Alterations in energy metabolism may drive fatigue in older age, but prior research primarily focused on skeletal muscle energetics without assessing other systems, and utilized self-reported measures of fatigue. We tested the association between energy metabolism in the brain and an objective measure of fatigability in the Study of Muscle, Mobility and Aging (N=119, age 76.8±4.0 years, 59.7% women). Total brain cerebral metabolic rate of oxygen (CMRO2) was measured using arterial spin labeling and T2-relaxation under spin tagging MRI protocols. Accelerometry-based fatigability status during a fast-paced 400m walk was determined using the Pittsburgh Fatigability Index (PPFI, higher=worse). Confounders included skeletal muscle energetics, measured in vivo using spectroscopy and ex vivo using respirometry, cardiorespiratory fitness (VO2peak), weight, medication count, and multimorbidity. Multivariable logistic regression models were used to estimate the association (odds ratio (OR)) of CMRO2 with PPFI>0 compared to the referent group PPFI=0. Models were first adjusted for age and sex, and further adjusted for confounders. In this sample, 41.2% had PPFI>0 (median 3.3% [0.4-8.0%]). CMRO2 was positively associated with PPFI>0 (age and sex adjusted OR=1.61, 95% CI: 1.06, 2.45, p=0.03); adjustment for confounders attenuated the association. The positive association of brain energetics and fatigability warrants further study in older adults.

The authors have declared no competing interest.

The Study of Muscle, Mobility and Aging is supported by funding from the National Institute on Aging (R01 AG 059416). Study infrastructure support was funded in part by NIA Claude D. Pepper Older American Independence Centers, at University of Pittsburgh (P30 AG024827) and Wake Forest University (P30 AG021332) and the Clinical and Translational Science Institutes, funded by the National Center for Advancing Translational Science, at Wake Forest University (UL1 TR001420). SOMMA-Brain is supported by NIA awards (R01AG075025 and U01AG061393). E.L.G is supported by the Pittsburgh Epidemiology of Aging Training Program (NIA T32 AG000181).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The WIRB-Copernicus Group Institutional Review Board approved the study, and all participants gave informed written consent (parent study and ancillary numbers 20180764 and 20110230).

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes