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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 ± 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 ± 0.9 kg (-11.3% ± 5.4%) over 18 weeks compared with +0.5 ± 0.9 kg (+0.03% ± 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., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Obesity compounds aging-related declines in cardiorespiratory fitness, with accompanying fatigue and disability. This study determined the effects of two different levels of caloric restriction (CR) during aerobic training on cardiorespiratory fitness, fatigue, physical function, and cardiometabolic risk., Methods: The INFINITE study was a 20-week randomized trial in 180 older (65-79 years) men and women with obesity (body mass index = 30-45 kg/m2). Participants were randomly assigned to (i) aerobic training (EX; treadmill 4 days/wk for 30 minutes at 65%-70% of heart rate reserve), (ii) EX with moderate (-250 kcal/d) CR (EX + Mod-CR), or (iii) EX with more intensive (-600 kcal/d) CR (EX + High-CR). Cardiorespiratory fitness (peak aerobic capacity, VO2 peak, primary outcome) was determined during a graded exercise test., Results: One hundred and fifty-five participants returned for 20-week data collection (87% retention). VO2 peak increased by 7.7% with EX, by 13.8% with EX + Mod-CR, and by 16.0% with EX + High-CR, and there was a significant treatment effect (EX + High-CR = 21.5 mL/kg/min, 95% confidence interval = 19.8-23.2; EX + Mod-CR = 21.2 mL/kg/min, 95% confidence interval = 19.4-23.0; EX = 20.1 mL/kg/min, 95% confidence interval = 18.4-21.9). Both CR groups exhibited significantly greater improvement in self-reported fatigue and disability and in glucose control, compared with EX., Conclusion: Combining aerobic exercise with even moderate CR is more efficacious for improving cardiorespiratory fitness, fatigue and disability, and glucose control than exercise alone and is as effective as higher-dose CR., (© The Author(s) 2018. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Previous studies support beneficial effects of both resistance exercise training (RT) and caloric restriction (CR) on skeletal muscle strength and physical performance. The goal of this study was to determine the effects of adding CR to RT on single-muscle fiber contractility responses to RT in older overweight and obese adults., Methods: We analyzed contractile properties in 1,253 single myofiber from muscle biopsies of the vastus lateralis, as well as physical performance and thigh muscle volume, in 31 older (65-80 years), overweight or obese (body mass index = 27-35 kg/m2) men (n = 19) and women (n = 12) who were randomly assigned to a standardized, progressive RT intervention with CR (RT+CR; n = 15) or without CR (RT; n = 16) for 5 months., Results: Both interventions evoked an increase in force normalized to cross-sectional area (CSA), in type-I and type-II fibers and knee extensor quality. However, these improvements were not different between intervention groups. In the RT group, changes in total thigh fat volume inversely correlated with changes in type-II fiber force (r = -.691; p = .019). Within the RT+CR group, changes in gait speed correlated positively with changes in type-I fiber CSA (r = .561; p = .030). In addition, increases in type-I normalized fiber force were related to decreases in thigh intermuscular fat volume (r = -0.539; p = .038)., Conclusion: Single muscle fiber force and knee extensor quality improve with RT and RT+CR; however, CR does not enhance improvements in single muscle fiber contractility or whole muscle in response to RT in older overweight and obese men and women., (© The Author(s) 2018. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Cognitive impairment and decline may signal the increased risk of incident cardiovascular disease (CVD). We examined associations of global cognitive function, as measured by the Modified Mini-Mental State Examination (3MS) and changes in 3MS over time, with incident CVD, individual CVD outcomes, CVD death, and all-cause mortality., Methods: A total of 5,596 women (≥ 60) from the Women's Health Initiative Memory Study free of CVD at baseline were followed for an average of 7.1 years. The 3MS was measured at baseline and annually thereafter. Cox proportional hazards regressions were used to model associations between baseline 3MS and changes in 3MS and time to events., Results: In the fully-adjusted models for every 5-point lower baseline 3MS score, the risk was 12% greater for incident CVD, 37% for HF, 35% for CVD death, and 24% for all-cause mortality. No significant relationships were found for coronary heart disease (CHD), angina, stroke/transient ischemic attack (TIA), or coronary revascularization. When change in 3MS was added as a time-varying covariate in the fully-adjusted models, for every 1-point/year greater decline in 3MS, the risk was 4% greater for incident CVD, 10% for CHD, 9% for Stroke/TIA, 17% for CVD death, and 13% for all-cause mortality., Conclusions: In older women free of prevalent CVD at baseline, lower baseline global cognitive function or decline in global cognitive function over time, increased risk of incident CVD, CVD death, and all-cause mortality.

Background: The Women's Health Initiative has collected data on the aging process of postmenopausal women for over two decades, including data on many women who have achieved age 80 years and older. However, there has not been any previous effort to characterize the 80+ cohort and to identify associated retention factors., Methods: We include all women at baseline of the Women's Health Initiative who would be at least 80 years of age as of September 17, 2012. We summarize retention rates during the study and across two re-enrollment campaigns as well as the demographic and health-related characteristics that predicted retention. Further, we describe the longitudinal change from baseline in the women identified as members of the 80+ cohort., Results: Retention rates were lower during each of two re-enrollment periods (74% and 83% retained during re-enrollment periods 1 and 2, respectively) than during the first and second data collection periods (90% each). Women who were retained were more likely to be white, educated, and healthier at baseline. Women age 80 and older saw modest changes in body mass index and depression burden, despite lower physical activity and increased cardiovascular disease., Conclusions: The characteristics of women who were retained in the 80+ cohort differ in significant ways compared with their peers at baseline. Identifying the characteristics associated with attrition in older cohorts is important because aging and worsening health has a negative impact on study attrition. Strategies should be implemented to improve retention rates among less healthy older adults., (© The Author 2015. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Females 80 years and older comprise 22% of the total U.S. survivor population, yet the impact of cancer on the physical well-being of women is this age group has not been well characterized., Methods: We compared women, 80 years of age and older in the Women's Health Initiative extension 2, who did (n = 2,270) and did not (n = 20,272) have an adjudicated history of cancer during Women's Health Initiative enrollment; analyses focused on women >2-years postcancer diagnosis. The physical functioning subscale of the RAND-36 was the primary outcome. Demographic, health-status, and psychosocial covariates were drawn from Women's Health Initiative assessments. Analysis of covariance was used to examine the effect of cancer history on physical function, with and without adjustment for covariates., Results: In adjusted models, women with a history of cancer reported significantly lower mean physical functioning (56.6, standard error [SE] 0.4) than those without a cancer history (58.0, SE 0.1), p = .002. In these models, younger current age, lower body mass index, increased physical activity, higher self-rated health, increased reported happiness, and the absence of noncancer comorbid conditions were all associated with higher physical functioning in both women with and without a history of cancer., Conclusions: Women older than 80 years of age with a cancer history have only a moderately lower level of physical function than comparably aged women without a cancer history. Factors associated with higher levels of physical functioning were similar in both groups., (© The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: We examined physical functioning (PF) trajectories (maintaining, slowly declining, and rapidly declining) spanning 15 years in older women aged 65-80 and protective factors that predicted better current levels and less decline in functional independence outcomes after age 80., Methods: Women's Health Initiative extension participants who met criteria (enrolled in either the clinical trial or observational study cohort, >80 years at the data release cutoff, PF survey data from initial enrollment to age 80, and functional independence survey data after age 80) were included in these analyses (mean [SD] age = 84.0 [1.4] years; N = 10,478). PF was measured with the SF-36 (mean = 4.9 occasions). Functional independence was measured by self-reported level of dependence in basic and instrumental activities of daily living (ADLs and IADLs) (mean = 3.4 and 3.3 occasions)., Results: Maintaining consistent PF in older adulthood extends functional independence in ADL and IADL in late-life. Protective factors shared by ADL and IADL include maintaining PF over time, self-reported excellent or very good health, no history of hip fracture after age 55, and no history of cardiovascular disease. Better IADL function is uniquely predicted by a body mass index less than 25 and no depression. Less ADL and IADL decline is predicted by better self-reported health, and less IADL decline is uniquely predicted by having no history of hip fracture after age 55., Conclusions: Maintaining or improving PF and preventing injury and disease in older adulthood (ages 65-80) has far-reaching implications for improving late-life (after age 80) functional independence., (© The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Physical function declines, and markers of inflammation increase with advancing age, even in healthy persons. Microbial translocation (MT) is the systemic exposure to mucosal surface microbes/microbial products without overt bacteremia and has been described in a number of pathologic conditions. We hypothesized that markers of MT, soluble CD14 (sCD14) and lipopolysaccharide (LPS) binding protein (LBP), may be a source of chronic inflammation in older persons and be associated with poorer physical function., Methods: We assessed cross-sectional relationships among two plasma biomarkers of MT (sCD14 and LBP), physical function (hand grip strength, short physical performance battery [SPPB], gait speed, walking distance, and disability questionnaire), and biomarkers of inflammation (C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), TNF-α soluble receptor 1 [TNFsR1]) in 59 older (60-89 years), healthy (no evidence of acute or chronic illness) men and women., Results: LBP was inversely correlated with SPPB score and grip strength (p = .02 and p < .01, respectively) and positively correlated with CRP (p = 0.04) after adjusting for age, gender, and body mass index. sCD14 correlated with IL-6 (p = .01), TNF-α (p = .05), and TNFsR1 (p < .0001). Furthermore, the correlations between LBP and SPPB and grip strength remained significant after adjusting for each inflammatory biomarker., Conclusions: In healthy older individuals, LBP, a surrogate marker of MT, is associated with worse physical function and inflammation. Additional study is needed to determine whether MT is a marker for or a cause of inflammation and the associated functional impairments.

Background: Recently, subclinical aspiration has been identified in approximately 30% of community-dwelling older adults. Given that the tongue is a key component of the safe swallow, we hypothesized healthy older adults who aspirate will generate less tongue strength than adults who do not aspirate. Furthermore, as muscle weakness may reflect a global effect of aging, we further investigated whether tongue strength is correlated with handgrip strength., Methods: We assessed 78 healthy community-dwelling older adults (M = 77.3 years, SD = 7.26) for aspiration status (37% aspirators) via flexible endoscopic evaluation of swallowing. Maximal isometric anterior and posterior tongue strength, anterior and posterior swallowing tongue strength, and maximum handgrip strength were measured., Results: Isometric tongue strength was significantly lower in aspirators versus nonaspirators (p = .03) at both the anterior (463 vs 548 mmHg, respectively) and posterior lingual locations (285 vs 370 mmHg, respectively). Likewise, swallowing tongue strength was significantly lower in aspirators versus nonaspirators at both the anterior (270 vs 317 mmHg, respectively) and posterior lingual locations (220 vs 267 mmHg, respectively). There was no difference between aspirators and nonaspirators' handgrip strength (p > .05), although handgrip strength was correlated with posterior tongue strength (r = .34, p = .005)., Conclusions: Lower anterior and posterior isometric and swallowing tongue strength were dependent on aspiration status. Lower lingual strength in healthy adults may predispose them to aspiration. The correlation between tongue and handgrip strength is consistent with the hypothesis that impaired oropharyngeal strength reflects global age-related declines in muscle strength.

Background: Chronic subclinical inflammation may contribute to impaired physical function in older adults; however, more data are needed to determine whether inflammation is a common mechanism for functional decline, independent of disease or health status., Methods: We examined associations between physical function and inflammatory biomarkers in 542 older men and women enrolled in four clinical studies at Wake Forest University between 2001 and 2006. All participants were at least 55 years and had chronic obstructive pulmonary disease, congestive heart failure, high cardiovascular risk, or self-reported physical disability. Uniform clinical assessments were used across studies, including grip strength; a Short Physical Performance Battery (SPPB; includes balance, 4-m walk, and repeated chair stands); inflammatory biomarker assays for interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), and C-reactive protein (CRP); and anthropometric measures., Results: Higher levels of CRP and IL-6, but not TNF-alpha, were associated with lower grip strength and SPPB scores and longer times to complete the 4-m walk and repeated chair stands tests, independent of age, gender, and race. More importantly, these relationships were generally independent of disease status. Further adjustment for fat mass, lean mass, or percent body fat altered some of these relationships but did not significantly change the overall results., Conclusions: Elevated CRP and IL-6 levels are associated with poorer physical function in older adults with various comorbidities, as assessed by a common battery of clinical assessments. Chronic subclinical inflammation may be a marker of functional limitations in older persons across several diseases/health conditions.

We investigated whether caloric restriction (CR) improves physical performance in a rodent model of aging, and whether this effect is accompanied with a decrease in visceral adipose tissue production of proinflammatory cytokines. Body composition, standardized physical performance measures, as well as in vitro visceral adipose tissue cytokine secretion and circulating levels of an inflammatory marker were cross-sectionally assessed in ad libitum (AL)-fed and lifelong CR Fischer 344 x Brown Norway male rats aged 18, 24, and 29 months. Fat to lean mass ratio increased and physical performance declined with age in the AL rats. Compared to AL rats, CR rats had lower fat mass, fat to lean ratio, adipose tissue secretion of interleukin-6, and circulating levels of C-reactive protein, and higher physical performance scores. Therefore, CR may be an effective intervention for improving functional status into advanced age and is perhaps mediated via a reduction in adipose tissue-generated proinflammatory cytokine production.