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Principal Investigator: Paul Martin Coen
Organization: ADVENTHEALTH ORLANDO
Fiscal Year: 2024
Award: $576,804
Funding agency: National Institute on Aging
PROJECT SUMMARY
Older adults experience a loss of mobility that leads to disability, which is a serious health care issue in an
aging US population. Furthermore, the incidence of mobility disability is greater in older African Americans
compared to Caucasians. The mechanisms behind these observations are not well understood.
We have shown that mitochondrial function is a key property of skeletal muscle that supports walking speed,
physical function, and cardiorespiratory fitness in older adults. Cross-sectional and longitudinal studies reveal
lower levels of mitochondrial content and function, lower cardiorespiratory fitness and slowing walking speed
with aging. We recently demonstrated lower mitochondrial function in skeletal muscle in African American
compared to Caucasian women that is associated with lower cardiovascular fitness and metabolic rate.
The role of mitochondrial DNA (mtDNA) in age related changes in muscle oxidative capacity has not been
explored. Our novel preliminary data suggest that mtDNA haplotype is an important determinant of lower
mitochondrial function and cardiovascular fitness in African Americans. We have also shown that mtDNA
variants are associated with walking speed in older AA and C adults. Furthermore, recent studies have
revealed that change in peak VO2 in response to an exercise training program is associated with mtDNA
haplogroup. Based on these observations we hypothesize that mtDNA haplotype plays an important role in
cross sectional variation and more importantly, longitudinal declines in mitochondrial function, cardiovascular
fitness, and walking speed in older adults. Variations in mtDNA that have been shown to impact aging
phenotypes can be divided into 1) inherited variants, which are maternally inherited single nucleotide
polymorphisms (SNPs), many of which differentiate the mtDNA haplogroups, and many that do not, or 2)
acquired variation including heteroplasmy, or percentage of mutated vs normal mtDNA at any site across
genome and decreased mtDNA copy number that occurs with aging.
This ancillary study to The Study of Muscle, Mobility, and Aging will explore the role of inherited and acquired
variations in mtDNA in mitochondrial function from muscle biopsies in a large cohort of well phenotyped
humans. We will also explore the role of nuclear encoded mitochondrial proteins (NEMP) and crosstalk
between mitochondrial DNA and Nuclear DNA in the mitochondrial and physiological differences observed. We
will relate these findings to the clinically important endpoint of mobility in the entire cohort, as well as the role in
the greater mobility declines in mobility in African Americans.
Our study will be the first to show that mtDNA variation is predictive of greater declines in mitochondrial and
physiological function, which are associated with mobility disability. These findings could allow us to assess
mtDNA variation using a simple blood draw to identify those at risk for low function and to implement targeted
therapies, e.g., physical activity, which has been shown to improve mitochondrial function.
Terms: <21+ years old><AD dementia><Address><Admixture><Adult><Adult Human><Adult-Onset Diabetes Mellitus><African><African American><African American Females><African American Women><African American group><African American individual><African American people><African American population><African Americans><African Females><African Women><Afro American><Afroamerican><Aging><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimers Dementia><Amerindian><Ancillary Study><Basal Metabolism><Basal metabolic rate><Biological><Biopsy><Biopsy Sample><Biopsy Specimen><Blood><Blood Cells><Blood Reticuloendothelial System><Caucasian><Caucasian Females><Caucasian Race><Caucasian Women><Caucasians><Caucasoid><Caucasoid Race><Causality><Clinical><Complex><DNA><Data><Decline in mobility><Decrease in mobility><Decreased mobility><Deoxyribonucleic Acid><Diminished mobility><East Asian><Epistasis><Epistatic Deviation><Etiology><European><Freezing><GWA study><GWAS><Genetic><Genetic Alteration><Genetic Change><Genetic Epistasis><Genetic defect><Genome><Genomics><Goals><Haplogroup><Haplotypes><Healthcare><Hereditary><High Prevalence><Human><Incidence><Individual><Inherited><Interaction Deviation><Ketosis-Resistant Diabetes Mellitus><Knee Osteoarthritis><Leanness><Length of Life><Link><Longevity><Longitudinal Studies><Maturity-Onset Diabetes Mellitus><Mitochondria><Mitochondrial DNA><Mitochondrial Proteins><Mobility decline><Mobility disability><Mobility impairment><Modern Man><Muscle><Muscle Mitochondria><Muscle Tissue><Muscle function><Mutate><Mutation><NIDDM><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Nuclear><Occidental><Peripheral Blood Cell><Personalized medical approach><Phenotype><Physical Fitness><Physical Function><Physical activity><Physiologic><Physiological><Play><Population><Primary Senile Degenerative Dementia><Property><Race><Races><Reduced mobility><Reduction in mobility><Respiration><Risk><Role><Sampling><Sarcosomes><Single Base Polymorphism><Single Nucleotide Polymorphism><Site><Skeletal Muscle><Slow-Onset Diabetes Mellitus><Stable Diabetes Mellitus><T2 DM><T2D><T2DM><Thinness><Time><Training Programs><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><Variant><Variation><Voluntary Muscle><Walking><White Females><White Women><Woman><adult onset diabetes><adulthood><age associated alterations><age associated changes><age correlated alterations><age correlated changes><age dependent alterations><age dependent changes><age related alterations><age related changes><age specific alterations><age specific changes><aged><alterations with age><biologic><cardiorespiratory fitness><cardiorespiratory health><cardiovascular fitness><causation><changes with age><cohort><design><designing><differences due to race><differences in race><differs by race><differs in race><disability><disability risk><disease causation><epistatic relationship><exercise training><experience><fitness><gene x gene interaction><genetic epistases><genome mutation><genome wide association><genome wide association scan><genome wide association studies><genome wide association study><genomewide association scan><genomewide association studies><genomewide association study><health care><heteroplasmy><human disease><improved><individualized approach><ketosis resistant diabetes><knee OA><knee joint OA><knee joint osteoarthritis><long-term study><longitudinal outcome studies><longterm study><maturity onset diabetes><men><metabolic rate><mitochondrial><mtDNA><muscular><novel><older adult><older adulthood><personalized approach><phenotypic data><precision approach><precision medicine><precision-based medicine><prevent><preventing><primary degenerative dementia><race based differences><race differences><race related differences><racial><racial background><racial determinant><racial difference><racial origin><racially different><respiratory mechanism><response><resting metabolic rate><senile dementia of the Alzheimer type><single nucleotide variant><social role><tailored approach><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><type 2 DM><type II DM><type two diabetes><walking pace><walking speed><white race><whole genome association analysis><whole genome association studies><whole genome association study>