Christopher R. Martens, Ph.D. - US grants

PROJECT SUMMARY CANDIDATE: Christopher R. Martens, Ph.D., is a fellow training in the integrative physiology of aging at the University of Colorado Boulder. In this K01 application, Dr. Martens aims to study the efficacy of a novel NAD+ boosting and calorie restriction-mimetic compound, nicotinamide riboside (NR), for reducing large elastic artery stiffness and blood pressure in older adults with amnestic mild cognitive impairment (aMCI) and to relate these outcomes to improvements in cerebrovascular, cognitive and neuronal function. His immediate goal is to acquire the research training and professional skills necessary to transition to an independent investigator. His long- term goal is to establish his own research program, with a focus on identifying strategies for improving cerebrovascular and cognitive/neuronal function and reducing risk of Alzheimer's disease (AD) in older adults. CAREER DEVELOPMENT PLAN: Dr. Martens proposes to enhance his career development by: 1) acquiring new skills in the assessment of cerebrovascular, cognitive and neuronal function to support his proposed research plan; 2) receiving training in aMCI and AD pathophysiology, geriatrics and biostatistics; and 3) refining his professional skills through formal course work, attendance and presentations at weekly journal clubs, university seminars, and national scientific meetings, and through regular interactions with his mentoring team. ENVIRONMENT: Dr. Martens will train in an outstanding aging research environment supported by a multi- disciplinary team of mentors who will provide him with research and career development training. The primary mentor, Dr. Seals, is an internationally recognized NIA-funded scientist with a strong record of successful mentoring in vascular aging research. Co-Mentor Dr. Hughson is a leading expert in cerebrovascular function and brain aging, and Dr. Bettcher has extensive experience assessing cognitive function in patients with aMCI. Dr. Banich is director of the neuroimaging center at CU-Boulder and has extensive experience with the proposed MRI-based assessments of neuronal function and structure. Dr. McQueen is director of biostatistics at the CU-Boulder Clinical and Translational Research Center (CTRC) and regularly provides mentoring and consulting to trainees and faculty conducting clinical trials. Co-mentors Dr. Potter and Dr. Schwartz are senior NIA investigators with expertise in AD and geriatric medicine, respectively, and their mentorship will complement the research training & objectives. RESEARCH: aMCI is the earliest symptomatic stage in the development of AD, which is among the fastest growing causes of morbidity and mortality in the US. Stiffening of the large elastic arteries (i.e., the aorta and carotid arteries) occurs with aging and has been linked to the development of aMCI and AD, primarily through the transmission of damaging pressure waves to the cerebral vasculature, resulting in cerebrovascular dysfunction and neuronal damage. The proposed research seeks to test the efficacy a novel CR-mimicking dietary supplement, NR, for lowering arterial stiffness in patients with aMCI and associating these changes with improved cerebrovascular, cognitive and neuronal function.

ABSTRACT Aging is the primary risk factor for Alzheimer's disease (AD) which is the most common form of dementia and among the fastest growing causes of morbidity and mortality in the United States. The risk factors for AD emerge during midlife and are similar to cardiovascular and cerebrovascular diseases. In this regard, stiffening of the large elastic arteries (i.e., the aorta and carotid arteries) and cerebral hypoperfusion occur with aging and are linked to age-related cognitive impairment, primarily through the transmission of damaging pressure waves to the cerebral vasculature, resulting in cerebrovascular dysfunction and neuronal damage. The impact of midlife vascular changes on the brain are further exacerbated by poor lifestyle habits, including the consumption of a diet that contains high amounts of added sugar (e.g., from ultra-processed foods containing high amounts of fructose). While the exact mechanisms are not known, a high sugar diet is associated with elevated plasma triglycerides (TGs), which may exacerbate age-related arterial dysfunction and memory impairment through a mechanism involving increased systemic inflammation. Our cross-sectional preliminary data suggest that plasma TGs are strongly associated with increased arterial stiffness, reduced cerebrovascular function, lower memory scores and decreased integrity of the hippocampus, a brain structure that is critical for encoding and recalling memories; however, it remains unknown how these factors are influenced by the consumption of added sugars. The purpose of this project is to establish preliminary evidence for a causal link between added sugar intake and adverse changes to vascular and brain health in midlife adults. Our central hypothesis is that excess added sugar intake causes reductions and hippocampal structure and function though adverse changes to arteries via a mechanism involving increased plasma TGs and systemic inflammation. We will conduct a randomized, single-blind, controlled-feeding study to determine the effects of consuming a diet containing low (5% of total energy intake) vs. high (25% of total energy intake) added sugar for 10-days each on measures of large elastic artery stiffness, cerebrovascular function and hippocampal structure and function. The expected outcome is evidence of a causal relation between added sugar intake and reductions in vascular and brain functions through a mechanism involving increased TG's and inflammation. The data generated from this project will support a future NIH R01 proposal for a randomized controlled trial aimed at lowering added sugar intake in mid-life adults.