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

NCT06433427 | Not Yet Recruiting

• 1 other identifier: 653/2023/Oss/AOUFe
• Study Type: observational
• Target: 75
• Locations: 0 countries
• Sites: N/A

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.

Conditions

Aging; Frailty; Mitochondrial Dysfunction; Chronic Disease

Keywords

Metabolic dysregulation

Outcome Measures

Primary Outcomes (2)

• Difference in the mtDNA copy number between frail individuals with vs without multimorbidity

  mtDNA copies isolated from total PBMCs and from T and B lymphocytes and monocytes, obtained from the participants, with JetQuick™ Blood and Cell Culture DNA Midiprep Kit (Invitrogen), and 10 ng of DNA will be used for analysis on QuantumStudio 7 Real Time PCR (Applied Biosystems). mtDNA copy number will be calculated by normalising the mitochondrial ND1 gene (mtND1) levels to nuclear Beta-2 microglobulin (B2M) levels. The number mtDNA copies will be compared between individuals with frailty and multimorbidity vs individuals with frailty without multimorbidity. Frailty will be derived based on the presence of at least three criteria among: involuntary weight loss ≥ 4.5 kg, muscle weakness measured by handgrip, self-reported fatigue on ≥ 3 days per week, low physical activity (assessed with the IPAQ questionnaire), and reduced gait speed (measured by the 4-m walking test). Multimorbidity will be defined as the presence of at least two chronic diseases.

  Baseline

• Difference in the mtDNA copy number between non-frail vs frail individuals without multimorbidity

  mtDNA copies isolated from total PBMCs and from T and B lymphocytes and monocytes, obtained from the participants, with JetQuick™ Blood and Cell Culture DNA Midiprep Kit (Invitrogen), and 10 ng of DNA will be used for analysis on QuantumStudio 7 Real Time PCR (Applied Biosystems). mtDNA copy number will be calculated by normalising the mitochondrial ND1 gene (mtND1) levels to nuclear Beta-2 microglobulin (B2M) levels. The number mtDNA copies will be compared between individuals with frailty and multimorbidity vs individuals with frailty without multimorbidity. Frailty will be derived based on the presence of at least three criteria among: involuntary weight loss ≥ 4.5 kg, muscle weakness measured by handgrip, self-reported fatigue on ≥ 3 days per week, low physical activity (assessed with the IPAQ questionnaire), and reduced gait speed (measured by the 4-m walking test). Multimorbidity will be defined as the presence of at least two chronic diseases.

  Baseline

Secondary Outcomes (6)

• Variation in the mean intensity of mitochondrial fluorescence between non-frail vs frail individuals without multimorbidity

  Baseline

• Variation in the mean intensity of mitochondrial fluorescence between frail individuals with vs without multimorbidity

  Baseline

• Difference of intracellular Reactive Oxygen Species (ROS) between non-frail vs frail individuals without multimorbidity

  Baseline

• Difference of intracellular Reactive Oxygen Species (ROS) between frail individuals with vs without multimorbidity

  Baseline

• Qualitative difference in metabolomics profiles of PBMCs and PBMC subpopulations between non-frail vs frail individuals without multimorbidity

  Baseline

Study Arms (3)

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.

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.

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.

Eligibility Criteria

• Age: 65 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

The study will enroll individuals aged 65 years or older. The enrollment will take place among patients accessing geriatric outpatient clinics or being discharged from geriatric wards in clinically stable conditions.

You may qualify if:

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

You may not qualify if:

• \- Acute or unstable clinical conditions

Sponsors & Collaborators

• University Hospital of Ferrara: lead
• University of Milano Bicocca: collaborator

Related Publications (1)

• 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.

  PMID: 40043348 DERIVED

Biospecimen

Retention: SAMPLES WITH DNA

The laboratory of Oncology and Molecular Pathology of the University of Milano Bicocca will perform DNA extraction and the mtDNA damage evaluation by Real Time PCR analysis on PBMCs and sorted T and B lymphocytes and monocytes, obtained from each participant.

MeSH Terms

Conditions

Frailty; Mitochondrial Diseases; Chronic Disease

Condition Hierarchy (Ancestors)

Pathologic Processes; Pathological Conditions, Signs and Symptoms; Metabolic Diseases; Nutritional and Metabolic Diseases; Disease Attributes

Study Officials

• Caterina Trevisan, PhD

  Università degli Studi di Ferrara

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Caterina Trevisan, PhD

CONTACT

00393896743650; caterina.trevisan@unife.it

Study Design

• Study Type: observational
• Observational Model: OTHER
• Time Perspective: CROSS SECTIONAL
• Target Duration: 1 Day
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 14, 2024
• First Posted: May 29, 2024
• Study Start: May 29, 2024
• Primary Completion: May 30, 2025
• Study Completion: February 22, 2026
• Last Updated: May 29, 2024

Record last verified: 2024-01