Trioxidized cysteine and aging: a molecular binomial that extends far beyond classical proteinopathic paradigms.

Increased oxidative stress (OS) and the disruption of the equilibrium between the production of reactive oxygen species and antioxidants are key molecular features of unhealthy aging. OS results in the formation of oxidative posttranslational modifications (PTMs), some of which involve cysteine (Cys) residues in aging proteomes, and specifically, the formation of trioxidized Cys (t-Cys), which leads to permanent protein damage. Recent findings in rodents have uncovered that irregular regulation of t-Cys residues in the aging proteome disrupts homeostatic phosphorylation signaling, resulting in alterations to proteins that are analogous to those caused by phosphorylated serine (p-Ser) residues. This work contextualizes these significant findings and discusses the implications and molecular role(s) of t-Cys in the aging proteome. Furthermore, we present novel data, validating the increase of specific t-Cys sites associated with aging in a blood-related circulating human proteome. The scope and findings included here support the hypothesis that t-Cys residues may serve as important mechanistic and biological markers, warranting further exploration in the context of unhealthy aging and age-related major diseases.

Integrating transcriptomic and proteomic data for a comprehensive molecular perspective on the association between sarcopenia and osteoporosis.

BACKGROUND: Osteoporosis and sarcopenia are common age-related conditions characterized by the progressive loss of bone density and muscle mass, respectively. Their co-occurrence, often referred to as osteosarcopenia, presents significant challenges in elderly care due to increased fragility and functional impairment. Existing studies have identified shared pathological mechanisms between these conditions, including inflammation, hormonal imbalances, and metabolic dysregulation, but a comprehensive understanding of their molecular interplay remains incomplete. OBJECTIVE: This study aims to deepen our understanding of the molecular interactions between sarcopenia and osteoporosis through an integrated omics approach, revealing potential therapeutic targets and biomarkers. METHODS: Employing a combination of proteomics and transcriptomics analyses, this study analyzed bone and muscle tissue samples from patients diagnosed with osteoporosis and osteosarcopenia. Techniques included high-throughput sequencing and label-free proteomics, supported by advanced bioinformatics tools for data analysis and functional annotation of genes and proteins. RESULTS: The study found marked differences in gene and protein expressions between osteoporosis and osteosarcopenia tissues. Specifically, genes like PDIA5, TUBB1, and CYFIP2 in bone, along with MYH7 and NCAM1 in muscle, exhibited differential expression at both mRNA and protein levels. Pathway analyses revealed the significance of oxidative-reduction balance, cellular metabolism, and immune response in the progression of these conditions. Importantly, the study pinpointed osteoclast differentiation and NF-kappa B signaling pathways as critical in the molecular dynamics of osteosarcopenia, suggesting potential targets for therapy. CONCLUSIONS: This study utilized transcriptomics and proteomics to identify key genes and proteins impacting sarcopenia and osteoporosis, employing advanced network tools to delineate interaction networks and crucial signaling pathways. It highlighted genes like PDIA5 and TUBB1, consistently expressed in both analyses, involved in pathways such as osteoclast differentiation and cytokine interactions. These insights enhance understanding of the molecular interplay in bone and muscle degeneration with aging, suggesting directions for future research into therapeutic interventions and prevention strategies for age-related degenerative diseases.

Arachidonic acid in aging: New roles for old players.

BACKGROUND: Arachidonic acid (AA), one of the most ubiquitous polyunsaturated fatty acids (PUFAs), provides fluidity to mammalian cell membranes. It is derived from linoleic acid (LA) and can be transformed into various bioactive metabolites, including prostaglandins (PGs), thromboxanes (TXs), lipoxins (LXs), hydroxy-eicosatetraenoic acids (HETEs), leukotrienes (LTs), and epoxyeicosatrienoic acids (EETs), by different pathways. All these processes are involved in AA metabolism. Currently, in the context of an increasingly visible aging world population, several scholars have revealed the essential role of AA metabolism in osteoporosis, chronic obstructive pulmonary disease, and many other aging diseases. AIM OF REVIEW: Although there are some reviews describing the role of AA in some specific diseases, there seems to be no or little information on the role of AA metabolism in aging tissues or organs. This review scrutinizes and highlights the role of AA metabolism in aging and provides a new idea for strategies for treating aging-related diseases. KEY SCIENTIFIC CONCEPTS OF REVIEW: As a member of lipid metabolism, AA metabolism regulates the important lipids that interfere with the aging in several ways. We present a comprehensivereviewofthe role ofAA metabolism in aging, with the aim of relieving the extreme suffering of families and the heavy economic burden on society caused by age-related diseases. We also collected and summarized data on anti-aging therapies associated with AA metabolism, with the expectation of identifying a novel and efficient way to protect against aging.

The dual face of microglia (M1/M2) as a potential target in the protective effect of nutraceuticals against neurodegenerative diseases.

The pathophysiology of different neurodegenerative illnesses is significantly influenced by the polarization regulation of microglia and macrophages. Traditional classifications of macrophage phenotypes include the pro-inflammatory M1 and the anti-inflammatory M2 phenotypes. Numerous studies demonstrated dynamic non-coding RNA modifications, which are catalyzed by microglia-induced neuroinflammation. Different nutraceuticals focus on the polarization of M1/M2 phenotypes of microglia and macrophages, offering a potent defense against neurodegeneration. Caeminaxin A, curcumin, aromatic-turmerone, myricetin, aurantiamide, 3,6'-disinapoylsucrose, and resveratrol reduced M1 microglial inflammatory markers while increased M2 indicators in Alzheimer's disease. Amyloid beta-induced microglial M1 activation was suppressed by andrographolide, sulforaphane, triptolide, xanthoceraside, piperlongumine, and novel plant extracts which also prevented microglia-mediated necroptosis and apoptosis. Asarone, galangin, baicalein, and a-mangostin reduced oxidative stress and pro-inflammatory cytokines, such as interleukin (IL)-1, IL-6, and tumor necrosis factor-alpha in M1-activated microglia in Parkinson's disease. Additionally, myrcene, icariin, and tenuigenin prevented the nod-like receptor family pyrin domain-containing 3 inflammasome and microglial neurotoxicity, while a-cyperone, citronellol, nobiletin, and taurine prevented NADPH oxidase 2 and nuclear factor kappa B activation. Furthermore, other nutraceuticals like plantamajoside, swertiamarin, urolithin A, kurarinone, Daphne genkwa flower, and Boswellia serrata extracts showed promising neuroprotection in treating Parkinson's disease. In Huntington's disease, elderberry, curcumin, iresine celosia, Schisandra chinensis, gintonin, and pomiferin showed promising results against microglial activation and improved patient symptoms. Meanwhile, linolenic acid, resveratrol, Huperzia serrata, icariin, and baicalein protected against activated macrophages and microglia in experimental autoimmune encephalomyelitis and multiple sclerosis. Additionally, emodin, esters of gallic and rosmarinic acids, Agathisflavone, and sinomenine offered promising multiple sclerosis treatments. This review highlights the therapeutic potential of using nutraceuticals to treat neurodegenerative diseases involving microglial-related pathways.

Research progress of NLRP3 inflammasome and its inhibitors with aging diseases.

In recent years, a new target closely linked to a variety of diseases has appeared in the researchers' vision, which is the NLRP3 inflammasome. With the deepening of the study of NLRP3 inflammasome, it was found that it plays an extremely important role in a variety of physiological pathological processes, and NLRP3 inflammasome was also found to be associated with some age-related diseases. It is associated with the development of insulin resistance, Alzheimer's disease, Parkinson's, cardiovascular aging, hearing and vision loss. At present, the only clinical approach to the treatment of NLRP3 inflammasome-related diseases is to use anti-IL-1ß antibodies, but NLRP3-specific inhibitors may be better than the IL-1ß antibodies. This article reviews the relationship between NLRP3 inflammasome and aging diseases: summarizes some of the relevant experimental results reported in recent years, and introduces the biological signals or pathways closely related to the NLRP3 inflammasome in a variety of aging diseases, and also introduces some promising small molecule inhibitors of NLRP3 inflammasome for clinical treatment, such as: ZYIL1, DFV890 and OLT1177, they have excellent pharmacological effects and good pharmacokinetics.

Autophagy-related proteins: Potential diagnostic and prognostic biomarkers of aging-related diseases.

Autophagy plays a key role in cellular, tissue and organismal homeostasis and in the production of the energy load needed at critical times during development and in response to nutrient shortage. Autophagy is generally considered as a pro-survival mechanism, although its deregulation has been linked to non-apoptotic cell death. Autophagy efficiency declines with age, thus contributing to many different pathophysiological conditions, such as cancer, cardiomyopathy, diabetes, liver disease, autoimmune diseases, infections, and neurodegeneration. Accordingly, it has been proposed that the maintenance of a proper autophagic activity contributes to the extension of the lifespan in different organisms. A better understanding of the interplay between autophagy and risk of age-related pathologies is important to propose nutritional and life-style habits favouring disease prevention as well as possible clinical applications aimed at promoting long-term health.

Transcription Factor Nrf2 and Mitochondria - Friends or Foes in the Regulation of Aging Rate.

At the first sight, the transcription factor Nrf2 as a master regulator of cellular antioxidant systems, and mitochondria as the main source of reactive oxygen species (ROS), should play the opposite roles in determining the pace of aging. However, since the causes of aging cannot be confined to the oxidative stress, the role of Nrf2 role cannot be limited to the regulation of antioxidant systems, and moreover, the role of mitochondria is not confined to the ROS production. In this review, we discussed only one aspect of this problem, namely, the molecular mechanisms of interaction between Nrf2 and mitochondria that influence the rate of aging and the lifespan. Experimental data accumulated so far show that the Nrf2 activity positively affects both the mitochondrial dynamics and mitochondrial quality control. Nrf2 influences the mitochondrial function through various mechanisms, e.g., regulation of nuclear genome-encoded mitochondrial proteins and changes in the balance of ROS or other metabolites that affect the functioning of mitochondria. In turn, multiple regulatory proteins functionally associated with the mitochondria affect the Nrf2 activity and even form mutual regulatory loops with Nrf2. We believe that these loops enable the fine-tuning of the cellular redox balance and, possibly, of the cellular metabolism as a whole. It has been commonly accepted for a long time that all mitochondrial regulatory signals are mediated by the nuclear genome-encoded proteins, whereas the mitochondrial genome encodes only a few respiratory chain proteins and two ribosomal RNAs. Relatively recently, mtDNA-encoded signal peptides have been discovered. In this review, we discuss the data on their interactions with the nuclear regulatory systems, first of all, Nrf2, and their possible involvement in the regulation of the aging rate. The interactions between regulatory cascades that link the programs ensuring the maintenance of cellular homeostasis and cellular responses to the oxidative stress are a significant part of both aging and anti-aging programs. Therefore, understanding these interactions will be of great help in searching for the molecular targets to counteract aging-associated diseases and aging itself.

Functional heterogeneity of mesenchymal stem cells from natural niches to culture conditions: implications for further clinical uses.

Mesenchymal stem cells (MSC) are present in all organs and tissues. Several studies have shown the therapeutic potential effect of MSC or their derived products. However, the functional heterogeneity of MSC constitutes an important barrier for transferring these capabilities to the clinic. MSC heterogeneity depends on their origin (biological niche) or the conditions of potential donors (age, diseases or unknown factors). It is accepted that many culture conditions of the artificial niche to which they are subjected, such as O2 tension, substrate and extracellular matrix cues, inflammatory stimuli or genetic manipulations can influence their resulting phenotype. Therefore, to attain a more personalized and precise medicine, a correct selection of MSC is mandatory, based on their functional potential, as well as the need to integrate all the existing information to achieve an optimal improvement of MSC features in the artificial niche.

Senile disease regulates aging-related secretion phenotype through cGAS-STING pathway / 中国药理学通报

Aging is one of the most important risk factors for human diseases such as cancer, cardiovascular diseases, diabetes and neurodegenerative diseases, and many aging diseases are related to cellular aging. Cells show profound phenotypic changes during aging, which are driven by changes in metabolism, chromatin organizationand transcriptional activity. A significant feature of aging is the secretion of inflammatory mediators, including various cytokines, chemokines, extracellular matrix proteins and growth factors, collectively known as the aging-related secreted phenotype (SASP). By secreting SASP, senescent cells have important effects on many biological processes, such as wound healing, tissue repair, tumor formation, or in vivo reorganization. In addition, the inflammatory response associated with SASP is considered to be the basis of aging-related diseases, and the discovery of new targets to control the response of aging effects is crucial. Recent scientific advances have shown that innate immune responses, particularly those involving the cGAS-STING pathway, trigger SASP. In this article, we review the biological function and regulatory mechanism of SASP through the cGAS-STING signaling pathway in aging diseases.

Mesenchymal Stem Cells in Homeostasis and Systemic Diseases: Hypothesis, Evidences, and Therapeutic Opportunities.

Mesenchymal stem cells (MSCs) are present in all organs and tissues, playing a well-known function in tissue regeneration. However, there is also evidence indicating a broader role of MSCs in tissue homeostasis. In vivo studies have shown MSC paracrine mechanisms displaying proliferative, immunoregulatory, anti-oxidative, or angiogenic activity. In addition, recent studies also demonstrate that depletion and/or dysfunction of MSCs are associated with several systemic diseases, such as lupus, diabetes, psoriasis, and rheumatoid arthritis, as well as with aging and frailty syndrome. In this review, we hypothesize about the role of MSCs as keepers of tissue homeostasis as well as modulators in a variety of inflammatory and degenerative systemic diseases. This scenario opens the possibility for the use of secretome-derived products from MSCs as new therapeutic agents in order to restore tissue homeostasis, instead of the classical paradigm "one disease, one drug".

Analysis on associated factors of elderly patients' stay in emergency department of a hospital in Shanghai / 上海交通大学学报（医学版）

Objective·To investigate the effect of population aging on health condition of Emergency Department (ED) visitors, the disease constitution of ED, the pressure of emergency treatment and the emergency department length of stay (EDLOS). Methods·Patient data from ED of a tertiary hospital in Shanghai from Jan. 2014 to Dec. 2016 were collected and retrospectively analyzed, including gender, age, arrival time, diagnosis, EDLOS, outcome, chronic disease, infection or tumor, etc. Statistics was used to determine possible factors associated with prolonged EDLOS. Results·A total of 15429 cases were selected. The number of the elderly patients (≥65 years old) was 8480 (54.96%). The elderly patients' EDLOS was significantly longer than patients younger than 65 years (P=0.000). The incidence of chronic aging diseases was significantly higher in elderly patients (67%) than in who were below 65 years old (52%). Tumor and infection were independent risk factors for EDLOS (P=0.000). The proportion of elderly patients with acute onset and unknown diseases was only 14%. Conclusion·The increasing proportion of elderly patients in ED is the main reason leading to the pressure of emergency treatment. The elderly patients who had chronic diseases prolong the EDLOS and cost the most medical resources of emergency treatment. So the gerontology should be rapidly expanding. Meanwhile, the complex chronic aging diseases, acute onset of chronic disease and varying severity of disease in the elderly patients should be treated by the new stepping mode "Family- Hospitalization-Emergency".

Analysis on associated factors of elderly patients' stay in emergency department of a hospital in Shanghai / 上海交通大学学报（医学版）

Objective·To investigate the effect of population aging on health condition of Emergency Department (ED) visitors, the disease constitution of ED, the pressure of emergency treatment and the emergency department length of stay (EDLOS). Methods·Patient data from ED of a tertiary hospital in Shanghai from Jan. 2014 to Dec. 2016 were collected and retrospectively analyzed, including gender, age, arrival time, diagnosis, EDLOS, outcome, chronic disease, infection or tumor, etc. Statistics was used to determine possible factors associated with prolonged EDLOS. Results·A total of 15429 cases were selected. The number of the elderly patients (≥65 years old) was 8480 (54.96%). The elderly patients' EDLOS was significantly longer than patients younger than 65 years (P=0.000). The incidence of chronic aging diseases was significantly higher in elderly patients (67%) than in who were below 65 years old (52%). Tumor and infection were independent risk factors for EDLOS (P=0.000). The proportion of elderly patients with acute onset and unknown diseases was only 14%. Conclusion·The increasing proportion of elderly patients in ED is the main reason leading to the pressure of emergency treatment. The elderly patients who had chronic diseases prolong the EDLOS and cost the most medical resources of emergency treatment. So the gerontology should be rapidly expanding. Meanwhile, the complex chronic aging diseases, acute onset of chronic disease and varying severity of disease in the elderly patients should be treated by the new stepping mode "Family- Hospitalization-Emergency".

From cellular to chemical approach for acute neural and alternative options for age-induced functional diseases.

Endogenous "stem cell niche" (SCN) accompanying vessels contains immune system components which in vivo determine differentiation of multi potent stem cells toward proper cell types in given tissue. Combinations of sex steroids may represent novel chemical approach for neuronal areas of regenerative medicine, since they cause transformation of vascular smooth muscle stem cells into differentiating neuronal cells. Circulating sex steroids are present during pregnancy and can be utilized where needed, when various embryonic/fetal tissues develop from their stem cells. Utilization of induced regeneration of tissues (regenerative medicine) is expected being more effective in sudden failures of younger individuals carrying intact SCN, as compared to established chronic disorders caused by SCN alteration. An essential component of SCN are monocyte-derived cells exhibiting tissue-specific "stop effect" (SE) preventing, for instance, an aging of neuronal cells. Its alteration causes that implantation of neuronal stem cells will also result in their differentiation toward aging cells. When we repair the SE by supply of circulating mononuclear cells from young healthy individuals, we may be able to provide novel regenerative treatments of age-induced neural diseases by sex steroid combinations. Questions regarding some age-induced body alterations are also addressed.

Nuclear matrix, nuclear envelope and premature aging syndromes in a translational research perspective.

Lamin A-related progeroid syndromes are genetically determined, extremely rare and severe. In the past ten years, our knowledge and perspectives for these diseases has widely progressed, through the progressive dissection of their pathophysiological mechanisms leading to precocious and accelerated aging, from the genes mutations discovery until therapeutic trials in affected children. A-type lamins are major actors in several structural and functional activities at the nuclear periphery, as they are major components of the nuclear lamina. However, while this is usually poorly considered, they also play a key role within the rest of the nucleoplasm, whose defects are related to cell senescence. Although nuclear shape and nuclear envelope deformities are obvious and visible events, nuclear matrix disorganization and abnormal composition certainly represent the most important causes of cell defects with dramatic pathological consequences. Therefore, lamin-associated diseases should be better referred as laminopathies instead of envelopathies, this later being too restrictive, considering neither the key structural and functional roles of soluble lamins in the entire nucleoplasm, nor the nuclear matrix contribution to the pathophysiology of lamin-associated disorders and in particular in defective lamin A processing-associated aging diseases. Based on both our understanding of pathophysiological mechanisms and the biological and clinical consequences of progeria and related diseases, therapeutic trials have been conducted in patients and were terminated less than 10 years after the gene discovery, a quite fast issue for a genetic disease. Pharmacological drugs have been repurposed and used to decrease the toxicity of the accumulated, unprocessed and truncated prelaminA in progeria. To date, none of them may be considered as a cure for progeria and these clinical strategies were essentially designed toward reducing a subset of the most dramatic and morbid features associated to progeria. New therapeutic strategies under study, in particular targeting the protein expression pathway at the mRNA level, have shown a remarkable efficacy both in vitro in cells and in vivo in mice models. Strategies intending to clear the toxic accumulated proteins from the nucleus are also under evaluation. However, although exceedingly rare, improving our knowledge of genetic progeroid syndromes and searching for innovative and efficient therapies in these syndromes is of paramount importance as, even before they can be used to save lives, they may significantly (i) expand the affected childrens' lifespan and preserve their quality of life; (ii) improve our understanding of aging-related disorders and other more common diseases; and (iii) expand our fundamental knowledge of physiological aging and its links with major physiological processes such as those involved in oncogenesis.