Zebrafish as a Human Muscle Model for Studying Age-Dependent Sarcopenia and Frailty.

Currently, there is an increase in the aging of the population, which represents a risk factor for many diseases, including sarcopenia. Sarcopenia involves progressive loss of mass, strength, and function of the skeletal muscle. Some mechanisms include alterations in muscle structure, reduced regenerative capacity, oxidative stress, mitochondrial dysfunction, and inflammation. The zebrafish has emerged as a new model for studying skeletal muscle aging because of its numerous advantages, including histological and molecular similarity to human skeletal muscle. In this study, we used fish of 2, 10, 30, and 60 months of age. The older fish showed a higher frailty index with a value of 0.250 ± 0.000 because of reduced locomotor activity and alterations in biometric measurements. We observed changes in muscle structure with a decreased number of myocytes (0.031 myocytes/µm2 ± 0.004 at 60 months) and an increase in collagen with aging up to 15% ± 1.639 in the 60-month group, corresponding to alterations in the synthesis, degradation, and differentiation pathways. These changes were accompanied by mitochondrial alterations, such as a nearly 50% reduction in the number of intermyofibrillar mitochondria, 100% mitochondrial damage, and reduced mitochondrial dynamics. Overall, we demonstrated a similarity in the aging processes of muscle aging between zebrafish and mammals.

Mitochondrial Oxidative Stress Regulates FOXP3+ T-Cell Activity and CD4-Mediated Inflammation in Older Adults with Frailty.

In healthy older adults, the immune system generally preserves its response and contributes to a long, healthy lifespan. However, rapid deterioration in immune regulation can lead to chronic inflammation, termed inflammaging, which accelerates pathological aging and diminishes the quality of life in older adults with frailty. A significant limitation in current aging research is the predominant focus on comparisons between young and older populations, often overlooking the differences between healthy older adults and those experiencing pathological aging. Our study elucidates the intricate immunological dynamics of the CD4/Treg axis in frail older adults compared to comparable age-matched healthy older adults. By utilizing publicly available RNA sequencing and single-cell RNA sequencing (scRNAseq) data from peripheral blood mononuclear cells (PBMCs), we identified a specific Treg cell subset and transcriptional landscape contributing to the dysregulation of CD4+ T-cell responses. We explored the molecular mechanisms underpinning Treg dysfunction, revealing that Tregs from frail older adults exhibit reduced mitochondrial protein levels, impairing mitochondrial oxidative phosphorylation. This impairment is driven by the TNF/NF-kappa B pathway, leading to cumulative inflammation. Further, we gained a deeper understanding of the CD4/Treg axis by predicting the effects of gene perturbations on cellular signaling networks. Collectively, these findings highlight the age-related relationship between mitochondrial dysfunction in the CD4/Treg axis and its role in accelerating aging and frailty in older adults. Targeting Treg dysfunction offers a critical basis for developing tailored therapeutic strategies aimed at improving the quality of life in older adults.

The intersection of frailty and metabolism.

On average, aging is associated with unfavorable changes in cellular metabolism, which are the processes involved in the storage and expenditure of energy. However, metabolic dysregulation may not occur to the same extent in all older individuals as people age at different rates. Those who are aging rapidly are at increased risk of adverse health outcomes and are said to be "frail." Here, we explore the links between frailty and metabolism, including metabolic contributors and consequences of frailty. We examine how metabolic diseases may modify the degree of frailty in old age and suggest that frailty may predispose toward metabolic disease. Metabolic interventions that can mitigate the degree of frailty in people are reviewed. New treatment strategies developed in animal models that are poised for translation to humans are also considered. We suggest that maintaining a youthful metabolism into older age may be protective against frailty.

Biomarkers of frailty.

Several biomarkers have been proposed to identify frailty, a multisystemic age-related syndrome. However, the complex pathophysiology and the absence of a consensus on a comprehensive and universal definition make it challenging to pinpoint a singular biomarker or set of biomarkers that conclusively characterize frailty. This review delves into the main laboratory biomarkers, placing special emphasis on those associated with various pathways closely tied to the frailty condition, such as inflammation, oxidative stress, mitochondrial dysfunction, metabolic and endocrine alterations and microRNA. Additionally, we provide a summary of different clinical biomarkers encompassing different tools that have been proposed to assess frailty. We further address various imaging biomarkers such as Dual Energy X-ray Absorptiometry, Bioelectrical Impedance analysis, Computed Tomography and Magnetic Resonance Imaging, Ultrasound and D3 Creatine dilution. Intervention to treat frailty, including non-pharmacological ones, especially those involving physical exercise and nutrition, and pharmacological interventions, that include those targeting specific mechanisms such as myostatin inhibitors, insulin sensitizer metformin and with special relevance for hormonal treatments are mentioned. We further address the levels of different biomarkers in monitoring the potential positive effects of some of these interventions. Despite the availability of numerous biomarkers, their performance and usefulness in the clinical arena are far from being satisfactory. Considering the multicausality of frailty, there is an increasing need to assess the role of sets of biomarkers and the combination between laboratory, clinical and image biomarkers, in terms of sensitivity, specificity and predictive values for the diagnosis and prognosis of the different outcomes of frailty to improve detection and monitoring of older people with frailty or at risk of developing it, being this a need in the everyday clinical practice.

Impact of menopause-associated frailty on traumatic brain injury.

Navigating menopause involves traversing a complex terrain of hormonal changes that extend far beyond reproductive consequences. Menopausal transition is characterized by a decrease in estradiol-17ß (E2), and the impact of menopause resonates not only in the reproductive system but also through the central nervous system, musculoskeletal, and gastrointestinal domains. As women undergo menopausal transition, they become more susceptible to frailty, amplifying the risk and severity of injuries, including traumatic brain injury (TBI). Menopause triggers a cascade of changes leading to a decline in muscle mass, accompanied by diminished tone and excitability, thereby restricting the availability of irisin, a crucial hormone derived from muscles. Concurrently, bone mass undergoes reduction, culminating in the onset of osteoporosis and altering the dynamics of osteocalcin, a hormone originating from bones. The diminishing levels of E2 during menopause extend their influence on the gut microbiota, resulting in a reduction in the availability of tyrosine, tryptophan, and serotonin metabolites, affecting neurotransmitter synthesis and function. Understanding the interplay between menopause, frailty, E2 decline, and the intricate metabolisms of bone, gut, and muscle is imperative when unraveling the nuances of TBI after menopause. The current review underscores the significance of accounting for menopause-associated frailty in the incidence and consequences of TBI. The review also explores potential mechanisms to enhance gut, bone, and muscle health in menopausal women, aiming to mitigate frailty and improve TBI outcomes.

Effect of Lactobacillus plantarum BFS1243 on a female frailty model induced by fecal microbiota transplantation in germ-free mice.

Frailty, a complex geriatric syndrome, significantly impedes the goal of achieving 'healthy aging'. Increasing evidence suggests a connection between gut microbiota, systemic inflammation, and disease. However, it remains to be determined whether interventions targeting the intestinal flora can effectively ameliorate frailty. Our research involved fecal microbiota transplantation (FMT) experiments on germ-free (GF) mice, dividing these mice into three groups: a group receiving transplants from healthy elderly individuals (HF group), a group of frailty patients (FF group), and the FF group supplemented with Lactobacillus plantarum BFS1243 (FFL group). Our findings indicated a significant shift in the gut microbiota of the FF group, in contrast to the HF group, characterized by decreased Akkermansia and increased Enterocloster, Parabacteroides, and Eisenbergiella. Concurrently, there was a reduction in amino acids and SCFAs, with BFS1243 partially mitigating these changes. The FF group exhibited an upregulation of inflammatory markers, including PGE2, CRP, and TNF-α, and a downregulation of irisin, all of which were moderated by BFS1243 treatment. Furthermore, BFS1243 improved intestinal barrier integrity and physical endurance in the FF mice. Correlation analysis revealed a negative association between SCFA-producing species and metabolites like lysine and butyric acid with pro-inflammatory factors. In conclusion, our study conclusively demonstrated that alterations in the gut microbiota of elderly individuals can lead to physical frailty, likely due to detrimental effects on the intestinal barrier and a pro-inflammatory state. These findings underscore the potential of gut microbiome modulation as a clinical strategy for treating frailty.

Metabolic dysfunction and the development of physical frailty: an aging war of attrition.

The World Health Organization recently declared 2021-2030 the decade of healthy aging. Such emphasis on healthy aging requires an understanding of the biologic challenges aging populations face. Physical frailty is a syndrome of vulnerability that puts a subset of older adults at high risk for adverse health outcomes including functional and cognitive decline, falls, hospitalization, and mortality. The physiology driving physical frailty is complex with age-related biological changes, dysregulated stress response systems, chronic inflammatory pathway activation, and altered energy metabolism all likely contributing. Indeed, a series of recent studies suggests circulating metabolomic distinctions can be made between frail and non-frail older adults. For example, marked restrictions on glycolytic and mitochondrial energy production have been independently observed in frail older adults and collectively appear to yield a reliance on the highly fatigable ATP-phosphocreatine (PCr) energy system. Further, there is evidence that age-associated impairments in the primary ATP generating systems (glycolysis, TCA cycle, electron transport) yield cumulative deficits and fail to adequately support the ATP-PCr system. This in turn may acutely contribute to several major components of the physical frailty phenotype including muscular fatigue, weakness, slow walking speed and, over time, result in low physical activity and accelerate reductions in lean body mass. This review describes specific age-associated metabolic declines and how they can collectively lead to metabolic inflexibility, ATP-PCr reliance, and the development of physical frailty. Further investigation remains necessary to understand the etiology of age-associated metabolic deficits and develop targeted preventive strategies that maintain robust metabolic health in older adults.

Physical Interventions Restore Physical Frailty and the Expression of CXCL-10 and IL-1ß Inflammatory Biomarkers in Old Individuals and Mice.

BACKGROUND: Frailty is a geriatric syndrome associated with negative health outcomes that represents a dynamic condition with a potential of reversibility after physical exercise interventions. Typically, inflammatory and senescence markers are increased in frail individuals. However, the impact that physical exercise exerts on inflammatory and senescence biomarkers remains unknown. We assessed the effect of physical intervention in old individuals and mice and determined the expression of inflammatory and senescence markers. METHODS: Twelve elderly individuals were enrolled from a primary care setting to a 3-month intervention. Frailty was measured by SPPB and the expression of biomarkers by cytokine array and RT-qPCR. In addition, 12 aged C57BL/6 mice completed an intervention, and inflammation and senescence markers were studied. RESULTS: The physical intervention improved the SPPB score, reducing frail and pre-frail individuals. This was correlated with a reduction in several pro-inflammatory biomarkers such as IL-6, CXCL-1, CXCL-10, IL-1ß, IL-7, GM-CSF as well as p16INK4a and p21CIP1 senescence markers. Otherwise, the levels of anti-inflammatory biomarker IL-4 were significantly increased. Moreover, the physical intervention in mice also improved their functional capacity and restored the expression of inflammatory (Il-1ß, Cxcl-10, Il-6, and Cxcl-1) and senescence (p21Cip1) markers. Additionally, PLSDA and ROC curve analysis revealed CXCL-10 and IL-1ß to be the biomarkers of functional improvement in both cohorts. CONCLUSIONS: Our results showed that a physical intervention improves physical frailty, and reverses inflammation and senescence biomarkers comprising CXCL-10 and IL-1ß.

Age-Dependent Effects of Voluntary Wheel Running Exercise on Voiding Behavior and Potential Age-Related Molecular Mechanisms in Mice.

BACKGROUND: Older men frequently develop lower urinary tract symptoms attributed to benign prostatic hyperplasia (LUTS/BPH). Risk factors for LUTS/BPH include sedentary lifestyle, anxiety/depression, obesity, and frailty, which all increase with age. Although physical exercise may reduce the progression and/or severity of LUTS/BPH, the age-related mechanisms responsible remain unknown. METHODS: Voiding symptoms, body mass, and frailty were assessed after 4-weeks of voluntary wheel running in 2-month (n = 10) and 24-month (n = 8) old C57Bl/6J male mice. In addition, various social and individual behaviors were examined in these cohorts. Finally, cellular and molecular markers of inflammation and mitochondrial protein expression were assessed in prostate tissue and systemically. RESULTS: Despite running less (aged vs young X¯ = 12.3 vs 30.6 km/week; p = .04), aged mice had reduced voiding symptoms (X¯ = 67.3 vs 23.7; p < .0001) after 1 week of exercise, which was sustained through week 4 (X¯ = 67.3 vs 21.5; p < .0001). Exercise did not affect voiding symptoms in young mice. Exercise also increased mobility and decreased anxiety in both young and aged mice (p < .05). Exercise decreased expression of a key mitochondrial protein (PINK1; p < .05) and inflammation within the prostate (CD68; p < .05 and plasminogen activator inhibitor-1; p < .05) and in the serum (p < .05). However, a frailty index (X¯ = 0.17 vs 0.15; p = .46) and grip strength (X¯ = 1.10 vs 1.19; p = .24) were unchanged after 4 weeks of exercise in aged mice. CONCLUSIONS: Voluntary aerobic exercise improves voiding behavior and mobility, and decreases prostatic mitochondrial protein expression and inflammation in aged mice. This promising model could be used to evaluate molecular mechanisms of aerobic exercise as a novel lifestyle intervention for older men with LUTS/BPH.

Indoxyl sulfate induced frailty in patients with end-stage renal disease by disrupting the PGC-1α-FNDC5 axis.

OBJECTIVE: Sarcopenia or frailty is common among patients with chronic kidney disease (CKD). The protein-bound uremic toxin indoxyl sulfate (IS) is associated with frailty. IS induces apoptosis and disruption of mitochondrial activity in skeletal muscle. However, the association of IS with anabolic myokines such as irisin in patients with CKD or end-stage renal disease (ESRD) is unclear. This study aims to elucidate whether IS induces frailty by dysregulating irisin in patients with CKD. MATERIALS AND METHODS: The handgrip strength of 53 patients, including 28 patients with ESRD, was examined. Serum concentrations of IS and irisin were analyzed. CKD was established in BALB/c mice through 5/6 nephrectomy. Pathologic analysis of skeletal muscle was assessed through haematoxylin and eosin and Masson's trichrome staining. Expression of peroxisome proliferator-activated receptor-gamma coactivator PGC-1α and irisin were analyzed using real-time polymerase chain reaction and Western blotting. RESULTS: Handgrip strength was lower among patients with ESRD than among those without ESRD. In total, 64.3% and 24% of the patients in the ESRD and control groups had low handgrip strength, respectively (p < 0.05). Serum concentrations of IS were significantly higher in the ESRD group than in the control group (222.81 ± 90.67 µM and 23.19 ± 33.28 µM, respectively, p < 0.05). Concentrations of irisin were lower in the ESRD group than in the control group (64.62 ± 32.64 pg/mL vs. 99.77 ± 93.29 pg/mL, respectively, p < 0.05). ROC curves for low handgrip strength by irisin and IS were 0.298 (95% confidence interval (CI): 0.139-0.457, p < 0.05) and 0.733 (95% CI: 0.575-0.890, p < 0.05), respectively. The percentage of collagen was significantly higher in mice with 5/6 nephrectomy than in the control group. After resveratrol (RSV) treatment, the percentage of collagen significantly decreased. RSV modulates TGF-ß signaling. In vitro analysis revealed that IS treatment suppressed expression of PGC-1α and FNDC5 in a dose-dependent manner, whereas RSV treatment attenuated IS-induced phenomena in C2C12 cells. CONCLUSION: IS was positively correlated with frailty in patients with ESRD through the modulation of the PGC-1α-FNDC5 axis. RSV may be a potential drug for reversing IS-induced suppression of the PGC-1α-FNDC5 axis in skeletal muscle.

The Regulation of Neutrophil Migration in Patients with Sepsis: The Complexity of the Molecular Mechanisms and Their Modulation in Sepsis and the Heterogeneity of Sepsis Patients.

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Common causes include gram-negative and gram-positive bacteria as well as fungi. Neutrophils are among the first cells to arrive at an infection site where they function as important effector cells of the innate immune system and as regulators of the host immune response. The regulation of neutrophil migration is therefore important both for the infection-directed host response and for the development of organ dysfunctions in sepsis. Downregulation of CXCR4/CXCL12 stimulates neutrophil migration from the bone marrow. This is followed by transmigration/extravasation across the endothelial cell barrier at the infection site; this process is directed by adhesion molecules and various chemotactic gradients created by chemotactic cytokines, lipid mediators, bacterial peptides, and peptides from damaged cells. These mechanisms of neutrophil migration are modulated by sepsis, leading to reduced neutrophil migration and even reversed migration that contributes to distant organ failure. The sepsis-induced modulation seems to differ between neutrophil subsets. Furthermore, sepsis patients should be regarded as heterogeneous because neutrophil migration will possibly be further modulated by the infecting microorganisms, antimicrobial treatment, patient age/frailty/sex, other diseases (e.g., hematological malignancies and stem cell transplantation), and the metabolic status. The present review describes molecular mechanisms involved in the regulation of neutrophil migration; how these mechanisms are altered during sepsis; and how bacteria/fungi, antimicrobial treatment, and aging/frailty/comorbidity influence the regulation of neutrophil migration.

Role of Endothelial Progenitor Cells in Frailty.

Frailty is a clinical condition closely related to aging which is characterized by a multidimensional decline in biological reserves, a failure of physiological mechanisms and vulnerability to minor stressors. Chronic inflammation, the impairment of endothelial function, age-related endocrine system modifications and immunosenescence are important mechanisms in the pathophysiology of frailty. Endothelial progenitor cells (EPCs) are considered important contributors of the endothelium homeostasis and turn-over. In the elderly, EPCs are impaired in terms of function, number and survival. In addition, the modification of EPCs' level and function has been widely demonstrated in atherosclerosis, hypertension and diabetes mellitus, which are the most common age-related diseases. The purpose of this review is to illustrate the role of EPCs in frailty. Initially, we describe the endothelial dysfunction in frailty, the response of EPCs to the endothelial dysfunction associated with frailty and, finally, interventions which may restore the EPCs expression and function in frail people.

Platelet response to influenza vaccination reflects effects of aging.

Platelets are uniquely positioned as mediators of not only hemostasis but also innate immunity. However, how age and geriatric conditions such as frailty influence platelet function during an immune response remains unclear. We assessed the platelet transcriptome at baseline and following influenza vaccination in Younger (age 21-35) and Older (age ≥65) adults (including community-dwelling individuals who were largely non-frail and skilled nursing facility (SNF)-resident adults who nearly all met criteria for frailty). Prior to vaccination, we observed an age-associated increase in the expression of platelet activation and mitochondrial RNAs and decrease in RNAs encoding proteins mediating translation. Age-associated differences were also identified in post-vaccination response trajectories over 28 days. Using tensor decomposition analysis, we found increasing RNA expression of genes in platelet activation pathways in young participants, but decreasing levels in (SNF)-resident adults. Translation RNA trajectories were inversely correlated with these activation pathways. Enhanced platelet activation was found in community-dwelling older adults at the protein level, compared to young individuals both prior to and post-vaccination; whereas SNF residents showed decreased platelet activation compared to community-dwelling older adults that could reflect the influence of decreased translation RNA expression. Our results reveal alterations in the platelet transcriptome and activation responses that may contribute to age-associated chronic inflammation and the increased incidence of thrombotic and pro-inflammatory diseases in older adults.

Circulating miRNAs are associated with frailty and ST-elevation myocardial infarction pathways.

BACKGROUND: Frailty and ST-Elevation Myocardial Infarction (STEMI) share similar molecular pathways. Specific biomarkers, such as microRNAs (miRNAs), may provide insights into the molecular mechanisms that cause the relationship between frailty and STEMI. OBJECTIVE: Our aim was to identify and compare circulating miRNA levels between frail and non-frail older adults following STEMI and comprehend the regulatory miRNA-gene networks and pathways involved in this condition. METHODS: This exploratory study is a subanalysis of a larger observational study. In this study, we selected patients ≥ 65 years old, following STEMI, with pre-frail/frail (n=5) and non-frail (n=4) phenotype evaluated using the Clinical Frailty Scale and serum circulating miRNA levels were analyzed. RESULTS: Pre-frail/frail patients had greater serum levels of 53 miRNAs, compared with non-frail patients. Notably, miR-103a-3p, miR-598-3p, and miR-130a-3p were the top three significantly deregulated miRNAs predicted to modulate gene expression associated with aging. Additional computational analyses showed 7,420 predicted miRNA gene targets, which were regulated by at least two of the 53 identified miRNAs. Pathway enrichment analysis showed that axon guidance and MAPK signaling were among pathways regulated by miRNA target genes. CONCLUSIONS: These novel findings suggest a correlation between the identified miRNAs, target genes, and pathways in pre-frail and frail patients with myocardial infarction.

Single nuclei profiling identifies cell specific markers of skeletal muscle aging, frailty, and senescence.

Aging is accompanied by a loss of muscle mass and function, termed sarcopenia, which causes numerous morbidities and economic burdens in human populations. Mechanisms implicated in age-related sarcopenia or frailty include inflammation, muscle stem cell depletion, mitochondrial dysfunction, and loss of motor neurons, but whether there are key drivers of sarcopenia are not yet known. To gain deeper insights into age-related muscle loss, we performed transcriptome profiling on lower limb muscle biopsies from 72 young, elderly, and frail human subjects using bulk RNA-seq (N = 72) and single-nuclei RNA-seq (N = 17). This combined approach revealed changes in gene expression that occur with age and frailty in multiple cell types comprising mature skeletal muscle. Notably, we found increased expression of the genes MYH8 and PDK4, and decreased expression of the gene IGFN1, in aged muscle. We validated several key genes changes in fixed human muscle tissue using digital spatial profiling. We also identified a small population of nuclei that express CDKN1A, present only in aged samples, consistent with p21cip1-driven senescence in this subpopulation. Overall, our findings identify unique cellular subpopulations in aged and sarcopenic skeletal muscle, which will facilitate the development of new therapeutic strategies to combat age-related frailty.

Slc12a8 in the lateral hypothalamus maintains energy metabolism and skeletal muscle functions during aging.

Sarcopenia and frailty are urgent socio-economic problems worldwide. Here we demonstrate a functional connection between the lateral hypothalamus (LH) and skeletal muscle through Slc12a8, a recently identified nicotinamide mononucleotide transporter, and its relationship to sarcopenia and frailty. Slc12a8-expressing cells are mainly localized in the LH. LH-specific knockdown of Slc12a8 in young mice decreases activity-dependent energy and carbohydrate expenditure and skeletal muscle functions, including muscle mass, muscle force, intramuscular glycolysis, and protein synthesis. LH-specific Slc12a8 knockdown also decreases sympathetic nerve signals at neuromuscular junctions and ß2-adrenergic receptors in skeletal muscle, indicating the importance of the LH-sympathetic nerve-ß2-adrenergic receptor axis. LH-specific overexpression of Slc12a8 in aged mice significantly ameliorates age-associated decreases in energy expenditure and skeletal muscle functions. Our results highlight an important role of Slc12a8 in the LH for regulation of whole-body metabolism and skeletal muscle functions and provide insights into the pathogenesis of sarcopenia and frailty during aging.

FGF21 is required for protein restriction to extend lifespan and improve metabolic health in male mice.

Dietary protein restriction is increasingly recognized as a unique approach to improve metabolic health, and there is increasing interest in the mechanisms underlying this beneficial effect. Recent work indicates that the hormone FGF21 mediates the metabolic effects of protein restriction in young mice. Here we demonstrate that protein restriction increases lifespan, reduces frailty, lowers body weight and adiposity, improves physical performance, improves glucose tolerance, and alters various metabolic markers within the serum, liver, and adipose tissue of wildtype male mice. Conversely, mice lacking FGF21 fail to exhibit metabolic responses to protein restriction in early life, and in later life exhibit early onset of age-related weight loss, reduced physical performance, increased frailty, and reduced lifespan. These data demonstrate that protein restriction in aging male mice exerts marked beneficial effects on lifespan and metabolic health and that a single metabolic hormone, FGF21, is essential for the anti-aging effect of this dietary intervention.

Phenotypic frailty in people living with HIV is not correlated with age or immunosenescence.

BACKGROUND: It has been hypothesized that HIV-1 infection prematurely "ages" individuals phenotypically and immunologically. We measured phenotypic frailty and immune "aging" markers on T-cells of people living with HIV on long term, suppressive anti-retroviral therapy (ART) to determine if there is an association between frailty and immunosenescence. METHODS: Thirty-seven (37) community-dwelling people living with HIV were measured for frailty using a sensor-based frailty meter that quantifies weakness, slowness, rigidity, and exhaustion. An immunological profile of the patients' CD4+ and CD8+ T-cell expression of cell surface proteins and cytokines was performed (n = 20). RESULTS: Phenotypic frailty prevalence was 19% (7/37) and correlated weakly with the number of past medical events accrued by the patient (r = 0.34, p = .04). There was no correlation of frailty with age, sex, prior AIDS diagnosis or HIV-1 viral load, or IFN-γ expression by CD4+ or CD8+ T-cells. There were more immune competent (CD28+ CD57-) cells than exhausted/senescent (CD28- CD57+) T cells. CONCLUSION: Frailty in people living with HIV on long term, suppressive ART did not correlate with aging or T cell markers of exhaustion or immunosenescence.

Dasatinib plus quercetin attenuates some frailty characteristics in SAMP10 mice.

Senolytics are a class of drugs that selectively remove senescent cells. Dasatinib and quercetin have been discovered, and their combination has shown various anti-ageing effects. The SAMP10 mouse strain is a model of brain ageing. Here, we investigated the effect of combination on frailty characteristics in SAMP10. By comparing SAMP10 with SAMR1 mice as normal ageing controls, we investigated some frailty characteristics. Frailty was assessed at 18-38 weeks of age with a clinical frailty index. Motor and cognitive function of these mice were evaluated using behavioral experiments. SAMP10 mice were divided into vehicle and combination, and these functions and histological changes in the brain hippocampus were investigated. Finally, the in vitro effects of combination on oxidative stress-induced senescent muscle and neuronal cells were investigated. As a result, we found that frailty index was higher in SAMP10 than SAMR1. Motor and cognitive function were worse in SAMP10 than SAMR1. Furthermore, combination therapy improved frailty, motor and cognitive function, and the senescent phenotype of the hippocampus compared with vehicle in SAMP10. In summary, SAMP10 showed more marked frailty characteristics than SAMR1, and dasatinib and quercetin attenuated them in SAMP10. From our results, senolytic therapy might contribute protective effects against frailty.