Elsevier

Experimental Gerontology

Volume 144, February 2021, 111177
Experimental Gerontology

Short report
Age-related fatigue is associated with reduced mitochondrial function in peripheral blood mononuclear cells

https://doi.org/10.1016/j.exger.2020.111177Get rights and content

Abstract

Background

Fatigue is a complex syndrome associated with exhaustion not relieved by sleep. It occurs frequently in older adults in the context of chronic disease and is associated with decreased physical capacity. Whether a mitochondrial dysfunction and therefore an impaired energy production might contribute to the development of fatigue during aging is yet unknown. The aim of this study was to evaluate mitochondrial respiration of peripheral blood mononuclear cells (PBMCs) in older patients with and without fatigue.

Method

Fatigue was determined according to the Brief Fatigue Inventory. Mitochondrial respiration of freshly isolated PBMCs was investigated by high-resolution respirometry using the Oroboros Oxygraph-O2k. Functional impairment and depressive symptoms were assessed using questionnaires.

Results

23 geriatric patients (77.8 ± 4.9 years; 43.5% female) with fatigue and 22 without fatigue (75.4 ± 5.4 years; 45.5% female) were analyzed. Patients with fatigue exhibited more functional limitations and more depressive symptoms. High-resolution respirometry of intact PBMCs revealed a lower routine (4.82 ± 1.14 pmol/s versus 5.89 ± 1.90 pmol/s, p = 0.041) and maximum (6.55 ± 1.51 pmol/s versus 8.43 ± 3.67 pmol/s, p = 0.013) oxygen consumption rate, resulting in a reduced ATP-linked respiration (4.26 ± 1.00 pmol/s versus 5.09 ± 1.53 pmol/s, p = 0.035) of PBMCs from geriatric patients with fatigue compared to controls without.

Conclusions

This short report shows that in this group of older patients, fatigue is associated with lower PBMC mitochondrial respiration. Whether the impaired mitochondrial respiration is accompanied by a reduced mitochondrial activity in other organs (e.g. muscle) remains to be elucidated.

Introduction

Fatigue is a complex syndrome described as persistent exhaustion not relieved by sleep that affects the capacity to execute mental and physical activities (Zengarini et al., 2015) and is known to frequently occur in chronic disease and malnutrition (Franz et al., 2019a). Moreover, fatigue negatively influences quality of life and is a predictor for disability and mortality (Moreh et al., 2010). Due to a prevalence of 29–68% in community-dwelling older adults and its detrimental effects, it is crucial to understand the manifestation of fatigue (Moreh et al., 2010). However, the underlying molecular mechanisms and the pathophysiology of fatigue are yet not fully understood (Zengarini et al., 2015). Mitochondria can be linked to various processes associated with aging such as formation of reactive oxygen species, inflammation, cellular senescence and decline of tissue and organ function (Sun et al., 2016). Furthermore, mitochondrial functions such as mitochondrial dynamics and respiratory capacity decline with age (Sebastian et al., 2017). As circulating blood cells e.g. peripheral blood mononuclear cells (PBMCs) are able to reflect ongoing metabolic stress, they represent a suitable tool to evaluate mitochondrial bioenergetics in the clinical setting (Ost et al., 2018). Impaired mitochondrial function in PBMCs has been observed in i.a. major depression (Karabatsiakis et al., 2014) as well as sepsis (Cheng et al., 2016) and associations of mitochondrial respiration with gait speed, grip strength and inflammation have been shown (Tyrrell et al., 2015a; Tyrrell et al., 2015b). It has been suggested that impaired bioenergetics e.g. mitochondrial respiration, might contribute to the pathogenesis of chronic fatigue (Tomas et al., 2020). Tomas et al. recently reported altered mitochondrial function in PBMCs in younger patients with chronic fatigue syndrome (Tomas et al., 2020). However, mitochondrial function in PBMCs (or other tissues) has yet not been studied in older adults with fatigue. In this short report we therefore evaluated bioenergetic profiles in older patients with and without fatigue and explored a potential association with functional impairment.

Section snippets

Participants

This is an analysis of a study described elsewhere (Franz et al., 2019b). In brief, geriatric patients above 60 years, without cognitive impairment (mini mental state examination score ≥ 24) and without severe neurodegenerative disease, were consecutively recruited upon admission to hospital. Additionally, to in order to investigate cancer-unrelated fatigue, patients with cancer were not included. All participants signed written informed consent and the study was approved by the ethics

Results

Forty-five patients were included in this analysis and their characteristics are listed in Table 1. Orthopedic disorders were the most frequent reason for admission to hospital accounting for 57.8% of the study cohort, followed by cardiovascular disease with 15.6%. 51.1% of patients reported moderate to severe fatigue. Patients with and without fatigue were similar regarding age, sex, BMI, number of comorbidities and reason for admission. Fatigue score was correlated with higher functional

Discussion

The pathophysiology of fatigue in older adults is not yet fully understood. To our knowledge, this is the first study investigating mitochondrial respiration in PBMCs of older patients with fatigue in comparison to patients without fatigue.

A recent study by Tomas et al. likewise showed lower mitochondrial respiration in PBMCs of younger patients with chronic fatigue syndrome compared to control subjects (24–58 years) (Tomas et al., 2020), which prompted them to propose that PBMCs of patients

Funding

This work was supported by the Focus Area DynAge “Disease in Human Aging” (5.1.: 07/2016 - 06/2017) a collaboration of the Charité - Universitätsmedizin Berlin, the German Institute of Human Nutrition Potsdam - Rehbrücke, the Freie Universität Berlin and the Robert Koch Institute.

CRediT authorship contribution statement

Catrin Herpich: Investigation, formal analysis, Writing - Original Draft, Kristina Franz: Investigation, Writing - Review & Editing, Susanne Klaus: Conceptualization, Writing - Review & Editing, Ursula Müller-Werdan: Conceptualization, Writing - Review & Editing, Mario Ost: investigation, formal analysis, conceptualization, Kristina Norman: Conceptualization, Writing - Original Draft.

All authors commented on previous versions of the manuscript and approved the final manuscript.

Declaration of competing interest

None.

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