse causal relationships between age-related diseases and ASI. We verified the causal relationship between eight age-related diseases and ASI, of which cardiovascular disease (β = 0.19), gallbladder disease (β = 0.85), liver, biliary, or pancreas problem (β = 1.02), hypertension (β = 0.19), joint disorder (β = 0.53), and esophageal disorder (β = 2.10) elevated ASI. In contrast, hyperthyroidism or thyrotoxicosis (β = −2.17) and bowel problems (β = −1.83) may reduce ASI. This MR analysis reveals causal relationships between ASI and several age-related diseases. ASI is expected to be a potential indicator of health conditions for older populations. [ABSTRACT FROM AUTHOR]

Aging is a natural and inevitable physiological process that poses a serious threat to physical health, leading to age-related diseases and placing a heavy burden on the public health system. This study explores intervention measures to promote healthy aging and prolong lifespan. Anthocyanins (ACNs), as a class of flavonoids widely presented in fruits, vegetables and grains, exhibit strong antioxidant and anti-inflammatory activities. Recent studies indicate that ACNs exert health effects primarily by interacting with gut microbiota. Here, we introduced the digestion and absorption of ACNs, and mainly elaborated on the role of ACNs in delaying aging through gut microbiota. In addition, we described the changes in gut microbiota mediated by ACNs and their impact on age-related chronic diseases, including cardiovascular diseases, neurodegenerative diseases, cancer, and sarcopenia. Therefore, ACNs have a broad application prospect in the development of functional foods with anti-aging effects by regulating gut microbiota.

All linear chromosomal ends have specific DNA-protein complexes called telomeres. Telomeres serve as a "molecular clock" to estimate the potential length of cell replication. Shortening of telomere length (TL) is associated with cellular senescence, aging, and various age-related diseases in humans. Here we reviewed the structure, function, and regulation of telomeres and the age-related diseases associated with telomere attrition. Among the various determinants of TL, we highlight the connection between TL and heredity to provide a new overview of genetic determinants for TL. Studies across multiple species have shown that maternal and paternal TL influence the TL of their offspring, and this may affect life span and their susceptibility to age-related diseases. Hence, we reviewed the linkage between TL and parental influences and the proposed mechanisms involved. More in-depth studies on the genetic mechanism for TL attrition are needed due to the potential application of this knowledge in human medicine to prevent premature frailty at its earliest stage, as well as promote health and longevity. [ABSTRACT FROM AUTHOR]

Accumulation of senescent endothelial cells (ECs) in vasculature represents a key step in the development of vascular aging and ensuing age-related diseases. Given that removal of senescent ECs may prevent disease and improve health and wellbeing, the discovery of novel biomarkers that effectively identify senescent cells is of particular importance. As crucial elements for biological pathways and reliable bioindicators of cellular processes, metabolites demand attention in this context. Using senescent human brain microvascular endothelial cells (HBMECs) displaying a secretory phenotype and significant morphological, nuclear, and enzymatic changes compared to their young counterparts, this study has shown that senescent HBMECs lose their endothelial characteristics as evidenced by the disappearance of CD31/PECAM-1 from interendothelial cell junctions. The metabolic profiling of young versus senescent HBMECs also indicates significant differences in glucose, glutamine, and fatty acid metabolism. The analysis of intracellular and secreted metabolites proposes L-proline, L-glutamate, NAD+, and taurine/hypotaurine pathway components as potential biomarkers. However, further studies are required to assess the value of these agents as potential biomarkers and therapeutic targets. [ABSTRACT FROM AUTHOR]

Aging is a complex biological process characterized by the gradual decline of cellular functions, increased susceptibility to diseases, and impaired stress responses. Hypoxia, defined as reduced oxygen availability, is a critical factor that influences aging through molecular pathways involving hypoxia‐inducible factors (HIFs), oxidative stress, inflammation, and epigenetic modifications. This review explores the interconnected roles of hypoxia in aging, highlighting how hypoxic conditions exacerbate cellular damage, promote senescence, and contribute to age‐related pathologies, including cardiovascular diseases, neurodegenerative disorders, cancer, metabolic dysfunctions, and pulmonary conditions. By examining the molecular mechanisms linking hypoxia to aging, we identify key pathways that serve as potential therapeutic targets. Emerging interventions such as HIF modulators, antioxidants, senolytics, and lifestyle modifications hold promise in mitigating the adverse effects of hypoxia on aging tissues. However, challenges such as the heterogeneity of aging, lack of reliable biomarkers, and safety concerns regarding hypoxia‐targeted therapies remain. This review emphasizes the need for personalized approaches and advanced technologies to develop effective antiaging interventions. By integrating current knowledge, this review provides a comprehensive framework that underscores the importance of targeting hypoxia‐induced pathways to enhance healthy aging and reduce the burden of age‐related diseases. [ABSTRACT FROM AUTHOR]

Cellular senescence, first described in 1961, was initially observed in normal human fibroblasts that ceased proliferating after a finite number of divisions in culture. This process is triggered by various stimuli, including oxidative stress, chromatin modifications and oncogene activation, characterized by irreversible cell-cycle arrest, resistance to apoptosis and the induction of a complex senescent associated secretory phenotype (SASP). Over the past decade, emerging evidence has linked cellular senescence to the aging process and a wide range of chronic age-related diseases. Consequently, research focused on targeting senescence to alleviate or delay age-related disease, referred to as senotherapy, has been conducted rapidly. Therefore, elucidating the mechanisms of cellular senescence is essential for providing practical strategies aimed at addressing this condition.

The composition of the human gut microbiome has been observed to change over the course of an individual’s life. From birth, it is shaped by mode of delivery, diet, environmental exposures, geographic location, exposures to medications, and by aging itself. Here, we present a narrative review of the gut microbiome across the lifespan with a focus on its impacts on aging and age-related diseases in humans. We will describe how it is shaped, and features of the gut microbiome that have been associated with diseases at different phases of life and how this can adversely affect healthy aging. Across the lifespan, and especially in old age, a diverse microbiome that includes organisms suspected to produce anti-inflammatory metabolites such as short-chain fatty acids, has been reported to be associated with healthy aging. These findings have been remarkably consistent across geographic regions of the world suggesting that they could be universal features of healthy aging across all cultures and genetic backgrounds. Exactly how these features of the microbiome affect biologic processes associated with aging thus promoting healthy aging will be crucial to targeting the gut microbiome for interventions that will support health and longevity.

Dietary restriction (DR) has long been recognized as a powerful intervention for extending lifespan and improving metabolic health across species. In laboratory animals, DR—typically a 30%–40% reduction in caloric intake—delays aging and enhances mitochondrial function, oxidative defense, and anti-inflammatory pathways. In humans, findings from the CALERIE™ trial confirm DR's potential benefits, with a 25% caloric reduction over 2 years resulting in reduced visceral fat, improved cardiometabolic health, and favorable gene expression changes linked to proteostasis, DNA repair, and inflammation. However, recent research in genetically diverse mouse populations reveals that the impact of DR on lifespan is substantially modulated by genetic background, underscoring the importance of individual variability. Additionally, emerging evidence challenges previous assumptions that lower body temperature universally benefits lifespan extension, with data indicating complex relationships between thermoregulation, sex, and longevity. These findings underscore the need for nuanced approaches to DR in both research and potential therapeutic applications, with considerations for genetic and sex-specific factors to maximize healthspan and lifespan outcomes. [ABSTRACT FROM AUTHOR]

Aging delay is an intricate thing that involves efforts of stress minimization and organism resilience enhancement so that homeostasis can be maintained in order to survive longer in healthy settings. Lately, metformin has become the most common drug used as a pharmacological intervention in both pre-clinical and clinical anti-aging research. Unfortunately, even though metformin research has progressed to clinical trials, the molecular mechanism behind metformin's impact in delaying aging and age-related diseases remains unknown. Countless hypotheses exist regarding the role of mTOR as a crucial gene in the emergence of aging, but there is no systematic explanation that can relate the gene's contribution to modest molecular processes such as cellular senescence, the aging process, and its association with the deceleration provided by metformin. This narrative review discusses the involvement of mTOR in the aging process. Understanding the core molecular pathway of metformin through its primary target gene will help determine the effective dose that provides the maximum slowing effect of aging along with the emphasis on minimum undesirable side effects, both short and long-term. [ABSTRACT FROM AUTHOR]

In older horses, basal metabolic rate decreases, and plasma metabolite and hormone concentrations related to energy metabolism change. The occurrence of age-related diseases, which increases in old animals, may enhance inflammatory reactivity (inflammaging). Finding the appropriate treatment for inflammaging at an early stage may prevent various age-related diseases. Changes in metabolite and hormone concentrations and enzyme activities involved in energy metabolism in the plasma of clinically healthy riding horses of various ages were measured to identify biomarkers of inflammaging (persistent low-grade inflammation that occurs with aging). All horses were clinically healthy, and their body condition scores (BCSs) were 4 or 5 (9-point scale). Plasma triglyceride (TG), total cholesterol (T-Cho), blood urea nitrogen (BUN), insulin concentrations, malondialdehyde (MDA), and serum amyloid A (SAA) concentrations generally increased with age. Adiponectin concentrations, plasma superoxide dismutase (SOD), and leukocyte AMP-activated protein kinase (AMPK) activities decreased, while plasma aspartate aminotransferase (AST), alanine aminotransferase (ALT), and glutathione peroxidase (GPx) remained unchanged as horses aged. Although riding horses that partake in continuous exercise seems to be less likely to develop inflammaging, horses over 17 years of age tend to show proinflammatory signs with disordered lipid metabolism. In riding horses, SAA, in combination with other markers, may be a useful biomarker for inflammaging and dysregulated lipid metabolism in aging horses. [ABSTRACT FROM AUTHOR]

Abstract Aging is a complex biological process characterized by the gradual decline of cellular functions, increased susceptibility to diseases, and impaired stress responses. Hypoxia, defined as reduced oxygen availability, is a critical factor that influences aging through molecular pathways involving hypoxia‐inducible factors (HIFs), oxidative stress, inflammation, and epigenetic modifications. This review explores the interconnected roles of hypoxia in aging, highlighting how hypoxic conditions exacerbate cellular damage, promote senescence, and contribute to age‐related pathologies, including cardiovascular diseases, neurodegenerative disorders, cancer, metabolic dysfunctions, and pulmonary conditions. By examining the molecular mechanisms linking hypoxia to aging, we identify key pathways that serve as potential therapeutic targets. Emerging interventions such as HIF modulators, antioxidants, senolytics, and lifestyle modifications hold promise in mitigating the adverse effects of hypoxia on aging tissues. However, challenges such as the heterogeneity of aging, lack of reliable biomarkers, and safety concerns regarding hypoxia‐targeted therapies remain. This review emphasizes the need for personalized approaches and advanced technologies to develop effective antiaging interventions. By integrating current knowledge, this review provides a comprehensive framework that underscores the importance of targeting hypoxia‐induced pathways to enhance healthy aging and reduce the burden of age‐related diseases.

Growth and aging are fundamental elements of human development. Aging is defined by a decrease in physiological activities and higher illness vulnerability. Affected by lifestyle, environmental, and hereditary elements, aging results in disorders including cardiovascular, musculoskeletal, and neurological diseases, which accounted for 16.1 million worldwide deaths in 2019. Stress-induced cellular senescence, caused by DNA damage, can reduce tissue regeneration and repair, promoting aging. The root cause of many age-related disorders is inflammation, encouraged by the senescence-associated secretory phenotype (SASP). Aging’s metabolic changes and declining immune systems raise illness risk via promoting microbiome diversity. Stable, individual-specific skin and oral microbiomes are essential for both health and disease since dysbiosis is linked with periodontitis and eczema. Present from birth to death, the human microbiome, under the influence of diet and lifestyle, interacts symbiotically with the body. Poor dental health has been linked to Alzheimer’s and Parkinson’s diseases since oral microorganisms and systemic diseases have important interactions. Emphasizing the importance of microbiome health across the lifetime, this study reviews the understanding of the microbiome’s role in aging-related diseases that can direct novel diagnosis and treatment approaches.

Abstract With increasing proportion of the elderly in the population, age-related diseases (ARD) lead to a considerable healthcare burden to society. Prevention and treatment of ARD can decrease the negative impact of aging and the burden of disease. The aging rate is closely associated with the production of high levels of reactive oxygen species (ROS). ROS-mediated oxidative stress in aging triggers aging-related changes through lipid peroxidation, protein oxidation, and DNA oxidation. Antioxidants can control autoxidation by scavenging free radicals or inhibiting their formation, thereby reducing oxidative stress. Benefiting from significant advances in nanotechnology, a large number of nanomaterials with ROS-scavenging capabilities have been developed. ROS-scavenging nanomaterials can be divided into two categories: nanomaterials as carriers for delivering ROS-scavenging drugs, and nanomaterials themselves with ROS-scavenging activity. This study summarizes the current advances in ROS-scavenging nanomaterials for prevention and treatment of ARD, highlights the potential mechanisms of the nanomaterials used and discusses the challenges and prospects for their applications. Graphical Abstract

With increasing proportion of the elderly in the population, age-related diseases (ARD) lead to a considerable healthcare burden to society. Prevention and treatment of ARD can decrease the negative impact of aging and the burden of disease. The aging rate is closely associated with the production of high levels of reactive oxygen species (ROS). ROS-mediated oxidative stress in aging triggers aging-related changes through lipid peroxidation, protein oxidation, and DNA oxidation. Antioxidants can control autoxidation by scavenging free radicals or inhibiting their formation, thereby reducing oxidative stress. Benefiting from significant advances in nanotechnology, a large number of nanomaterials with ROS-scavenging capabilities have been developed. ROS-scavenging nanomaterials can be divided into two categories: nanomaterials as carriers for delivering ROS-scavenging drugs, and nanomaterials themselves with ROS-scavenging activity. This study summarizes the current advances in ROS-scavenging nanomaterials for prevention and treatment of ARD, highlights the potential mechanisms of the nanomaterials used and discusses the challenges and prospects for their applications. [ABSTRACT FROM AUTHOR]

The expanding geriatric population, whose predisposition toward disabling morbidities and age-related diseases (ARD) is well-documented, has become a paramount social issue, exerting an onerous burden on both the healthcare industry and wider society. ARD manifest as the progressive deterioration of bodily tissues and organs, eventually resulting in the failure of these vital components. At present, no efficacious measures exist to hinder the onset of ARD. Copper, an essential trace element, is involved in a wide range of physiological processes across different cell types. In recent research, a novel variant of copper-dependent cell death, termed cuproptosis, has been identified. This mode of cellular demise stands apart from previously recognized types of cell death. Cuproptosis occurs when copper binds with acyl-CoA synthetase in the tricarboxylic acid (TCA) cycle, resulting in protein aggregation and protein toxicity stress, ultimately leading to cell death. In this paper, we provide a concise overview of the current understanding concerning the metabolism of copper, copper-related diseases, the hallmarks of copper toxicity, and the mechanisms that regulate copper toxicity. Additionally, we discuss the implications of cuproptosis mutations in the development of ARD, as well as the potential for targeting cuproptosis as a treatment for ARD. [ABSTRACT FROM AUTHOR]

Background: There is evidence that complex diseases and mortality are associated with DNA methylation and age acceleration. Numerous epigenetic clocks, including Horvath, Hannum, DNA PhenoAge, DNA GrimAge, and Dunedin Pace of Aging Methylation, continue to be developed in this young scientific field. The most well-known epigenetic clocks are presented here, along with information about how they relate to chronic disease. Summary: We examined all the literature until January 2023, investigating associations between measures of age acceleration and complex and age-related diseases. We focused on the scientific literature and research that are most strongly associated with epigenetic clocks and that have shown promise as biomarkers for obesity, cardiovascular illness, type 2 diabetes, and neurodegenerative disease. Key Messages: Understanding the complex interactions between accelerated epigenetic clocks and chronic diseases may have significant effects on both the early diagnosis of disease and health promotion. Additionally, there is a lot of interest in developing treatment plans that can delay the onset of illnesses or, at the very least, alter the underlying causes of such disorders. [ABSTRACT FROM AUTHOR]

Aging is a complex biological process that is influenced by both intrinsic and extrinsic factors. Recently, it has been discovered that reactive oxygen species can accelerate the aging process, leading to an increased incidence of age-related diseases that are characteristic of aging. This review aims to discuss the potential of mushrooms as a dietary intervention for anti-aging, focusing on their nutritional perspective. Mushrooms contain various bioactive compounds, including carbohydrates, bioactive proteins, fungal lipids, and phenolic compounds. These compounds have shown promising effectiveness in combating skin aging and age-related diseases. In vitro and in vivo studies have demonstrated that treatments with mushrooms or their extracts can significantly extend lifespan and improve health span. Furthermore, studies have aimed to elucidate the precise cellular and molecular mechanisms of action and the structure–activity relationship of mushroom bioactive compounds. These findings provide a strong basis for further research, including human clinical trials and nutritional investigations, to explore the potential benefits of mushrooms in real-life anti-aging practices. By exploring the anti-aging effects of mushrooms, this review aims to provide valuable insights that can contribute to the development of broader strategies for healthy aging. [ABSTRACT FROM AUTHOR]

Abstract Background This study aimed to identify and select age-related diseases (ARDs) in Korea, which is about to have a super-aged society, and to elucidate patterns in their incidence rates. Methods The National Health Insurance Service–National Sample Cohort, comprising 1 million health insurance and medical benefit beneficiaries in Korea from 2002 to 2019, was utilized. We selected 14 diseases with high disease burden and prevalence among Koreans from the 92 diseases defined in the Global Burden of Diseases, Injuries, and Risk Factors Study as ARDs. The annual incidence rate represented the number of patients newly diagnosed with an ARD each year from 2006 to 2019, excluding those with a history of ARD diagnosis from 2002 to 2005. The incidence rate by age was categorized into 10-year units based on age as of 2019. The number of patients with ARDs in each age group was used as the numerator, and the incidence rate for each age group was calculated with the age group as the denominator. Results Regarding the annual incidence rates of ARDs from 2006 to 2019, chronic obstructive pulmonary disease, congestive heart failure, and ischemic heart disease decreased annually, whereas dyslipidemia, chronic kidney disease, cataracts, hearing loss, and Parkinson's disease showed a significant increase. Hypertension, diabetes, cerebrovascular disease, osteoporosis, osteoarthritis, and age-related macular degeneration initially displayed a gradual decrease in incidence but exhibited a tendency to increase after 2015. Concerning age-specific incidence rates of ARDs, two types of curves emerged. The first type, characterized by an exponential increase with age, was exemplified by congestive heart failure. The second type, marked by an exponential increase peaking between ages 60 and 80, followed by stability or decrease, was observed in 13 ARDs, excluding congestive heart failure. However, hypertension, ischemic heart disease, cerebrovascular disease, chronic obstructive pulmonary disease, and hearing loss in men belonged to the first type. Conclusions From an epidemiological perspective, there are similar characteristics in age-specific ARDs that increase with age, reaching a peak followed by a plateau or decrease in Koreans.

Abstract TLR4, a transmembrane receptor, plays a central role in the innate immune response. TLR4 not only engages with exogenous ligands at the cellular membrane’s surface but also interacts with intracellular ligands, initiating intricate intracellular signaling cascades. Through MyD88, an adaptor protein, TLR4 activates transcription factors NF-κB and AP-1, thereby facilitating the upregulation of pro-inflammatory cytokines. Another adapter protein linked to TLR4, known as TRIF, autonomously propagates signaling pathways, resulting in heightened interferon expression. Recently, TLR4 has garnered attention as a significant factor in the regulation of symptoms in aging-related disorders. The persistent inflammatory response triggered by TLR4 contributes to the onset and exacerbation of these disorders. In addition, alterations in TLR4 expression levels play a pivotal role in modifying the manifestations of age-related diseases. In this review, we aim to consolidate the impact of TLR4 on cellular senescence and aging-related ailments, highlighting the potential of TLR4 as a novel therapeutic target that extends beyond immune responses.

Here, we summarize the current knowledge on eight promising drugs and natural compounds that have been tested in the clinic: metformin, NAD+ precursors, glucagon-like peptide-1 receptor agonists, TORC1 inhibitors, spermidine, senolytics, probiotics, and anti-inflammatories. Multiple clinical trials have commenced to evaluate the efficacy of such agents against age-associated diseases including diabetes, cardiovascular disease, cancer, and neurodegenerative diseases. There are reasonable expectations that drugs able to decelerate or reverse aging processes will also exert broad disease-preventing or -attenuating effects. Hence, the outcome of past, ongoing, and future disease-specific trials may pave the way to the development of new anti-aging medicines. Drugs approved for specific disease indications may subsequently be repurposed for the treatment of organism-wide aging consequences. Aging research has identified several pathways that hold promise as targets for interventions that slow aging and forestall or treat diseases. Guarente et al. review the status of human clinical trials on eight pathways that may provide health benefits by slowing aging. [ABSTRACT FROM AUTHOR]

Background: This study aimed to identify and select age-related diseases (ARDs) in Korea, which is about to have a super-aged society, and to elucidate patterns in their incidence rates. Methods: The National Health Insurance Service–National Sample Cohort, comprising 1 million health insurance and medical benefit beneficiaries in Korea from 2002 to 2019, was utilized. We selected 14 diseases with high disease burden and prevalence among Koreans from the 92 diseases defined in the Global Burden of Diseases, Injuries, and Risk Factors Study as ARDs. The annual incidence rate represented the number of patients newly diagnosed with an ARD each year from 2006 to 2019, excluding those with a history of ARD diagnosis from 2002 to 2005. The incidence rate by age was categorized into 10-year units based on age as of 2019. The number of patients with ARDs in each age group was used as the numerator, and the incidence rate for each age group was calculated with the age group as the denominator. Results: Regarding the annual incidence rates of ARDs from 2006 to 2019, chronic obstructive pulmonary disease, congestive heart failure, and ischemic heart disease decreased annually, whereas dyslipidemia, chronic kidney disease, cataracts, hearing loss, and Parkinson's disease showed a significant increase. Hypertension, diabetes, cerebrovascular disease, osteoporosis, osteoarthritis, and age-related macular degeneration initially displayed a gradual decrease in incidence but exhibited a tendency to increase after 2015. Concerning age-specific incidence rates of ARDs, two types of curves emerged. The first type, characterized by an exponential increase with age, was exemplified by congestive heart failure. The second type, marked by an exponential increase peaking between ages 60 and 80, followed by stability or decrease, was observed in 13 ARDs, excluding congestive heart failure. However, hypertension, ischemic heart disease, cerebrovascular disease, chronic obstructive pulmonary disease, and hearing loss in men belonged to the first type. Conclusions: From an epidemiological perspective, there are similar characteristics in age-specific ARDs that increase with age, reaching a peak followed by a plateau or decrease in Koreans. [ABSTRACT FROM AUTHOR]

This editorial published in the journal Frontiers in Endocrinology explores the connection between endocrine regulation and aging. It compiles research articles that investigate the role of hormonal and circulating factors in influencing the aging process. The document includes summaries of specific studies that examine various aspects of aging, such as NAD+ levels, metabolite levels and age-induced kidney dysfunction, FSH levels and the risk of developing rheumatoid arthritis, and the role of the somatotropic axis in vascular aging and cognitive impairment. The editorial also discusses the use of animal models to study the effects of PACAP deficiency on age-related degenerative signs and the relationship between circulating galectin-3 and frailty in elderly patients. The papers collectively provide insights into the mechanisms of aging and potential interventions. [Extracted from the article]

TLR4, a transmembrane receptor, plays a central role in the innate immune response. TLR4 not only engages with exogenous ligands at the cellular membrane's surface but also interacts with intracellular ligands, initiating intricate intracellular signaling cascades. Through MyD88, an adaptor protein, TLR4 activates transcription factors NF-κB and AP-1, thereby facilitating the upregulation of pro-inflammatory cytokines. Another adapter protein linked to TLR4, known as TRIF, autonomously propagates signaling pathways, resulting in heightened interferon expression. Recently, TLR4 has garnered attention as a significant factor in the regulation of symptoms in aging-related disorders. The persistent inflammatory response triggered by TLR4 contributes to the onset and exacerbation of these disorders. In addition, alterations in TLR4 expression levels play a pivotal role in modifying the manifestations of age-related diseases. In this review, we aim to consolidate the impact of TLR4 on cellular senescence and aging-related ailments, highlighting the potential of TLR4 as a novel therapeutic target that extends beyond immune responses. [ABSTRACT FROM AUTHOR]

Dysfunction of lysosomes, the primary hydrolytic organelles in animal cells, is frequently associated with aging and age‐related diseases. At the cellular level, lysosomal dysfunction is strongly linked to cellular senescence or the induction of cell death pathways. However, the precise mechanisms by which lysosomal dysfunction participates in these various cellular or organismal phenotypes have remained elusive. The ability of lysosomes to degrade diverse macromolecules including damaged proteins and organelles puts lysosomes at the center of multiple cellular stress responses. Lysosomal activity is tightly regulated by many coordinated cellular processes including pathways that function inside and outside of the organelle. Here, we collectively classify these coordinated pathways as the lysosomal processing and adaptation system (LYPAS). We review evidence that the LYPAS is upregulated by diverse cellular stresses, its adaptability regulates senescence and cell death decisions, and it can form the basis for therapeutic manipulation for a wide range of age‐related diseases and potentially for aging itself. [ABSTRACT FROM AUTHOR]

The trajectory of human aging varies widely from one individual to the next due to complex interactions between the genome and the environment that influence the aging process. Such differences in age-specific mortality and disease risk among same-aged individuals reflect variation in the pace of biological aging. Certain mechanisms involved in the progression of biological aging originate in the epigenome, where chemical modifications to the genome are able to alter gene expression without modifying the underlying DNA sequence. The epigenome serves as an interface for environmental signals, which are able to "get under the skin" to influence health and aging. A number of the molecular mechanisms involved in the aging process have been identified, although few aging phenotypes have been definitively traced to their underlying molecular causes thus far. In this review, we discuss variation in human biological aging and the epigenome's role in promoting heterogeneity in human longevity and healthspan. [ABSTRACT FROM AUTHOR]

Ageing is inevitable in all living organisms and is associated with physical deterioration, disease and eventually death. Dysbiosis, which is the alteration of the gut microbiome, occurs in individuals during ageing, and plenty of studies support that gut dysbiosis is responsible for the progression of different types of age-related diseases. The economic burden of age-linked health issues increases as ageing populations increase. Hence, an improvement in disease prevention or therapeutic approaches is urgently required. In recent years, vitamin E has garnered significant attention as a promising therapeutic approach for delaying the ageing process and potentially impeding the development of age-related disease. Nevertheless, more research is still required to understand how vitamin E affects the gut microbiome and how it relates to age-related diseases. Therefore, we gathered and summarized recent papers in this review that addressed the impact of the gut microbiome on age-related disease, the effect of vitamin E on age-related disease along with the role of vitamin E on the gut microbiome and the relationship with age-related diseases which are caused by ageing. Based on the studies reported, different bacteria brought on various age-related diseases with either increased or decreased relative abundances. Some studies have also reported the positive effects of vitamin E on the gut microbiome as beneficial bacteria and metabolites increase with vitamin E supplementation. This demonstrates how vitamin E is vital as it affects the gut microbiome positively to delay ageing and the progression of age-related diseases. The findings discussed in this review will provide a simplified yet deeper understanding for researchers studying ageing, the gut microbiome and age-related diseases, allowing them to develop new preclinical and clinical studies. [ABSTRACT FROM AUTHOR]

Genome‐wide association studies (GWAS) have pinpointed the chromosomal locus 9p21.3 as a genetic hotspot for various age‐related disorders. Common genetic variants in this locus are linked to multiple traits, including coronary artery diseases, cancers, and diabetes. Centenarians are known for their reduced risk and delayed onset of these conditions. To investigate whether this evasion of disease risks involves diminished genetic risks in the 9p21.3 locus, we sequenced this region in an Ashkenazi Jewish centenarian cohort (centenarians: n = 450, healthy controls: n = 500). Risk alleles associated with cancers, glaucoma, CAD, and T2D showed a significant depletion in centenarians. Furthermore, the risk and non‐risk genotypes are linked to two distinct low‐frequency variant profiles, enriched in controls and centenarians, respectively. Our findings provide evidence that the extreme longevity cohort is associated with collectively lower risks of multiple age‐related diseases in the 9p21.3 locus. [ABSTRACT FROM AUTHOR]

The relationship between polyamines and healthy longevity has received much attention in recent years. However, conducting research without understanding the properties of polyamines can lead to unexpected pitfalls. The most fundamental consideration in conducting polyamine studies is that bovine serum used for cell culture contains bovine serum amine oxidase. Bovine serum amine oxidase, which is not inactivated by heat treatment, breaks down spermine and spermidine to produce the highly toxic aldehyde acrolein, which causes cell damage and activates autophagy. However, no such enzyme activity has been found in humans. Polyamine catabolism does not produce toxic aldehydes under normal conditions, but inflammation and some pathogens provoke an inducible enzyme, spermine oxidase, which only breaks down spermine to produce acrolein, resulting in cytotoxicity and the activation of autophagy. Therefore, spermine oxidase activation reduces spermine concentration and the ratio of spermine to spermidine, a feature recently reported in patients with age-related diseases. Spermine, which is increased by a long-term, continuous high polyamine diet, suppresses aberrant gene methylation and the pro-inflammatory status that progress with age and are strongly associated with the development of several age-related diseases and senescence. Changes in spermine concentration and the spermine/spermidine ratio should be considered as indicators of human health status. [ABSTRACT FROM AUTHOR]

Early identification and intervention of abnormal brain development individual subjects are of great significance, especially during the earliest and most active stage of brain development in children aged under 3. Neuroimage-based brain's biological age has been associated with health, ability, and remaining life. However, the existing brain age prediction models based on neuroimage are predominantly adult-oriented. Here, we collected 658 T1-weighted MRI scans from 0 to 3 years old healthy controls and developed an accurate brain age prediction model for young children using deep learning techniques with high accuracy in capturing age-related changes. The performance of the deep learning-based model is comparable to that of the SVR-based model, showcasing remarkable precision and yielding a noteworthy correlation of 91% between the predicted brain age and the chronological age. Our results demonstrate the accuracy of convolutional neural network (CNN) brain-predicted age using raw T1-weighted MRI data with minimum preprocessing necessary. We also applied our model to children with low birth weight, premature delivery history, autism, and ADHD, and discovered that the brain age was delayed in children with extremely low birth weight (less than 1000 g) while ADHD may cause accelerated aging of the brain. Our child-specific brain age prediction model can be a valuable quantitative tool to detect abnormal brain development and can be helpful in the early identification and intervention of age-related brain disorders. [ABSTRACT FROM AUTHOR]

Disease and ageing are linked in many ways and especially by the mechanisms they share. For many diseases, the process of ageing is the main culprit leading to the pathology. Hence, it is crucial to understand the process of ageing, and its molecular and cellular mechanisms to have a better understanding and perspective on these age-related diseases. Neurodegenerative diseases are probably the most common types of age-related diseases. Their pathology is complex, however, changes in neurotransmitter levels are almost always present. These types of changes occur during ageing as well, therefore, exploring the link between those processes can give a clue for possible treatments. Monoamine oxidases (MAOs) are enzymes that break down monoamine neurotransmitters and their dysregulation has long been recorded in age-related neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. There is strong evidence that modulating the MAOs’ expression and activity can be beneficial for patients suffering from these illnesses. Herein we critically analyze the literature and make associations among ageing, MAOs’ activity and neurotransmitters’ levels, thus highlighting their role in neurodegenerative diseases.,,,,,

Omega-3 polyunsaturated fatty acids (PUFA) have demonstrated anti-inflammatory properties, while Omega-6 have pro-inflammatory effects, and the balance between the two is an important aspect of healthy nutrition. Over the last 30 years, however, the Western diet has shifted largely from Omega-3 to Omega-6 consumption. Uncontrolled aberrant and chronic inflammation is a leading component of many common diseases, including arthritis, cardiovascular diseases, neurodegenerative diseases, cancer, obesity, autoimmune diseases, and infective diseases. Eicosanoids derived from Omega-6 participate in the inflammatory process, while Omega-3 PUFA have the opposite effect. Many favorable effects of Omega-3 are believed to result from their anti-inflammatory properties, but eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) also have inhibitory effects on immune cells and reduce proinflammatory cytokine release. All these mechanisms can be beneficial in autoimmunity. No effective preventions or definite cures for autoimmune diseases are yet known because pathophysiology is also unclear. Omega-3 fatty acid supplementation is associated with a significant reduction in disease activity in several autoimmune diseases, like type 1 diabetes (T1D), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and multiple sclerosis (MS). Studies of viral diseases, including COVID-19, show improvement in symptom severity, recovery prognosis, and probability of survival with the use of Omega-3. Finally, the evidence of the beneficial effect of Omega-3 on metabolic diseases associated with aging is persuasive; various studies have demonstrated that their consumption improves lipids, fatty liver disease, obesity, cognitive function, and cardiovascular complications of chronic kidney disease (CKD). Omega-3 PUFA have also been shown to support an anti-inflammatory effect in older age and to have favorable effects on age-related disease's complications, frailty, and mortality. A healthy Omega-6/3 PUFA ratio should be targeted for the modulation of low-grade inflammation, as well as for the prevention of immune dysregulation and complications of uncontrolled inflammation triggered by infections, development, and progression of autoimmune disorders, and the consequences of oxidative stress due to aging. There is still a need for randomized clinical studies to validate current evidence supporting supplementation with correct doses of Omega-3 PUFA in autoimmune and chronic disease prevention. [ABSTRACT FROM AUTHOR]

Cellular senescence is a complex cell state that can occur during physiological ageing or after exposure to stress signals, regardless of age. It is a dynamic process that continuously evolves in a context-dependent manner. Senescent cells interact with their microenvironment by producing a heterogenous and plastic secretome referred to as the senescence-associated secretory phenotype (SASP). Hence, understanding the cross-talk between SASP and the microenvironment can be challenging due to the complexity of signal exchanges. In this review, we first aim to update the definition of senescence and its associated biomarkers from its discovery to the present day. We detail the regulatory mechanisms involved in the expression of SASP at multiple levels and develop how SASP can orchestrate microenvironment modifications, by focusing on extracellular matrix modifications, neighboring cells' fate, and intercellular communications. We present hypotheses on how these microenvironmental events may affect dynamic changes in SASP composition in return. Finally, we discuss the various existing approaches to targeting SASP and clarify what is currently known about the biological effects of these modified SASPs on the cellular environment. [ABSTRACT FROM AUTHOR]

Cellular senescence describes a stable cell cycle arrest state with a characteristic phenotype. Senescent cells accumulate in the human body during normal aging, limiting the lifespan and promoting aging-related, but also several non-related, pathologies. We propose to refer to all diseases whose pathogenesis or progression is associated with cellular senescence as "senopathies". Targeting senescent cells with senolytics or senomorphics is likely to mitigate these pathologies. Examples of senopathies include cardiovascular, metabolic, musculoskeletal, liver, kidney, and lung diseases and neurodegeneration. For all these pathologies, animal studies provide clear mechanistic evidence for a connection between senescent cell accumulation and disease progression. The major persisting challenge in developing novel senotherapies is the heterogeneity of senescence phenotypes, causing a lack of universal biomarkers and difficulties in discriminating senescent from non-senescent cells. [ABSTRACT FROM AUTHOR]

Over the last few decades, frailty has become a pillar of research and clinical assessment in human gerontology. This complex syndrome, characterized by loss of physiologic reserves leading to decreased resilience to stressors, is of critical importance because it predicts higher risks of poor health outcomes, including mortality. Thus, identifying frailty among the elderly human population has become a key focus of gerontology. This narrative review presents current scientific literature on frailty in both humans and animals. The authors discuss the need for an accessible frailty instrument for companion dogs suitable for general use in veterinary medicine and the advances that would be facilitated by this instrument. A phenotypic frailty instrument for companion dogs, utilizing components that are easily collected by owners, or in the general practice setting, is proposed. The authors elaborate on the domains (physical condition, physical activity, mobility, strength, cognitive task performance, and social behavior), factors that will be included, and the data from the Dog Aging Project that inform each domain.

Variation in apolipoprotein E (APOE) has been shown to have the strongest genetic effect on human longevity. The aim of this study was to unravel the evolutionary history of the three major APOE alleles in Europe by analysing ancient samples up to 12,000 years old. We detected significant allele frequency shifts between populations and over time. Our analyses indicated that selection led to large frequency differences between the earliest European populations (i.e., hunter‐gatherers vs. first farmers), possibly due to changes in diet/lifestyle. In contrast, the allele distributions in populations from ~4000 BCE onward can mainly be explained by admixture, suggesting that it also played an important role in shaping current APOE variation. In any case, the resulting allele frequencies strongly influence the predisposition for longevity today, likely as a consequence of past adaptations and demographic processes. [ABSTRACT FROM AUTHOR]

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The immune system is the central regulator of tissue homeostasis, ensuring tissue regeneration and protection against both pathogens and the neoformation of cancer cells. Its proper functioning requires homeostatic properties, which are maintained by an adequate balance of myeloid and lymphoid responses. Aging progressively undermines this ability and compromises the correct activation of immune responses, as well as the resolution of the inflammatory response. A subclinical syndrome of "homeostatic frailty" appears as a distinctive trait of the elderly, which predisposes to immune debilitation and chronic low-grade inflammation (inflammaging), causing the uncontrolled development of chronic and degenerative diseases. The innate immune compartment, in particular, undergoes to a sequela of age-dependent functional alterations, encompassing steps of myeloid progenitor differentiation and altered responses to endogenous and exogenous threats. Here, we will review the age-dependent evolution of myeloid populations, as well as their impact on frailty and diseases of the elderly. [ABSTRACT FROM AUTHOR]

Age‐related diseases represent some of the largest unmet clinical needs of our time. While treatment of specific disease‐related signs has had some success (for example, the effect of statin drugs on slowing progression of atherosclerosis), slowing biological ageing itself represents a target that could significantly increase health span and reduce the prevalence of multiple age‐related diseases. Mechanistic target of rapamycin complex 1 (mTORC1) is known to control fundamental processes in ageing: inhibiting this signalling complex slows biological ageing, reduces age‐related disease pathology and increases lifespan in model organisms. How mTORC1 inhibition achieves this is still subject to ongoing research. However, one mechanism by which mTORC1 inhibition is thought to slow ageing is by activating the autophagy–lysosome pathway. In this review, we examine the special bidirectional relationship between mTORC1 and the lysosome. In cells, mTORC1 is located on lysosomes. From this advantageous position, it directly controls the autophagy–lysosome pathway. However, the lysosome also controls mTORC1 activity in numerous ways, creating a special two‐way relationship. We then explore specific examples of how inhibition of mTORC1 and activation of the autophagy–lysosome pathway slow the molecular hallmarks of ageing. This body of literature demonstrates that the autophagy–lysosome pathway represents an excellent target for treatments that seek to slow biological ageing and increase health span in humans.

Chitin, one of the most abundant biopolymers on Earth, is bound and degraded by chitinases, specialized enzymes that are similarly widespread in nature. Chitin catabolism affects global carbon and nitrogen cycles through a host of diverse biological processes, but recent work has focused attention on systems of chitin recognition and degradation conserved in mammals, connecting an ancient pathway of polysaccharide processing to human diseases influenced by persistent immune triggering. Here we review current advances in our understanding of how chitin-chitinase interactions affect mucosal immune feedback mechanisms essential to maintaining homeostasis and organ health.

Mainstream transcriptome profiling of susceptibility versus resistance to age-related diseases (ARDs) is focused on differentially expressed genes (DEGs) specific to gender, age, and pathogeneses. This approach fits in well with predictive, preventive, personalized, participatory medicine and helps understand how, why, when, and what ARDs one can develop depending on their genetic background. Within this mainstream paradigm, we wanted to find out whether the known ARD-linked DEGs available in PubMed can reveal a molecular marker that will serve the purpose in anyone's any tissue at any time. We sequenced the periaqueductal gray (PAG) transcriptome of tame versus aggressive rats, identified rat-behavior-related DEGs, and compared them with their known homologous animal ARD-linked DEGs. This analysis yielded statistically significant correlations between behavior-related and ARD-susceptibility-related fold changes (log2 values) in the expression of these DEG homologs. We found principal components, PC1 and PC2, corresponding to the half-sum and the half-difference of these log2 values, respectively. With the DEGs linked to ARD susceptibility and ARD resistance in humans used as controls, we verified these principal components. This yielded only one statistically significant common molecular marker for ARDs: an excess of Fcγ receptor IIb suppressing immune cell hyperactivation. [ABSTRACT FROM AUTHOR]

Background Previous research has suggested that individuals with Type 2 diabetes and initiated on metformin monotherapy present with a survival advantage compared with the general population without diabetes. This finding has generated considerable interest in the prophylactic use of metformin against age-related morbidity. Methods Utilizing Danish National Health Registers, we assessed differences in survival associated with metformin monotherapy for Type 2 diabetes compared with no diagnosis of diabetes in both singleton and discordant twin populations between 1996 and 2012. Data were analysed in both nested case–control and matched cohort study designs, with incidence rate ratios (IRRs) and hazard ratios estimated using conditional logistic regression and Cox proportional hazards regression, respectively. Results In case–control pairs matched on birth year and sex or co-twin (sex, birth year and familial factors), incident Type 2 diabetes with treatment by metformin monotherapy initiation compared with no diagnosis of diabetes was associated with increased mortality in both singletons (IRR = 1.52, 95% CI: 1.37, 1.68) and discordant twin pairs (IRR = 1.90, 95% CI: 1.35, 2.67). After adjusting for co-morbidities and social indicators, these associations were attenuated to 1.32 (95% CI: 1.16, 1.50) and 1.64 (95% CI: 1.10, 2.46), respectively. Increased mortality was observed across all levels of cumulative use and invariant to a range of study designs and sensitivity analyses. Conclusions Treatment initiation by metformin monotherapy in Type 2 diabetes was not associated with survival equal or superior to that of the general population without diabetes. Our contrasting findings compared with previous research are unlikely to be the result of differences in epidemiological or methodological parameters. [ABSTRACT FROM AUTHOR]