Aging Frailty Research Articles

Safety and efficacy of umbilical cord tissue-derived mesenchymal stem cells in the treatment of patients with aging frailty: a phase I/II randomized, double-blind, placebo-controlled study

BackgroundMesenchymal stem cells (MSCs) hold a great promise for cell-based therapy in the field of regenerative medicine. In this study, we aimed to evaluate the safety and efficacy of intravenous infusion of human umbilical cord-derived MSCs (HUC-MSCs) in patients with aging frailty.MethodsIn this randomized, double-blind, placebo-controlled trial, participants diagnosed with aging frailty were randomly assigned to receive intravenous administrations of HUC-MSCs or placebo. All of serious adverse events and AEs were monitored to evaluate the safety of treatment during the 6-month follow-up. The primary efficacy endpoint was alteration of physical component scores (PCS) of SF-36 qualities of life at 6 months. The secondary outcomes including physical performance tests and pro-inflammatory cytokines, were also observed and compared at each follow-up visits. All evaluations were performed at 1 week, 1, 2, 3 and 6 months following the first intravenous infusion of HUC-MSCs.ResultsIn the MSCs group, significant improvements in PCS of SF-36 were observed from first post-treatment visit and sustained throughout the follow-up period, with greater changes compared to the placebo group (p = 0.042). EQ-VAS scores of MSCs group improved significantly at 2 month (p = 0.023) and continued until the end of the 6-month visit (p = 0.002) in comparison to the placebo group. The timed up and go (TUG) physical performance test revealed significant group difference and showed continual enhancements over 6 months (p < 0.05). MSC transplantation improved the function of 4-m walking test (4MWT) compared with the placebo group with a decrease of 2.05 s at 6 months of follow-up (p = 0.21). The measurement of grip strength revealed group difference with MSCs group demonstrating better performance, particularly at 6 months (p = 0.002). Inflammatory cytokines (TNF-α, IL-17) exhibited declines in MSCs group at 6 months compared to the placebo group (p = 0.034 and 0.033, respectively). There was no difference of incidence of AEs between the two groups.ConclusionIntravenous transplantation of HUC-MSCs is a safe and effective therapeutic approach on aging frailty. The positive outcomes observed in improving quality of life, physical performance, and reducing chronic inflammation, suggest that HUC-MSC therapy may be a promising potential treatment option for aging frailty.Trial Registration: Clinicaltrial.gov; NCT04314011; https://clinicaltrials.gov/ct2/show/NCT04314011.

LONG-TERM NMN TREATMENT INCREASES LIFESPAN AND HEALTHSPAN IN MICE IN A SEX DEPENDENT MANNER

Abstract Levels of nicotinamide adenine dinucleotide (NAD+) decline by up to 50% in aging. NAD+ is an essential co-factor for many metabolic processes, including the deacetylase activity of sirtuins, and previous studies have demonstrated that supplementing NAD+ levels has a range of health benefits in both mice and humans. Here we investigate the effect of long-term (from 13 months of age) administration of the NAD+ precursor nicotinamide mononucleotide (NMN) on frailty and lifespan in male and female mice. NMN treatment delayed the onset of frailty in both sexes, improved metabolic health in male mice, and increased median lifespan by 8.5% in female mice. Exploration of the potential mechanisms of this protection showed that NMN treatment prevented age-related gene expression changes in skeletal muscle and led to a large increase in levels of Anaerotruncus colihominis, a microbe associated with reduced inflammation, in the gut. A thorough characterization of NMN metabolism across age, sex and tissues shows context-specific sex differences in metabolic pathways, including greater Preiss-Handler pathway metabolism in females than males, which may contribute to observed sex differences in health and lifespan. Overall, this data provides preclinical evidence that chronic NMN treatment increases lifespan and improves frailty and metabolic health in aging, and highlights the importance of using both sexes for interventional lifespan studies.

The association between anticholinergic/sedative burden and physical frailty in people aging with HIV.

This study aimed to estimate the strength of the association between anticholinergic/sedative burden and concurrent physical frailty in people aging with HIV. This cross-sectional analysis examined baseline data from 824 adults with a mean age of 53 enrolled in the Positive Brain Health Now study. Anticholinergic medications were identified using four methods: Anticholinergic Cognitive Burden (ACB) Scale, Anticholinergic Risk Scale (ARS), Anticholinergic Drug Scale (ADS), and the anticholinergic list of the Anticholinergic and Sedative Burden Catalog (ACSBC). Sedatives were identified using the Sedative Load Model (SLM) and the sedative list of the ACSBC. Physical frailty was assessed using a modified Fried Frailty Phenotype (FFP) based on self-report items. Multivariable logistic regression models, adjusted for sociodemographic factors, lifestyle considerations, HIV-related variables, comorbidities, and co-medication use, were used to estimate odds ratios (ORs). Anticholinergic burden demonstrated associations with frailty across various methods: total anticholinergic burden (OR range: 1.22-1.32; 95% confidence interval (CI) range: 1.03-1.66), sedative burden (OR range: 1.18-1.24; 95% CI range: 1.02-1.45), high anticholinergic burden (OR range: 2.12-2.74; 95% CI range: 1.03-6.19), and high sedative burden (OR range: 1.94-2.18; 95% CI: 1.01-4.34). The anticholinergic and sedative burdens may represent modifiable risk factors for frailty in people aging with HIV. Future studies should evaluate the effects of reducing anticholinergic and sedative burdens on frailty outcomes and explore the prognostic value of diverse scoring methods.

Abstract 18211: Does Frailty Matter in High Risk PCI

Background: There are limited data depicting the relationship between frailty and in-hospital outcomes for high-risk PCI. Methods: The Cath-PCI registry (2018 - 2020) was used to examine the association of frailty as defined by the Canadian Study of Health and Aging (CSHA) frailty index and in-hospital complications for patients undergoing PCI. We conducted a logistic regression analysis for in-hospital mortality. Results: The sample size was 1,316,390 individuals aged ≥ 65 years undergoing PCI. The frailty distribution was: 78,921 not frail (6.0%), 892,695 pre-frail (67.8%), 284,444 frail (21.6%), and 60,330 severely frail (2.2%). The median age of patients who were frail was 76 years, 39.4% were female, and 87.2% were white. In-hospital rates for any bleeding stratified by frailty status were: not frail: 1.0%, pre-frail: 1.5%, frail 3.3%, severely frail 8.9%. The adjusted odds ratio (aOR) regarding in-hospital mortality among PCI patients at high bedside mortality risk for pre-frail, 2.58 (95% CI: 1.42 - 1.80) for frail, and 5.14 (95% CI: 4.56 - 5.80) for severely frail. The adjusted association for in-hospital mortality across sub-groups stratified by frailty status was: left main PCI ~ pre-frail aOR 1.44 (95% CI: 1.01 - 2.05), frail aOR 2.18 (95% CI: 1.53 - 3.11) and severely frail aOR 3.98 (95% CI: 2.79 - 5.70). While the aORs for chronic total occlusion were ~ pre-frail 1.57 (95% CI: 0.97 - 2.52), frail 2.31 (95% CI: 1.43 - 3.75) and severely frail 6.04 (5.40 - 6.75) and cardiogenic shock ~ pre-frail 1.33 (95% CI: 1.08 - 1.64), frail 1.54 (95% CI: 1.25 - 1.90) and severely frail 2.44 (1.99 - 3.00). Conclusions: Contemporary PCI is commonly performed on frail patients. Frailty is associated with higher risk of mortality across high-risk PCI categories; however, severe frailty depicts a distinct and exceptionally high-risk cohort.

High blood galectin-3 level associated with risk of frailty in aging.

Frailty is one of the most problematic expressions of population aging, but its underlying mechanism has not been fully elucidated. Circulating galectin-3 (Gal-3) is involved in the pathogenesis of many age-related diseases. This study aims to explore the influence of circulating Gal-3 on the regulation of frailty and aging and to identify the potential mechanism further. In this cross-sectional analysis, the Fried frailty phenotype (FP) was assessed among 149 community elderly residents in Shanghai. Peripheral blood mononuclear cells (PBMCs) were isolated by the Ficoll-Paque density gradient method, and differentially expressed genes (DEGs) encoding transcription factors in frailty were detected by Illumina and bioinformatics analyzed with R software. Gene Ontology (GO) enrichment analyses and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to explore the functional roles of these DEGs and the target genes related to frailty phenotypes. The serum Gal-3 concentration was tested by enzyme-linked immunosorbent assay (ELISA). Mouse frailty phenotype was used to construct an in vivo model of frailty, after which the serum levels of circulating Gal-3 and its gene expression levels in mouse tissues were determined. Participants' mean age was 72.04 ± 7.05 years. In total, 21.48% were frail and 36.91% were pre-frail. The mean serum Gal-3 concentration was 46.34 ± 17.99 ng/mL in frail participants, 32.30 ± 8.14 ng/mL in pre-frail participants, and 26.00 ± 5.87 ng/mL in non-frail individuals (p < 0.001). Significant positive correlations between serum Gal-3 level and FP score, SARC-F score, C-reactive protein (CRP), interleukin-6, etc., were observed. In addition, the KEGG pathway and GO enrichment analyses showed that 265 DEGs in PBMCs of frail participants were mainly related to inflammatory response, translation, RNA binding, protein binding, ribosome, and primary immunodeficiency. LGALS3 was identified as the overlapping gene between frailty-related DEGs and aging-related DEGs. The elevated serum Gal-3 concentration in the in vivo model of frailty was consistent with the results in participants. In both community-dwelling older adults and aged mice, serum Gal-3 concentration was positively correlated with frailty. This circulating mediator may be a promising indicator of frailty. Chinese Clinical Trial Registry identifier, ChiCTR2000036399.

Protectin DX as a therapeutic strategy against frailty in mice

Frailty in aging is driven by the dysregulation of multiple biological pathways. Protectin DX (PDX) is a docosahexaenoic acid (DHA)-derived molecule that alleviates many chronic inflammatory disorders, but its potential effects on frailty remain unknown. Our goal is to identify age-related impairments in metabolic systems and to evaluate the therapeutic potential of PDX on frailty, physical performance, and health parameters. A set of 22-month-old C57BL/6 male and female mice were assigned to vehicle (Old) or PDX daily gavage treatment for 9 weeks, whereas 6-month-old (Adult) mice received only vehicle. Forelimb and hindlimb strength, endurance, voluntary wheel activity and walking speed determined physical performance and were combined with a frailty index score and body weight loss to determine frailty status. Our data shows that old vehicle-treated mice from both sexes had body weight loss paralleling visceromegaly, and Old females also had impaired insulin clearance as compared to the Adult group. Aging was associated with physical performance decline together with higher odds of frailty development. There was also age-driven mesangial expansion and glomerular hypertrophy as well as bone mineral density loss. All of the in vivo and in vitro impairments observed with aging co-occurred with upregulation of inflammatory pathways and Myc signaling as well as downregulation of genes related to adipogenesis and oxidative phosphorylation in liver. PDX attenuated the age-driven physical performance (strength, exhaustion, walking speed) decline, promoted robustness, prevented bone losses and partially reversed changes in hepatic expression of Myc targets and metabolic genes. In conclusion, our data provides evidence of the beneficial therapeutic effect of PDX against features of frailty in mice. Further studies are warranted to investigate the mechanisms of action and the potential for human translation.

Polarized Anti-Inflammatory Mesenchymal Stem Cells Increase Hippocampal Neurogenesis and Improve Cognitive Function in Aged Mice.

Age-related decline in cognitive functions is associated with reduced hippocampal neurogenesis caused by changes in the systemic inflammatory milieu. Mesenchymal stem cells (MSC) are known for their immunomodulatory properties. Accordingly, MSC are a leading candidate for cell therapy and can be applied to alleviate inflammatory diseases as well as aging frailty via systemic delivery. Akin to immune cells, MSC can also polarize into pro-inflammatory MSC (MSC1) and anti-inflammatory MSC (MSC2) following activation of Toll-like receptor 4 (TLR4) and TLR3, respectively. In the present study, we apply pituitary adenylate cyclase-activating peptide (PACAP) to polarize bone-marrow-derived MSC towards an MSC2 phenotype. Indeed, we found that polarized anti-inflammatory MSC were able to reduce the plasma levels of aging related chemokines in aged mice (18-months old) and increased hippocampal neurogenesis following systemic administration. Similarly, aged mice treated with polarized MSC displayed improved cognitive function in the Morris water maze and Y-maze assays compared with vehicle- and naïve-MSC-treated mice. Changes in neurogenesis and Y-maze performance were negatively and significantly correlated with sICAM, CCL2 and CCL12 serum levels. We conclude that polarized PACAP-treated MSC present anti-inflammatory properties that can mitigate age-related changes in the systemic inflammatory milieu and, as a result, ameliorate age related cognitive decline.

A PSYCHOMETRICALLY ROBUST LONGITUDINAL RESEARCH MEASURE OF FRAILTY: FIVE DIMENSIONS ACROSS AGE AND TIME

Abstract The research construct of frailty in aging requires a measure with sound psychometric properties, that is stable across longitudinal points of observation. Using Exploratory Factor Analysis and Longitudinal Mixed Methods, we developed a five-factor research measures of frailty that is robust across time. Standardized regression scores for each factor allow us to estimate the change in severity of dysfunction as individuals age. We propose a system for developing research tools for the concept of frailty in large longitudinal data sets, and present our findings of five factors of frailty for females and males from the English Longitudinal Study on Ageing.

Aging and Mesenchymal Stem Cells: Basic Concepts, Challenges and Strategies.

Aging and frailty are complex processes implicating multifactorial mechanisms, such as replicative senescence, oxidative stress, mitochondrial dysfunction, or autophagy disorder. All of these mechanisms drive dramatic changes in the tissue environment, such as senescence-associated secretory phenotype factors and inflamm-aging. Thus, there is a demand for new therapeutic strategies against the devastating effects of the aging and associated diseases. Mesenchymal stem cells (MSC) participate in a "galaxy" of tissue signals (proliferative, anti-inflammatory, and antioxidative stress, and proangiogenic, antitumor, antifibrotic, and antimicrobial effects) contributing to tissue homeostasis. However, MSC are also not immune to aging. Three strategies based on MSC have been proposed: remove, rejuvenate, or replace the senescent MSC. These strategies include the use of senolytic drugs, antioxidant agents and genetic engineering, or transplantation of younger MSC. Nevertheless, these strategies may have the drawback of the adverse effects of prolonged use of the different drugs used or, where appropriate, those of cell therapy. In this review, we propose the new strategy of "Exogenous Restitution of Intercellular Signalling of Stem Cells" (ERISSC). This concept is based on the potential use of secretome from MSC, which are composed of molecules such as growth factors, cytokines, and extracellular vesicles and have the same biological effects as their parent cells. To face this cell-free regenerative therapy challenge, we have to clarify key strategy aspects, such as establishing tools that allow us a more precise diagnosis of aging frailty in order to identify the therapeutic requirements adapted to each case, identify the ideal type of MSC in the context of the functional heterogeneity of these cellular populations, to optimize the mass production and standardization of the primary materials (cells) and their secretome-derived products, to establish the appropriate methods to validate the anti-aging effects and to determine the most appropriate route of administration for each case.

Retinal microvasculature and imaging markers of brain frailty in normal aging adults.

BackgroundThe retina and brain share a similar embryologic origin, blood barriers, and microvasculature features. Thus, retinal imaging has been of interest in the aging population to help in the early detection of brain disorders. Imaging evaluation of brain frailty, including brain atrophy and markers of cerebral small vessel disease (CSVD), could reflect brain health in normal aging, but is costly and time-consuming. In this study, we aimed to evaluate the retinal microvasculature and its association with radiological indicators of brain frailty in normal aging adults.MethodsSwept-source optical coherence tomography angiography (SS-OCTA) and 3T-MRI brain scanning were performed on normal aging adults (aged ≥ 50 years). Using a deep learning algorithm, microvascular tortuosity (VT) and fractal dimension parameter (Dbox) were used to evaluate the superficial vascular complex (SVC) and deep vascular complex (DVC) of the retina. MRI markers of brain frailty include brain volumetric measures and CSVD markers that were assessed.ResultsOf the 139 normal aging individuals included, the mean age was 59.43 ± 7.31 years, and 64.0% (n = 89) of the participants were females. After adjustment of age, sex, and vascular risk factors, Dbox in the DVC showed a significant association with the presence of lacunes (β = 0.58, p = 0.007), while VT in the SVC significantly correlated with the score of cerebral deep white matter hyperintensity (β = 0.31, p = 0.027). No correlations were found between brain volumes and retinal microvasculature changes (P > 0.05).ConclusionOur report suggests that imaging of the retinal microvasculature may give clues to brain frailty in the aging population.

Assessing Frailty Risk in Clinical Practice

Assessing Frailty Risk in Clinical Practice

Individualized perioperative management in transoral spine surgery: a single-center cohort study evaluating surgical wound complications and wound infections

BackgroundTransoral spine surgery is specific due to both its surgical approach and the spectrum of diseases it targets. Patients with high age and elevated clinical frailty scores are often involved, and there are reports of increased risks of surgical site infection (SSI) due to extended exposures requiring maxilotomy or mandibulotomy. Our case series describes surgical wound complications under the meticulous application of individualized perioperative multimodal management.MethodsOur primary outcome was the occurrence of SSI and the secondary outcome was the occurrence of other noninfectious wound complications evaluated in 22 adult patients who consecutively underwent the transoral spine surgery from 2001 to 2018 (trauma – C2, cervical nonunion: 6 patients, 27%; tumor: 4 patients, 18%; osteomyelitis: 6 patients, 27%; other non-traumatic cases: 6 patients, 27%). Structuralized data comprising parameters related to nosocomial infections after spine surgery were continuously processed and put into specialized database of preventive multimodal nosocomial infection control protocol that was used as a main source of analyzed parameters. The mean age of studied cohort was 54.9 pm 15.5 years, with 68% males, mean body mass index (BMI) 24.9 pm 5.22, and the mean clinical frailty score was 2.59 pm 1.07. There were 7 patients (32%) who only had the transoral approach and 15 patients (68%) having this approach followed by additional posterior approach. We observed SSI from all wound complications for up to one year after surgery.ResultsThere were 4 (18%) superficial wound complications from transoral approach, but none of them were infected. We had 2 patients (13%) with deep wound infections after subsequent posterior approach, but only one (4.5%) was classified as SSI.ConclusionsWe describe the wound complications and the incidence of SSI in a series of 22 patients after the transoral surgery. Considering the average values of the clinical frailty score reaching 2.59, American Society of Anesthesiologists score of 2.73, and the BMI of 26.87, the transoral spine surgery did not seem to be a considerable risk for SSI in the analyzed cohort, provided preventive perioperative multimodal management is properly individualized and followed.

Study protocol: MyoFit46\u2014the cardiac sub-study of the MRC National Survey of Health and Development

BackgroundThe life course accumulation of overt and subclinical myocardial dysfunction contributes to older age mortality, frailty, disability and loss of independence. The Medical Research Council National Survey of Health and Development (NSHD) is the world’s longest running continued surveillance birth cohort providing a unique opportunity to understand life course determinants of myocardial dysfunction as part of MyoFit46–the cardiac sub-study of the NSHD.MethodsWe aim to recruit 550 NSHD participants of approximately 75 years+ to undertake high-density surface electrocardiographic imaging (ECGI) and stress perfusion cardiovascular magnetic resonance (CMR). Through comprehensive myocardial tissue characterization and 4-dimensional flow we hope to better understand the burden of clinical and subclinical cardiovascular disease. Supercomputers will be used to combine the multi-scale ECGI and CMR datasets per participant. Rarely available, prospectively collected whole-of-life data on exposures, traditional risk factors and multimorbidity will be studied to identify risk trajectories, critical change periods, mediators and cumulative impacts on the myocardium.DiscussionBy combining well curated, prospectively acquired longitudinal data of the NSHD with novel CMR–ECGI data and sharing these results and associated pipelines with the CMR community, MyoFit46 seeks to transform our understanding of how early, mid and later-life risk factor trajectories interact to determine the state of cardiovascular health in older age.Trial registration: Prospectively registered on ClinicalTrials.gov with trial ID: 19/LO/1774 Multimorbidity Life-Course Approach to Myocardial Health- A Cardiac Sub-Study of the MCRC National Survey of Health and Development (NSHD).

Prospective telehealth analysis of functional performance, frailty, quality of life, and mental health after COVID-19 hospitalization

BackgroundCOVID-19 is a global pandemic with poorly understood long-term consequences. Determining the trajectory of recovery following COVID-19 hospitalization is critical for prioritizing care, allocating resources, facilitating prognosis, and informing rehabilitation. The purpose of this study was to prospectively evaluate recovery following COVID-19 hospitalization.MethodsParticipants age 18 years or older who were hospitalized for ≥24 h due to COVID-19 completed phone/video call virtual assessments (including the 10-time chair rise test) and survey forms at three time points (2–6, 12, and 18 weeks) after hospital discharge. Univariate logistic and linear regression models assessed the associations of the outcomes with primary predictors (categorical age, sex, race/ethnicity group, and categorical pre-hospitalization frailty) at baseline; the same were used to assess differences in change from week 2–6 (continuous outcomes) or outcome persistence/worsening (categorical) at last contact.ResultsOne hundred nine adults (age 53.0 [standard deviation 13.1]; 53% female) participated including 43 (39%) age 60 or greater; 59% identified as an ethnic and/or racial minority. Over 18 weeks, the mean time to complete the 10-time chair rise test decreased (i.e., improved) by 6.0 s (95% CI: 4.1, 7.9 s; p < 0.001); this change did not differ by pre-hospital frailty, race/ethnicity group, or sex, but those age ≥ 60 had greater improvement. At weeks 2–6, 67% of participants reported a worse Clinical Frailty Scale category compared to their pre-hospitalization level, whereas 42% reported a worse frailty score at 18 weeks. Participants who did not return to pre-hospitalization levels were more likely to be female, younger, and report a pre-hospitalization category of ‘very fit’ or ‘well’.ConclusionsWe found that functional performance improved from weeks 2–6 to 18 weeks of follow-up; that incident clinical frailty developed in some individuals following COVID-19; and that age, sex, race/ethnicity, and pre-hospitalization frailty status may impact recovery from COVID-19. Notably, individuals age 60 and older were more likely than those under age 45 years to return to their pre-hospitalization status and to make greater improvements in functional performance. The results of the present study provide insight into the trajectory of recovery among a representative cohort of individuals hospitalized due to COVID-19.

Factors partitioning physical frailty in people aging with HIV: A classification and regression tree approach.

To estimate the extent to which comorbidity and lifestyle factors were associated with physical frailty in middle-aged and older Canadians living with HIV. Cross-sectional analysis of 856 participants from the Canadian Positive Brain Health Now cohort. The frailty indicator phenotype was adapted from Fried's criteria using self-report items. Univariate logistic regression and classification and regression tree (CaRT) models were used to identify the most relevant independent contributors to frailty. In all, 100men (14.0%) and 26 women (19.7%) were identified as frail (≥3/5 criteria) for an overall prevalence of 15.2%. Nine comorbidities showed an influential association with frailty. The most influential comorbidities were hypothyroidism [odds ratio (OR) = 2.55, 95% confidence interval (CI): 1.29-5.03] and arthritis (OR = 2.54, 95% CI: 1.58-4.09). Additionally, tobacco (OR = 1.79, 95% CI: 1.05-3.04) showed an association. Any level of alcohol consumption showed a protective effect for frailty. The CaRT model showed nine pathways that led to frailty. Arthritis was the most discriminatory variable followed by alcohol, hypothyroidism, tobacco, cancer, cannabis, liver disease, kidney disease, osteoporosis, lung disease and peripheral vascular disease. The prevalence of physical frailty for people with arthritis was 27.4%; with additional cancer or tobacco and alcohol the prevalence rates were 47.1% and 46.1%, respectively. The protective effect of alcohol consumption evident in the univariate model appeared again in the CaRT model, but this effect varied. Cognitive frailty (19.5% overall) and emotional frailty (37.9% overall) were higher than the prevalence of physical frailty. Specific comorbidities and tobacco use were implicated in frailty, suggesting that it is comorbidities causing frailty. However, some frailty still appears to be HIV-related. The higher prevalence of cognitive and emotional frailty highlights the fact that physical frailty should not be the only focus in HIV.

Potential of Stem Cell-Based Therapy to Restore Function in Aging Systems: Are We There Yet?

While there is extensive interest in geroscience approaches to health and disease, few basic science discoveries have made their way into clinical trials. Herein, we comment on cell-based therapies, in which supplementing robust stem cell capacity to aged systems theoretically could lead to sustained improvement. This exciting approach has undergone translational development, and we highlight studies targeting a single system and others aimed at treating overall aging frailty by restoring the aged stem cell niches that underly diminished endogenous regenerative capacity.

A Phase 2b Clinical Trial Assessing Lomecel-B Infusion in Individuals with Aging Frailty: Study Design and Rationale

Frailty is a common and important geriatric syndrome characterized by age-associated declines in physiology and function across multiple organ systems, which lead to increased vulnerability to adverse health outcomes. A biological mechanism that underlies the decline in physical function associated with aging frailty is chronic inflammation. The MSCs in Lomecel-B have immuno-modulatory capacity and control inflammation and the cytokine production of lymphocytes. An individual’s endogenous stem cell production decreases with age, this decrease likely contributes to reduced ability to regenerate and repair organs and tissues. Aging Frailty represents an exciting potential indication for cellular based therapies like Lomecel-B. This study is intended to evaluate the effects of Lomecel-B infusion compared to placebo on mobility and exercise tolerance, patient-reported physical function assessments and biomarkers for inflammation in individuals with Aging Frailty. This is a randomized, double-blind placebo-controlled, parallel multi-arm multicenter study enrolling adults aged 70-85 years identified as mildly or moderately frail per the CSHA Clinical Frailty Scale (CFS), with reduced six minute walk test (6MWT) and elevated Tumor Necrosis Factor-α (TNF-α), at screening. 150 subjects (30 per group) were randomized to receive a single peripheral intravenous infusion of 25, 50, 100, or 200 million doses, or placebo. Safety and efficacy assessments were conducted at 30, 90, 180, and 270 days after infusion. A follow up telephone call to subjects was placed at 365 days. We describe the design and rationale in detail of this 2b study assessing the effects of Lomecel-B on older adults with Aging Frailty.

The Interactome in the Evolution From Frailty to Sarcopenic Dependence.

Biomarkers are essential tools for accurate diagnosis and effective prevention, but their validation is a pending challenge that limits their usefulness, even more so with constructs as complex as frailty. Sarcopenia shares multiple mechanisms with frailty which makes it a strong candidate to provide robust frailty biomarkers. Based on this premise, we studied the temporal evolution of cellular interactome in frailty, from independent patients to dependent ones. Overweight is a recognized cause of frailty in aging, so we studied the altered mechanisms in overweight independent elderly and evaluated their aggravation in dependent elderly. This evidence of the evolution of previously altered mechanisms would significantly support their role as real biomarkers of frailty. The results showed a preponderant role of autophagy in interactome control at both different functional points, modulating other essential mechanisms in the cell, such as mitochondrial capacity or oxidative stress. Thus, the overweight provoked in the muscle of the elderly an overload of autophagy that kept cell survival in apparently healthy individuals. This excessive and permanent autophagic effort did not seem to be able to be maintained over time. Indeed, in dependent elderly, the muscle showed a total autophagic inactivity, with devastating effects on the survival of the cell, which showed clear signs of apoptosis, and reduced functional capacity. The frail elderly are in a situation of weakness that is a precursor of dependence that can still be prevented if detection is early. Hence biomarkers are essential in this context.

Colorectal Cancer Screening in the Elderly: Is Age Just a Number?

IntroductionColorectal cancer screening improved outcomes for patients diagnosed between the age of 45-75. Present life expectancy is beyond this limit, yet there are no guidelines for these ages. We aim to identify outcomes after screening and intervention in patients ≥75 years and correlate with frailty. Materials and methodsRecords between 2011 and 2019 were queried. Patients ≥75 screened and treated for colorectal cancer were included. Patient demographics, perioperative mortality, age at last colonoscopy and frailty score were calculated. A Modified Frailty Index from the Canadian Study of Health and Aging Frailty Index was used. A score of 1 to 11 was calculated based on patient comorbidities. The MFI was assigned from 0 to 11: 0 signified absence of frailty and 11 indicated maximum frailty. ResultsOf 179 patients were identified, 46.3% males. 171(95%) had elective and 8 (5%) had emergent surgery. The average age was 81.8 years. All colonoscopies were performed for symptoms. A modified frailty index was retrospectively calculated; 75% of patients scored between 0 and 2 and 1% scored >6. ConclusionOlder patients who underwent colonoscopy and surgery for symptomatic colon cancer had a low mortality, 2%. The average age was 6.8 years older than the recommended cutoff for colonoscopy screening. Most patients scored 0 to 2 on the modified frailty index, suggesting that not only are older patients more fit than previously thought, but also able to tolerate colorectal interventions more liberally. Utilizing frailty indices to identify screening patterns beyond 75 years of age might prove beneficial for this patient population. Further studies are recommended.

Impact of frailty on perioperative and oncologic outcomes in patients undergoing surgery or ablation for renal cancer: a systematic review.

Frailty has been recognized as a major risk factor for adverse perioperative and oncological outcomes in patients with genitourinary malignancies. Yet, the evidence supporting such an association in patients with renal cell carcinoma (RCC) is still sparse. Herein we provide an updated comprehensive overview of the impact of frailty on perioperative and oncologic outcomes in patients undergoing surgery or ablation for RCC. A systematic review of the English-language literature was conducted using the MEDLINE (via PubMed), Web of Science and the Cochrane Library databases according to the principles highlighted by the EAU Guidelines Office and the PRISMA statement recommendations. The review protocol was registered on PROSPERO (CRD42021242516). The overall quality of evidence was assessed according to GRADE recommendations. Overall, 18 studies were included in the qualitative analysis. Most of these were retrospective single-center series including patients undergoing surgery for non-metastatic RCC. The overall quality of evidence was low. A variety of measures were used for frailty assessment, including the Canadian Study of Health and Aging Frailty Index, the five-item frailty index, the Modified Rockwood's Clinical Frailty Scale Score, the Hopkins Frailty score, the Groningen Frailty Index, and the Geriatric nutritional risk index. Sarcopenia was defined based on the Lumbar skeletal muscle mass at cross-sectional imaging, the skeletal muscle index, the total psoas area, or the Psoas Muscle Index. Overall, available studies point to frailty and sarcopenia as potential independent risk factors for worse perioperative and oncological outcomes after surgery or ablation for different RCC stages. Increased patient's frailty was indeed associated with higher risk of perioperative complications, healthcare resources utilization, readmission rates and longer hospitalization periods, as well as potentially lower cancer specific or overall survival. Frailty has been consistently associated with worse outcomes after surgery for RCC, reinforcing the value of preoperative frailty assessment in carefully selected patients. Given the low quality of the available evidence (especially in the setting of tumor ablation), prospective studies are needed to standardize frailty assessments and to identify patients who are expected to benefit most from preoperative geriatric evaluation, aiming to optimize decision-making and postoperative outcomes in patients with RCC.