Frailty is a condition of global impairment due to depletion of physiological reserves. However, the underlying biological mechanisms are poorly understood. The aims of the current study were to identify the differences in mitochondrial function and iron metabolism between frail and nonfrail populations, and to investigate the contribution of different methodological approaches to the results. Searches were performed, using five online databases up to November 2019. Studies reporting measurements of mitochondrial function or iron metabolism in frail and nonfrail subjects or subjects with and without sarcopenia, were included. Pooled effect estimates were expressed as Standardized Mean Differences. Heterogeneity, expressed as I2, was explored using regression analyses. In total, 107 studies, reporting 75 measures of mitochondrial function or iron metabolism, using six different experimental approaches, in three species were identified. Significant decreases in measures of oxygen consumption were observed for frail humans but not in animal models. Conversely, no differences between frail and nonfrail humans were observed for apoptosis and autophagy, in contrast to animal models. The most significant effect of the type of frailty assessment was observed for respiratory chain complexes where only subjects categorized as frail by the Fried Frailty Index showed a significant decrease in activity. We identified iron metabolism in frailty as an important knowledge gap, highlighted the need of consistent frailty diagnostic tools, and pointed out the limited translational potential of animal models. Inconsistency between studies evaluating the molecular mechanisms underlying frailty may present a barrier to the development of effective therapies.
Background Two-thirds of people over 65 have two or more underlying chronic conditions. Patients with multimorbidities are likely to classify as frail and have worse outcomes after cardiac surgery. We hypothesized that metabolite and transcript profiles could identify multimorbidity-specific mechanisms for clinical interventions. Methods and Results The multimorbidity was defined as two or more coexisting chronic conditions. Analysis of the metabolome was performed in 30 sequential patients. Measurements of transcriptome and metabolites involved in energy production were performed in 53 and 57 sequential patients, respectively. Mitochondrial function in circulating monocytes was performed in 63 sequential patients. Our analysis distinguished three major processes that are affected by multimorbidity: innate immune response, DNA damage and associated epigenetic changes, and mitochondrial energy production. The innate immune response was upregulated in multimorbidity and most of the included comorbidities. The DNA damage, epigenetic changes and aspects of mitochondrial function were specific for multimorbidity. Histone 2B, its ubiquitination enzymes and AKT3 were upregulated in the multimorbid group suggesting senescence-like changes in gene expression. That was confirmed by the detection of senescence-associated secretory phenotype analytes, IL-1β, its receptor and fractalkine that increased with the number of accumulating comorbidities. DNA damage was confirmed by independent immunohistochemistry experiments, which also identified nucleolar instability as more prominent in the multimorbid myocardium. The nucleolar stress is potentially responsible for higher expression of ribosomal proteins and decreased mitochondrial function. Conclusions Our results suggest that accumulating comorbidities increase levels of innate immune response and lead to DNA damage, senescence-like changes in gene expression and consequently decreased mitochondrial function.
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