A Pilot Study to Examine the Effects of Vitamin D Supplementation on Mitochondrial Bioenergetics in Older Adults
Condition: Low 25-hydroxyvitamin D Concentrations
Study type: Interventional
Phase: Early Phase 1

Summary: 
      This pilot study is a 4-month open label trial in 15 older (65-89 yrs) men and women with
      initial 25(OH)D concentrations of 12-<18 ng/mL to explore the effect of increasing 25(OH)D
      concentrations to ≥30 ng/mL through vitamin D3 supplementation on changes in mitochondrial
      bioenergetics. We will assess the bioenergetic profile of blood cells isolated mitochondria,
      and muscle fibers as well as the expression of mitochondrial proteins and regulators of
      mitochondria biogenesis before and after supplementation. All participants will be given
      vitamin D3 (4,000 IU/d) for 4 months.
    

Detailed description: 
      In the past two decades, the role of vitamin D has extended beyond bone health to encompass a
      wide range of biological activities important to muscle function in older adults. Low
      25-hydroxyvitamin D (25[OH]D) concentrations (<30 ng/mL) are associated with lower extremity
      muscle weakness, impaired physical performance, and slower walking speed,(1-8) known risk
      factors for disability.(9-15) Low 25(OH)D concentrations in older adults have also been
      associated with frailty as well as the individual frailty components including muscle
      weakness, slow walking speed, and exhaustion/fatigue.(16-18) Clinical findings of vitamin D
      deficiency (25(OH)D <12 ng/mL) include proximal muscle weakness, muscle pain, and gait
      impairments which are often reversed with vitamin D supplementation.(19;20) However, vitamin
      D's effects on the mechanisms underlying muscle function are not well understood. Recent
      evidence supports a role for vitamin D in skeletal muscle mitochondrial metabolism. Using
      31P-MRS imaging, an increase in maximal mitochondrial oxidative phosphorylation (OXPHOS) has
      been reported following vitamin D supplementation.(21) Thus, we hypothesize that muscle
      weakness and slow walking speed in individuals with low 25(OH)D concentrations may in part be
      due to diminished OXPHOS activity and lower ATP generation in skeletal muscle mitochondria.

      Vitamin D insufficiency is common in older adults, ranging from approximately one-third to
      three-fourths of community-dwelling adults aged ≥70 years depending on the cut-point used
      (25(OH)D <20 ng/mL or <30 ng/mL, respectively).(22;23) Similarly, bioenergetic decline is
      broadly associated with increasing age.(24) Thus, examining the association between vitamin D
      and mitochondrial bioenergetics can improve our understanding of the underlying mechanisms
      and range of potential benefits of remediating low 25(OH)D concentrations in older adults.

      The objective of the study is to obtain preliminary data on the effect of increasing 25(OH)D
      concentrations among older adults with vitamin D insufficiency to ≥30 ng/mL through vitamin
      D3 supplementation on 1) bioenergetic profiles of multiple blood cell populations, skeletal
      muscle mitochondria, and muscle fibers and 2) skeletal muscle mitochondrial mass and
      biogenesis.

      Hypothesis 1: Bioenergetic capacity as well as respiratory control in muscle mitochondria,
      muscle fibers, and blood cells will be improved following 4 months of vitamin D3
      supplementation.

      Hypothesis 2: Expression of key mitochondrial proteins (VDAC/Porin and COX4) and regulators
      of mitochondria biogenesis (PGC1a, SIRT1, SIRT3, and TFAM) will be higher following 4 months
      of vitamin D3 supplementation.

      We plan to recruit individuals only from screen fails of the EVIDENCE study (IRB00022395).
      The EVIDENCE study is enrolling 200 participants whose 25(OH)D concentrations are 18-<30
      ng/mL. Those whose concentrations are 12-<18 ng/mL at their EVIDENCE screening visit will be
      approached about participating in this pilot study. We will utilize the EVIDENCE screen fails
      because this is a pilot study with limited funding, the screening labs (25(OH)D) are
      expensive and the number needed to screen would be cost-prohibitive in a pilot study, and
      these two studies are run in the same clinic with the same staff. All screening measures will
      occur during the EVIDENCE study and measures will begin for this study at the baseline visit.

      All persons who screen fail for EVIDENCE with a 25(OH)D concentration of 12-<18 ng/mL will be
      informed that they are not eligible for the EVIDENCE study and will be called with these
      results. If they meet all of the same eligibility criteria for this study which eliminates
      participants with conditions that may affect their ability to safely perform the
      neuromuscular function tests, consume vitamin D supplements, or undergo a muscle biopsy,
      these people will be informed that we have another study for those whose vitamin D levels are
      insufficient. If interested, they will be asked to come in for a baseline visit (as long as
      this visit can occur within 2 months of their EVIDENCE screening visit). Those persons who
      screened more than 2 months ago for the EVIDENCE study will not be eligible for this study as
      the lab work and other tests performed may no longer be accurate.
    

Intervention name(s): Vitamin D3
Intervention type(s): Dietary Supplement
Intervention MeSH terms: Vitamin D; Cholecalciferol
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Other
Keywords: Vitamin D