FRAMITO - Metabolic dysregulation as biomarker of frailty: role of the mitochondrial dysfunction

Abstract:

Frailty is a geriatric syndrome characterized by a reduced resilience to external stressors. This syndrome predisposes to the development of disability and other adverse health-related outcomes and is associated with high costs related to healthcare services and assistance. Frailty often co-exists with multimorbidity, defined as the presence of two or more chronic diseases. Although frailty and multimorbidity share common risk factors and related outcomes, they present some distinctive features only partially clear. For instance, one of the main physiopathological mechanisms supporting the development of frailty, i.e. chronic inflammation, may be both cause and consequence of a faster accumulation of diseases. These considerations strengthen the need for taking into account multimorbidity when exploring the biomarkers of frailty.
In the latter years, several studies have considered different possible biomarkers of frailty, but their sensibility and specificity was quite low. Moreover, although great attention has been paid to inflammatory mediators, some other molecules linked to DNA damage and oxidative stress, as a function of mitochondrial dysfunction, have not yet been explored. The potential involvement of this pathway in frailty onset is of special interest and could support the existence of a mitochondriaging phenomenon, in addition to the well-known inflammaging.
In this project, we aim to evaluate the presence of mitochondrial dysfunction related to oxidative stress and its possible role in frailty, with and without multimorbidity, and to identify possible frailty biomarkers correlated with mitochondrial dysfunction.
For this purpose, we will enrol a sample of 75 individuals aged 65 years or older accessing geriatric outpatient clinics or being discharged from two geriatric wards in clinically stable conditions. Of these 75 participants, 25 will be non-frail without multimorbidity, 25 frail without multimorbidity, and 25 frail with multimorbidity. Each individual will undergo an assessment of frailty phenotype and multimorbidity, and the collection of blood samples to isolate PBMCs. The identification of frailty biomarkers in each group of participants will be performed by combining untargeted metabolomics-based approaches and functional studies on specific mitochondrial dysfunctions performed on PBMCs and their subpopulations. Multivariate statistical and machine learning techniques will characterise the three clinical phenotype groups based on molecular data.
This project may pave the way for deepening the study of the role of mitochondrial dysfunctions in frailty development and to disentangle the physiopathological mechanisms of frailty and multimorbidity. The project’s results could lead to the identification of potential targets of preventive and therapeutic interventions influencing frailty development and/or its reversion, preventing the development of disability and the occurrence of adverse health-related outcomes.