Metabolic Dysregulation as Biomarker of Frailty: Role of the Mitochondrial Dysfunction

NCT ID: NCT06433427

Last Updated: 2024-05-29

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Total Enrollment: 75 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2024-05-29
• Study Completion Date: 2026-02-22

Brief Summary

The goal of this observational study is 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. The main questions it aims to answer are:

• What is the role of oxidative stress-related mitochondrial dysfunction in frailty, taking into account the interaction with multimorbidity.
• What could be the specific biomarkers associated with mitochondrial dysfunction in the assessment of frailty.

In order to reach the study goals, we will enroll three categories of older adults:

• Non-Frail without Multimorbidity (NFWoM);
• Frail with Multimorbidity (FWM);
• Frail without Multimorbidity (FWoM).

Each individual will undergo an assessment of frailty phenotype and multimorbidity, and the collection of blood samples to isolate Peripheral Blood Mononuclear Cells (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 characterize the three clinical phenotype groups based on molecular data.

Detailed Description

Study type: observational prospective study. Primary aim: is to evaluate the presence of mitochondrial dysfunction related to oxidative stress and its possible role in frailty, with and without multimorbidity.

Primary endpoint: mitochondrial dysfunction in frailty. Secondary aims: to combine untargeted metabolomics-based approaches and functional studies on specific mitochondrial dysfunctions performed on PBMCs and PBMC subpopulations (B lymphocytes, T lymphocytes and monocytes).

The research activities are organized in the following tasks:

• Task 1, Patient Enrollment: We will enroll individuals aged 65 years or older from geriatric outpatient clinics or geriatric wards. For each individual, we will perform an assessment of frailty and multimorbidity, and collect blood samples to isolate Peripheral Blood Mononuclear Cells (PBMCs). Three categories of individuals will be enrolled: 25 non-frail individuals without multimorbidity (NFWoM), 25 frail individuals with multimorbidity (FWM), and 25 frail individuals without multimorbidity (FWoM).
• Task 2, Separation of PBMC Subpopulations: T lymphocytes, B lymphocytes, and monocytes will be separated from frozen PBMCs using the Cell Sorting Facility for Fluorescence-Activated Cell Sorting (FACS) separation and the MoFlo Astrios cell sorter. The analyses on CD45+/CD3+/CD19-/CD14- T lymphocytes, CD45+/CD3-/CD19+/CD14- B lymphocytes, CD45+/CD3-/CD19-/CD14+ monocytes.
• Task 3, Mitochondrial Dysfunction Analysis on PBMCs and PBMC Subpopulations: For each individual, mitochondrial dysfunction will be evaluated by analyzing mtDNA damage (by Real-Time PCR), mitochondrial mass alteration (by Mitotracker staining), and intracellular and mitochondrial Reactive Oxygen Species (by DCF and MitoSOX staining). Moreover, we will evaluate alteration of glycolytic and mitochondrial metabolism using Agilent Seahorse Extracellular Flux Analyzer XFe96.
• Task 4, Untargeted Metabolomics on PBMCs and PBMC Subpopulations: To assess metabolic signature of PBMCs and subpopulations and highlight metabolic dysregulations linked to frailty, we will perform untargeted LC-MS-based metabolomics on PBMCs, T lymphocytes, B lymphocytes, and monocytes. The analysis on the polar metabolome will allow us to understand better the metabolic alterations associated with mitochondrial dysregulation.
• Task 5, Characterization of Biomarkers and Molecular Mechanism of Frailty: The potential biomarkers of frailty and the molecular mechanisms involved in mitochondrial dysfunction will be studied using statistical and machine learning techniques on molecular, metabolic and clinical data. This step will help characterize clinical phenotypes based on molecular measurements.

Conditions

Aging; Frailty; Mitochondrial Dysfunction; Chronic Disease

Study Design

• Observational Model Type: OTHER
• Study Time Perspective: CROSS_SECTIONAL

Study Groups

Non-Frail without Multimorbidity (NFWoM)

Individuals aged 65 years or older without frailty and without multimorbidity. This group will serve as a reference for participants who are not frail and do not have multiple chronic conditions.

No interventions assigned to this group

Frail with Multimorbidity (FWM)

Frail individuals aged 65 years or older who have multimorbidity. This group will include participants who exhibit frailty and have two or more chronic diseases.

No interventions assigned to this group

Frail without Multimorbidity (FWoM)

Frail individuals aged 65 years or older without multimorbidity. This group will help assess frailty in the absence of multiple chronic conditions.

No interventions assigned to this group

Eligibility Criteria

Inclusion Criteria

• Age ≥ 65 years
• Stable clinical conditions
• Willingness to participate in the study (provision of informed consent)
• Proficiency in the Italian language

Exclusion Criteria

• Acute or unstable clinical conditions

• Minimum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

University of Milano Bicocca

OTHER

Sponsor Role: collaborator

University Hospital of Ferrara

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Caterina Trevisan, PhD

Role: PRINCIPAL_INVESTIGATOR

Università degli Studi di Ferrara

Central Contacts

Caterina Trevisan, PhD

Role: CONTACT

caterina.trevisan@unife.it

00393896743650

References

Locatelli E, Torsello B, De Marco S, Lombardi M, Remelli F, Pampolini G, Ferrighi E, Bursi M, Bellotti A, Pasquale V, Ducci G, Navaei O, Candeloro R, Ferrara MC, Guo W, Cucini E, Bellelli G, Castellazzi M, Sacco E, Paglia G, Mazzola P, Bernasconi DP, Bianchi C, Trevisan C. Mitochondrial dysfunction as a biomarker of frailty: The FRAMITO study protocol. Arch Gerontol Geriatr. 2025 Jun;133:105803. doi: 10.1016/j.archger.2025.105803. Epub 2025 Feb 26.

Reference Type: DERIVED

PMID: 40043348 (View on PubMed)

Other Identifiers

653/2023/Oss/AOUFe

Identifier Type: -

Identifier Source: org_study_id