Background Fatigability is a construct that measures whole-body tiredness anchored to activities of a fixed intensity and duration; little is known about its epidemiology and heritability. Methods Two generations of family members enriched for exceptional longevity and their spouses were enrolled (2006–2009) in the Long Life Family Study (LLFS). At Visit 2 (2014–2017, N = 2,355) perceived physical fatigability was measured using the 10-item self-administered Pittsburgh Fatigability Scale (PFS), along with demographic, medical, behavioral, physical, and cognitive risk factors. Results Residual genetic heritability of fatigability was 0.263 (p = 6.6 × 10–9) after adjustment for age, sex, and field center. PFS physical scores (mean ± SD) and higher physical fatigability prevalence (% PFS ≥ 15) were greater with each age strata: 60–69 (n = 1,009, 11.0 ± 7.6, 28%), 70–79 (n = 847, 12.5 ± 8.1, 37%), 80–89 (n = 253, 19.3 ± 9.9, 65.2%), and 90–108 (n = 266, 28.6 ± 9.8, 89.5%), p < .0001, adjusted for sex, field center, and family relatedness. Women had a higher prevalence of perceived physical fatigability compared to men, with the largest difference in the 80–89 age strata, 74.8% versus 53.5%, p < .0001. Those with greater body mass index, worse physical and cognitive function, and lower physical activity had significantly higher perceived physical fatigability. Conclusions Perceived physical fatigability is highly prevalent in older adults and strongly associated with age. The family design of LLFS allowed us to estimate the genetic heritability of perceived physical fatigability. Identifying risk factors associated with higher perceived physical fatigability can inform the development of targeted interventions for those most at risk, including older women, older adults with depression, and those who are less physically active.

MEASUREMENTS: Development Sample, Validation Sample I-BLSA, and Validation Sample II-LLFS participants self-administered the 10-item Pittsburgh Fatigability Scale. Validation Sample II-LLFS completed cognition measures (Trail Making Tests A and B), depressive symptomatology (Center for Epidemiologic Studies-Depression Scale, CES-D), and global fatigue from two CES-D items. RESULTS: In the Development Sample and Validation Sample I-BLSA, confirmatory factor analysis showed all 10 items loaded on two factors: social and physical activities (fit indices: SRMSR = 0.064, RMSEA = 0.095, CFI = 0.91). PFS Mental scores had strong internal consistency (Cronbach's α = 0.85) and good test-retest reliability (ICC = 0.78). Validation Sample II-LLFS PFS Mental scores demonstrated moderate concurrent and construct validity using Pearson (r) or Spearman (ρ) correlations against measures of cognition (Trail Making Tests A (r = 0.14) and B (r = 0.17) time), depressive symptoms (r = 0.31), and global fatigue (ρ = 0.21).Additionally, the PFS Mental subscale had strong convergent validity, discriminating according to established clinical or cognitive testing cut points, with differences in PFS Mental scores ranging from 3.9 to 7.6 points (all P < .001). All analyses were adjusted for family relatedness, field center, age, sex, and education. CONCLUSIONS: The validated PFS Mental subscale may be used in clinical and research settings as a sensitive, onepage self-administered tool of perceived mental fatigability 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 to alive (12.2, [SE, 0.4]) overall, as well as across age strata (P&lt;.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 (HR, 2.33 [95% CI, 1.65 to 3.28]) compared to those with less severe fatigability (PFS Physical scores &lt;25) after adjustment. Conclusions This 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.

Background and Objectives Fatigue is a common complaint and shares many risk factors with falls, yet the independent contribution of fatigue on fall risk is unclear. This study’s primary aim was to assess the association between fatigue and prospective fall risk in 5,642 men aged 64-100 enrolled in the Osteoporotic Fractures in Men Study (MrOS). The secondary aim was to examine the association between fatigue and recurrent fall risk. Research Design and Methods Fatigue was measured at baseline using the Medical Outcomes Study (short form) single-item question “during the past four weeks, how much of the time did you feel energetic?” Responses were then classified: higher fatigue=“none”, “little”, or “some” of the time and lower fatigue=“a good bit”, “most”, or “all” of the time. We assessed falls using triannual questionnaires. Fall risk was examined prospectively over three years; recurrent falling was defined as ≥2 falls within the first year. Generalized estimating equations and multinomial logistic regression modeled prospective and recurrent fall risk as a function of baseline fatigue status, adjusted for demographics, medications, physical activity, and gait speed. Results Men with higher (26%) vs. lower baseline fatigue were older (75.1±6.2 vs.73.2±5.7 years), 24% less active, and had worse function (gait speed=1.09±0.24 vs. 1.24±0.21 m/s), all p&lt;0.0001. Within one year, 25.4% (N=1,409) had fallen at least once, of which 47.4% (N=668) were recurrent fallers. Men with higher vs. lower fatigue had 25% increased fall risk (RR=1.25, 95% CI:1.14, 1.36) over 3 years follow-up, but had 50% increased odds of recurrent falling (OR 1.50, 95% CI: 1.22, 1.85) within the first year. Discussion and Implications Fatigue is an important risk factor of falling independent of established risk factors. Reductions in fatigue (i.e., increased energy) may lessen the burden of falls in older men and provide a novel avenue for fall risk intervention.

Background: Fatigue, inflammation, and physical activity (PA) are all independently associated with gait speed but their directionality is not fully elucidated.Aims: Evaluate the bidirectional associations amongst fatigue, inflammation, and PA on gait speed. Methods:This cross-sectional study included probands (n=1,280, aged 49-105) and offspring (n=2,772, aged 24-88) in the Long Life Family Study. We assessed gait speed, fatigue with the question "I could not get going", inflammation using fasting interleukin-6 (IL-6) and high sensitivity C-reactive protein (CRP), and self-reported PA as walking frequency in the past two weeks. The two generations were examined separately using linear mixed modeling.Results: Lower fatigue, lower IL-6, and greater PA were all associated with faster gait speed in both generations (all p<0.05); lower CRP was only associated with faster gait speed in the