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Rationale: Sepsis is a life-threatening, dysregulated response to infection. Lipid biomarkers including cholesterol are dynamically regulated during sepsis and predict short-term outcomes. In this study, we investigated the predictive ability of lipid biomarkers for physical function and long-term mortality after sepsis. Methods: Prospective cohort study of sepsis patients admitted to a surgical intensive-care unit (ICU) within 24 h of sepsis bundle initiation. Samples were obtained at enrollment for lipid biomarkers. Multivariate regression models determined independent risk factors predictive of poor performance status (Zubrod score of 3/4/5) or survival at 1-year follow-up. Measurements and main results: The study included 104 patients with surgical sepsis. Enrollment total cholesterol and high-density lipoprotein (HDL-C) levels were lower, and myeloperoxidase (MPO) levels were higher for patients with poor performance status at 1 year. A similar trend was seen in comparisons based on 1-year mortality, with HDL-C and ApoA-I levels being lower and MPO levels being higher in non-survivors. However, multivariable logistic regression only identified baseline Zubrod and initial SOFA score as significant independent predictors of poor performance status at 1 year. Multivariable Cox regression modeling for 1-year survival identified high Charlson comorbidity score, low ApoA-I levels, and longer vasopressor duration as predictors of mortality over 1-year post-sepsis. Conclusions: In this surgical sepsis study, lipoproteins were not found to predict poor performance status at 1 year. ApoA-I levels, Charlson comorbidity scores, and duration of vasopressor use predicted 1 year survival. These data implicate cholesterol and lipoproteins as contributors to the underlying pathobiology of sepsis. [ABSTRACT FROM AUTHOR]

Aging and diseases such as cancer, peripheral artery disease (PAD) are associated with skeletal muscle inflammation, oxidative stress, increased senescense, altered muscle metabolism; and mitochondrial dysfunction [1-3]. Many of the biological changes in calf skeletal muscle have been associated with functional impairment and mobility loss [2]. We will discuss several recent studies which show that specific genes, miRNA, and biological pathways in skeletal muscle are tightly associated with functional performance in aging and clinical progression of PAD [3-6]. We found damage in the genes encoding polypeptides for the electron transport chain (ETC) in skeletal muscle was associated with walking performance in people with and without PAD [5]. We also found marked changes in cellular pathways in subjects with peripheral artery disease progression in specific genes and pathways involve in cellular senescense, inflammation and muscle contraction. Identifying what biological pathways are specifically associated with impaired skeletal muscle function may lead to new effective strategies that can reverse muscle dysfunction and in turn, can improve mobility. [ABSTRACT FROM AUTHOR]

Controversy exists as to whether lifelong 40% calorie restriction (CR) enhances, has no effect on, or disrupts cognitive function during aging. Here, we report the effects of CR versus ad-lib feeding on cognitive function in male Brown Norway x Fisher344 rats across a range of ages (8-38 months), using two tasks that are differentially sensitive to age-related cognitive decline: object recognition and Morris water maze (MWM). All ages performed equally in object recognition, whereas, as a group, CR rats were impaired. In contrast, there was an age-related impairment in the MWM that was attenuated by CR as measured by time in proximity with and latency to reach the platform. Distance to the platform, a more sensitive measure, was not affected by CR. Finally, CR resulted in an overall increase in physical activity, one of several behavioral confounders to consider in the interpretation of cognitive outcomes in both tasks. [ABSTRACT FROM AUTHOR]

Studies show that the plant polyphenol resveratrol can extend the life span of yeast, worms, flies, and fish. It also mitigates the metabolic dysfunction of mice fed high-fat diets. Resveratrol appears to mediate these effects partly by activating SIRT1, a deacetylase enzyme that regulates the activity of several transcriptional factors and enzymes responsive to nutrient availability. However, few foods contain resveratrol and humans metabolize it extensively, resulting in very low systemic bioavailability. Substantial research effort now focuses on identifying and testing more bioavailable and potent activators of SIRT1 for use as pharmacologic interventions in aging and age-related disorders. [ABSTRACT FROM AUTHOR]

Abstract: Aging is associated with a progressive loss of skeletal muscle mass and strength and the mechanisms mediating these effects likely involve mitochondrial DNA (mtDNA) mutations, mitochondrial dysfunction and the activation of mitochondrial-mediated apoptosis. Because the mitochondrial genome is densely packed and close to the main generator of reactive oxygen species (ROS) in the cell, the electron transport chain (ETC), an important role for mtDNA mutations in aging has been proposed. Point mutations and deletions in mtDNA accumulate with age in a wide variety of tissues in mammals, including humans, and often coincide with significant tissue dysfunction. Here, we examine the evidence supporting a causative role for mtDNA mutations in aging and sarcopenia. We review experimental outcomes showing that mtDNA mutations, leading to mitochondrial dysfunction and possibly apoptosis, are causal to the process of sarcopenia. Moreover, we critically discuss and dispute an important part of the mitochondrial ‘vicious cycle’ theory of aging which proposes that accumulation of mtDNA mutations may lead to an enhanced mitochondrial ROS production and ever increasing oxidative stress which ultimately leads to tissue deterioration and aging. Potential mechanism(s) by which mtDNA mutations may mediate their pathological consequences in skeletal muscle are also discussed. [Copyright &y& Elsevier]

Mitochondria have been a central focus of several theories of aging as a result of their critical role in bioenergetics, oxidant production, and regulation of cell death. A decline in cardiac mitochondrial function coupled with the accumulation of oxidative damage to macromolecules may be causal to the decline in cardiac performance with age. In contrast, regular physical activity and lifelong caloric restriction can prevent oxidative stress, delay the onset of morbidity, increase life span, and reduce the risk of developing several pathological conditions. The health benefits of life long exercise and caloric restriction may be, at least partially, due to a reduction in the chronic amount of mitochondrial oxidant production. In addition, the available data suggest that chronic exercise may serve to enhance antioxidant enzyme activities, and augment certain repair/removal pathways, thereby reducing the amount of oxidative tissue damage. However, the characterization of age-related changes to cardiac mitochondria has been complicated by the fact that two distinct populations of mitochondria exist in the myocardium: subsarcolemmal mitochondria and interfibrillar mitochondria. Several studies now suggest the importance of studying both mitochondrial populations when attempting to elucidate the contribution of mitochondrial dysfunction to myocardial aging. The role that mitochondrial dysfunction and oxidative Stress play in contributing to cardiac aging will be discussed along with the use of lifelong exercise and calorie restriction as countermeasures to aging. [ABSTRACT FROM AUTHOR]

Abstract: The loss of muscle mass and strength with aging, also referred to as sarcopenia of aging, is a highly prevalent condition among older adults and predicts several adverse outcomes, including disability, institutionalization and mortality. Although the exact mechanisms underlying sarcopenia are far to be unveiled, accumulating preclinical evidence suggests that an age-related acceleration of myocytes loss via apoptosis might represent a key mechanism driving the onset and progression of muscle loss. Furthermore, increased levels of apoptosis have also been reported in old rats undergoing acute muscle atrophy subsequent to muscle unloading, a condition that mimics the muscle loss observed during prolonged bed rest. Notably, preliminary evidence seems to confirm a causative role for apoptosis in age-related muscle loss in human subjects. Several signaling pathways of skeletal muscle apoptosis are currently under intense investigation, with a particular focus on the role played by mitochondria. Here, we will review the most recent evidence regarding various pathways of muscle apoptosis and their modulation by several interventions (caloric restriction, physical exercise, muscle unloading). [Copyright &y& Elsevier]

Abstract: Past the age of 50 years, aging individuals lose muscle mass at an approximate rate of 1–2% per year. This age-related muscle atrophy, termed sarcopenia, can have significant effects on individual health and quality of life and can also impact the socioeconomic status. Sarcopenia is due to both a decrease in the number of fibers and the atrophy of the remaining fibers. The mechanisms causing loss of fibers have not been clearly defined, but may likely involve apoptosis. Elevated levels of circulating tumor necrosis factor α (TNF-α) and adaptations in TNF-α signaling in aged skeletal muscle may be contributing factors for the activation of apoptosis. These adaptations may be fiber-type specific, which could explain the selective loss of type II fibers, vs. type I fibers, in the aging process. Caloric restriction, a proven antiaging intervention, is known to attenuate the loss of muscle mass and function with age. Furthermore, caloric restriction has been shown to attenuate the age-associated adaptations in TNF-α signaling in skeletal muscle, which may be a possible mechanism by which CR prevents apoptosis and the loss of muscle fibers with age. The potential role of TNF-α in the progression of sarcopenia will be discussed, as well as the effects of life-long caloric restriction on TNF-α signaling. [Copyright &y& Elsevier]

Muscle atrophy is associated with a loss of muscle fiber nuclei, most likely through apoptosis. We investigated age-related differences in the extent of apoptosis in soleus muscle of young (6 mo) and old (32 mo) male Fischer 344 × Brown Norway rats subjected to acute disuse atrophy induced by 14 days of hindlimb suspension (HS). HS-induced atrophy (reduction in muscle weight and cross-sectional area) was associated with loss of myofiber nuclei in soleus muscle of young, but not old, rats. This resulted in a significant decrease in the myonuclear domain (cross-sectional area per nucleus) in young and old rats, with changes being more pronounced in old animals. Levels of apoptosis (TdT-mediated dUTP nick end labeling and DNA fragmentation) were higher in soleus muscles of old control rats than young animals. Levels were significantly increased with HS in young and old rats, with the greatest changes in old animals. Caspase-3 activity in soleus muscle tended to be increased with age, but changes were not statistically significant (P = 0.052). However, with HS, caspase-3 activity significantly increased in young, but not old, rats. Immunohistochemistry showed that the proapoptotic endonuclease G (EndoG, a mitochondrion-specific nuclease) was localized in the subsarcolemmal mitochondria in control muscles, and translocation to the nucleus occurred in old, but not young, control animals. There was no difference between EndoG total protein content in young and old control rats, but EndoG increased almost fivefold in soleus muscle of old, but not young, rats after HS. These results show that deregulation of myonuclear number occurs in old skeletal muscle and that the pathways involved in apoptosis are distinct in young and old muscles. Apoptosis in skeletal muscle is partly mediated by the subsarcolemmal mitochondria through EndoG translocation to the nucleus in response to HS. [ABSTRACT FROM AUTHOR]

Skeletal myocyte atrophy and death contribute to sarcopenia, a condition associated with normal aging. By 80 years of age, it is estimated that humans generally lose 30–40% of skeletal muscle fibres. The mechanism for this loss is unknown; however, it may involve apoptosis. Mitochondrial dysfunction and sarcoplasmic reticulum (SR) stress that occurs with age may be possible stimuli inducing apoptosis. Hence, mitochondria and SR may be important organelles within skeletal myocytes responsible for apoptosis signalling. The activation of apoptosis may be partly responsible for the initiation of muscle protein degradation, loss of muscle nuclei associated with local atrophy, and cell death of the myocyte. Exercise training and caloric restriction are two interventions known to enhance skeletal muscle function. The effects of these interventions on apoptosis are discussed. [ABSTRACT FROM AUTHOR]

The mechanisms of apoptosis in the loss of myocytes in skeletal muscle with age and the role of mitochondrial and sarcoplasmic reticulum-mediated pathways of apoptosis are unknown. Moreover, it is unknown whether lifelong calorie restriction prevents apoptosis in skeletal muscle and reverses age-related alterations in apoptosis signaling. We investigated key apoptotic regulatory proteins in the gastrocnemius muscle of 12 and 26 month old ad libitum fed and 26 month old calorie-restricted male Fischer-344 rats. We found that apoptosis increased with age and that calorie-restricted rats showed less apoptosis compared with their age-matched cohorts. Moreover, pro- and cleaved caspase-3 levels increased significantly with age and calorie-restricted rats had significantly lower levels than the aged ad libitum group. Neither age nor calorie restriction had any effect on muscle caspase-3 enzyme activity, but the levels of X-linked inhibitor of apoptosis, particularly an inhibitor of caspase-3, increased with age and were reduced significantly in the 26 month old calorie-restricted cohort. The apoptotic inhibitor apoptosis repressor with a caspase recruitment domain (ARC), which inhibits cytochrome c release, underwent an age-associated decline in the cytosol but increased with calorie restriction. In contrast, mitochondrial ARC levels increased with age and were lower in calorie-restricted rats than in age-matched controls, suggesting a translocation of this protein to attenuate oxidative stress. The translocation of ARC may explain the reduction in cytosolic cytochrome c levels observed with age and calorie restriction. Moreover, we found a striking ∼350% increase in the expression of procaspase-12 (caspase located at the sarcoplasmic reticulum) with age which was significantly lower in the 26 month old calorie-restricted group. The total protein level of apoptosis-inducing factor in the plantaris muscle increased with age and was reduced calorie-restricted rats compared with age-matched controls, but there were no significant changes in this pro-apoptotic protein in the isolated nuclei. Calorie restriction is able to lower the apoptotic potential in aged skeletal muscle by altering several key apoptotic proteins toward cellular survival, thereby reducing the potential for sarcopenia. [Copyright &y& Elsevier]

The production of ATP is vital for muscle contraction, chemiosmotic homeostasis, and normal cellular function. Many studies have measured ATP content or qualitative changes in ATP production, but few have quantified ATP production in vivo in isolated mitochondria. Because of the importance of understanding the energy capacity of mitochondria in biology, physiology, cellular dysfunction, and ultimately, disease pathologies and normal aging, we modified a commercially available bioluminescent ATP determination assay for quantitatively measuring ATP content and rate of ATP production in isolated mitochondria. The bioluminescence assay is based on the reaction of ATP with recombinant firefly luciferase and its substrate luciferin. The stabilities of the reaction mixture as well as relevant ATP standards were quantified. The luminescent signals of the reaction mixture and a 0.5 µM ATP standard decreased linearly at rates of 2.16 and 1.39% decay/min, respectively. For a 25 µM ATP standard, the luminescent signal underwent a logarithmic decay, due to intrinsic deviations from the Beer-Lambert law. Moreover, to test the functionality of isolated mitochondria, they were incubated with 1 and 5 mM oligomycin, an inhibitor of oxidative phosphorylation. The rate of ATP production in the mitochondria declined by 34 and 83%, respectively. Due to the sensitivity and stability of the assay and methodology, we were able to quantitatively measure in vivo the effects of age and caloric restriction on the ATP content and production in isolated mitochondria from the brain and liver of young and old Fischer-344 rats. In both tissues, neither age nor caloric restriction had any significant effect on the ATP content or the rate of ATP production. This study introduces a highly sensitive, reproducible, and quick methodology for measuring ATP in isolated mitochondria. [ABSTRACT FROM AUTHOR]

Generation of reactive oxygen species and mitochondrial dysfunction has been implicated in doxorubicin-induced cardiotoxicity. This study examined pro-apoptotic mitochondrial cell death signals in an H9C2 myocyte rat cell line and in isolated rat heart mitochondria exposed to doxorubicin. Mitochondrial and cellular viability were assessed using an MTT viability assay (formazan product formed by functional mitochondrial dehydrogenases) and calcein AM dye (fluoresces upon cleavage by cytosolic esterases). Mitochondrial dysfunction followed by cell death was observed using nM concentrations of doxorubicin. Significant doxorubicin-induced cell death was not apparent until after 6 h following doxorubicin exposure using the calcein AM assay. The involvement of apoptosis is evidenced by an increase in TUNEL (terminal (TdT)-mediated dUTP-biotin nick end labeling)-positive nuclei following doxorubicin treatment. Furthermore, doxorubicin administered to isolated mitochondria induced a rapid increase in superoxide production, which persisted for at least 1 h and was followed by increased cytochrome c efflux. In addition, caspase-3 activity was increased with doxorubicin administration in the H9C2 myocyte cell line. An oxidant-mediated threshold of mitochondrial death may be required for doxorubicin-induced apoptosis. [Copyright &y& Elsevier]

Investigates age-related alterations in the mitochondria-mediated pathway leading to apoptosis in the gastrocnemius muscle from six-month-old and 24-month-old rats. Discussion of the changes in aging skeletal muscle; Correlation between caspase-3 activity and apoptosis in old rats; Limitation the activation of caspase cascade.

Examines the role that mitochondria may play in influencing the apoptic process in vivo in the aging heart. Definition of aging and apoptosis; Measurement of isolated cardiac mitochondria and cytosol to determine whether or not the level of apoptosis changes with age; Release of cytochrome c release from the mitochondria and its use in determining the increase in apoptosis in the aging heart.

Apoptosis research is a rapidly developing area, but the role of apoptosis is still unclear and controversial. For example, several studies document a significant loss of cardiac and skeletal myocytes during normal aging, possibly by apoptotic mechanisms. This loss in cells may be directly mediated by mitochondrial dysfunction caused by chronic exposure to oxidants and increased activation of mitochondrial permeability transition pores. This review will discuss apoptosis in the context of normal aging of T cells, cardiac myocytes, skeletal muscle, and brain cortex. Particular attention is paid to the role of the mitochondria, because they have been implicated as a major control center regulating apoptosis. Mitochondrial oxidative stress and a decline in mitochondrial energy production in vitro often leads to activation of apoptotic pathways, but whether this occurs in vivo is unclear. [ABSTRACT FROM AUTHOR]

The article discusses a study by M. Chondronikola et al on the effect of prolonged cold-induced BAT activation on whole-body glucose homeostasis and insulin sensitivity involving 7 middle aged, overweight men. Topicis discussed include the study's use of an individualized and prolonged CE protocol that characterized changes induced by maximal nonshivering brown adipose tissue (BAT) thermogenesis and findings that BAT can be exploited for improving systemic glucose homeostasis.

In addition to their well-characterized roles in metabolism, lipids and lipoproteins have pleiotropic effects on the innate immune system. These undergo clinically relevant alterations during sepsis and acute inflammatory responses. High-density lipoprotein (HDL) plays an important role in regulating the immune response by clearing bacterial toxins, supporting corticosteroid release, decreasing platelet aggregation, inhibiting endothelial cell apoptosis, reducing the monocyte inflammatory response, and inhibiting expression of endothelial cell adhesion molecules. It undergoes quantitative as well as qualitative changes which can be measured using the HDL inflammatory index (HII). Pro-inflammatory, or dysfunctional HDL (dysHDL) lacks the ability to perform these functions, and we have also found it to independently predict adverse outcomes and organ failure in sepsis. Another important class of lipids known as specialized pro-resolving mediators (SPMs) positively affect the escalation and resolution of inflammation in a temporal fashion. These undergo phenotypic changes in sepsis and differ significantly between survivors and non-survivors. Certain subsets of sepsis survivors go on to have perilous post-hospitalization courses where this inflammation continues in a low grade fashion. This is associated with immunosuppression in a syndrome of persistent inflammation, immunosuppression, and catabolism syndrome (PICS). The continuous release of tissue damage-related patterns and viral reactivation secondary to immunosuppression feed this chronic cycle of inflammation. Animal data indicate that dysregulation of endogenous lipids and SPMs play important roles in this process. Lipids and their associated pathways have been the target of many clinical trials in recent years which have not shown mortality benefit. These results are limited by patient heterogeneity and poor animal models. Considerations of sepsis phenotypes and novel biomarkers in future trials are important factors to be considered in future research. Further characterization of lipid dysregulation and chronic inflammation during sepsis will aid mortality risk stratification, detection of sepsis, and inform individualized pharmacologic therapies. [ABSTRACT FROM AUTHOR]

Offers a look on a study which investigated the amino acids in the urine of aging rats that assaying could provide a noninvasive way to determine levels of protein oxidation in vivo. Experimental procedures; Effect of antioxidant therapy on o,o'-dityrosine in skeletal muscle; Effects of exercise on antioxidant enzymes in skeletal muscle.

Investigates the possibility that oxidized amino acids in urine may serve as potential markers for assessment of oxidative stress. Role of oxidants in human disease; Interventions for skeletal muscle and urine aging; Application of antioxidant therapy to reduce levels of protein-bound o,o'-dityrosine in skeletal muscle.

The present study examined the effect of glutathione (GSH) and glutathione ethyl ester (GSH-E) supplementation on GSH homeostasis and exercise-induced oxidative stress. Male Swiss-Webster mice were randomly divided into 4 groups: starved for 24 h and injected with GSH or GSH-E (6 mmol/kg body wt, i.p.) 1 h before exercise, starved for 24 h and injected with saline (S); and having free access to food and injected with saline (C). Half of each group of mice was killed either after an acute bout of exhaustive swimming (E) or after rest (R). Plasma GSH concentration was 100-160% (P < 0.05) higher in GSH mice vs. C or S mice at rest, whereas GSH-E injection had no effect. Plasma GSH was not affected by exercise in C or S mice, but was 44 and 34% lower (P < 0.05) in E vs. R mice with GSH or GSH-E injection, respectively. S, GSH- and GSH-E-treated mice had significantly lower liver GSH concentration and the GSH:glutathione disulfide (GSSG) ratio than C mice. Hepatic and renal GSH and the GSH:GSSG ratio were significantly lower in E vs. R mice in all groups. GSH-E-treated mice had a significantly smaller exercise-induced decrease in GSH vs. C, S, and GSH-treated mice and no difference in the GSH:GSSG ratio in the kidney. Activities of gamma-glutamylcysteine synthetase and gamma-glutamyltranspeptidase in the liver and kidney were not affected by either GSH treatment or exercise. GSH concentration and the GSH:GSSG ratio in quadriceps muscle were not different among C, S and GSH-treated mice, but significantly lower in GSH-E-treated mice (P < 0.05). Hepatic malondialdehyde (MDA) content was greater in exercised mice in all but GSH-E-treated groups. GSH and GSH-E increased MDA levels in the kidney of E vs. R mice, but attenuated exercise-induced lipid peroxidation in muscle. Swim endurance time was approximately 2 h longer in GSH (351 +/- 22 min) and GSH-E (348 +/- 27) than S mice (237 +/- 17). We conclude that 1) acute GSH and GSH-E supplementation at the given doses does not increase tissue GSH content or redox status; 2) both GSH and GSH-E improve endurance performance and prevent muscle lipid peroxidation during prolonged exercise; and 3) while both compounds may impose a metabolic and oxidative stress to the kidney, this side effect is smaller with GSH-E supplementation. [ABSTRACT FROM AUTHOR]

Describes markers of protein oxidation and hydroxyl radical and reactive nitrogen species in tissues of aging rats. Evidences of oxidative damage of cellular constituents in aging; Effect of reactive oxygen intermediates to nucleic acid, lipids and fats.

Investigates the adaptations of the glutathione antioxidant system to endurance training in the skeletal muscle, heart and liver of female Sprague-Dawley rats. Development of tissue- and muscle fiber-specific adaptation of antioxidant systems; Determination of glutathione homeostasis by use and uptake of glutathione through the gamma-glutamyl cycle.

Presents information pertaining to the markers of protein oxidation through hydroxyl radical and reactive nitrogen species in tissues of aging rats. What many lines of evidence implicate; Suggestions of results; Measurement of the markers in young adult and old rats; Indication of observations.

Compromised autophagy fails at recycling obsolete cell components and contributes to the accumulation of intracellular protein aggregates, damaged mitochondria, and lipofuscin deposits. Conversely, an age-associated increase in the protein expression of the autophagy inhibitor Rubicon was observed in postmortem brains and human-induced pluripotent stem cells of people with Alzheimer's disease (AD), as well as in transgenic mice and neuroblastoma cells [[15]]. 34440632 7 Warnsmann V., Marschall L.M., Osiewacz H.D. Impaired F1 Fo-ATP-synthase dimerization leads to the induction of cyclophilin d-mediated autophagy-dependent cell death and accelerated aging. [Extracted from the article]

Abstract: Aging is associated with a host of biological changes that contribute to a progressive decline in cognitive and physical function, ultimately leading to a loss of independence, and increased risk of mortality. To date, prolonged caloric restriction (i.e., a reduction in caloric intake without malnutrition) is the only non-genetic intervention that has consistently been found to extend both mean and maximal life span across a variety of species. Most individuals have difficulty sustaining prolonged caloric restriction, which has led to a search for alternative approaches that can produce similar to benefits as caloric restriction. A growing body of evidence indicates that fasting periods and intermittent fasting regimens in particular can trigger similar biological pathways as caloric restriction. For this reason, there is increasing scientific interest in further exploring the biological and metabolic effects of intermittent fasting periods, as well as whether long-term compliance may be improved by this type of dietary approach. This special will highlight the latest scientific findings related to the effects of both caloric restriction and intermittent fasting across various species including yeast, fruit flies, worms, rodents, primates, and humans. A specific emphasis is placed on translational research with findings from basic bench to bedside reviewed and practical clinical implications discussed. [Copyright &y& Elsevier]

An introduction is presented in which the author discusses various reports within the issue on topics including aging, mitochondria and myoblasts.

Presents a study on the effects of aging and life-long calorie restriction on tumor necrosis factor-α (TNF-α) signaling and skeletal muscle atrophy in a type I and type II muscle. Catabolic cytokine found to increase with age and with the ability to signal cell survival and cell death; Manner in which the TNF-α signaling pathways were demonstrated; Type of muscle in which the evidence of DNA fragmentation was apparent.

Skeletal muscle atrophy and the loss of myofibers contribute to sarcopenia, a condition associated with normal aging. However, relatively little is known regarding the relevance of apoptosis to skeletal muscle homeostasis and the possible mechanisms involved, although evidence suggests that apoptosis may play a role during muscle aging. By age 80 it is estimated that humans generally lose 30%-40% of skeletal muscle fibers, particularly from muscles containing type II fibers such as the vastus lateralis muscle. Studies using rodents show that between a 20%-50% loss in muscle fibers occurs depending on the specific fiber type studied. Caspases (cysteine-dependent, aspartate-specific proteases) such as caspase-3 play an important role in mediating cell death in that many of the apoptotic signaling pathways, such as the mitochondrial-mediated, receptor-mediated, and sarcoplasmic-reticulum-mediated pathways, converge at caspase-3 in the caspase cascade. Studies show that with age the levels of several caspases are significantly increased. Therefore, the activation of these proteolytic caspases may be partly responsible for the initiation of muscle protein degradation, loss of muscle nuclei, which is associated with local atrophy, and finally into cell death of the myocyte. [ABSTRACT FROM AUTHOR]

Studies in mice and cross-sectional studies in humans support the premise that cellular senescence is a contributing mechanism to age-associated deficits in physical function. We tested the hypotheses that circulating proteins secreted by senescent cells are (i) associated with the incidence of major mobility disability (MMD), the development of persistent mobility disability (PMMD), and decrements in physical functioning in older adults, and (ii) influenced by physical activity (PA). Using samples and data obtained longitudinally from the Lifestyle Interventions in Elders Study clinical trial, we measured a panel of 27 proteins secreted by senescent cells. Among 1 377 women and men randomized to either a structured PA intervention or a healthy aging (HA) intervention, we observed significant associations between several senescence biomarkers, most distinctly vascular endothelial growth factor A (VEGFA), tumor necrosis factor receptor 1 (TNFR1), and matrix metallopeptidase 7 (MMP7), and the onset of both MMD and PMMD. Moreover, VEGFA, GDF15, osteopontin, and other senescence biomarkers were associated with reductions in short physical performance battery scores. The change in senescence biomarkers did not differ between PA and HA participants. In the whole cohort, higher levels of PA were associated with significantly greater reductions in 10 senescence-related proteins at 12 and/or 24 months. These data reinforce cellular senescence as a contributing mechanism of age-associated functional decline and the potential for PA to attenuate this hallmark of aging. Clinical Trials Registration Number: NCT01072500 [ABSTRACT FROM AUTHOR]

At the end of the 2023 Padua Days of Muscle and Mobility Medicine the next year's meeting was scheduled from 27 February to 2 March 2024 (2024Pdm3). During the summer and autumn the program was confirmed with Scientific Sessions that will take place over five days, starting in the afternoon of February 27, 2024 at the Conference Room of the Hotel Petrarca, Thermae of Euganean Hills (Padua), Italy. As usual, the next day will be spent in Padua, in this occasion at the San Luca Hall of the Santa Giustina monastery in Prato della Valle, Padua, Italy. Collected during Autumn 2023, many more titles and abstracts than expected were submitted, forcing the organization of parallel sessions both on March 1 and March 2 2024 confirming attractiveness of the 2024 Pdm3. The five days will include oral presentations of scientists and clinicians from Argentina, Austria, Belgium, Brazil, Canada, Denmark, Egypt, France, Germany, Iceland, Ireland, Italy, Romania, Russia, Slovenia, Switzerland, UK and USA. Together with the preliminary Program at December 1, 2023, the early submitted Abstracts is e-published in this Issue 33 (4) 2023 of the European Journal of Translational Myology (EJTM). You are invited to join, submitting your Last Minute Abstracts to ugo.carraro@unipd.it by February 1, 2024. Furthermore, with the more generous deadline of May 20, 2024, submit please “Communications” to the European Journal of Translational Myology (Clarivate’s ESCI Impact factor 2.2; SCOPUS Cite Score: 3.2). See you soon at the Hotel Petrarca in Montegrotto Terme, Padua, on February 27, 2024, but the complete program can be followed from home via zoom connection. [ABSTRACT FROM AUTHOR]

This document discusses the association between hospitalizations and the response to exercise interventions in individuals with peripheral artery disease (PAD). The study combines data from two randomized clinical trials of home-based walking exercise for PAD patients. The results show that hospitalizations were common among participants, and those who were hospitalized during the exercise intervention had significantly less improvement in their walking performance compared to those who were not hospitalized. The study suggests the need for targeted interventions to help PAD patients maximize the benefits of exercise after a hospitalization. [Extracted from the article]

Objective: High density lipoprotein (HDL) is important for defense against sepsis but becomes dysfunctional (Dys-HDL) during inflammation. We hypothesize that Dys-HDL correlates with organ dysfunction (sequential organ failure assessment (SOFA) score) early sepsis. Methods: A prospective cohort study of adult ED sepsis patients enrolled within 24 hours. Results: Eighty eight patients were analyzed. Dys-HDL (expressed as HDL inflammatory index (HII)) correlated with SOFA at enrollment (r = 0.23, p = 0.024) and at 48 hours (r = 0.24, p = 0.026) but HII change over the first 48 hours did not correlate with change in SOFA (r = 0.06, p = 0.56). Enrollment HII was significantly different in patients with most severe organ failure (2.31, IQR 1.33–5.2) compared to less severe organ failure (1.81, IQR 1.23–2.64, p = 0.043). Change in HII over 48 hours was significantly different for in-hospital non-survivors (-0.45, IQR-2.6, -0.14 p = 0.015) and for 28-day non-survivors (-1.12, IQR -1.52, 0.12, p = 0.044). In a multivariable linear regression equation (R2 = 0.13), for each unit HII increase, 48-hour SOFA increased by 0.72 (p = 0.009). Conclusion: HII correlated with SOFA and predicted 48-hour SOFA score in early sepsis. Future studies are needed to delineate potential mechanisms. Trial registration: . Registered February 24, 2015. [ABSTRACT FROM AUTHOR]

Mitochondrial structural and functional integrity is maintained through the coordination of several processes (e.g., biogenesis, dynamics, mitophagy), collectively referred to as mitochondrial quality control (MQC). Dysfunctional MQC and inflammation are hallmarks of aging and are involved in the pathogenesis of muscle wasting disorders, including sarcopenia and cachexia. One of the consequences of failing MQC is the release of mitochondria-derived damage-associated molecular patterns (DAMPs). By virtue of their bacterial ancestry, these molecules can trigger an inflammatory response by interacting with receptors similar to those involved in pathogen-associated responses. Mitochondria-derived DAMPs, especially cell-free mitochondrial DNA, have recently been associated with conditions characterized by chronic inflammation, such as aging and degenerative diseases. Yet, their actual implication in the aging process and muscle wasting disorders is at an early stage of investigation. Here, we review the contribution of mitochondria-derived DAMPs to age-related systemic inflammation. We also provide arguments in support of the exploitation of such signaling pathways for the management of muscle wasting conditions. [ABSTRACT FROM AUTHOR]

Reports that A.L. Lambert and B.J. Merry have provided the first evidence that caloric restriction decreases the mitochondrial proton motive force by increasing the mitochondrial proton leak. Dependence of this leak, at least in part, on plasma insulin levels; Isolation of liver mitochondria from three groups of male rats which are ad libitum-fed, caloric-restricted and caloric-restricted rats supplemented with insulin.

Editorial. Discusses a study by S.E. Alway, et al, on the role of the regulatory transcription factor inhibitor-of-differentiation 2 (Id2) and apoptosis during skeletal muscle remodeling. Possible role of apoptosis in muscular aging, dystrophy, denervation and unloading; Activation of several caspases during muscular unloading.

Mitochondrial remodeling is crucial to meet the bioenergetic demand to support muscle contractile activity during daily tasks and muscle regeneration following injury. A set of mitochondrial quality control (MQC) processes, including mitochondrial biogenesis, dynamics, and mitophagy, are in place to maintain a well-functioning mitochondrial network and support muscle regeneration. Alterations in any of these pathways compromises mitochondrial quality and may potentially lead to impaired myogenesis, defective muscle regeneration, and ultimately loss of muscle function. Among MQC processes, mitophagy has gained special attention for its implication in the clearance of dysfunctional mitochondria via crosstalk with the endo-lysosomal system, a major cell degradative route. Along this pathway, additional opportunities for mitochondrial disposal have been identified that may also signal at the systemic level. This communication occurs via inclusion of mitochondrial components within membranous shuttles named mitochondrial-derived vesicles (MDVs). Here, we discuss MDV generation and release as a mitophagy-complementing route for the maintenance of mitochondrial homeostasis in skeletal myocytes. We also illustrate the possible role of muscle-derived MDVs in immune signaling during muscle remodeling and adaptation. [ABSTRACT FROM AUTHOR]

Background: This study evaluated the association of smoking with mitochondrial function in gastrocnemius muscle of people with peripheral artery disease (PAD). Methods: Participants were enrolled from Chicago, Illinois and consented to gastrocnemius biopsy. Mitochondrial oxidative capacity was measured in muscle with respirometry. Abundance of voltage-dependent anion channel (VDAC) (mitochondrial membrane abundance), peroxisome proliferator-activated receptor-γ coactivator (PGC-1α) (mitochondrial biogenesis), and electron transport chain complexes I–V were measured with Western blot. Results: Fourteen of 31 people with PAD (age 72.1 years, ABI 0.64) smoked cigarettes currently. Overall, there were no significant differences in mitochondrial oxidative capacity between PAD participants who currently smoked and those not currently smoking (complex I+II-mediated oxidative phosphorylation: 86.6 vs 78.3 pmolO2/s/mg, respectively [ p = 0.39]). Among participants with PAD, those who currently smoked had a higher abundance of PGC-1α (p < 0.01), VDAC (p = 0.022), complex I (p = 0.021), and complex III (p = 0.021) proteins compared to those not currently smoking. People with PAD who currently smoked had lower oxidative capacity per VDAC unit (complex I+II-mediated oxidative phosphorylation [137.4 vs 231.8 arbitrary units, p = 0.030]) compared to people with PAD not currently smoking. Among people without PAD, there were no significant differences in any mitochondrial measures between currently smoking (n = 5) and those not currently smoking (n = 63). Conclusions: Among people with PAD, cigarette smoking may stimulate mitochondrial biogenesis to compensate for reduced oxidative capacity per unit of mitochondrial membrane, resulting in no difference in overall mitochondrial oxidative capacity according to current smoking status among people with PAD. However, these results were cross-sectional and a longitudinal study is needed. [ABSTRACT FROM AUTHOR]

Among the complex determinants of aging, mitochondrial dysfunction has been in the spotlight for a long time. As the hub for many cellular functions, the maintenance of an adequate pool of functional mitochondria is crucial for tissue homeostasis. Their unique role in energy supply makes these organelles essential, especially in those tissues strictly dependent on oxidative metabolism. Mitochondrial quality control (MQC) is ensured by pathways related to protein folding and degradation as well as by processes involving the entire organelle, such as biogenesis, dynamics, and mitophagy. Dysfunctional MQC, oxidative stress and inflammation are hallmarks of senescence and chronic degenerative diseases. One of the consequences of age-related failing MQC and oxidative stress is the release of mitochondria-derived damage-associated molecular patterns (DAMPs). Through their bacterial ancestry, these molecules contribute to mounting an inflammatory response by interacting with receptors similar to those involved in pathogen-associated responses. Mitochondrial DAMPs, especially cell-free mitochondrial DNA, have recently become the subject of intensive research because of their possible involvement in conditions associated with inflammation, such as aging and degenerative diseases. Here, we review the contribution of mitochondrial DAMPs to inflammation and discuss some of the mechanisms at the basis of their generation. [ABSTRACT FROM AUTHOR]

Mitochondria are negatively affected by ageing leading to their inability to adapt to higher levels of oxidative stress and this ultimately contributes to the systemic loss of muscle mass and function termed sarcopenia. Since mitochondria are central mediators of muscle health, they have become highly sought-after targets of physiological and pharmacological interventions. Exercise is the only known strategy to combat sarcopenia and this is largely mediated through improvements in mitochondrial plasticity. More recently a critical role for mitochondrial turnover in preserving muscle has been postulated. Specifically, cellular pathways responsible for the regulation of mitochondrial turnover including biogenesis, dynamics and autophagy may become dysregulated during ageing resulting in the reduced clearance and accumulation of damaged organelles within the cell. When mitochondrial quality is compromised and homeostasis is not re-established, myonuclear cell death is activated and muscle atrophy ensues. In contrast, acute and chronic exercise attenuates these deficits, restoring mitochondrial turnover and promoting a healthier mitochondrial pool that leads to the preservation of muscle. Additionally, the magnitude of these exercise-induced mitochondrial adaptations is currently debated with several studies reporting a lower adaptability of old muscle relative to young, but the processes responsible for this diminished training response are unclear. Based on these observations, understanding the molecular details of how advancing age and exercise influence mitochondria in older muscle will provide invaluable insight into the development of exercise protocols that will maximize beneficial adaptations in the elderly. This information will also be imperative for future research exploring pharmacological targets of mitochondrial plasticity. [ABSTRACT FROM AUTHOR]

Altered mitochondrial quality and function in muscle may be involved in age-related physical function decline. The role played by the autophagy–lysosome system, a major component of mitochondrial quality control (MQC), is incompletely understood. This study was undertaken to obtain initial indications on the relationship between autophagy, mitophagy, and lysosomal markers in muscle and measures of physical performance and lower extremity tissue composition in young and older adults. Twenty-three participants were enrolled, nine young (mean age: 24.3 ± 4.3 years) and 14 older adults (mean age: 77.9 ± 6.3 years). Lower extremity tissue composition was quantified volumetrically by magnetic resonance imaging and a tissue composition index was calculated as the ratio between muscle and intermuscular adipose tissue volume. Physical performance in older participants was assessed via the Short Physical Performance Battery (SPPB). Protein levels of the autophagy marker p62, the mitophagy mediator BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3), the lysosomal markers transcription factor EB, vacuolar-type ATPase, and lysosomal-associated membrane protein 1 were measured by Western immunoblotting in vastus lateralis muscle biopsies. Older adults had smaller muscle volume and lower tissue composition index than young participants. The protein content of p62 and BNIP3 was higher in older adults. A negative correlation was detected between p62 and BNIP3 and the tissue composition index. p62 and BNIP3 were also related to the performance on the 5-time sit-to-stand test of the SPPB. Our results suggest that an altered expression of markers of the autophagy/mitophagy–lysosomal system is related to deterioration of lower extremity tissue composition and muscle dysfunction. Additional studies are needed to clarify the role of defective MQC in human muscle aging and identify novel biological targets for drug development. [ABSTRACT FROM AUTHOR]

Importance: Patients with lower extremity peripheral artery disease (PAD) have reduced lower extremity perfusion, impaired lower extremity skeletal muscle function, and poor walking performance. Telmisartan (an angiotensin receptor blocker) has properties that reverse these abnormalities.Objective: To determine whether telmisartan improves 6-minute walk distance, compared with placebo, in patients with lower extremity PAD at 6-month follow-up.Design, Setting, and Participants: Double-blind, randomized clinical trial conducted at 2 US sites and involving 114 participants. Enrollment occurred between December 28, 2015, and November 9, 2021. Final follow-up occurred on May 6, 2022.Interventions: The trial randomized patients using a 2 × 2 factorial design to compare the effects of telmisartan plus supervised exercise vs telmisartan alone and supervised exercise alone and to compare telmisartan alone vs placebo. Participants with PAD were randomized to 1 of 4 groups: telmisartan plus exercise (n = 30), telmisartan plus attention control (n = 29), placebo plus exercise (n = 28), or placebo plus attention control (n = 27) for 6 months. The originally planned sample size was 240 participants. Due to slower than anticipated enrollment, the primary comparison was changed to the 2 combined telmisartan groups vs the 2 combined placebo groups and the target sample size was changed to 112 participants.Main Outcomes and Measures: The primary outcome was the 6-month change in 6-minute walk distance (minimum clinically important difference, 8-20 m). The secondary outcomes were maximal treadmill walking distance; Walking Impairment Questionnaire scores for distance, speed, and stair climbing; and the 36-Item Short-Form Health Survey physical functioning score. The results were adjusted for study site, baseline 6-minute walk distance, randomization to exercise vs attention control, sex, and history of heart failure at baseline.Results: Of the 114 randomized patients (mean age, 67.3 [SD, 9.9] years; 46 were women [40.4%]; and 81 were Black individuals [71.1%]), 105 (92%) completed 6-month follow-up. At 6-month follow-up, telmisartan did not significantly improve 6-minute walk distance (from a mean of 341.6 m to 343.0 m; within-group change: 1.32 m) compared with placebo (from a mean of 352.3 m to 364.8 m; within-group change: 12.5 m) and the adjusted between-group difference was -16.8 m (95% CI, -35.9 m to 2.2 m; P = .08). Compared with placebo, telmisartan did not significantly improve any of the 5 secondary outcomes. The most common serious adverse event was hospitalization for PAD (ie, lower extremity revascularization, amputation, or gangrene). Three participants (5.1%) in the telmisartan group and 2 participants (3.6%) in the placebo group were hospitalized for PAD.Conclusions and Relevance: Among patients with PAD, telmisartan did not improve 6-minute walk distance at 6-month follow-up compared with placebo. These results do not support telmisartan for improving walking performance in patients with PAD.Trial Registration: ClinicalTrials.gov Identifier: NCT02593110. [ABSTRACT FROM AUTHOR]

BACKGROUND: Epidemiologic evidence reporting the role of frailty in survival among older adults with a prior cancer diagnosis is limited. METHODS: A total of 2050 older adults (≥60 years old) surviving for at least 1 year after a cancer diagnosis and 9474 older adults without a cancer history from the National Health and Nutrition Examination Survey (1999‐2014) were included for analysis. The exposure variable, a 45‐item frailty index (FI), was categorized on the basis of validated cutoffs (FI ≤ 0.10 [fit], 0.10 < FI ≤ 0.21 [prefrail], and FI > 0.21 [frail]). All‐cause mortality was ascertained via the National Death Index. Multivariable Cox proportional hazards models were used to estimate adjusted hazard ratios (aHRs) and 95% confidence interval (CIs) for the FI, and this was followed by restricted cubic splines depicting dose‐response curves. RESULTS: For older cancer survivors, the mean age at the baseline was 72.6 years (SD, 7.1 years); 5.9% were fit, 38.2% were prefrail, and 55.9% were frail. Older adults without a cancer history were slightly younger (mean age, 70.0 years) and less frail (47.9% were frail). At each level of the FI, cancer survivors (1.9 per 100 person‐years for FI ≤ 0.10, 3.4 per 100 person‐years for 0.10 < FI ≤ 0.21, and 7.5 per 100 person‐years for FI > 0.21) had higher mortality than their cancer‐free counterparts (1.4 per 100 person‐years for FI ≤ 0.10, 2.4 per 100 person‐years for 0.10 < FI ≤ 0.21, and 5.4 per 100 person‐years for FI > 0.21). The multivariable model suggested a positive association between the FI and all‐cause mortality for survivors (aHR for FI > 0.21 vs FI ≤ 0.10, 2.80; 95% CI, 1.73‐4.53) and participants without a cancer history (aHR for FI > 0.21 vs FI ≤ 0.10, 2.75; 95% CI, 2.29‐3.32). Restricted cubic splines indicated that all‐cause mortality risk increased with the FI in a monotonic pattern. CONCLUSIONS: Frailty is associated with a higher risk of death in older cancer survivors and the elderly without a cancer history.; Older cancer survivors will be at higher risk for mortality if they are living with substantial burdens of frailty. Understanding the frailty status is informative for developing long‐term interventions for promoting the health of older cancer survivors. [ABSTRACT FROM AUTHOR]

Among all non-communicable diseases, Cardiovascular Diseases (CVDs) stand as the leading global cause of mortality. Within this spectrum, Myocardial Infarction (MI) strikingly accounts for over 15 % of all deaths. The intricate web of risk factors for MI, comprising family history, tobacco use, oral health, hypertension, nutritional pattern, and microbial infections, is firmly influenced by the human gut and oral microbiota, their diversity, richness, and dysbiosis, along with their respective metabolites. Host genetic factors, especially allelic variations in signaling and inflammatory markers, greatly affect the progression or severity of the disease. Despite the established significance of the human microbiome-nutrient-metabolite interplay in associations with CVDs, the unexplored terrain of the gut-heart-oral axis has risen as a critical knowledge gap. Moreover, the pivotal role of the microbiome and the complex interplay with host genetics, compounded by age-related changes, emerges as an area of vital importance in the development of MI. In addition, a distinctive disease susceptibility and severity influenced by gender-based or ancestral differences, adds a crucial insights to the association with increased mortality. Here, we aimed to provide an overview on interactions of microbiome (oral and gut) with major risk factors (tobacco use, alcohol consumption, diet, hypertension host genetics, gender, and aging) in the development of MI and therapeutic regulation. [Display omitted] • Interactions of Microbiome in humans is associated with development of Myocardial Infarction (MI). • Short Chain Fatty Acids (SCFA) play an essential role in the maintenance of intestinal homeostasis. • Elevated levels of TMAO associated with development of MI. [ABSTRACT FROM AUTHOR]

The 2023 Padua Days of Muscle and Mobility Medicine (Pdm3) were held from March 29th to April 1st, 2023. Most of the abstracts were published electronically in the European Journal of Translational Myology (EJTM) 33 (1) 2023. Here we report the complete book of abstracts that confirms the interest of more than 150 scientists and clinicians from Austria, Bulgaria, Canada, Denmark, France, Georgia, Germany, Iceland, Ireland, Italy, Mongolia, Norway, Russia, Slovakia, Slovenia, Spain, Switzerland, The Netherlands and USA to gather to the Hotel Petrarca of Thermae of Euganean Hills, Padua, Italy for contributing and attending the Pdm3 (https://www.youtube.com/watch?v=zC02D4uPWRg). The 2023 Pdm3 started March 29th in the historic Aula Guariento of thePadua Galilean Academy of Letters, Arts and Sciences with the Lecture of Prof. Carlo Reggiani and ended in the late afternoon with the Lecture of Professor Terje Lømo after introductory words of Professor Stefano Schiaffino. The program followed in the Hotel Petrarca Conferenece Halls from March 30 to April 1, 2023. The extended topic interests of specialists in basic myology sciences and clinicians, collected under the umbrella neologism of Mobility Medicine, is stressed also by expansion of Sections of the EJTM Editorial Board (https://www.pagepressjournals.org/index.php/bam/board). We hope that Speakers of the 2023 Pdm3 and readers of EJTM will submit "EJTM Communications" to the European Journal of Translational Myology (PAGEpress, Pavia, Italy) by May 31, 2023 and/or invited review and original articles for the 2023 special issue: "Pdm3" of Diagnostics, MDPI, Basel, Switzerland due September 30, 2023. [ABSTRACT FROM AUTHOR]

Despite COVID-19 outbreak, the program of the 2022 Padua Days of Muscle and Mobility Medicine (PDM3) was confirmed On-site in February from March 30 to April 2, 2022 to be held at the University of Padua Aula Magna and at Conference Hall of the Hotel Petrarca of Thermae of Euganean Hills (Padua), Italy. Over 130 abstracts, including the last-minute submissions listed below, convinced organizers to extend the program to five days. The sponsorship of the University of Florida and the willingness of attendees to meet friends after two years of virtual conferences were the keys of success, despite concerns for current events in East Europe. Only fourteen Virtual presentations were in the final program, eight due to last-minute Coronavirus infections and six for East Europe problems. The first two days of the programincluded scientists and clinicians of the University of Florida, USA and their invitees from Canada, France, Italy, Swiden, Swiss, UK and USA. Researchers and clinicians from Austria, Belgium, France, Germany, Iceland, Ireland, Italy, Russia, Slovakia, Slovenia, UK and USA filled the program of last three days more oriented to aging and rehabilitation. The large majority of abstracts was epublished before the meeting; here are last-minute abstracts and the final program. The program of the 2023 On-site PDM3 was informally designed during the Meeting, but will be circulated during 2022 summer. Fix the dates in your agenda from Thursday March 28 to Friday March 31. For now, please, submit Communications to the European Journal of Translational Myology, PAGEpress, Pavia, Italy and Original Articles or Reviews to the Journal Diagnostics, MDPI, Basel, Swiss. Both journals will host Special PDM3 Sections and will apply 50% discount on editorial processing fees to the first 15 accepted typescripts. [ABSTRACT FROM AUTHOR]

Iron is indispensable for normal body functions across species because of its critical roles in red blood cell function and many essential proteins and enzymes required for numerous physiological processes. Regulation of iron homeostasis is an intricate process involving multiple modulators at the systemic, cellular, and molecular levels. Interestingly, emerging evidence has demonstrated that many modulators of iron homeostasis contribute to organismal aging and longevity. On the other hand, the age-related dysregulation of iron homeostasis is often associated with multiple age-related pathologies including bone resorption and neurodegenerative diseases such as Alzheimer's disease. Thus, a thorough understanding on the interconnections between systemic and cellular iron balance and organismal aging may help decipher the etiologies of multiple age-related diseases, which could ultimately lead to developing therapeutic strategies to delay aging and treat various age-related diseases. Here we present the current understanding on the mechanisms of iron homeostasis. We also discuss the impacts of aging on iron homeostatic processes and how dysregulated iron metabolism may affect aging and organismal longevity. • Tight regulation of physiological Fe levels is essential for normal body functions • Complex systemic, cellular, and molecular mechanisms maintain Fe homeostasis • Age-associated Fe dyshomeostasis and cellular Fe deposition are hallmarks of aging • Fe dyshomeostasis accelerates cellular senescence and organismal aging in animals • Fe overload leads to multiple age-related pathologies in humans [ABSTRACT FROM AUTHOR]

Background: Hospital deaths after sepsis have decreased substantially and most young adult survivors rapidly recover (RAP). However, many older survivors develop chronic critical illness (CCI) with poor long-term outcomes. The etiology of CCI is multifactorial and the relative importance remains unclear. Sepsis is caused by a dysregulated immune response and biomarkers reflecting a persistent inflammation, immunosuppression, and catabolism syndrome (PICS) have been observed in CCI after sepsis. Therefore, the purpose of this study was to compare serial PICS biomarkers in (i) older (vs young) adults and (ii) older CCI (vs older RAP) patients to gain insight into underlying pathobiology of CCI in older adults.Method: Prospective longitudinal study with young (≤45 years) and older (≥65 years) septic adults, who were characterized by (i) baseline predisposition, (ii) hospital outcomes, (iii) serial Sequential Organ Failure Assessment (SOFA) organ dysfunction scores over 14 days, (iv) Zubrod Performance status at 3-, 6-, and 12-month follow-up, and (v) mortality over 12 months, was conducted. Serial blood samples over 14 days were analyzed for selected biomarkers reflecting PICS.Results: Compared to the young, more older adults developed CCI (20% vs 42%) and had markedly worse serial SOFA scores, performance status, and mortality over 12 months. Additionally, older (vs young) and older CCI (vs older RAP) patients had more persistent aberrations in biomarkers reflecting inflammation, immunosuppression, stress metabolism, lack of anabolism, and antiangiogenesis over 14 days after sepsis.Conclusion: Older (vs young) and older CCI (vs older RAP) patient subgroups demonstrate early biomarker evidence of the underlying pathobiology of PICS. [ABSTRACT FROM AUTHOR]