Validation of perceived physical fatigability using the simplified-Chinese version of the Pittsburgh Fatigability Scale.

BACKGROUND: The Pittsburgh Fatigability Scale (PFS) was developed to capture fatigue and demand in a single tool, filling a gap that no validated questionnaire existed to measure perceived fatigability. Since fatigability is a more sensitive measure of a person's susceptibility to fatigue, we validated the simplified-Chinese version of the PFS among Chinese community-dwelling older adults. METHODS: This cross-sectional study was conducted in an urban community in Beijing between November 2018 and July 2019. The PFS was translated into simplified-Chinese by the translation, retro-translation method. Internal consistency of the Physical subscale of the PFS was evaluated by Cronbach's alpha. Convergent validity and discriminant validity were evaluated against physical performance measures (i.e., Short Physical Performance Battery & Timed Up and Go Test) and daily living performance (i.e., Barthel Index & Instrumental activity of daily living). RESULTS: Our study included 457 participants, including 182 men (39.8%) and 275 women (60.2%). The age range of the included participants was 61-96 years (mean = 84.8 years, SD = 5.8 years). The simplified-Chinese version of PFS Physical scores showed strong internal consistency (Cronbach's alpha = 0.81). Higher PFS Physical scores were associated with worse physical performance, and daily living performance (|correlation coefficient| range: 0.36-0.56, p < .001). Age- and sex-adjusted PFS Physical scores had moderate to good overall discrimination for correctly classifying people by their physical performance and daily living performance (AUCs range 0.70-0.87, p < .001). CONCLUSIONS: The PFS simplified-Chinese version is a valid instrument to assess perceived physical fatigability in Chinese-speaking older adults with good convergent validity. Thus, the PFS, with low cost and greater feasibility, is a desired tool to measure fatigability in large population studies.

Profiles of Accelerometry-Derived Physical Activity Are Related to Perceived Physical Fatigability in Older Adults.

Physical activity (PA) is associated with greater fatigability in older adults; little is known about magnitude, shape, timing and variability of the entire 24-h rest-activity rhythm (RAR) associated with fatigability. We identified which features of the 24-h RAR pattern were independently and jointly associated with greater perceived physical fatigability (Pittsburgh Fatigability Scale, PFS, 0-50) in older adults (n = 181, 71.3 ± 6.7 years). RARs were characterized using anti-logistic extended cosine models and 4-h intervals of PA means and standard deviations across days. A K-means clustering algorithm approach identified four profiles of RAR features: "Less Active/Robust", "Earlier Risers", "More Active/Robust" and "Later RAR". Quantile regression tested associations of each RAR feature/profile on median PFS adjusted for age, sex, race, body mass index and depression symptomatology. Later rise times (up mesor; ß = 1.38, p = 0.01) and timing of midpoint of activity (acrophase; ß = 1.29, p = 0.01) were associated with higher PFS scores. Lower PA between 4 a.m. and 8 a.m. was associated with higher PFS scores (ß = -4.50, p = 0.03). "Less Active/Robust" (ß = 6.14, p = 0.01) and "Later RAR" (ß = 3.53, p = 0.01) patterns were associated with higher PFS scores compared to "Earlier Risers". Greater physical fatigability in older adults was associated with dampened, more variable, and later RARs. This work can guide development of interventions aimed at modifying RARs to reduce fatigability in older adults.

The association between frailty and perceived physical and mental fatigability: The Long Life Family Study.

BACKGROUND: Higher levels of frailty, quantified by a frailty index (FI), may be linked to fatigue severity as tasks become more physically and mentally demanding. Fatigue, a component of frailty research, has been ambiguous and inconsistent in its operationalization. Fatigability-the quantification of vulnerability to fatigue in relation to specific intensity and duration of activities-offers a more sensitive and standardized approach, though the association between frailty and fatigability has not been assessed. METHODS: Using cross-sectional data from the Long Life Family Study at Visit 2 (2014-2017; N = 2524; mean age ± standard deviation (SD) 71.4 ± 11.2 years; 55% women; 99% White), we examined associations between an 83-item FI after excluding fatigue items (ratio of number of health problems reported (numerator) out of the total assessed (denominator); higher ratio = greater frailty) and perceived physical and mental fatigability using the Pittsburgh Fatigability Scale (PFS) (range 0-50; higher scores = greater fatigability). RESULTS: Participants had mean ± standard deviation FI (0.08 ± 0.06; observed range: 0.0-0.43), PFS Physical (13.7 ± 9.6; 39.5% more severe, ≥15), and PFS Mental (7.9 ± 8.9; 22.8% more severe, ≥13). The prevalence of more severe physical and mental fatigability was higher across FI quartiles. In mixed effects models accounting for family structure, a clinically meaningful 3%-higher FI was associated with 1.9 points higher PFS Physical score (95% confidence interval (CI) 1.7-2.1) and 1.7 points higher PFS Mental score (95% CI 1.5-1.9) after adjusting for covariates. CONCLUSIONS: Frailty was associated with perceived physical and mental fatigability severity. Understanding this association may support the development of interventions to mitigate the risks associated with greater frailty and perceived fatigability. Including measurements of perceived fatigability, in lieu of fatigue, in frailty indices has the potential to alleviate the inconsistencies and ambiguity surrounding the operationalization of fatigue and provide a more precise and sensitive measurement of frailty.

Role of Walking Energetics and Perceived Fatigability Differs by Gait Speed: The Study of Muscle, Mobility and Aging (SOMMA).

BACKGROUND: Slower gait speed may be driven by greater energy deficits and fatigability among older adults. We examined associations of walking energetics and perceived physical fatigability with gait speed among slower and faster walkers. Additionally, we used statistical mediation to examine the role of fatigability in the associations of walking energetics and gait speed using the Study of Muscle, Mobility and Aging (SOMMA). METHODS: Perceived physical fatigability was assessed using the Pittsburgh Fatigability Scale (PFS) Physical score (range 0-50, higher = greater). A 3-phase cardiopulmonary exercise treadmill test collected peak oxygen consumption (VO2peak, mL/kg/min), energetic cost of walking (ECW, mL/kg/m), and cost-capacity ratio (VO2/VO2peak*100, %). Slower (<1.01 m/s) versus faster (≥1.01 m/s) walkers were classified using median 4-m gait speed. Linear regressions and statistical mediation analyses were conducted. RESULTS: Slower walkers had lower VO2peak, higher ECW at preferred walking speed (PWS), and greater PFS Physical score compared to faster walkers (all p < .05; N = 849). One standard deviation (1-SD) higher VO2peak was associated with 0.1 m/s faster gait speed, while 1-SD higher ECW PWS, cost-capacity ratio at PWS and slow walking speed (SWS), and PFS Physical score were associated with 0.02-0.23 m/s slower gait speed. PFS Physical score was a significant statistical mediator in the associations between VO2peak (15.2%), SWS cost-capacity ratio (15.9%), and ECW PWS (10.7%) with gait speed and was stronger among slower walkers. CONCLUSIONS: Slower walkers may be more influenced by perceptions of fatigue in addition to walking energetics. Our work highlights the importance of targeting both energetics and perceived fatigability to prevent mobility decline.

Age Is Associated With Dampened Circadian Patterns of Rest and Activity: The Study of Muscle, Mobility, and Aging (SOMMA).

BACKGROUND: The effects of aging on circadian patterns of behavior are insufficiently described. To address this, we characterized age-specific features of rest-activity rhythms (RAR) in community-dwelling older adults both overall, and in relation, to sociodemographic characteristics. METHODS: We examined cross-sectional associations between RAR and age, sex, race, education, multimorbidity burden, financial, work, martial, health, and smoking status using assessments of older adults with wrist-worn free-living actigraphy data (N = 820, age = 76.4 years, 58.2% women) participating in the Study of Muscle, Mobility, and Aging (SOMMA). RAR parameters were determined by mapping an extension to the traditional cosine curve to activity data. Functional principal component analysis determined variables accounting for variance. RESULTS: Age was associated with several metrics of dampened RAR; women had stronger and more robust RAR versus men (all p < .05). Total activity (56%) and time of activity (20%) accounted for most of the RAR variance. Compared to the latest decile of acrophase, those in the earliest decile had higher average amplitude (p < .001). Compared to the latest decile of acrophase, those in the earliest and midrange categories had more total activity (p = .02). Being in a married-like relationship and a more stable financial situation were associated with stronger rhythms; higher education was associated with less rhythm strength (all p < .05). CONCLUSIONS: Older age was associated with dampened circadian behavior; behaviors were sexually dimorphic. Some sociodemographic characteristics were associated with circadian behavior. We identified a behavioral phenotype characterized by early time of day of peak activity, high rhythmic amplitude, and more total activity.

Associations of accelerometry-measured and self-reported physical activity and sedentary behavior with skeletal muscle energetics: The Study of Muscle, Mobility and Aging (SOMMA).

BACKGROUND: Skeletal muscle energetics decline with age, and physical activity (PA) has been shown to offset these declines in older adults. Yet, many studies reporting these effects were based on self-reported PA or structured exercise interventions. Therefore, we examined the associations of accelerometry-measured and self-reported PA and sedentary behavior (SB) with skeletal muscle energetics and explored the extent to which PA and sedentary behavior would attenuate the associations of age with muscle energetics. METHODS: As part of the Study of Muscle, Mobility and Aging, enrolled older adults (n = 879), 810 (age = 76.4 ± 5.0 years old, mean ± SD; 58% women) had maximal muscle oxidative capacity measured ex vivo via high-resolution respirometry of permeabilized myofibers (maximal oxidative phosphorylation (maxOXPHOS)) and in vivo by 31phosphorus magnetic resonance spectroscopy (maximal adenosine triphosphate (ATPmax)). Accelerometry-measured sedentary behavior, light activity, and moderate-to-vigorous PA (MVPA) were assessed using a wrist-worn ActiGraph GT9X over 7 days. Self-reported sedentary behavior, MVPA, and all PA were assessed with the Community Healthy Activities Model Program for Seniors (CHAMPS) questionnaire. Linear regression models with progressive covariate adjustments evaluated the associations of sedentary behavior and PA with muscle energetics, as well as the attenuation of the age/muscle energetics association by MVPA and sedentary behavior. As a sensitivity analysis, we also examined activPAL-measured daily step count and time spent in sedentary behavior and their associations with muscle energetics. RESULTS: Every 30 min/day more of ActiGraph-measured MVPA was associated with 0.65 pmol/(s × mg) higher maxOXPHOS and 0.012 mM/s higher ATPmax after adjusting for age, site/technician, and sex (p < 0.05). Light activity was not associated with maxOXPHOS or ATPmax. Meanwhile, every 30 min/day spent in ActiGraph-measured sedentary behavior was associated with 0.39 pmol/s × mg lower maxOXPHOS and 0.006 mM/s lower ATPmax (p < 0.05). Only associations with ATPmax held after further adjusting for socioeconomic status, body mass index, lifestyle factors, and multimorbidity. CHAMPS MVPA and all PA yielded similar associations with maxOXPHOS and ATPmax (p < 0.05), but sedentary behavior did not. Higher activPAL step count was associated with higher maxOXHPOS and ATPmax (p < 0.05), but time spent in sedentary behavior was not. Additionally, age was significantly associated with muscle energetics for men only (p < 0.05); adjusting for time spent in ActiGraph-measured MVPA attenuated the age association with ATPmax by 58% in men. CONCLUSION: More time spent in accelerometry-measured or self-reported daily PA, especially MVPA, was associated with higher skeletal muscle energetics. Interventions aimed specifically at increasing higher intensity activity might offer potential therapeutic interventions to slow age-related decline in muscle energetics. Our work also emphasizes the importance of taking PA into consideration when evaluating associations related to skeletal muscle energetics.

Sex Differences in the Association between Skeletal Muscle Energetics and Perceived Physical Fatigability: The Study of Muscle, Mobility and Aging (SOMMA).

Greater perceived physical fatigability and lower skeletal muscle energetics are predictors of mobility decline. Characterizing associations between muscle energetics and perceived fatigability may provide insight into potential targets to prevent mobility decline. We examined associations of in vivo (maximal ATP production, ATPmax) and ex vivo (maximal carbohydrate supported oxidative phosphorylation [max OXPHOS] and maximal fatty acid supported OXPHOS [max FAO OXPHOS]) measures of mitochondrial energetics with two measures of perceived physical fatigability, Pittsburgh Fatigability Scale (PFS, 0-50, higher=greater) and Rating of Perceived Exertion (RPE Fatigability, 6-20, higher=greater) after a slow treadmill walk. Participants from the Study of Muscle, Mobility and Aging (N=873) were 76.3±5.0 years old, 59.2% women, and 85.3% White. Higher muscle energetics (both in vivo and ex vivo ) were associated with lower perceived physical fatigability, all p<0.03. When stratified by sex, higher ATPmax was associated with lower PFS Physical for men only; higher max OXPHOS and max FAO OXPHOS were associated with lower RPE fatigability for both sexes. Higher skeletal muscle energetics were associated with 40-55% lower odds of being in the most (PFS≥25, RPE Fatigability≥12) vs least (PFS 0-4, RPE Fatigability 6-7) severe fatigability strata, all p<0.03. Being a woman was associated with 2-3 times higher odds of being in the most severe fatigability strata when controlling for ATPmax but not the in vivo measures (p<0.05). Better mitochondrial energetics were linked to lower fatigability and less severe fatigability in older adults. Findings imply that improving skeletal muscle energetics may mitigate perceived physical fatigability and prolong healthy aging.

Sex differences in the association between skeletal muscle energetics and perceived physical fatigability: the Study of Muscle, Mobility and Aging (SOMMA).

Greater perceived physical fatigability and lower skeletal muscle energetics are both predictors of mobility decline. Characterizing associations between muscle energetics and perceived fatigability may provide insight into potential targets to prevent mobility decline. We examined associations of in vivo (maximal ATP production, ATPmax) and ex vivo (maximal carbohydrate supported oxidative phosphorylation [max OXPHOS] and maximal fatty acid supported OXPHOS [max FAO OXPHOS]) measures of mitochondrial energetics with two measures of perceived physical fatigability, Pittsburgh Fatigability Scale (PFS, 0-50, higher = greater) and Rating of Perceived Exertion (RPE Fatigability, 6-20, higher = greater) after a slow treadmill walk. Participants from the Study of Muscle, Mobility and Aging (N = 873) were 76.3 ± 5.0 years old, 59.2% women, and 85.3% White. Higher muscle energetics (both in vivo and ex vivo) were associated with lower perceived physical fatigability, all p < 0.03. When stratified by sex, higher ATPmax was associated with lower PFS Physical for men only; higher max OXPHOS and max FAO OXPHOS were associated with lower RPE Fatigability for both sexes. Higher skeletal muscle energetics were associated with 40-55% lower odds of being in the most (PFS ≥ 25, RPE Fatigability ≥ 12) vs least (PFS 0-4, RPE Fatigability 6-7) severe fatigability strata, all p < 0.03. Being a woman was associated with 2-3 times higher odds of being in the most severe fatigability strata when controlling for ATPmax but not the ex vivo measures (p < 0.05). Better mitochondrial energetics were linked to lower fatigability and less severe fatigability in older adults. Findings imply that improving skeletal muscle energetics may mitigate perceived physical fatigability and prolong healthy aging.

Measuring and Understanding the Health Impact of Greater Fatigability in Older Adults: A Call to Action and Opportunities.

Different from fatigue, an instantaneous state of tiredness, weakness and lack of energy, fatigability is a trait that contextualizes whole-body fatigue to the level of activity (i.e., intensity and duration) with which the fatigue is associated. Fatigability can be perceived or performance-related. Measuring fatigability improves upon traditional fatigue measures by accounting for self-pacing as older adults likely slow down or limit their daily activity to maintain fatigue in a tolerable range. Anchoring fatigue to activities/tasks improves sensitivity and allows for meaningful comparisons across individuals/between studies, as well as evaluating change over time and treatment effects. Two well-validated approaches are utilized to measure perceived fatigability: 1) a 5-minute slow-paced (1.5 mph/0.67 m/s, 0% grade) treadmill walk immediately followed by Borg rating of perceived exertion; and 2) a self-administered 10-item questionnaire, Pittsburgh Fatigability Scale, with both physical and mental subscales. Many walking-based performance fatigability measures are based on certain lap time or distance, while the Pittsburgh Performance Fatigability Index uses raw accelerometry data to quantify percent of cadence decline over the entire long distance walking tasks. Perceived fatigability prevalence ranges from 20-90% in older adults varying by assessment tool, and is higher with advancing age and in women compared to men. Fatigability is associated with physical and cognitive function, fall risk, mobility decline, and mortality. Unfortunately, the available research lacks representativeness in terms of racial and ethnic diversity. The time is now to incorporate our established sensitive and validated fatigability measures into global research and clinical practice to better understand mechanistic underpinnings and reveal intervention effects to reduce the burden and lessen the consequences of greater fatigability worldwide.

The association between daily sedentary and active bout frequency with mortality risk in older men using accelerometry.

BACKGROUND: Time awake with advancing age is increasingly spent sedentary and has several negative health consequences. We examined associations between the frequency of daily sedentary and active bouts with all-cause mortality. METHODS: Data are from 2816 men in the Osteoporotic Fractures in Men (MrOS) Study (mean age ± SD: 79.1 ± 5.2 years) with free-living activity monitor (SenseWear® Pro3 Armband) data (5.1 ± 0.3 days worn >90%) at the Year 7 visit (2007-2009). Sedentary bout frequency was defined as the number of sedentary bouts per day lasting 5+ min to activity of any intensity. Active bout frequency was defined as the number of active bouts per day lasting 5+ min to sedentary behavior. Sleep time was excluded from the analysis. Deaths were centrally adjudicated using death certificates. Cox proportional hazard models were used to separately examine associations between quartiles of sedentary (Q1 referent, <13.6 bouts/day) or active (Q1 referent, <5 bouts/day) bout frequency with mortality. RESULTS: After 9.3 ± 3.8 years of follow-up, 1487 (52.8%) men died. Men averaged 16.8 ± 5.1 and 8.2 ± 4.2 sedentary and active bouts/day, respectively. After full covariate adjustment, each quartile reflecting more frequent sedentary bouts (Q4 vs. Q1 HR: 0.69, 95%CI: 0.58, 0.81, p-trend <0.001) was associated with lower mortality risk. Likewise, each quartile reflecting more frequent active bouts (Q4 vs. Q1 HR: 0.58, 95%CI: 0.49, 0.70, p-trend <0.001) was associated with lower mortality risk. Results for the sedentary bouts model remained significant after adjusting for total minutes per day in sedentary behavior (Q4 vs. Q1 HR: 0.63, 95%CI: 0.61, 0.86, p-trend = 0.001). The association between active bout frequency with mortality was attenuated after adjusting for total minutes per day active. CONCLUSIONS: Regardless of total time spent sedentary, reducing duration of sedentary bouts with more frequent and shorter bouts may be a simple and feasible method to delay mortality risk among community-dwelling older men.

Dual Roles of Cardiorespiratory Fitness and Fatigability in the Life-Space Mobility of Older Adults: The Study of Muscle, Mobility and Aging (SOMMA).

BACKGROUND: Cardiorespiratory fitness and perceived fatigability are interrelated components of physical capacity that may jointly influence movement within one's living environment (life-space mobility). We examined whether fitness and fatigability were associated with life-space mobility in community-dwelling older adults, and whether the association of fitness with life-space varied by the level of perceived fatigability. METHODS: Participants were from the Study of Muscle, Mobility and Aging (SOMMA) baseline cohort (N = 775, mean age 76.1 years). Life Space Assessment scores incorporated level, frequency, and assistance used (personal, devices) for life-space mobility. Fitness was measured as VO2peak from symptom-limited treadmill testing. Fatigability cut-points included: (i) Borg Rating of Perceived Exertion (RPE) ≥ 10 after a fixed-speed (1.5 mph) treadmill test, (ii) the Pittsburgh Fatigability Scale (PFS) Physical ≥ 15, and (iii) PFS Mental ≥ 13. The total count of cut-points was used as a composite fatigability measure (range: 0-3). Linear regressions were adjusted for demographic, lifestyle, and health confounders. RESULTS: Better fitness was associated with greater life-space, but the association plateaued at higher fitness levels (VO2peak > 18). Life-space was significantly lower for individuals meeting ≥2 fatigability criteria (vs none), attributable mainly to more severe physical, but not mental, fatigability. In moderation analyses, the fitness-life-space association was significant only for those with RPE ≥ 10 but did not differ by PFS. CONCLUSION: Fitness below a critically low threshold was associated with limited life-space mobility, suggesting that certain older individuals may need to operate close to their maximum aerobic capacity to traverse daily environments; these associations were driven by those with more severe physical fatigability.

Age is Associated with Dampened Circadian Patterns of Rest and Activity: The Study of Muscle, Mobility and Aging (SOMMA).

Background: Aging is associated with declines in circadian functions. The effects of aging on circadian patterns of behavior are insufficiently described. We characterized age-specific features of rest-activity rhythms (RAR) in community dwelling older adults, both overall, and in relation, to sociodemographic characteristics. Methods: We analyzed baseline assessments of older adults with wrist-worn free-living wrist-worn actigraphy data (N=820, Age=76.4 yrs, 58.2% women) participating in the Study of Muscle, Mobility and Aging (SOMMA). We applied an extension to the traditional cosine curve to map RAR to activity data, calculating the parameters: rhythmic strength (amplitude); robustness (pseudo-F statistic); and timing of peak activity (acrophase). We also used function principal component analysis to determine 4 components describing underlying patterns of activity accounting for RAR variance. Linear models were used to examine associations between RAR and sociodemographic variables. Results: Age was associated with several metrics of dampened RAR; women had stronger and more robust RAR metrics vs. men (all P < 0.05). Total activity (56%) and time of activity (20%) accounted for most the RAR variance. Compared to the latest decile of acrophase, those in the earliest decile had higher average amplitude (P <0.001). Compared to the latest decile of acrophase, those is the earliest and midrange categories had more total activity (P=0.02). RAR was associated with some sociodemographic variables. Conclusions: Older age was associated with dampened circadian behavior; and behaviors were sexually dimorphic. We identified a behavioral phenotype characterized by early time-of-day of peak activity, high rhythmic amplitude, and more total activity.

Lower Physical Activity Modifies the Association between Perceived Fatigability and Executive Function but not Memory: The Study of Muscle, Mobility and Aging (SOMMA).

OBJECTIVE: Emerging evidence shows that perceived fatigability-the quantification of vulnerability to fatigue in relation to specific intensity and duration of activities-may be associated with cognitive function. We sought to quantify associations with multiple domains of cognitive function and the role of physical activity (PA). METHODS: SOMMA participants completed the Pittsburgh Fatigability Scale (PFS) Physical and Mental subscales (each range 0-50; higher scores=greater fatigability) and three cognitive function assessments [Digit Symbol Substitution Test (DSST), executive function; Montreal Cognitive Assessment (MoCA), general function; and California Verbal Learning Test (CVLT), memory]. Linear regression quantified associations cross-sectionally between each PFS subscale and cognitive assessment scores adjusting for covariates. Effect modification by volume and intensity of accelerometer-measured PA was assessed. RESULTS: In 873 participants (59.2% women; age 76.3±5.0; 85% White), mean PFS Physical, Mental, and DSST scores were 15.8±8.7, 7.7±7.8, and 55.4±13.7. After adjustments, for each 4-point higher PFS Physical and 3-point higher PFS Mental, participants had nearly one fewer correct DSST items [ß coefficient and 95% confidence interval for PFS Physical: -0.69 (-1.09, - 0.29); PFS Mental: -0.64 (-0.97, -0.30)]. Volume and intensity of PA modified the association of PFS Mental and DSST ( P interactions <0.01). All associations were strongest in those with the lowest volume and intensity of PA. PFS was not associated with MoCA or CVLT. DISCUSSION: Greater perceived fatigability may be associated with poorer executive function, but not memory. Individuals with greater perceived fatigability, particularly those less active, might benefit from interventions that reduce fatigability and may beneficially influence cognitive function.

Validation of the Pittsburgh Performance Fatigability Index in the Study of Muscle, Mobility and Aging.

BACKGROUND: The Pittsburgh Performance Fatigability Index (PPFI) quantifies the percent decline in cadence using accelerometry during standardized walking tasks. Although PPFI has shown strong correlations with physical performance, the developmental sample was relatively homogenous and small, necessitating further validation. METHODS: Participants from the Study of Muscle, Mobility and Aging (N = 805, age = 76.4 ±â€…5.0 years, 58% women, 85% White) wore an ActiGraph GT9X on the nondominant wrist during usual-paced 400 m walk. Tri-axial accelerations were analyzed to compute PPFI (higher score = greater fatigability). To evaluate construct and discriminant validity, Spearman correlations (rs) between PPFI and gait speed, Short Physical Performance Battery (SPPB), chair stand speed, leg peak power, VO2peak, perceived fatigability, and mood were examined. Sex-specific PPFI cut-points that optimally discriminated gait speed using classification and regression tree were then generated. Their discriminate power in relation to aforementioned physical performance were further evaluated. RESULTS: Median PPFI score was 1.4% (25th-75th percentile range: 0%-21.7%), higher among women than men (p < .001). PPFI score was moderate-to-strongly correlated with gait speed (rs = -0.75), SPPB score (rs = -0.38), chair stand speed (rs = -0.36), leg peak power (rs = -0.34) and VO2peak (rs = -0.40), and less strongly with perceived fatigability (rs = 0.28-0.29), all p < .001. PPFI score was not correlated with mood (|rs| < 0.08). Sex-specific PPFI cut-points (no performance fatigability: PPFI = 0%; mild performance fatigability: 0% < PPFI < 3.5% [women], 0% < PPFI < 5.4% [men]; moderate-to-severe performance fatigability: PPFI ≥ 3.5% [women], PPFI ≥ 5.4% [men]) discriminated physical performance (all p < .001), adjusted for demographics and smoking status. CONCLUSION: Our work underscores the utility of PPFI as a valid measure to quantify performance fatigability in future longitudinal epidemiologic studies and clinical/pharmaceutical trials.

Associations between skeletal muscle energetics and accelerometry-based performance fatigability: Study of Muscle, Mobility and Aging.

Performance fatigability is typically experienced as insufficient energy to complete daily physical tasks, particularly with advancing age, often progressing toward dependency. Thus, understanding the etiology of performance fatigability, especially cellular-level biological mechanisms, may help to delay the onset of mobility disability. We hypothesized that skeletal muscle energetics may be important contributors to performance fatigability. Participants in the Study of Muscle, Mobility and Aging completed a usual-paced 400-m walk wearing a wrist-worn ActiGraph GT9X to derive the Pittsburgh Performance Fatigability Index (PPFI, higher scores = more severe fatigability) that quantifies percent decline in individual cadence-versus-time trajectory from their maximal cadence. Complex I&II-supported maximal oxidative phosphorylation (max OXPHOS) and complex I&II-supported electron transfer system (max ETS) were quantified ex vivo using high-resolution respirometry in permeabilized fiber bundles from vastus lateralis muscle biopsies. Maximal adenosine triphosphate production (ATPmax ) was assessed in vivo by 31 P magnetic resonance spectroscopy. We conducted tobit regressions to examine associations of max OXPHOS, max ETS, and ATPmax with PPFI, adjusting for technician/site, demographic characteristics, and total activity count over 7-day free-living among older adults (N = 795, 70-94 years, 58% women) with complete PPFI scores and ≥1 energetics measure. Median PPFI score was 1.4% [25th-75th percentile: 0%-2.9%]. After full adjustment, each 1 standard deviation lower max OXPHOS, max ETS, and ATPmax were associated with 0.55 (95% CI: 0.26-0.84), 0.39 (95% CI: 0.09-0.70), and 0.54 (95% CI: 0.27-0.81) higher PPFI score, respectively. Our findings suggested that therapeutics targeting muscle energetics may potentially mitigate fatigability and lessen susceptibility to disability among older adults.

Associations of Objective and Self-Reported Physical Activity and Sedentary Behavior with Skeletal Muscle Energetics: The Study of Muscle, Mobility and Aging (SOMMA).

Background: Skeletal muscle energetics decline with age, and physical activity (PA) has been shown to counteract these declines in older adults. Yet, many studies were based on self-reported PA or structured exercise interventions. We examined the associations of objective daily PA and sedentary behavior (SB) with skeletal muscle energetics and also compared with self-reported PA and SB. We also explored the extent to which PA would attenuate the associations of age with muscle energetics. Methods: Among the Study of Muscle, Mobility and Aging (SOMMA) enrolled older adults, 810 (mean age=76±5, 58% women) had maximal muscle oxidative capacity measured ex vivo via high-resolution respirometry of permeabilized myofibers (maxOXPHOS) and in vivo by 31 Phosphorus magnetic resonance spectroscopy (ATP max ). Objective PA was measured using the wrist-worn ActiGraph GT9X over 7-days to capture sedentary behavior (SB), light, and moderate-to-vigorous PA (MVPA). Self-reported SB, MVPA, and all exercise-related PA were assessed with The Community Healthy Activities Model Program for Seniors questionnaire. Linear regression models with progressive covariate adjustments evaluated the associations between SB, PA and muscle energetics, and the attenuation of the age / muscle energetic association by PA. Results: Every 30 minutes more objective MVPA was associated with 0.65 pmol/s*mg higher maxOXPHOS and 0.012 mM/sec higher ATP max , after adjustment for age, site/technician and sex. More time spent in objective light+MVPA was significantly associated with higher ATP max , but not maxOXPHOS. In contrast, every 30 minutes spent in objective SB was associated with 0.43 pmol/s*mg lower maxOXPHOS and 0.004 mM/sec lower ATP max . Only associations with ATP max held after further adjusting for socioeconomic status, body mass index, lifestyle factors and multimorbidities. Self-reported MVPA and all exercise-related activities, but not SB, yielded similar associations with maxOXPHOS and ATP max . Lastly, age was only significantly associated with muscle energetics in men. Adjusting for objective time spent in MVPA attenuated the age association with ATP max by nearly 60% in men. Conclusion: More time spent in daily PA, especially MVPA, were associated with higher muscle energetics. Interventions that increase higher intensity activity might offer potential therapeutic interventions to slow the age-related decline in muscle energetics. Our work also emphasizes the importance of taking PA into consideration when evaluating associations related to skeletal muscle energetics.

Prospective Associations Between Physical Activity and Perceived Fatigability in Older Men: Differences by Activity Type and Baseline Marital Status.

BACKGROUND: Lower physical activity has been cross-sectionally associated with greater perceived fatigability, defined as self-reported fatigue anchored to activity intensity and duration. The temporality of this relationship, and whether it differs by activity type or marital status, remains unclear. METHODS: In the Osteoporotic Fractures in Men Study (N = 1 759), self-reported total, exercise, and household activity were assessed using the Physical Activity Scale for the Elderly across 7 visits (2000-2016). The Pittsburgh Fatigability Scale (range: 0-50; higher scores = greater fatigability) measured physical (mean = 16.6 ± 9.7) and mental (mean = 7.8 ± 8.3) fatigability at Year 14. Least absolute deviation and linear regression were used to examine associations between baseline and change in activity over 14 years with subsequent fatigability. Models were adjusted for demographic, health, and lifestyle factors. RESULTS: After adjustment, lower baseline (ß= -0.08, 95% confidence interval [CI]: -0.12, -0.04) and greater annual declines in total activity (ß = -0.09, 95% CI: -0.14, -0.05) were prospectively associated with higher Pittsburgh Fatigability Scale (PFS) Physical scores. Associations were similar for mental fatigability (both p < .05). Lower baseline leisure exercise, but not baseline household activity, predicted higher PFS Physical scores (ß = -0.10 vs -0.001). In contrast, greater declines in household activity, but not declines in exercise, were associated with higher PFS Physical scores (ß = -0.09 vs -0.03). Lower baseline household activity predicted higher PFS Mental scores only for unmarried men (ß = -0.15, 95% CI: -0.29, -0.01, interaction p = .019). CONCLUSIONS: Baseline total activity and leisure exercise, and declines in total and household activity, were associated with higher subsequent perceived fatigability in older men. Marital status may mitigate the contribution of household activity to subsequent fatigability.

Life-space Mobility in Older Men: The Role of Perceived Physical and Mental Fatigability.

BACKGROUND: Physical performance and fatigue can limit mobility within the larger environment (life-space mobility). It is unknown whether perceived fatigability, self-reported fatigue anchored to activity intensity and duration, is independently associated with life-space. METHODS: We assessed this cross-sectionally in Visit 4 (2014-2016) of the Osteoporotic Fractures in Men Study (MrOS; N = 1 672, Age: Mean = 84.2 ± 4.0 years). The Pittsburgh Fatigability Scale (PFS, range: 0-50; higher = greater fatigability) measured physical (Mean = 16.1 ± 9.4) and mental fatigability (Mean = 7.5 ± 7.9). Life Space Assessment scores incorporated level, frequency, and assistance used for life-space mobility (range: 0-120, higher = greater life-space mobility; life-space constriction: inability to leave neighborhood without assistance). Separate multiple linear and logistic regressions for physical and mental fatigability were sequentially adjusted for demographic, health/lifestyle, and performance measures. RESULTS: The mean life-space mobility score was 84.6 ± 21.8, and 18% (n = 296) of men had life-space constriction. Higher physical and mental fatigability were both associated with lower life-space mobility in models adjusted for health and lifestyle factors (Physical PFS: B = -2.37, 95% confidence interval [CI]: [-3.39, -1.35]; Mental PFS: B = -1.79, 95% CI: [-2.73, -0.84]). Men with higher fatigability also had increased risk of life-space constriction (Physical PFS: OR = 1.59, 95% CI: [1.32, 1.92]; Mental PFS: OR = 1.25, 95% CI: [1.08, 1.46]). Associations were larger in magnitude for physical versus mental fatigability. Adjusting for physical performance measures more strongly attenuated associations for physical compared to mental fatigability. CONCLUSIONS: Fatigability is linked with real-world mobility in older men, independent of their physical health. This association may be driven by separate physical and cognitive mechanisms worth examining further in longitudinal studies.

Perceived Physical Fatigability Predicts All-Cause Mortality in Older Adults.

BACKGROUND: Perceived physical fatigability is highly prevalent in older adults and associated with mobility decline and other health consequences. We examined the prognostic value of perceived physical fatigability as an independent predictor of risk of death among older adults. METHODS: Participants (N = 2 906), mean age 73.5 [SD, 10.4] years, 54.2% women, 99.7% white enrolled in the Long Life Family Study, were assessed at Visit 2 (2014-2017) with 2.7 [SD, 1.0] years follow-up. The Pittsburgh Fatigability Scale (PFS), a 10-item, self-administered validated questionnaire (score range 0-50, higher = greater fatigability) measured perceived physical fatigability at Visit 2. Deaths post-Visit 2 through December 31, 2019 were identified by family members notifying field centers, reporting during another family member's annual phone follow-up, an obituary, or Civil Registration System (Denmark). We censored all other participants at their last contact. Cox proportional hazard models predicted mortality by fatigability severity, adjusted for family relatedness and other covariates. RESULTS: Age-adjusted PFS Physical scores were higher for those who died (19.1 [SE, 0.8]) compared with alive (12.2, [SE, 0.4]) overall, as well as across age strata (p < .001), except for those 60-69 years (p = .79). Participants with the most severe fatigability (PFS Physical scores ≥ 25) were over twice as likely to die (hazard ratio, 2.33 [95% CI, 1.65-3.28]) compared with those who had less severe fatigability (PFS Physical scores < 25) after adjustment. CONCLUSIONS: Our work underscores the utility of the PFS as a novel patient-reported prognostic indicator of phenotypic aging that captures both overt and underlying disease burden that predicts death.

Development of a Novel Accelerometry-Based Performance Fatigability Measure for Older Adults.

INTRODUCTION: Efforts to study performance fatigability have been limited because of measurement constrains. Accelerometry and advanced statistical methods may enable us to quantify performance fatigability more granularly via objective detection of performance decline. Thus, we developed the Pittsburgh Performance Fatigability Index (PPFI) using triaxial raw accelerations from wrist-worn accelerometer from two in-laboratory 400-m walks. METHODS: Sixty-three older adults from our cross-sectional study (mean age, 78 yr; 56% women; 88% White) completed fast-paced ( n = 59) and/or usual-paced 400-m walks ( n = 56) with valid accelerometer data. Participants wore ActiGraph GT3X+ accelerometers (The ActiGraph LLC, Pensacola, FL) on nondominant wrist during the walking task. Triaxial raw accelerations from accelerometers were used to compute PPFI, which quantifies percentage of area under the observed gait cadence-versus-time trajectory during a 400-m walk to a hypothetical area that would be produced if the participant sustained maximal cadence throughout the entire walk. RESULTS: Higher PPFI scores (higher score = greater fatigability) correlated with worse physical function, slower chair stands speed and gait speed, worse cardiorespiratory fitness and mobility, and lower leg peak power (| ρ | = 0.36-0.61 from fast-paced and | ρ | = 0.28-0.67 from usual-paced walks, all P < 0.05). PPFI scores from both walks remained associated with chair stands speed, gait speed, fitness, and mobility, after adjustment for sex, age, race, weight, height, and smoking status; PPFI scores from the fast-paced walk were associated with leg peak power. CONCLUSIONS: Our findings revealed that the objective PPFI is a sensitive measure of performance fatigability for older adults and can serve as a risk assessment tool or outcome measure in future studies and clinical practice.