Antioxidants for Vascular and Muscle Health During Inactivity

Overseen By Joel D Trinity, PhD

Age: 65+

Sex: Any

Trial Phase: Academic

Sponsor: Joel Trinity

Must not be taking: Anticoagulants, Antioxidants, Corticosteroids, others

Disqualifiers: Cardiac abnormalities, Diabetes, Hypertension, Obesity, others

Compensation: Varies

Number of Visits: 1

Duration: 5 days

72 Participants Needed

Trial Summary

What is the purpose of this trial?

Prolonged periods of reduced activity are associated with decreased vascular function and muscle atrophy. Physical inactivity due to acute hospitalization is also associated with impaired recovery, hospital readmission, and increased mortality. Older adults are a particularly vulnerable population as functional (vascular and skeletal muscle mitochondrial dysfunction) and structural deficits (loss in muscle mass leading to a reduction in strength) are a consequence of the aging process. The combination of inactivity and aging poses an added health threat to these individuals by accelerating the negative impact on vascular and skeletal muscle function and dysfunction. The underlying factors leading to vascular and skeletal muscle dysfunction are unknown, but have been linked to increases in oxidative stress. Additionally, there is a lack of understanding of how vascular function is impacted by inactivity in humans and how these changes are related to skeletal muscle function. It is our goal to investigate the mechanisms that contribute to disuse muscle atrophy and vascular dysfunction in order to diminish their negative impact, and preserve vascular and skeletal muscle function across all the lifespan.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you must stop taking dietary supplements 4 weeks before starting the study. If you are on anticoagulant therapy or mitochondrial targeted antioxidants, you cannot participate.

What evidence supports the effectiveness of the treatment MITO-AO, PB-125 for vascular and muscle health during inactivity?

Research shows that mitochondrial-targeted antioxidants can protect muscles from damage during periods of inactivity by reducing harmful molecules called reactive oxygen species (ROS). Similar antioxidants have improved muscle and vascular health in other conditions, suggesting potential benefits for this treatment. ^{1 2 3 4 5}

Is the antioxidant treatment safe for humans?

The research suggests that antioxidants, including vitamins C and E and alpha-lipoic acid, have been used safely in studies with humans and animals, showing benefits like improved muscle function and reduced oxidative stress without reported adverse effects. ^{1 3 6 7 8}

How does this antioxidant treatment help with muscle health during inactivity?

This treatment uses a unique approach by targeting mitochondria (the energy-producing parts of cells) with antioxidants to reduce oxidative stress and prevent muscle atrophy (muscle wasting) during periods of inactivity. Unlike other treatments, it specifically addresses the source of reactive oxygen species (ROS) in muscle cells, which are responsible for muscle damage when you're not active. ^{1 3 8 9 10}

Eligibility Criteria

This trial is for older adults aged 65-85 with good cognitive health (MOCA score ≥26) and normal kidney function. They must not be on a weight-loss diet, have a BMI over 35, or smoke. Those with recent cancer treatment, heavy smoking history, drug/alcohol abuse, or who exercise regularly are excluded.

Inclusion Criteria

Ability to sign informed consent

Montreal cognitive assessment (MOCA) exam score greater-than or equal to 26

Free-living, prior to admission

Exclusion Criteria

My kidney function is very low or I have kidney disease/failure.

Inability to abstain from smoking for duration of study

My thyroid and sugar levels are under control.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either MITO-AO, PB-125, or placebo during a 5-day bed rest to assess vascular and skeletal muscle function

5 days

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• MITO-AO
• PB-125

Trial Overview The study tests the effects of bed rest combined with antioxidants (MITO-AO and PB-125) versus placebo on vascular and muscle function in aging individuals. It includes passive leg movements and strength tests to understand how oxidative stress contributes to dysfunction during inactivity.

Participant Groups

Group I: PB-125 Experimental Treatment 5 Interventions

Healthy older adult subjects ages 65-75 will take the supplement PB-125 during a 5 day bed rest and will be assessed for vascular function independent of metabolism with passive leg movement (PLM), skeletal muscle bioenergetics independent of vascular constraints (i.e. blood flow and O2 supply) with phosphorous magnetic resonance spectroscopy (P-MRS), and skeletal muscle bioenergetics under normal blood flow and O2 supply.

Group II: MITO-AO Experimental Treatment 5 Interventions

Healthy older adult subjects ages 65-75 will take the supplement MITO-AO during a 5 day bed rest and will be assessed for vascular function independent of metabolism with passive leg movement (PLM), skeletal muscle bioenergetics independent of vascular constraints (i.e. blood flow and O2 supply) with phosphorous magnetic resonance spectroscopy (31P-MRS), and skeletal muscle bioenergetics under normal blood flow and O2 supply.

Group III: Placebo Placebo Group 5 Interventions

Healthy older adult subjects ages 65-75 will take placebo during a 5 day bed rest and will be assessed for vascular function independent of metabolism with passive leg movement (PLM), skeletal muscle bioenergetics independent of vascular constraints (i.e. blood flow and O2 supply) with phosphorous magnetic resonance spectroscopy (P-MRS), and skeletal muscle bioenergetics under normal blood flow and O2 supply.

Who Is Running the Clinical Trial?

Joel Trinity

Lead Sponsor

Trials

1

Recruited

70+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Findings from Research

A study on muscle immobilization over 14 days showed that it leads to significant muscle atrophy and increased production of reactive oxygen species (ROS), which contribute to oxidative stress and muscle damage.

Using a mitochondrial-targeted antioxidant (SS-31) effectively reduced ROS production and prevented muscle atrophy, highlighting the role of mitochondria in muscle health during periods of inactivity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mitochondrial-targeted antioxidants protect skeletal muscle against immobilization-induced muscle atrophy. Min, K., Smuder, AJ., Kwon, OS., et al.[2021]

Acute intake of the mitochondrial-targeted antioxidant MitoQ significantly improved vascular endothelial function and increased superoxide dismutase levels in patients with peripheral artery disease (PAD), based on a study involving 11 participants.

MitoQ also enhanced walking capacity and delayed the onset of claudication, suggesting it may effectively restore mitochondrial function and improve overall leg performance in PAD patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute mitochondrial antioxidant intake improves endothelial function, antioxidant enzyme activity, and exercise tolerance in patients with peripheral artery disease. Park, SY., Pekas, EJ., Headid, RJ., et al.[2021]

In a study involving 12 healthy volunteers (6 young and 6 older), the administration of an antioxidant cocktail significantly improved muscle blood flow and oxidative capacity during exercise in older adults, suggesting that oxidative stress contributes to age-related declines in muscle function.

The antioxidant treatment did not affect muscle perfusion or recovery in younger individuals, indicating that the benefits of antioxidants on muscle function may be more pronounced in older adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antioxidants and aging: NMR-based evidence of improved skeletal muscle perfusion and energetics. Wray, DW., Nishiyama, SK., Monnet, A., et al.[2021]

In a study of six older men with mild hypertension, a 6-week aerobic exercise program significantly reduced both systolic and diastolic blood pressure and improved vascular function, as measured by flow-mediated vasodilation (FMD).

However, acute antioxidant supplementation (vitamins C and E, and alpha-lipoic acid) after exercise negated these benefits, returning blood pressure to hypertensive levels and blunting improvements in vascular function, indicating that combining exercise with antioxidant supplements may be counterproductive for cardiovascular health in older adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral antioxidants and cardiovascular health in the exercise-trained and untrained elderly: a radically different outcome. Wray, DW., Uberoi, A., Lawrenson, L., et al.[2022]

In a study involving 20 healthy older adults, 6 weeks of oral supplementation with the mitochondrial-targeted antioxidant MitoQ significantly improved endothelial function, as indicated by a 42% increase in brachial artery flow-mediated dilation compared to placebo.

MitoQ was well tolerated and also reduced aortic stiffness and plasma oxidized LDL levels, suggesting its potential as a therapeutic strategy for age-related vascular dysfunction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronic Supplementation With a Mitochondrial Antioxidant (MitoQ) Improves Vascular Function in Healthy Older Adults. Rossman, MJ., Santos-Parker, JR., Steward, CAC., et al.[2022]

This study utilized C2C12 myoblast and myotube cell cultures to investigate age-related changes in reactive oxygen and nitrogen species (RONS) signaling, finding that aged cells exhibited significantly increased levels of reactive oxygen species and lipid peroxidation, indicating oxidative stress in older muscle cells.

Among nine dietary polyphenols tested, only kaempferol and resveratrol effectively reduced multiple markers of RONS signaling in aged muscle cells, suggesting their potential as therapeutic agents to promote healthy skeletal muscle function in the context of aging.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Physiologically-obtainable polyphenol exposures modulate reactive oxygen and nitrogen species signaling in the C2C12 model of skeletal muscle ageing. Hayes, N., Fogarty, M., Sadofsky, L., et al.[2023]

Antioxidants, specifically vitamin C and tempol, significantly increased the muscle microvascular oxygen partial pressure (Pmv(O(2))) in aged rats, improving oxygen delivery during muscle contractions.

While antioxidants elevated Pmv(O(2)), they also reduced muscle blood flow and oxygen consumption during contractions, leading to decreased force production, suggesting a complex interaction between oxidative stress and muscle performance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of antioxidants on contracting spinotrapezius muscle microvascular oxygenation and blood flow in aged rats. Herspring, KF., Ferreira, LF., Copp, SW., et al.[2013]

Chronic exposure to stretch-shortening contractions (SSCs) in young rats helped prevent oxidative stress and improved their ability to scavenge hydrogen peroxide, indicating a protective effect of exercise against oxidative damage.

In older rats, however, SSCs did not alleviate oxidative stress, and instead, increased levels of malondialdehyde and hydrogen peroxide were observed, suggesting that aging may enhance vulnerability to oxidative stress despite some improvements in antioxidant capacity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of age and glutathione levels on oxidative stress in rats after chronic exposure to stretch-shortening contractions. Hollander, MS., Baker, BA., Ensey, J., et al.[2021]

Eccentric exercise leads to significant impairments in microvascular function, as evidenced by delayed and blunted blood flow responses in the exercised muscle, which were not improved by antioxidant or beetroot juice supplementation.

The study suggests that these impairments may be due to structural changes in the microvasculature rather than oxidative stress or nitric oxide availability, indicating a need for further investigation into the underlying mechanisms affecting blood flow regulation after eccentric exercise.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impaired microvascular reactivity after eccentric muscle contractions is not restored by acute ingestion of antioxidants or dietary nitrate. Larsen, RG., Thomsen, JM., Hirata, RP., et al.[2021]

An antioxidant cocktail consisting of polyphenols, omega-3, vitamin E, and selenium effectively prevented muscle deterioration and oxidative stress during bedrest in a study involving 20 healthy male subjects.

The treatment not only normalized key metabolic processes and protein levels associated with muscle health but also enhanced the antioxidant defense response, indicating its potential as a nutritional intervention for counteracting disuse-induced muscle atrophy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nitrosative Redox Homeostasis and Antioxidant Response Defense in Disused Vastus lateralis Muscle in Long-Term Bedrest (Toulouse Cocktail Study). Blottner, D., Capitanio, D., Trautmann, G., et al.[2021]

References

1. United States pubmed.ncbi.nlm.nih.gov

Mitochondrial-targeted antioxidants protect skeletal muscle against immobilization-induced muscle atrophy. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

Acute mitochondrial antioxidant intake improves endothelial function, antioxidant enzyme activity, and exercise tolerance in patients with peripheral artery disease. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

Antioxidants and aging: NMR-based evidence of improved skeletal muscle perfusion and energetics. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Oral antioxidants and cardiovascular health in the exercise-trained and untrained elderly: a radically different outcome. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Chronic Supplementation With a Mitochondrial Antioxidant (MitoQ) Improves Vascular Function in Healthy Older Adults. [2022]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Physiologically-obtainable polyphenol exposures modulate reactive oxygen and nitrogen species signaling in the C2C12 model of skeletal muscle ageing. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

Effects of antioxidants on contracting spinotrapezius muscle microvascular oxygenation and blood flow in aged rats. [2013]

8. Germany pubmed.ncbi.nlm.nih.gov

Effects of age and glutathione levels on oxidative stress in rats after chronic exposure to stretch-shortening contractions. [2021]

9. United States pubmed.ncbi.nlm.nih.gov

Impaired microvascular reactivity after eccentric muscle contractions is not restored by acute ingestion of antioxidants or dietary nitrate. [2021]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Nitrosative Redox Homeostasis and Antioxidant Response Defense in Disused Vastus lateralis Muscle in Long-Term Bedrest (Toulouse Cocktail Study). [2021]