- Background and Rationale Population aging is associated with an increasing prevalence of chronic diseases, functional decline, cognitive impairment, frailty, loss of independence, and reduced quality of life. Traditional medical care of older adults has largely focused on the diagnosis and treatment of individual diseases. However, contemporary geroscience emphasizes that age-related functional decline is not solely a consequence of individual diseases but results from the interaction of fundamental biological mechanisms of aging affecting multiple organ systems.
An important concept within geroscience is biological resilience, defined as the capacity of an organism to maintain homeostasis, functional capacity, and regenerative potential despite internal and external stressors. Biological resilience reflects the integrated function of multiple physiological systems, including mitochondrial bioenergetics, metabolic regulation, inflammatory responses, cellular stress responses, and tissue regeneration. With advancing age, physiological reserve and the ability to adapt to stressors progressively decline. Clinically, this may manifest as prefrailty, which represents an intermediate and potentially modifiable state between healthy aging and established frailty.
Current approaches to preventing or treating prefrailty primarily include physical exercise, resistance training, nutritional optimization, adequate protein intake, and prevention of malnutrition. Although these interventions can improve aspects of physical function, their effects vary between individuals, and there is currently limited evidence for biological interventions specifically targeting fundamental mechanisms contributing to reduced biological resilience.
Mitochondrial dysfunction is considered one of the central mechanisms of biological aging. Mitochondria play a critical role in cellular energy production, oxidative balance, cellular stress responses, and metabolic adaptation. Impaired mitochondrial function may therefore contribute to reduced physiological reserve and may represent a potentially modifiable component of biological resilience.
Coenzyme Q10 (CoQ10) is an essential component of the mitochondrial electron transport chain and participates in ATP production. Its reduced form, ubiquinol, also has an important antioxidant function. CoQ10 availability decreases with age, potentially contributing to impaired mitochondrial adaptation to metabolic and oxidative stress. Previous clinical studies have demonstrated that oral CoQ10 supplementation can increase circulating CoQ10 concentrations and may influence oxidative stress, inflammatory responses, mitochondrial function, and physical performance. However, it remains unclear whether CoQ10 supplementation can improve the broader multidimensional phenotype of reduced biological resilience in older adults.
Another important unanswered question is whether the response to CoQ10 depends on the individual's baseline biological phenotype. Chronological age alone does not adequately capture the biological heterogeneity of aging. Older adults of the same chronological age may differ substantially in mitochondrial function, inflammatory burden, metabolic health, functional reserve, and susceptibility to stress. Identification of biological characteristics associated with treatment response could therefore contribute to a more personalized approach to interventions aimed at maintaining functional health in older adults.
Because oral CoQ10 has limited water solubility and absorption, the bioavailability of the formulation is an important consideration. This study will use Q10Vital® (Valens Int. d.o.o., Komenda, Slovenia), a formulation containing ubiquinone in a β-cyclodextrin complex designed to improve solubility and absorption. Previous pharmacokinetic research has demonstrated substantially greater bioavailability of this formulation compared with standard crystalline ubiquinone and bioavailability comparable to ubiquinol.
- Study Objective The primary objective of this study is to determine whether 10 weeks of daily CoQ10 supplementation increases systemic CoQ10 availability and improves markers of mitochondrial functional resilience in community-dwelling adults aged 65 years or older with signs of reduced biological resilience or prefrailty.
Secondary objectives are to determine whether CoQ10 supplementation affects:
- markers of chronic low-grade inflammation; 2. metabolic health and insulin sensitivity; 3. physical performance and functional reserve; 4. cognitive function; 5. objective measures of skin barrier function and skin aging; 6. clinical measures of prefrailty and frailty.
An additional exploratory objective is to investigate whether baseline biological, functional, cognitive, metabolic, and clinical characteristics can predict the response to CoQ10 supplementation and to develop a multidimensional composite index of biological resilience.
- Study Design This is a prospective, randomized, double-blind, placebo-controlled, parallel-group clinical trial.
Eligible participants will be randomly assigned in a 1:1 ratio to receive either CoQ10 supplementation or matching placebo for 10 weeks. Participants, investigators, and outcome assessors will remain blinded to treatment allocation throughout the intervention period.
Assessments will be performed at baseline and after completion of the 10-week intervention. The study will compare changes from baseline between the CoQ10 and placebo groups.
- Study Population The study population will consist of community-dwelling adults aged 65 years or older who demonstrate early signs of reduced biological resilience or prefrailty.
Reduced biological resilience will be operationalized using functional and clinical indicators reflecting reduced physiological reserve. Eligible participants will meet at least one of the following criteria:
- prefrailty according to the Fried frailty phenotype, defined by the presence of 1-2 criteria;
- reduced physical performance, defined as an SPPB score of ≤9;
- increased vulnerability according to the Clinical Frailty Scale, defined as a score of ≥4.
The Fried phenotype will consider unintentional weight loss, exhaustion, reduced physical activity, slow walking speed, and reduced handgrip strength.
- Intervention Participants randomized to the intervention group will receive 200 mg of CoQ10 daily for 10 weeks.
The CoQ10 formulation will be Q10Vital®, containing ubiquinone in a β-cyclodextrin complex. The selected dose is based on previous clinical research demonstrating increased systemic CoQ10 availability and potential effects on mitochondrial and functional outcomes, while maintaining a favorable tolerability profile.
- Comparator Participants randomized to the control group will receive matching placebo for 10 weeks.
The placebo will be administered according to the same schedule and under the same conditions as the active intervention to maintain blinding.
- Randomization and Blinding Participants will be randomized in a 1:1 ratio to the CoQ10 or placebo group using a predefined randomization procedure.
The study will be double-blinded. Participants, investigators responsible for clinical assessments, laboratory personnel, and outcome assessors will be unaware of treatment allocation until completion of the blinded analysis, except where unblinding is required for participant safety.
- Outcome Assessments The study will use a multidimensional assessment of biological resilience, combining laboratory biomarkers with functional, cognitive, metabolic, and skin-related measures.
- Mitochondrial and biological resilience biomarkers
The following biomarkers will be assessed:
- plasma CoQ10 concentration;
- ubiquinol/ubiquinone ratio as a marker of CoQ10 redox status;
- growth differentiation factor 15 (GDF-15) as a marker of mitochondrial and cellular stress;
- fibroblast growth factor 21 (FGF-21) as a marker of mitochondrial and metabolic stress response.
Changes in circulating CoQ10 concentrations will also provide an objective measure of systemic exposure to the intervention.
Chronic low-grade inflammation will be assessed using:
- high-sensitivity C-reactive protein (hsCRP);
- interleukin-6 (IL-6);
- tumor necrosis factor alpha (TNF-α);
- soluble urokinase plasminogen activator receptor (suPAR).
These biomarkers will be used to characterize systemic inflammatory burden and immune activation associated with biological aging.
Metabolic status will be evaluated using:
- fasting insulin;
- HOMA-IR;
- HbA1c;
- total cholesterol;
- LDL cholesterol;
- HDL cholesterol;
- triglycerides;
- apolipoprotein B.
These parameters will be used to characterize glucose homeostasis, insulin resistance, and the atherogenic metabolic phenotype.
- Physical and functional assessment
Physical function will be assessed using a multidimensional battery including:
- Short Physical Performance Battery (SPPB);
- chair stand test;
- Timed Up and Go (TUG) test.
Changes in frailty status will additionally be assessed using the Fried frailty phenotype. The Rockwood Clinical Frailty Scale will be used as an additional measure of global functional vulnerability.
The SPPB provides an integrated assessment of lower-extremity function, including balance, gait speed, and repeated chair stands. Handgrip strength will be used as an indicator of muscle strength and functional reserve. Walking speed and TUG will provide measures of mobility and functional performance.
Cognitive function will be evaluated using a multidimensional assessment including:
- Montreal Cognitive Assessment (MoCA);
- Trail Making Test;
- verbal fluency testing;
- Subjective Cognitive Decline Questionnaire (SCD-Q).
These assessments will provide measures of global cognitive function, executive function, processing speed, verbal ability, and subjective cognitive status.
- Skin phenotype and regenerative function The skin will be assessed as a peripheral and objectively measurable phenotype potentially reflecting biological aging and tissue integrity.
The following parameters will be evaluated:
- skin hydration;
- transepidermal water loss (TEWL);
- skin elasticity;
- standardized digital photography and objective image-based assessment of visible skin aging.
Skin hydration and TEWL will provide measures of epidermal barrier function, while skin elasticity will provide an objective measure related to dermal structural integrity and extracellular matrix function.
- Laboratory Methods Blood samples will be collected at predefined study visits for measurement of biochemical and molecular biomarkers.
Plasma CoQ10 concentrations and the ubiquinol/ubiquinone ratio will be determined using high-performance liquid chromatography (HPLC) or an equivalent validated analytical method.
Protein biomarkers, including GDF-15, FGF-21, IL-6, TNF-α, and suPAR, will be measured using validated immunochemical methods, including enzyme-linked immunosorbent assays (ELISA) and/or multiplex immunoassays, depending on assay availability and laboratory validation.
Routine biochemical measurements will be performed using standard validated laboratory methods.
- Primary Outcome The primary outcome will be the between-group difference in change from baseline to the end of the 10-week intervention in markers of mitochondrial functional resilience.
The primary assessment will include systemic CoQ10 availability and predefined mitochondrial stress-response biomarkers, with particular emphasis on plasma CoQ10 concentration, ubiquinol/ubiquinone ratio, and GDF-15.
The primary analysis will compare the change in these predefined outcomes between the CoQ10 and placebo groups.
Secondary outcomes will include changes from baseline to 10 weeks in:
- inflammatory biomarkers (IL-6, TNF-α, hsCRP, and suPAR);
- metabolic parameters (glucose, insulin, HOMA-IR, HbA1c, lipid profile, and ApoB);
- SPPB score;
- handgrip strength;
- walking speed;
- chair stand performance;
- TUG performance;
- Fried frailty phenotype;
- Clinical Frailty Scale;
- MoCA score;
- Trail Making Test performance;
- verbal fluency;
- SCD-Q score;
- skin hydration;
- TEWL;
- skin elasticity;
- standardized measures of visible skin aging.
- Exploratory Outcomes Exploratory analyses will investigate relationships between changes in mitochondrial, inflammatory, metabolic, functional, cognitive, and skin-related measures.
The study will also investigate whether baseline characteristics predict treatment response. Candidate predictors will include mitochondrial biomarkers, inflammatory markers, metabolic parameters, functional performance, frailty status, cognitive measures, and skin phenotype.
An exploratory multidimensional composite index of biological resilience will be developed by integrating molecular, biochemical, functional, and clinical measures. The index will be evaluated for its ability to characterize baseline biological resilience and detect changes following intervention.
The study will additionally investigate whether the baseline biological resilience phenotype modifies the effect of CoQ10 supplementation. Particular attention will be given to participants with evidence of prefrailty, impaired physical performance, elevated inflammatory biomarkers, or increased mitochondrial stress markers.
- Statistical Analysis The primary analysis will compare changes from baseline between the CoQ10 and placebo groups. Depending on the distribution and characteristics of the outcomes, repeated-measures models and/or analysis of covariance (ANCOVA) will be used, with adjustment for relevant baseline values.
Secondary analyses will assess associations between changes in biological biomarkers and changes in clinical outcomes using correlation analyses and multivariable regression models.
Responder analyses will be performed to identify participants demonstrating a clinically or biologically meaningful response to CoQ10 supplementation.
Exploratory subgroup analyses will investigate whether treatment effects differ according to baseline biological resilience, prefrailty status, or other predefined characteristics.
Exploratory predictive models will be developed using combinations of mitochondrial, inflammatory, metabolic, functional, cognitive, and skin-related variables to investigate whether the baseline phenotype can predict response to CoQ10.
Where multiple biomarkers are evaluated simultaneously, appropriate methods for controlling the false discovery rate or other correction for multiple testing will be applied.
The primary analysis population will follow the intention-to-treat principle.
- Safety Assessment CoQ10 supplementation has a generally favorable safety and tolerability profile. Nevertheless, participants will be monitored throughout the study for adverse events, changes in health status, and any symptoms potentially related to the intervention.
Any adverse events occurring during the study will be documented and assessed for severity and potential relationship to the study intervention. Appropriate medical evaluation and management will be provided when necessary.
- Scientific Rationale and Expected Contribution The study is designed to investigate whether mitochondrial functional resilience represents a modifiable component of biological resilience in older adults.
Rather than evaluating CoQ10 solely on the basis of a single clinical outcome, this study uses a multidimensional approach integrating mitochondrial, inflammatory, metabolic, functional, cognitive, and skin-related measures. This approach is intended to determine whether a mitochondria-targeted intervention can influence multiple interconnected components of the aging phenotype.
A further objective is to move beyond an "one intervention for all" approach by investigating whether individual biological characteristics can predict treatment response. If specific baseline biomarkers or combinations of biological and functional characteristics are associated with greater benefit, these findings could provide a basis for future personalized interventions targeting reduced biological resilience.
The study may therefore contribute to the understanding of mitochondrial dysfunction as a potentially modifiable mechanism of functional aging and provide preliminary evidence for the use of multidimensional biological phenotyping in the identification of older adults who may benefit from targeted interventions.
- Ethical Considerations The study will be conducted in accordance with the principles of the Declaration of Helsinki, Good Clinical Practice, applicable national legislation, and European data protection requirements.
Approval from the relevant ethics committee will be obtained before initiation of the study.
All participants will receive comprehensive information about the purpose, procedures, potential benefits, and potential risks of the study before participation. Written informed consent will be obtained before any study-specific procedures are performed.
Participation will be voluntary, and participants may withdraw from the study at any time without consequences for their subsequent medical care.
Participant data and biological samples will be coded and handled confidentially. Personal data will be processed in accordance with applicable data protection legislation, including the General Data Protection Regulation (GDPR).
Biological phenotyping of aging and biological resilience will be used for research purposes and will not be used to stigmatize or clinically categorize participants beyond the purposes defined in the study protocol.
