The role of iron metabolism and mitochondrial function in frailty and multimorbidity

Abstract

Frailty is a clinical syndrome describing a state of increased vulnerability and a general lack of ability to thrive, most often observed in older adults. However, in current medical practice as well as in frailty research, there is great heterogeneity in definitions and diagnostic tools used to assess this syndrome and the risks that accompany it. This is caused by the fact that while the physical symptoms of frailty have been described in depth, the biological pathways that characterise frailty on a molecular level are largely unknown. Similarly, multimorbidity, most often defined as the presence of two or more chronic conditions, is another clinical syndrome where the underlying molecular mechanisms are still poorly defined. In this project, we aim to examine the molecular patterns of these two syndromes, specifically, to assess the role of dysregulated iron metabolism and mitochondrial dysfunction in frailty and multimorbidity. A systematic review and meta-analysis of the current literature confirmed the importance of mitochondrial dysfunction in the development and progression of frailty. An in-silico study of gene expression in frailty further confirmed the role of mitochondria in frailty and identified dysregulated nucleolar processes as one of the defining molecular characteristics of frailty and multimorbidity. The experimental procedures and protocols required for the examination of variables identified as significantly dysregulated in frailty and multimorbidity were developed and optimised on a mouse cohort. Then, the nucleolar processes, mitochondrial function and iron metabolism were examined in human cardiac tissue and plasma samples. All of them were significantly dysregulated in multimorbidity, specifically, DNA damage was increased, and the enzymatic activity of respiratory complex II and the protein expression of complex V were decreased. This was accompanied by lowered iron levels in cardiac biopsies and changes in the gene expression of ribosomal proteins. This data suggests a number of potential research avenues for further research into the mechanisms of frailty and multimorbidity.</p