Publications by authors named "Jack M Guralnik"

483 Publications

Nutritional Mediators of Cellular Decline and Mitochondrial Dysfunction in Older Adults.

Geriatrics (Basel) 2021 Apr 6;6(2). Epub 2021 Apr 6.

Nutrition, Exercise Physiology, and Sarcopenia Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111, USA.

Aging is a primary risk factor for the progressive loss of function, disease onset, and increased vulnerability to negative health-related outcomes. These clinical manifestations arise in part from declines in mitochondrial, metabolic, and other processes considered to be hallmarks of aging. Collectively, these changes can be defined as age-associated cellular decline (AACD) and are often associated with fatigue, reduced strength, and low physical activity. This manuscript summarizes a recent Gerontological Society of America Annual Scientific Meeting symposium that explored mechanisms, clinical signs, and emerging cellular nutrition interventions for AACD. The session opened by highlighting results of an expert consensus that developed an initial framework to identify self-reported symptoms and observable signs of AACD in adults aged >50 years. Next, findings from the multi-ethnic molecular determinants of sarcopenia study were discussed, showing impaired mitochondrial bioenergetic capacity and NAD metabolism in skeletal muscle of older adults with sarcopenia. Lastly, recent clinical evidence was presented linking urolithin A, a natural mitophagy activator, to improved mitochondrial and cellular health. The virtual panel discussed how stimulation of mitochondrial function via biological pathways, such as mitophagy and NAD augmentation, could improve cellular function and muscle health, potentially impacting clinical signs of AACD and overall healthy aging.
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http://dx.doi.org/10.3390/geriatrics6020037DOI Listing
April 2021

Sustained physical activity in peripheral artery disease: Associations with disease severity, functional performance, health-related quality of life, and subsequent serious adverse events in the LITE randomized clinical trial.

Vasc Med 2021 Apr 8:1358863X21989430. Epub 2021 Apr 8.

Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.

This study investigated cross-sectional associations of peripheral artery disease (PAD) severity (defined by the ankle-brachial index (ABI)) and amounts of daily sustained physical activity (PA) (defined as > 100 activity counts per minute lasting 5 consecutive minutes or more). This study also investigated associations of amounts of daily sustained PA with 6-minute walk (6MW) distance and the Short Form-36 physical functioning domain (SF-36 PF) score in cross-sectional analyses and with serious adverse events (SAEs) in longitudinal analyses of people with PAD. PA was measured continuously for 10 days using a tri-axial accelerometer at baseline in 277 participants with PAD randomized to the LITE clinical trial. In regression analyses, each 0.15 lower ABI value was associated with a 5.67% decrease in the number of daily bouts of sustained PA (95% CI: 3.85-6.54; < 0.001). Every additional bout of sustained PA per day was associated with a 4.56-meter greater 6MW distance (95% CI: 2.67-6.46; < 0.0001), and a 0.81-point improvement in SF-36 PF score (95% CI: 0.34-1.28; < 0.001). Participants with values of daily bouts of sustained PA below the median had higher rates of SAEs during follow-up, compared to participants above the median (41% vs 24%; = 0.002). In conclusion, among participants with PAD, lower ABI values were associated with fewer bouts of daily sustained PA. A greater number of bouts of daily sustained PA were associated with better 6MW performance and SF-36 PF score, and, in longitudinal analyses, lower rates of SAEs.
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http://dx.doi.org/10.1177/1358863X21989430DOI Listing
April 2021

Sex-specific 25-hydroxyvitamin D threshold concentrations for functional outcomes in older adults: PRoject on Optimal VItamin D in Older adults (PROVIDO).

Am J Clin Nutr 2021 Apr 7. Epub 2021 Apr 7.

California Pacific Medical Center Research Institute, San Francisco, CA, USA.

Background: Threshold serum 25-hydroxyvitamin D [25(OH)D] concentrations for extraskeletal outcomes are uncertain and could differ from recommendations (20-30 ng/mL) for skeletal health.

Objectives: We aimed to identify and validate sex-specific threshold 25(OH)D concentrations for older adults' physical function.

Methods: Using 5 large prospective, population-based studies-Age, Gene/Environment Susceptibility-Reykjavik (n = 4858, Iceland); Health, Aging, and Body Composition (n = 2494, United States); Invecchiare in Chianti (n = 873, Italy); Osteoporotic Fractures in Men (n = 2301, United States); and Study of Osteoporotic Fractures (n = 5862, United States)-we assessed 16,388 community-dwelling adults (10,376 women, 6012 men) aged ≥65 y. We analyzed 25(OH)D concentrations with the primary outcome (incident slow gait: women <0.8 m/s; men <0.825 m/s) and secondary outcomes (gait speed, incident self-reported mobility, and stair climb impairment) at median 3.0-y follow-up. We identified sex-specific 25(OH)D thresholds that best discriminated incident slow gait using machine learning in training data (2/3 cohort-stratified random sample) and validated using the remaining (validation) data and secondary outcomes.

Results: Mean age in the cohorts ranged from 74.4 to 76.5 y in women and from 73.3 to 76.6 y in men. Overall, 1112/6123 women (18.2%) and 494/3937 men (12.5%) experienced incident slow gait, 1098/7011 women (15.7%) and 474/3962 men (12.0%) experienced incident mobility impairment, and 1044/6941 women (15.0%) and 432/3993 men (10.8%) experienced incident stair climb impairment. Slow gait was best discriminated by 25(OH)D <24.0 ng/mL compared with 25(OH)D ≥24.0 ng/mL in women (RR: 1.29; 95% CI: 1.10, 1.50) and 25(OH)D <21.0 ng/mL compared with 25(OH)D ≥21.0 ng/mL in men (RR: 1.43; 95% CI: 1.01, 2.02). Most associations between 25(OH)D and secondary outcomes were modest; estimates were similar between validation and training datasets.

Conclusions: Empirically identified and validated sex-specific threshold 25(OH)D concentrations for physical function for older adults, 24.0 ng/mL for women and 21.0 ng/mL for men, may inform candidate reference concentrations or the design of vitamin D intervention trials.
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http://dx.doi.org/10.1093/ajcn/nqab025DOI Listing
April 2021

Effect of Low-Intensity vs High-Intensity Home-Based Walking Exercise on Walk Distance in Patients With Peripheral Artery Disease: The LITE Randomized Clinical Trial.

JAMA 2021 04;325(13):1266-1276

Wake Forest University, Winston-Salem, North Carolina.

Importance: Supervised high-intensity walking exercise that induces ischemic leg symptoms is the first-line therapy for people with lower-extremity peripheral artery disease (PAD), but adherence is poor.

Objective: To determine whether low-intensity home-based walking exercise at a comfortable pace significantly improves walking ability in people with PAD vs high-intensity home-based walking exercise that induces ischemic leg symptoms and vs a nonexercise control.

Design, Setting, And Participants: Multicenter randomized clinical trial conducted at 4 US centers and including 305 participants. Enrollment occurred between September 25, 2015, and December 11, 2019; final follow-up was October 7, 2020.

Interventions: Participants with PAD were randomized to low-intensity walking exercise (n = 116), high-intensity walking exercise (n = 124), or nonexercise control (n = 65) for 12 months. Both exercise groups were asked to walk for exercise in an unsupervised setting 5 times per week for up to 50 minutes per session wearing an accelerometer to document exercise intensity and time. The low-intensity group walked at a pace without ischemic leg symptoms. The high-intensity group walked at a pace eliciting moderate to severe ischemic leg symptoms. Accelerometer data were viewable to a coach who telephoned participants weekly for 12 months and helped them adhere to their prescribed exercise. The nonexercise control group received weekly educational telephone calls for 12 months.

Main Outcomes And Measures: The primary outcome was mean change in 6-minute walk distance at 12 months (minimum clinically important difference, 8-20 m).

Results: Among 305 randomized patients (mean age, 69.3 [SD, 9.5] years, 146 [47.9%] women, 181 [59.3%] Black patients), 250 (82%) completed 12-month follow-up. The 6-minute walk distance changed from 332.1 m at baseline to 327.5 m at 12-month follow-up in the low-intensity exercise group (within-group mean change, -6.4 m [95% CI, -21.5 to 8.8 m]; P = .34) and from 338.1 m to 371.2 m in the high-intensity exercise group (within-group mean change, 34.5 m [95% CI, 20.1 to 48.9 m]; P < .001) and the mean change for the between-group comparison was -40.9 m (97.5% CI, -61.7 to -20.0 m; P < .001). The 6-minute walk distance changed from 328.1 m at baseline to 317.5 m at 12-month follow-up in the nonexercise control group (within-group mean change, -15.1 m [95% CI, -35.8 to 5.7 m]; P = .10), which was not significantly different from the change in the low-intensity exercise group (between-group mean change, 8.7 m [97.5% CI, -17.0 to 34.4 m]; P = .44). Of 184 serious adverse events, the event rate per participant was 0.64 in the low-intensity group, 0.65 in the high-intensity group, and 0.46 in the nonexercise control group. One serious adverse event in each exercise group was related to study participation.

Conclusions And Relevance: Among patients with PAD, low-intensity home-based exercise was significantly less effective than high-intensity home-based exercise and was not significantly different from the nonexercise control for improving 6-minute walk distance. These results do not support the use of low-intensity home-based walking exercise for improving objectively measured walking performance in patients with PAD.

Trial Registration: ClinicalTrials.gov Identifier: NCT02538900.
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http://dx.doi.org/10.1001/jama.2021.2536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025122PMC
April 2021

Short Physical Performance Battery as a crosswalk between frailty phenotype and deficit-accumulation frailty index.

J Gerontol A Biol Sci Med Sci 2021 Mar 29. Epub 2021 Mar 29.

Marcus Institute for Aging Research, Hebrew SeniorLife, Boston, MA, USA.

Background: Growing evidence supports clinical importance of evaluating frailty in older adults, with its strong outcome relevance. We aimed to assess whether the Short Physical Performance Battery (SPPB) correlates with frailty status according to phenotype and deficit accumulation models and can be used as a link between these models.

Methods: We analyzed records of 1064 individuals from the Aging Study of Pyeongchang Rural Area, a population-based, prospective cohort from South Korea. Frailty was determined using the Cardiovascular Health Study (CHS) phenotype (phenotype model), 26- and 34-item frailty indice (deficit accumulation model). Associations of SPPB score and frailty with a composite outcome of mortality or long-term institutionalization were assessed. Crosswalks for SPPB, the CHS frailty phenotype and the frailty index were created.

Results: The mean age of the study population was 76.0 years, and 583 (54.8%) were women. According to the CHS phenotype, 26- and 34-item frailty index, 242 (22.7%), 161 (15.1%) and 280 (26.3%) participants, respectively, had frailty. Sensitivities/specificities for classifying CHS phenotype, 26- and 34- item frailty indices were 0.93/0.55, 0.71/0.84 and 0.80/0.83 by SPPB cut points of ≤9, ≤6 and ≤7, respectively. C-index of SPPB score (0.78) showed a predictive ability for the composite outcome that was comparable to that of CHS frailty phenotype (0.79), 26- (0.78) and 34-item frailty index (0.79).

Conclusion: We could create a crosswalk linking frailty phenotype and frailty index from correlations between SPPB and frailty models. This result may facilitate clinical adoption of the frailty concept in broader spectrum of older adults.
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http://dx.doi.org/10.1093/gerona/glab087DOI Listing
March 2021

A National Survey of Challenges Faced by Hospices During the Opioid Crisis: Estimates of Pain Medication Shortages, Missing Medications, and Opioids Left in the Home Post-Death.

J Pain Symptom Manage 2021 Feb 27. Epub 2021 Feb 27.

Department of Epidemiology & Public Health, University of Maryland School of Medicine (J.M.G.), Baltimore, Maryland, USA.

Context: No national data exist on hospice medication shortages, the frequency that opioid medications go missing, and drug disposal practices.

Objectives: To provide national estimates for hospices on: drug shortages; frequency of missing medications; and opioids left in the home post-death.

Methods: A national survey of 600 randomly selected hospices stratified by state and profit status (data collection 2018). Sample weights were applied to adjust for non-response. Respondents were hospice representatives knowledgeable about agency policies and practices. Participants reported their knowledge and perceptions about medication shortages, frequency that opioid medications go missing, and the proportion of hospice deaths in which opioids are left in the home. Findings were stratified by agency size.

Results: 371 hospices completed surveys (response rate = 62%), half (50%) of which were mid-sized (26-100 patients), and not-for-profit. Respondents had 7.5 years (SD = 7.7) of agency experience. 42% of hospices - and 61% of large hospices - reported medication shortages. Among the full sample, 28% of agencies indicated shortages of morphine; 20% reported shortages of hydromorphone. Nearly half (43%) of hospice representatives reported that missing opioid medications occurred within the last 90 days. 52% of representatives reported employees are not allowed to dispose of medications after a home death; and, among home deaths, unused opioids were left in the home 32% of the time. This suggests opioid medications are frequently left in U.S. households after a hospice home death.

Conclusion: Hospices face numerous challenges during the national opioid crisis. Interventions are needed to ensure access to needed treatments, mitigation of diversion, and safe medication disposal.
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http://dx.doi.org/10.1016/j.jpainsymman.2021.02.023DOI Listing
February 2021

Early detection of accelerated aging and cellular decline (AACD): A consensus statement.

Exp Gerontol 2021 Apr 20;146:111242. Epub 2021 Jan 20.

Department of Medicine, Division of Geriatric Medicine and Gerontology, John Hopkins University, 5501 Hopkins Bayview Circle, Suite 1A, 62, Baltimore, MD, 21224, USA. Electronic address:

The cellular hallmarks of accelerated aging and their clinical expression may be grouped using the terms 'accelerated aging and cellular decline' (AACD) and/or 'age-associated cellular decline'. This construct is designed to capture the biological background predisposing the development of age-related conditions. By classifying risk factors, early indicators, and clinical differentiators of AACD through expert consensus, this study aimed to identify the signs, symptoms, and markers indicative of AACD. In doing so, this work paves the way for future implementation of the AACD concept in the clinical and research settings. An interdisciplinary panel of experts with clinical and research expertise was selected to participate in a virtual workshop to discuss AACD. A modified nominal group technique was used to establish consensus among the group. An extended group of international experts critically reviewed an early draft of the manuscript, and their feedback was then incorporated into the model. Experts identified 13 factors predisposing to or clinically manifesting AACD. Among these, chronic diseases, obesity, and unfavorable genetic background were considered as the most important. There was a consensus that a gradual and nonspecific development often characterizes AACD, making its clinical detection potentially challenging. In addition, signs and symptoms might have multifactorial causes and overlapping origins, such as genetic and epigenetic predispositions. As a result, an initial checklist was outlined, listing clinical factors of special relevance (e.g., fatigue, low quality of sleep, and low mood) to represent early manifestations of the organism's exhaustion, which are also frequently neglected in the clinical setting. Differentiating AACD from other conditions is essential. The use of a combination of biomarkers was proposed as a viable method in a two-step process of differentiation: 1) identification of early AACD clinical indicators, followed by 2) symptom and biomarker confirmation with a focus on system domains (to be potentially targeted by future specific interventions). Although the AACD construct is not yet ready for routine use in clinical practice, its operationalization may support the early identification of age-related conditions (when this might still be amenable to reversion) and also encourage preventative interventions. Further investigation is needed to establish specific biomarkers that confirm independent risk factors for AACD and provide a more definitive structure to the concept of AACD (and age-associated cellular decline).
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http://dx.doi.org/10.1016/j.exger.2021.111242DOI Listing
April 2021

The Effects of Four Doses of Vitamin D Supplements on Falls in Older Adults : A Response-Adaptive, Randomized Clinical Trial.

Ann Intern Med 2021 02 8;174(2):145-156. Epub 2020 Dec 8.

Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland (C.M.M., A.L.S., J.A.S., J.C., M.M., S.N.B., J.C., L.T.D., D.M.S., J.T.).

Background: Vitamin D supplementation may prevent falls in older persons, but evidence is inconsistent, possibly because of dosage differences.

Objective: To compare the effects of 4 doses of vitamin D supplements on falls.

Design: 2-stage Bayesian, response-adaptive, randomized trial. (ClinicalTrials.gov: NCT02166333).

Setting: 2 community-based research units.

Participants: 688 participants, aged 70 years and older, with elevated fall risk and a serum 25-hydroxyvitamin D [25-(OH)D] level of 25 to 72.5 nmol/L.

Intervention: 200 (control), 1000, 2000, or 4000 IU of vitamin D per day. During the dose-finding stage, participants were randomly assigned to 1 of the 4 vitamin D doses, and the best noncontrol dose for preventing falls was determined. After dose finding, participants previously assigned to receive noncontrol doses received the best dose, and new enrollees were randomly assigned to receive 200 IU/d or the best dose.

Measurements: Time to first fall or death over 2 years (primary outcome).

Results: During the dose-finding stage, the primary outcome rates were higher for the 2000- and 4000-IU/d doses than for the 1000-IU/d dose, which was selected as the best dose (posterior probability of being best, 0.90). In the confirmatory stage, event rates were not significantly different between participants with experience receiving the best dose (events and observation time limited to the period they were receiving 1000 IU/d;  = 308) and those randomly assigned to receive 200 IU/d ( = 339) (hazard ratio [HR], 0.94 [95% CI, 0.76 to 1.15];  = 0.54). Analysis of falls with adverse outcomes suggested greater risk in the experience-with-best-dose group versus the 200-IU/d group (serious fall: HR, 1.87 [CI, 1.03 to 3.41]; fall with hospitalization: HR, 2.48 [CI, 1.13 to 5.46]).

Limitations: The control group received 200 IU of vitamin D per day, not a placebo. Dose finding ended before the prespecified thresholds for dose suspension and dose selection were reached.

Conclusion: In older persons with elevated fall risk and low serum 25-(OH)D levels, vitamin D supplementation at doses of 1000 IU/d or higher did not prevent falls compared with 200 IU/d. Several analyses raised safety concerns about vitamin D doses of 1000 IU/d or higher.

Primary Funding Source: National Institute on Aging.
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http://dx.doi.org/10.7326/M20-3812DOI Listing
February 2021

Functional Age Predicted by Electronic Short Physical Performance Battery Can Detect Frailty Status in Older Adults.

Clin Interv Aging 2020 11;15:2175-2182. Epub 2020 Nov 11.

Division of Geriatrics, Department of Internal Medicine, Asan Medical Center, Seoul, Republic of Korea.

Purpose: The importance of evaluating frailty status of older adults in clinical practice has been gaining attention with cumulative evidence showing its relevance in clinical outcomes and decision-making. We aimed to develop and validate whether the functional age predicted by an electronic continuous short physical performance battery (eSPPB) could predict frailty status.

Patients And Methods: We reviewed medical records of outpatients (N=834) of Asan Medical Center, aged 51-95 years. We used the eSPPB data of 717 patients as a development cohort, and that of 117 patients, who also underwent comprehensive geriatric assessments, as a validation cohort. Frailty index was calculated by counting deficits of 45 geriatric items including comorbidities, daily functions, mobility, mood, and cognition. For functional age, we used balance score (0-4), gait speed (m/s), and stand-up time (s) measured 5 times in the chair rise test.

Results: From the development cohort, we established a functional age using the formula (83.61 - 1.98*[balance score] - 5.21*[gait speed] + 0.23*[stand-up time]), by multivariate linear regression analysis with chronological age as a dependent variable (R = 0.233). In the validation cohort, the functional age positively correlated with frailty index (p < 0.001). C-statistics classifying frailty (defined as frailty index ≥0.25) was higher (p < 0.001) with functional age (0.912) than that with chronological age (0.637). A cut-off functional age of ≥77.2 years maximized Youden's J when screening for frailty, with sensitivity of 94.4% and specificity of 80.8%.

Conclusion: A newly developed functional age predictor using eSPPB parameters can predict the frailty status as defined by the deficit accumulation method and may serve as a physical biomarker of human aging.
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http://dx.doi.org/10.2147/CIA.S280542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667698PMC
March 2021

Mitochondrial DNA damage in calf skeletal muscle and walking performance in people with peripheral artery disease.

Free Radic Biol Med 2020 11 8;160:680-689. Epub 2020 Sep 8.

University of Florida, Institute on Aging, Department of Aging and Geriatric Research, Gainesville, FL, USA. Electronic address:

Background: Peripheral artery disease (PAD) is associated with mitochondrial dysfunction in calf skeletal muscle and a greater abundance of mitochondrial DNA (mtDNA) heteroplasmy. However, it is unknown whether calf skeletal muscle mtDNA of PAD participants harbors a greater abundance of mitochondrial DNA 4977-bp common deletion (mtDNA), strand breaks and oxidative damage (i.e., oxidized purines) compared to non-PAD participants and whether these mtDNA abnormalities are associated with poor walking performance in participants with PAD.

Methods: Calf muscle biopsies were obtained from 50 PAD participants (ankle-brachial index (ABI) < 0.95) and 25 non-PAD participants (ABI = 0.99-1.40) matched by age, sex, and race. The abundance of mtDNA copy number, mtDNA deletion, strand breaks, and oxidized purines in selected mtDNA regions coding for electron transport chain (ETC) constituents and the non-coding D-Loop region was determined in calf muscle. All participants completed measurement of 6-min walk and usual and fast-paced 4-m walking velocity test.

Results: Participants with PAD (mean age = 65.4 years, SD = 6.9; 14 (28%) women, 38 (76%) black) and without PAD (mean age = 65.2 years, SD = 6.7; 7 (28%) women, 16 (64%) black) did not differ in the abundance of calf muscle mtDNA deletion, mtDNA strand breaks, and oxidized purines. Though, a greater abundance of mtDNA strand breaks within ND4/5 genes was significantly associated with poorer 6-min walk distance, lower usual-paced 4-m walking velocity, and lower fast-paced 4-m walking velocity in non-PAD participants. Significant associations were also found in the density of strand break damage (i.e., damage per mtDNA copy) within ND1/2, ND4/5 and COII/ATPase 6/8 region with 6-min walk distance, usual-paced 4-m walking velocity and fast-paced 4-m walking velocity in non-PAD participants. Significant interactions were found between PAD presence vs. absence and density of strand break damage within ND1/2, ND4/5, COII/ATPase 6/8 regions for the associations with 6-min walk distance, usual-paced 4-m walking velocity, fast-paced 4-m walking velocity. Conversely, of the three walking performance measures only the usual-paced 4-m walking velocity showed a significant, although modest, negative association with the abundance of oxidized purines in the D-Loop (P = 0.031) and ND4/5 (P = 0.033) regions in the calf skeletal muscle of people with PAD.

Conclusion: Overall, these data suggest that the abundance of calf muscle mtDNA strand breaks and mtDNA common deletion are not associated with walking performance in people with PAD and may not be directly involved in the pathophysiology of PAD. Conversely, strand breaks in specific mtDNA regions may contribute to poor walking performance in people without PAD. Further study is needed to confirm whether usual-paced 4-m walking velocity is associated significantly with a greater abundance of oxidized purines in the D-loop, a "mutational hotspot" for oxidative damage, and why this association may differ from the association with 6-min walk distance and fast-paced 4-m walking velocity.
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http://dx.doi.org/10.1016/j.freeradbiomed.2020.09.004DOI Listing
November 2020

Associations of Poly (ADP-Ribose) Polymerase1 abundance in calf skeletal muscle with walking performance in peripheral artery disease.

Exp Gerontol 2020 10 2;140:111048. Epub 2020 Aug 2.

Northwestern University Feinberg School of Medicine, Department of Preventive Medicine, Chicago, IL, United States of America; Northwestern University Feinberg School of Medicine, Department of Medicine, Chicago, IL, United States of America. Electronic address:

Objective: This study investigated associations of markers of oxidative stress and mitochondrial function in calf muscle biopsies with walking performance in people with and without lower extremity peripheral artery disease (PAD).

Methods: Participants with PAD (ankle-brachial index (ABI) <0.90) and without PAD (ABI: 0.90-1.50) underwent calf muscle biopsy and measurement of 6-min walk and four-meter walking velocity. PARP1 (Poly (ADP-Ribose) Polymerase 1), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), silent information regulator 1 (SIRT1) and 4-hydroxynonenal (4HNE) expression were measured in calf muscle using western blot.

Results: Among 15 participants with PAD mean age: 66.8 years (standard deviation (SD): 6.4) and six without PAD (age: 64.4 years, SD: 5.9), mean PARP1-abundance in calf muscle was 1.16 ± 0.92 AU and 0.96 ± 0.38 AU, respectively (P = 0.61). Among participants with PAD after adjustment with ABI, a greater abundance of PARP1 was associated with poorer 6-min walking distance (r = -0.65, P = 0.01), usual-paced 4-m walking velocity (r = -0.73, P = 0.003) and slower fast-paced four-meter walking velocity (r = -0.51, P = 0.07). Among participants with PAD, ABI was not associated with PARP1 abundance in calf muscle (r = 0.02, P = 0.93). Among participants without PAD, skeletal muscle PARP1 abundance was not significantly associated with 6-min walk distance (r = -0.58; P = 0.22), usual-paced walking velocity (r = -0.26; P = 0.62), or fast-paced walking velocity (r = -0.21; P = 0.69), perhaps due to lack of statistical power. There were no associations of remaining calf muscle measures with walking performance.

Conclusions: These findings are consistent with the hypothesis that calf skeletal muscle characteristics are related to walking performance, independently of severity of lower extremity arterial obstruction in people with PAD.
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http://dx.doi.org/10.1016/j.exger.2020.111048DOI Listing
October 2020

Machine Learning in Aging: An Example of Developing Prediction Models for Serious Fall Injury in Older Adults.

J Gerontol A Biol Sci Med Sci 2021 Mar;76(4):647-654

Department of Biostatistics and Data Science, Wake Forest School of Medicine, Winston-Salem, North Carolina.

Background: Advances in computational algorithms and the availability of large datasets with clinically relevant characteristics provide an opportunity to develop machine learning prediction models to aid in diagnosis, prognosis, and treatment of older adults. Some studies have employed machine learning methods for prediction modeling, but skepticism of these methods remains due to lack of reproducibility and difficulty in understanding the complex algorithms that underlie models. We aim to provide an overview of two common machine learning methods: decision tree and random forest. We focus on these methods because they provide a high degree of interpretability.

Method: We discuss the underlying algorithms of decision tree and random forest methods and present a tutorial for developing prediction models for serious fall injury using data from the Lifestyle Interventions and Independence for Elders (LIFE) study.

Results: Decision tree is a machine learning method that produces a model resembling a flow chart. Random forest consists of a collection of many decision trees whose results are aggregated. In the tutorial example, we discuss evaluation metrics and interpretation for these models. Illustrated using data from the LIFE study, prediction models for serious fall injury were moderate at best (area under the receiver operating curve of 0.54 for decision tree and 0.66 for random forest).

Conclusions: Machine learning methods offer an alternative to traditional approaches for modeling outcomes in aging, but their use should be justified and output should be carefully described. Models should be assessed by clinical experts to ensure compatibility with clinical practice.
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http://dx.doi.org/10.1093/gerona/glaa138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011704PMC
March 2021

Serum metabolites associate with physical performance among middle-aged adults: Evidence from the Bogalusa Heart Study.

Aging (Albany NY) 2020 06 1;12(12):11914-11941. Epub 2020 Jun 1.

Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA 70112, USA.

Age-related declines in physical performance predict cognitive impairment, disability, chronic disease exacerbation, and mortality. We conducted a metabolome-wide association study of physical performance among Bogalusa Heart Study participants. Bonferroni corrected multivariate-adjusted linear regression was employed to examine cross-sectional associations between single metabolites and baseline gait speed (N=1,227) and grip strength (N=1,164). In a sub-sample of participants with repeated assessments of gait speed (N=282) and grip strength (N=201), significant metabolites from the cross-sectional analyses were tested for association with change in physical performance over 2.9 years of follow-up. Thirty-five and seven metabolites associated with baseline gait speed and grip strength respectively, including six metabolites that associated with both phenotypes. Three metabolites associated with preservation or improvement in gait speed over follow-up, including: sphingomyelin (40:2) (P=2.6×10) and behenoyl sphingomyelin (d18:1/22:0) and ergothioneine (both P<0.05). Seven metabolites associated with declines in gait speed, including: 1-carboxyethylphenylalanine (P=8.8×10), and N-acetylaspartate, N-formylmethionine, S-adenosylhomocysteine, N-acetylneuraminate, N2,N2-dimethylguanosine, and gamma-glutamylphenylalanine (all P<0.05). Two metabolite modules reflecting sphingolipid and bile acid metabolism associated with physical performance (minimum P=7.6×10). These results add to the accumulating evidence suggesting an important role of the human metabolome in physical performance and specifically implicate lipid, nucleotide, and amino acid metabolism in early physical performance decline.
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http://dx.doi.org/10.18632/aging.103362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343486PMC
June 2020

Clinical characteristics and response to supervised exercise therapy of people with lower extremity peripheral artery disease.

J Vasc Surg 2021 Feb 19;73(2):608-625. Epub 2020 May 19.

Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill; Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill. Electronic address:

Background: Among people with lower extremity peripheral artery disease (PAD), little is known about variation in response to supervised exercise therapy (SET). Clinical characteristics associated with greater responsiveness to SET have not been identified.

Methods: Data from participants with PAD in two randomized clinical trials comparing SET vs nonexercising control were combined. The exercise intervention consisted of three times weekly supervised treadmill exercise. The control groups received lectures on health-related topics.

Results: Of 309 unique participants randomized (mean age, 67.9 years [standard deviation, 9.3 years]; 132 [42.7%] women; 185 [59.9%] black), 285 (92%) completed 6-month follow-up. Compared with control, those randomized to SET improved 6-minute walk distance by 35.6 meters (95% confidence interval, 21.4-49.8; P < .001). In the 95 (62.1%) participants who attended at least 70% of SET sessions, change in 6-minute walk distance varied from -149.4 to +356.0 meters. Thirty-four (35.8%) had no 6-minute walk distance improvement. Among all participants, age, sex, race, body mass index, prior lower extremity revascularization, and other clinical characteristics did not affect the degree of improvement in 6-minute walk distance after SET relative to the control group. Participants with 6-minute walk distance less than the median of 334 meters at baseline had greater percentage improvement in 6-minute walk distance compared with those with baseline 6-minute walk distance above the median (+20.5% vs +5.3%; P for interaction = .0107).

Conclusions: Among people with PAD, substantial variability exists in walking improvement after SET. Shorter 6-minute walk distance at baseline was associated with greater improvement after SET, but other clinical characteristics, including age, sex, prior lower extremity revascularization, and disease severity, did not affect responsiveness to exercise therapy.
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http://dx.doi.org/10.1016/j.jvs.2020.04.498DOI Listing
February 2021

Correlations of Calf Muscle Macrophage Content With Muscle Properties and Walking Performance in Peripheral Artery Disease.

J Am Heart Assoc 2020 05 9;9(10):e015929. Epub 2020 May 9.

College of Health Sciences and Center for Muscle Biology University of Kentucky Lexington KY.

Background Peripheral artery disease (PAD) is a manifestation of atherosclerosis characterized by reduced blood flow to the lower extremities and mobility loss. Preliminary evidence suggests PAD damages skeletal muscle, resulting in muscle impairments that contribute to functional decline. We sought to determine whether PAD is associated with an altered macrophage profile in gastrocnemius muscles and whether muscle macrophage populations are associated with impaired muscle phenotype and walking performance in patients with PAD. Methods and Results Macrophages, satellite cells, and extracellular matrix in gastrocnemius muscles from 25 patients with PAD and 7 patients without PAD were quantified using immunohistochemistry. Among patients with PAD, both the absolute number and percentage of cluster of differentiation (CD) 11b+CD206+ M2-like macrophages positively correlated to satellite cell number (=0.461 [=0.023] and =0.416 [=0.042], respectively) but not capillary density or extracellular matrix. The number of CD11b+CD206- macrophages negatively correlated to 4-meter walk tests at normal (=-0.447, =0.036) and fast pace (=-0.510, =0.014). Extracellular matrix occupied more muscle area in PAD compared with non-PAD (8.72±2.19% versus 5.30±1.03%, <0.001) and positively correlated with capillary density (=0.656, <0.001). Conclusions Among people with PAD, higher CD206+ M2-like macrophage abundance was associated with greater satellite cell numbers and muscle fiber size. Lower CD206- macrophage abundance was associated with better walking performance. Further study is needed to determine whether CD206+ macrophages are associated with ongoing reparative processes enabling skeletal muscle adaptation to damage with PAD. Registration URL: https://www.clini​caltr​ials.gov; Unique identifiers: NCT00693940, NCT01408901, NCT0224660.
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http://dx.doi.org/10.1161/JAHA.118.015929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660852PMC
May 2020

Association of six-minute walk distance with subsequent lower extremity events in peripheral artery disease.

Vasc Med 2020 08 27;25(4):319-327. Epub 2020 Apr 27.

Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

The prognostic significance of the six-minute walk distance for lower extremity events in people with peripheral artery disease (PAD) is unknown. This longitudinal study assessed whether a poorer six-minute walk distance at baseline was associated with higher rates of subsequent lower extremity atherosclerotic disease events in PAD. A total of 369 patients (mean age 69.4 ± 10.0 years; mean ankle-brachial index (ABI) 0.67 ± 0.17; 31% women; 30% black individuals) from Chicago-area medical centers with PAD were enrolled. Participants underwent baseline six-minute walk testing and returned for annual study visits. Lower extremity events consisted of one or more of the following: ABI decline greater than 15% or medical record adjudicated lower extremity revascularization, critical limb ischemia, or amputation. At a mean follow-up of 33.3 months, lower extremity events occurred in 66/123 (53.7%) people in the first (worst) tertile of six-minute walk performance, 55/124 (44.4%) in the second tertile, and 56/122 (45.9%) in the third (best) tertile. After adjusting for age, sex, race, ABI, comorbidities, and other confounders, participants in the first (worst) tertile of six-minute walk distance at baseline had higher rates of lower extremity events during follow-up, compared to those in the best tertile at baseline (HR = 1.74, 95% CI 1.17-2.60, = 0.0067). Among people with PAD, a poorer six-minute walk distance was associated with higher rates of subsequent lower extremity PAD-related events after adjusting for confounders. Further study is needed to determine whether interventions that improve six-minute walk distance can reduce lower extremity adverse events in people with PAD.
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http://dx.doi.org/10.1177/1358863X20901599DOI Listing
August 2020

Meaningful change in 6-minute walk in people with peripheral artery disease.

J Vasc Surg 2021 01 23;73(1):267-276.e1. Epub 2020 Apr 23.

Department of Epidemiology, University of Maryland, College Park, Md.

Objective: The 6-minute walk test is a common outcome measure in clinical trials of people with lower extremity peripheral artery disease (PAD). However, what constitutes a meaningful change in the 6-minute walk distance has not been well defined for people with PAD. The present study related the change in the 6-minute walk distance to the degree of participant-reported improvement or decline in the 6-minute walk distance to define a meaningful change in the 6-minute walk distance for those with PAD.

Methods: Participants with PAD from three observational longitudinal studies completed the walking impairment questionnaire (WIQ) distance score and 6-minute walk at baseline and 1 year later. The WIQ distance score measures participants' perceived difficulty walking seven different distances without stopping (ranging from walking around the home to walking 5 blocks) on a 0 to 4 Likert scale, with 0 representing an inability to walk the distance and 4 representing no difficulty. The mean changes in the 6-minute walk distance corresponding to the participants' report of no change, 1-unit change, or 2-unit change, respectively, in the Likert scale score between the baseline and 1-year follow-up measures were calculated for each WIQ distance.

Results: A total of 777 participants with PAD (mean age, 71.2 ± 8.8 years; mean baseline 6-minute walk distance, 350.1 ± 118.1 meters) completed 5439 questions about their difficulty walking each WIQ distance at baseline and follow-up. Participants with PAD who reported no change in their difficulty in walking each WIQ distance between baseline and follow-up had a decline of 7.2 meters (95% confidence interval [CI], -11.6 to -2.8 meters) in the 6-minute walk test. Relative to those reporting no change in difficulty walking, the participants reporting 1- and 2-point improvements in walking ability showed 6-minute walk distance improvements of 7.8 meters (95% CI, -0.3 to 15.9 meters) and 20.1 meters (95% CI, 1.1-39.2 meters), respectively. Relative to those reporting no change in walking difficulty, those reporting 1- and 2-point declines in perceived walking difficulty showed declines of -11.2 meters (95% CI, -19.0 to -3.4 meters) and -23.8 meters (95% CI, -37.4 to -10.3 meters) in the 6-minute walk distance.

Conclusions: Among people with PAD, ∼8- and ∼20-meter improvements in the 6-minute walk distance represent small and large improvements in walking ability, respectively. People with PAD who reported no change in their ability to walk distances over 1 year simultaneously declined by a mean of 7 meters in the 6-minute walk test. These findings will be useful for interpreting the results from randomized trials of interventions to improve the walking performance of people with PAD.
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http://dx.doi.org/10.1016/j.jvs.2020.03.052DOI Listing
January 2021

Associations of Peripheral Artery Disease With Calf Skeletal Muscle Mitochondrial DNA Heteroplasmy.

J Am Heart Assoc 2020 04 21;9(7):e015197. Epub 2020 Mar 21.

National Institutes on Health National Institute on Aging Baltimore MD.

Background Patients with peripheral artery disease (PAD) undergo frequent episodes of ischemia-reperfusion in lower extremity muscles that may negatively affect mitochondrial health and are associated with impaired mobility. We hypothesized that skeletal muscle from PAD patients will show high mitochondrial DNA heteroplasmy, especially in regions more susceptible to oxidative damage, such as the displacement loop, and that the degree of heteroplasmy will be correlated with the severity of ischemia and mobility impairment. Methods and Results Mitochondrial mutations and deletions and their relative abundance were identified by targeted mitochondrial DNA sequencing in biopsy specimens of gastrocnemius muscle from 33 PAD (ankle brachial index <0.9) and 9 non-PAD (ankle brachial index >0.9) subjects aged ≥60 years. The probability of heteroplasmy per DNA base was significantly higher for PAD subjects than non-PAD within each region. In adjusted models, PAD was associated with higher heteroplasmy than non-PAD (=0.003), but the association was limited to microheteroplasmy, that is heteroplasmy found in 1% to 5% of all mitochondrial genomes (=0.004). Heteroplasmy in the displacement loop and coding regions were significantly higher for PAD than non-PAD subjects after adjustment for age, sex, race, and diabetes mellitus (=0.037 and 0.004, respectively). Low mitochondrial damage, defined by both low mitochondrial DNA copy number and low microheteroplasmy, was associated with better walking performance. Conclusions People with PAD have higher "low frequency" heteroplasmy in gastrocnemius muscle compared with people without PAD. Among people with PAD, those who had evidence of least mitochondrial damage, had better walking performance than those with more mitochondrial damage. Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT02246660.
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http://dx.doi.org/10.1161/JAHA.119.015197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428597PMC
April 2020

Sarcopenia Definition: The Position Statements of the Sarcopenia Definition and Outcomes Consortium.

J Am Geriatr Soc 2020 07 9;68(7):1410-1418. Epub 2020 Mar 9.

California Pacific Medical Center Research Institute, San Francisco Coordinating Center, San Francisco, California.

Objectives: To develop an evidence-based definition of sarcopenia that can facilitate identification of older adults at risk for clinically relevant outcomes (eg, self-reported mobility limitation, falls, fractures, and mortality), the Sarcopenia Definition and Outcomes Consortium (SDOC) crafted a set of position statements informed by a literature review and SDOC's analyses of eight epidemiologic studies, six randomized clinical trials, four cohort studies of special populations, and two nationally representative population-based studies.

Methods: Thirteen position statements related to the putative components of a sarcopenia definition, informed by the SDOC analyses and literature synthesis, were reviewed by an independent international expert panel (panel) iteratively and voted on by the panel during the Sarcopenia Position Statement Conference. Four position statements related to grip strength, three to lean mass derived from dual-energy x-ray absorptiometry (DXA), and four to gait speed; two were summary statements.

Results: The SDOC analyses identified grip strength, either absolute or scaled to measures of body size, as an important discriminator of slowness. Both low grip strength and low usual gait speed independently predicted falls, self-reported mobility limitation, hip fractures, and mortality in community-dwelling older adults. Lean mass measured by DXA was not associated with incident adverse health-related outcomes in community-dwelling older adults with or without adjustment for body size.

Conclusion: The panel agreed that both weakness defined by low grip strength and slowness defined by low usual gait speed should be included in the definition of sarcopenia. These position statements offer a rational basis for an evidence-based definition of sarcopenia. The analyses that informed these position statements are summarized in this article and discussed in accompanying articles in this issue of the journal. J Am Geriatr Soc 68:1410-1418, 2020.
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http://dx.doi.org/10.1111/jgs.16372DOI Listing
July 2020

The Tribulations of Trials: Lessons Learnt Recruiting 777 Older Adults Into REtirement in ACTion (REACT), a Trial of a Community, Group-Based Active Aging Intervention Targeting Mobility Disability.

J Gerontol A Biol Sci Med Sci 2020 11;75(12):2387-2395

School of Sport, Exercise and Rehabilitation Sciences, University of Birmingham, UK.

Background: Challenges of recruitment to randomized controlled trials (RCTs) and successful strategies to overcome them should be clearly reported to improve recruitment into future trials. REtirement in ACTion (REACT) is a United Kingdom-based multicenter RCT recruiting older adults at high risk of mobility disability to a 12-month group-based exercise and behavior maintenance program or to a minimal Healthy Aging control intervention.

Methods: The recruitment target was 768 adults, aged 65 years and older scoring 4-9 on the Short Physical Performance Battery (SPPB). Recruitment methods include the following: (a) invitations mailed by general practitioners (GPs); (b) invitations distributed via third-sector organizations; and (c) public relations (PR) campaign. Yields, efficiency, and costs were calculated.

Results: The study recruited 777 (33.9% men) community-dwelling, older adults (mean age 77.55 years (SD 6.79), mean SPPB score 7.37 (SD 1.56)), 95.11% white (n = 739) and broadly representative of UK quintiles of deprivation. Over a 20-month recruitment period, 25,559 invitations were issued. Eighty-eight percent of the participants were recruited via GP invitations, 5.4% via the PR campaign, 3% via word-of-mouth, and 2.5% via third-sector organizations. Mean recruitment cost per participant was £78.47, with an extra £26.54 per recruit paid to GPs to cover research costs.

Conclusions: REACT successfully recruited to target. Response rates were lower than initially predicted and recruitment timescales required adjustment. Written invitations from GPs were the most efficient method for recruiting older adults at risk of mobility disability. Targeted efforts could achieve more ethnically diverse cohorts. All trials should be required to provide recruitment data to enable evidence-based planning of future trials.
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http://dx.doi.org/10.1093/gerona/glaa051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662171PMC
November 2020

Impact and Lessons From the Lifestyle Interventions and Independence for Elders (LIFE) Clinical Trials of Physical Activity to Prevent Mobility Disability.

J Am Geriatr Soc 2020 04 27;68(4):872-881. Epub 2020 Feb 27.

Department of Internal Medicine and the Sticht Center for Healthy Aging and Alzheimer's Prevention, Wake Forest School of Medicine, Winston-Salem, North Carolina.

Background: Walking independently is basic to human functioning. The Lifestyle Interventions and Independence for Elders (LIFE) studies were developed to assess whether initiating physical activity could prevent major mobility disability (MMD) in sedentary older adults.

Methods: We review the development and selected findings of the LIFE studies from 2000 through 2019, including the planning phase, the LIFE-Pilot Study, and the LIFE Study.

Results: The planning phase and the LIFE-Pilot provided key information for the successful implementation of the LIFE Study. The LIFE Study, involving 1635 participants randomized at eight sites throughout the United States, showed that compared with health education, the physical activity program reduced the risk of the primary outcome of MMD (inability to walk 400 m: hazard ratio = 0.82; 95% confidence interval = 0.69-0.98; P = .03), and that the intervention was cost-effective. There were no significant effects on cognitive outcomes, cardiovascular events, or serious fall injuries. In addition, the LIFE studies provided relevant findings on a broad range of other outcomes, including health, frailty, behavioral outcomes, biomarkers, and imaging. To date, the LIFE studies have generated a legacy of 109 peer-reviewed publications, 19 ancillary studies, and 38 independently funded grants and clinical trials, and advanced the development of 59 early career scientists. Data and biological samples of the LIFE Study are now publicly available from a repository sponsored by the National Institute on Aging (https://agingresearchbiobank.nia.nih.gov).

Conclusions: The LIFE studies generated a wealth of important scientific findings and accelerated research in geriatrics and gerontology, benefiting the research community, trainees, clinicians, policy makers, and the general public. J Am Geriatr Soc 68:872-881, 2020.
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http://dx.doi.org/10.1111/jgs.16365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187344PMC
April 2020

Cocoa to Improve Walking Performance in Older People With Peripheral Artery Disease: The COCOA-PAD Pilot Randomized Clinical Trial.

Circ Res 2020 02 14;126(5):589-599. Epub 2020 Feb 14.

Department of Health Research and Policy, Stanford University, CA (L.T.).

Rationale: Cocoa and its major flavanol component, epicatechin, have therapeutic properties that may improve limb perfusion and increase calf muscle mitochondrial activity in people with lower extremity peripheral artery disease (PAD).

Objective: In a phase II randomized clinical trial, to assess whether 6 months of cocoa improved walking performance in people with PAD, compared with placebo.

Methods And Results: Six-month double-blind, randomized clinical trial in which participants with PAD were randomized to either cocoa beverage versus placebo beverage. The cocoa beverage contained 15 g of cocoa and 75 mg of epicatechin daily. The identical appearing placebo contained neither cocoa nor epicatechin. The 2 primary outcomes were 6-month change in 6-minute walk distance measured 2.5 hours after a study beverage at 6-month follow-up and 24 hours after a study beverage at 6-month follow-up, respectively. A 1-sided <0.10 was considered statistically significant. Of 44 PAD participants randomized (mean age, 72.3 years [±7.1]; mean ankle brachial index, 0.66 [±0.15]), 40 (91%) completed follow-up. Adjusting for smoking, race, and body mass index, cocoa improved 6-minute walk distance at 6-month follow-up by 42.6 m ([90% CI, +22.2 to +∞] =0.005) at 2.5 hours after a final study beverage and by 18.0 m ([90% CI, -1.7 to +∞] =0.12) at 24 hours after a study beverage, compared with placebo. In calf muscle biopsies, cocoa improved mitochondrial COX (cytochrome c oxidase) activity (=0.013), increased capillary density (=0.014), improved calf muscle perfusion (=0.098), and reduced central nuclei (=0.033), compared with placebo.

Conclusions: These preliminary results suggest a therapeutic effect of cocoa on walking performance in people with PAD. Further study is needed to definitively determine whether cocoa significantly improves walking performance in people with PAD.

Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02876887. Visual Overview: An online visual overview is available for this article.
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http://dx.doi.org/10.1161/CIRCRESAHA.119.315600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141749PMC
February 2020

Global cognition predicts the incidence of poor physical performance among older adults: A cross-national study.

Geriatr Gerontol Int 2020 Mar 20;20(3):218-222. Epub 2020 Jan 20.

School of Rehabilitation Therapy, Queen's University, Kingston, Ontario, Canada.

Aim: The relationship between physical performance and cognition is well established. However, findings on the relationship between global cognition and the incidence of functional disability has been inconsistent. Using data from the International Mobility in Aging Study, we investigated the relationship between baseline cognitive function and the incidence of poor physical performance 2 years later.

Methods: A total of 1071 community-dwelling participants (aged 64-75 years) from four sites in Canada and Latin America, with a Short Physical Performance Battery score ≥9 at baseline (good performance) were included. We carried out two sets of analyses, measuring cognition with either the Leganés Cognitive Test or the Montreal Cognitive Assessment. We used three logistic regression models, controlling for either no confounders, sociodemographic confounders or sociodemographic and health confounders. The full model was also stratified by site. A score <9 on the Short Physical Performance Battery indicated poor physical performance.

Results: In the fully adjusted model, each 1-point increase in the baseline Leganés Cognitive Test score (range 0-32) was associated with a 10% decrease in the odds of incidence of poor physical performance at the 2-year follow-up (P = 0.019). Likewise, each 1-point increase in the baseline Montreal Cognitive Assessment score (range 0-30) was associated with a 16% decrease in the odds of developing poor physical performance (P = 0.005). When stratified by site, the results were significant at the Latin American sites (P = 0.02), but not at the Canadian sites (P = 0.08).

Conclusions: Poor baseline cognition is associated with the incidence of poor physical performance in community-dwelling older adults. To prevent physical disability, interventions addressing both cognitive and physical performance are required. Geriatr Gerontol Int 2020; ••: ••-••.
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http://dx.doi.org/10.1111/ggi.13864DOI Listing
March 2020

Hospice Utilization in the United States: A Prospective Cohort Study Comparing Cancer and Noncancer Deaths.

J Am Geriatr Soc 2020 04 27;68(4):783-793. Epub 2019 Dec 27.

University of Maryland, School of Medicine, Baltimore, Maryland.

Objectives: Reliable national estimates of hospice use and underuse are needed. Additionally, drivers of hospice use in the United States are poorly understood, especially among noncancer populations. Thus the objectives of this study were to (1) provide reliable estimates of hospice use among adults in the United States; and (2) identify factors predicting use among decedents and within subsamples of cancer and noncancer deaths.

Design: We conducted a prospective cohort study using the Health and Retirement Study survey. Excluding sudden deaths, we used data from the 2012 survey wave to predict hospice use in general, and then separately for cancer and non-cancer deaths.

Setting: Study data were provided by a population-based sample of older adults from the U.S.

Participants: We constructed a sample of 1,209 participants who died between the 2012 and 2014 survey waves.

Measurements: Hospice utilization was reported by proxy. Exposure variables included demographics, functionality (activities of daily living [ADLs]), health, depression, dementia, advance directives, nursing home residency, and cause of death.

Results: Hospice utilization rate was 52.4% for the sample with 70.8% for cancer deaths and 45.4% for noncancer deaths. Fully adjusted model results showed being older (odds ratio [OR] = 1.54), less healthy (OR = .79), having dementia (OR = 1.52), and having cancer (OR = 5.47) were linked to greater odds of receiving hospice. Among cancer deaths, being older (OR = 1.64) and female (OR = 2.54) were the only predictors of hospice use. Among noncancer deaths, increased age (OR = 1.58), more education (OR = 1.56), being widowed (OR = 1.55), needing help with ADLs (OR = 1.13), and poor health (OR = .77) were associated with hospice utilization.

Conclusion: Findings suggest hospice remains underutilized, especially among individuals with noncancer illness. Extrapolating results to the US population, we estimate that annually nearly a million individuals who are likely eligible for hospice die without its services. Most (84%) of these decedents have a noncancer condition. Interventions are needed to increase appropriate hospice utilization, particularly in noncancer care settings. J Am Geriatr Soc 68:783-793, 2020.
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http://dx.doi.org/10.1111/jgs.16294DOI Listing
April 2020

Comparing 6-minute walk versus treadmill walking distance as outcomes in randomized trials of peripheral artery disease.

J Vasc Surg 2020 03 23;71(3):988-1001. Epub 2019 Dec 23.

Intramural Research Program, National Institute on Aging, Baltimore, Md.

Background: Randomized trials of people with peripheral artery disease (PAD) and intermittent claudication have traditionally used maximal treadmill walking distance as the primary outcome, but the 6-minute walk test is increasingly used as a primary outcome in randomized trials of PAD. This study compared relative changes in maximal treadmill walking distance versus 6-minute walk distance in response to a therapeutic intervention or control in randomized trials of participants with PAD.

Methods: Data from four randomized trials of therapeutic interventions in participants with PAD that measured both 6-minute walk and treadmill walking performance at baseline and the 6-month follow-up were combined. Two trials studied supervised treadmill exercise, one studied home-based walking exercise, and one studied resveratrol.

Results: Of 467 participants (mean age, 69.8; standard deviation, 9.7), the mean ankle-brachial index was 0.66 (standard deviation, 0.17). At the 6-month follow-up, participants with PAD randomized to control or placebo significantly declined in 6-minute walk distance (-10.2 m; 95% confidence interval, -18.2 to -2.2; P = .013), but improved maximal treadmill walking distance (+25.7 m; 95% CI, +6.0 to +45.3 m; P = .010; difference between change in 6-minute walk versus maximal treadmill walking distance: -37.3 m; 95% CI, -56.4 to -18.2; P < .001). Home-based exercise improved the 6-minute walk distance by 43.2 m (95% CI, +28.4 to +57.9), and supervised treadmill exercise improved the 6-minute walk distance by 25.0 m (95% CI, +14.7 to +35.2; mean difference, +18.2 m favoring home-based exercise [95% CI, +0.2 to +36.2 m; P = .048]). Among all participants, the presence (vs absence) of treadmill exercise training was associated with a 141.3-m greater improvement in maximal treadmill walking distance compared to 6-minute walk distance (95% CI, 88.2-194.4; P < .001), suggesting a benefit from treadmill training on the treadmill outcome.

Conclusions: Maximal treadmill walking distance and the 6-minute walk distance are not interchangeable outcomes in participants with PAD. Participants with PAD randomized to control groups improved treadmill walking distance but simultaneously meaningfully declined in 6-minute walk distance. Supervised treadmill exercise training amplified improvement in treadmill walking distance because of a training to the outcome measure phenomenon.
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http://dx.doi.org/10.1016/j.jvs.2019.05.058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141750PMC
March 2020

Accelerating the Search for Interventions Aimed at Expanding the Health Span in Humans: The Role of Epidemiology.

J Gerontol A Biol Sci Med Sci 2020 01;75(1):77-86

Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, Maryland.

Background: Extensive work in basic and clinical science suggests that biological mechanisms of aging are causally related to the development of disease and disability in late life. Modulation of the biological mechanisms of aging can extend both life span and health span in animal models, but translation to humans has been slow.

Methods: Summary of workshop proceedings from the 2018-2019 Epidemiology of Aging Workshop hosted by the Intramural Research Program at the National Institute on Aging.

Results: Epidemiologic studies play a vital role to progress in this field, particularly in evaluating new risk factors and measures of biologic aging that may influence health span, as well as developing relevant outcome measures that are robust and relevant for older individuals.

Conclusions: Appropriately designed epidemiological studies are needed to identify targets for intervention and to inform study design and sample size estimates for future clinical trials designed to promote health span.
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http://dx.doi.org/10.1093/gerona/glz230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175971PMC
January 2020

Asymptomatic carotid stenosis is associated with mobility and cognitive dysfunction and heightens falls in older adults.

J Vasc Surg 2020 06 4;71(6):1930-1937. Epub 2019 Nov 4.

Department of Vascular Surgery, University of Maryland School of Medicine, Baltimore, Md; Vascular Service, Veterans Affairs Medical Center, Baltimore, Md. Electronic address:

Background: Atherosclerosis of the carotid bifurcation with plaque formation causes asymptomatic carotid artery stenosis (ACAS), which may also be associated with cerebral hypoperfusion. Cerebral hypoperfusion adversely affects multiple aspects of mobility and cognition. This study tests the hypothesis that community-dwelling older adults with a 50% or greater diameter-reducing ACAS will have mobility and cognitive impairments that heighten their risk for falls.

Methods: Eighty community-dwelling adults completed a mobility assessment (Short Physical Performance Battery, Berg Balance Scale, Four Square Step Test, Dynamic Gait Index, Timed Up and Go, and gait speed), self-reported physical function (Activities-Specific Balance Confidence, SF-12 Physical Function Component), and cognitive tests (Mini-Mental State Examination). Falls were recorded for the past 6 months. Standardized carotid ultrasound examination classified participants into no stenosis (<50% diameter reduction) (n = 54), moderate stenosis (50%-69%) (n = 17), and high-grade stenosis (70%-99%) (n = 9) groups. Linear and logistic regression analyses determined the associations between these measures and the degree of stenosis (three groups).

Results: Logistic regression analysis showed their degree of stenosis was associated with reductions in mobility (Short Physical Performance Battery [P = .008], Berg Balance Scale [P = .0008], Four Square Step Test [P = .005], DGI [P = .0001], TUG [P = .0004], gait speed [P = .02]), perceived physical function (ABC [P < .0001], SF-12 Physical Function Component [P < .0001]), and cognition (MMSE [P = .003]). Adults with moderate- and high-grade stenosis had a greater incidence of falls compared with those without stenosis (relative risk, 2.86; P = .01). Results remained unchanged after adjustment for age, sex and cardiovascular risk factors.

Conclusions: ACAS is associated with impaired mobility and cognition that are accompanied with increased fall risk. These impairments increased with worsening severity.
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http://dx.doi.org/10.1016/j.jvs.2019.09.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196504PMC
June 2020

Factors associated with poor physical performance in older adults of 11 Peruvian high Andean communities.

F1000Res 2019 15;8:59. Epub 2019 Jan 15.

Universidad de San Martín de Porres, Facultad de Medicina Humana, Centro de Investigación del Envejecimiento (CIEN), Lima, Peru.

Physical performance in the older adult has been extensively studied. However, only a few studies have evaluated physical performance among older adults of high Andean populations and none have studied the factors associated with it. The objective of this study was to evaluate factors associated with poor physical performance by using the Short Physical Performance Battery (SPPB) in older adults living in 11 Peruvian high Andean communities. An analytical cross-sectional study was carried out in inhabitants aged 60 or over from 11 high-altitude Andean communities of Peru during 2013-2017. Participants were categorized in two groups according to their SPPB score: poor physical performance (0-6 points) and medium/good physical performance (7-12 points). Additionally, we collected socio-demographic, medical, functional and cognitive assessment information. Poisson regression models were constructed to identify factors associated with poor physical performance. Prevalence ratio (PR) with 95% confidence intervals (95 CI%) are presented. A total of 407 older adults were studied. The average age was 73.0 ± 6.9 years (range: 60-94 years) and 181 (44.5%) participants had poor physical performance (0-6 points). In the adjusted Poisson regression analysis, the factors associated with poor physical performance were: female gender (PR=1.29; 95%CI: 1.03-1.61), lack of social support (PR=2.10; 95%CI: 1.17-3.76), number of drugs used (PR=1.09; 95%CI: 1.01-1.17), urinary incontinence (PR=1.45; 95%CI: 1.16-1.82), exhaustion (PR=1.35; 95%CI: 1.03-1.75) and cognitive impairment (PR=1.89; 95%CI: 1.40-2.55). Almost half of the population evaluated had poor physical performance based on the SPPB. Factors that would increase the possibility of suffering from poor physical performance were: female gender, lack of social support, number of drugs used, urinary incontinence, exhaustion and cognitive impairment. Future studies with a larger sample and longitudinal follow-up are needed to design beneficial interventions for the high Andean population.
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http://dx.doi.org/10.12688/f1000research.17513.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6415321PMC
June 2020

Validation of a Multi-Sensor-Based Kiosk for Short Physical Performance Battery.

J Am Geriatr Soc 2019 12 23;67(12):2605-2609. Epub 2019 Aug 23.

Department of Rehabilitation Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam-si, Gyeonggi-do, South Korea.

Objectives: We aimed to validate a multi-sensor-based kiosk (automatically measured Short Physical Performance Battery [eSPPB] kiosk) that can perform automated measurement of the SPPB.

Design: Prospective, cross-sectional study.

Setting: Rehabilitation clinic of a tertiary-care hospital.

Participants: Ambulatory outpatients, aged 65 years or older (N = 40).

Measurements: The eSPPB kiosk was developed to measure the three components of the SPPB: standing balance, gait speed, and chair stand test with embedded sensors and algorithms. Correlations between the total and component-specific scores of the eSPPB and manually measured SPPB (mSPPB), assessed by a physical therapist, were assessed. Further, correlations between SPPB parameters and geriatric functional measures were also evaluated.

Results: This study included 40 participants with a mean age of 74.4 ± 6.5 years, a mean total eSPPB score of 10.1 ± 2.1, and a mean total mSPPB score of 10.2 ± 2.1. The intraclass correlation coefficient between the eSPPB and mSPPB total score was 0.97 (P < .001), and the κ agreement was 0.79 (P < .001). The intraclass coefficients between the components of eSPPB and mSPPB were 0.77 (P < .001), 0.88 (P < .001), and 0.99 (P < .001) for standing balance, gait speed, and chair stand test, respectively.

Conclusion: The newly developed kiosk might be a viable and efficient method for performing the SPPB in older adults. J Am Geriatr Soc 67:2605-2609, 2019.
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http://dx.doi.org/10.1111/jgs.16135DOI Listing
December 2019