Caloric Restriction Intervention Alters Specific Circulating Biomarkers of the Senescence-Associated Secretome in Middle-Aged and Older Adults With Obesity and Prediabetes in an 18-Week Randomized Controlled Trial.

Cellular senescence is a biological aging process that is exacerbated by obesity and leads to inflammation and age- and obesogenic-driven chronic diseases including type 2 diabetes. Caloric restriction (CR) may improve metabolic function in part by reducing cellular senescence and the pro-inflammatory senescence-associated phenotype (SASP). We conducted an ancillary investigation of an 18-week randomized controlled trial (RCT) of CR (n = 31) or Control (n = 27) in 58 middle-aged/older adults (57.6 ±â€…5.8 years; 75% Women) with obesity and prediabetes. We measured mRNA expression of select senescence and apoptosis genes in blood CD3 + T cells (qRT-PCR) and a panel of 25 plasma SASP proteins (Luminex/multiplex; ELISA). Participants randomized to CR lost -10.8 ±â€…0.9 kg (-11.3% ±â€…5.4%) over 18 weeks compared with +0.5 ±â€…0.9 kg (+0.03% ±â€…3.5%) in Control group. T-cell expression of senescence biomarkers, p16INK4a and p21CIP1/WAF1, and apoptosis markers, BCL2L1 and BAK1, was not different between CR and Control groups in age, race, and sex-adjusted mixed models (p > .05, all). Iterative principal axis factor analysis was used to develop composite SASP Factors, and the Factors comprising TNFRI, TNFRII, uPAR, MMP1, GDF15, OPN, Fas, and MPO were significantly altered with CR intervention (age, sex, race-adjusted mixed model time × treatment F = 4.17, p ≤ .05) and associated with the degree of weight loss (R2 = 0.12, p ≤ .05). Our study provides evidence from an RCT that specific circulating biomarkers of senescent cell burden are changed by CR in middle-aged and older adults with obesity and prediabetes. Future studies compare tissue and circulating levels of p16INK4a and pro-inflammatory SASP biomarkers in other populations, and interventions.

T cell exhaustion is associated with cognitive status and amyloid accumulation in Alzheimer's disease.

Studies over the last 100 years have suggested a link between inflammation, infectious disease, and Alzheimer's Disease (AD). Understanding how the immune system changes during the development of AD may facilitate new treatments. Here, we studied an aging cohort who had been assessed for AD pathology with amyloid positron emission tomography and cognitive testing, and conducted high dimensional flow cytometry on peripheral blood mononuclear and cerebrospinal fluid cells. Participants were assigned a classification of being amyloid negative cognitively normal, amyloid positive cognitively normal (APCN), or amyloid positive mild cognitive impairment (APMCI), an early stage of AD. We observed major alterations in the peripheral innate immune system including increased myeloid and plasmacytoid dendritic cells in the blood of APMCI participants. When the adaptive immune system was examined, amyloid positive participants, regardless of cognitive status, had increased CD3+ T cells. Further analyses of CD4+ and CD8+ T cells revealed that APMCI participants had an increase in more differentiated phenotype T cells, such as effector memory and effector memory CD45RA expressing (TEMRA), compared to those with normal cognition. When T cell function was measured, we observed that T cells from APCN participants had increased IFNγ+GzB- producing cells compared to the other participants. In contrast, we demonstrate that APMCI participants had a major increase in T cells that lacked cytokine production following restimulation and expressed increased levels of PD-1 and Tox, suggesting these are exhausted cells. Rejuvenation of these cells may provide a potential treatment for AD.

Self-reported mobility as a preoperative risk assessment tool in older surgical patients compared to the American College of Surgeons National Surgical Quality Improvement Program.

BACKGROUND: The American College of Surgeons National Surgical Quality Improvement Program (NSQIP®) developed a surgical risk calculator using data from 1.4 million patients and including 1557 unique Current Procedural Terminology (CPT) codes. Although this calculator demonstrated excellent performance in predicting postoperative mortality, morbidity, and six surgical complications, it was not developed specifically for use in older surgical patients who have worse surgical outcomes and additional unique risk factors compared to younger adults. We aimed to test the ability of a simple self-reported mobility tool to predict postoperative outcomes in the older surgical population compared to the NSQIP. METHODS: We used data from a prospective cohort study that enrolled 197 older surgical patients (≥ 69 years) undergoing various elective surgeries and assessed 30-day surgical outcomes. Statistical models included data from the Mobility Assessment Tool-short form (MAT-sf) alone, covariates alone, and MAT-sf data and covariates. We used leave-one-out (LOO) cross-validation of the models within our cohort and compared their performance for predicting postoperative outcomes against the NSQIP calculator based on receiver operating characteristic area under the curve (ROC AUC). RESULTS: Patients with poor self-reported mobility experienced higher rates of postoperative complications and nursing home placement. There was no difference in performance between any of our models and the NSQIP calculator (p > 0.1), with AUC between 0.604 and 0.697 for predicting postoperative complications and 0.653 and 0.760 for predicting nursing home placement. All models also predicted a length of stay (LOS) similar to the actual LOS. CONCLUSION: Mobility assessment alone using MAT-sf can predict postoperative complications, nursing home placement, and LOS for older surgical patients, with accuracy comparable to that of the NSQIP calculator. The simplicity of this noninvasive risk assessment tool makes it an attractive alternative to the NSQIP calculator that requires 20 patient predictors and the planned procedure, or CPT code to predict the chance that patients will have 15 different adverse outcomes following surgery.

Body Composition and Physical Function in Older Adults with Various Comorbidities.

BACKGROUND: Lower muscle and higher fat mass are characteristics of older adults; their physical function is also characterized by slower gait speed and weaker strength. However, the association between specific body composition and physical function is unclear. METHODS: We examined the association between body composition and physical performance using combined cross-sectional data of 1,821 participants from 13 clinical studies at Wake Forest University that used a consistent battery of tests. All participants were ≥60 years old and had one of the following conditions: healthy, osteoarthritis, coronary artery disease, obesity, heart failure, at elevated risk for disability, renal transplantation candidates, heart failure with preserved ejection fraction, moderate self-reported disability, hypertension, diabetes, or coronary artery disease, at high risk for cardiovascular disease. Data at enrollment from each study using uniform tools including body mass index (BMI), dual energy x-ray absorptiometry, physical performance assessment using 4 m walk speed, five chair rise time, handgrip strength, short physical performance battery (17), and Pepper Assessment Tool for Disability were analyzed. RESULTS: Increased BMI was associated with slower walk speed, lower short physical performance battery, and higher Pepper Assessment Tool for Disability score. Increased percentage of body fat was associated with slower walk speed, lower hand grip strength, lower short physical performance battery scores, and higher Pepper Assessment Tool for Disability scores. Percent appendicular lean mass was associated with faster walk speed, higher handgrip strength, higher short physical performance battery, and lower Pepper Assessment Tool for Disability score. There were no significant discrepancies in relationship between body composition and physical function by gender except gender and BMI on chair-rise time. CONCLUSIONS: Higher BMI and percent body fat were associated with poor physical function while percent appendicular lean mass was associated with better physical function. There was no significant discrepancy in the by gender.

Self-reported Mobility in Older Patients Predicts Early Postoperative Outcomes after Elective Noncardiac Surgery.

BACKGROUND: Specific geriatric assessment tools may complement traditional perioperative risk stratification. The aim of this study was to evaluate whether self-reported mobility is predictive of postoperative outcomes in older patients undergoing elective noncardiac surgery. METHODS: Patients aged 69 yr or older (n = 197) underwent (1) traditional risk assessments (American Society of Anesthesiologists physical status classification and Revised Cardiac Risk Index), (2) five-point frailty evaluation, (3) self-reported mobility assessment using the Mobility Assessment Tool-short form (range, 30.21 [poor] to 69.76 [excellent]), and (4) measurements of high-sensitivity C-reactive protein. Outcomes were postoperative complications, time to discharge, and nursing home placement (NHP). RESULTS: In the sample of this study (mean age, 75 ± 5 yr; 51% women), 72% had intermediate- or high-risk surgery. Median time to discharge was 3 days (interquartile range, 1 to 4 days). Thirty patients (15%) developed postoperative complications, and 27 (13%) required NHP. After controlling for age, sex, body mass index, pain score, Revised Cardiac Risk Index, American Society of Anesthesiologist physical status, surgical risk, and high-sensitivity C-reactive protein, worse self-reported mobility (per 10-point decrease in Mobility Assessment Tool, which is equivalent to 1 SD) was associated with more postoperative complications (odds ratio [OR], 1.69; 95% CI, 1.05 to 2.73), later time to discharge (hazards ratio, 0.81; 95% CI, 0.68 to 0.96), and increased NHP (OR, 2.01; 95% CI, 1.13 to 3.56). By using the same model, intermediate frailty or frailty increased NHP (OR, 3.11; 95% CI, 1.02 to 9.54) but was not related to either postoperative complications or time to discharge. CONCLUSIONS: Preoperative self-reported mobility using a novel and brief assessment may help identify elderly patients at risk for adverse postoperative events.