Current Postdoctoral Scholars
Kyle Edmunds, PhD
Faculty Mentor- Ozioma Okonkwo, PhD
“Brain-derived neurotrophic factor, cardiorespiratory fitness, and sleep in preclinical Alzheimer’s disease”
Emerging evidence on the risk and resilience factors in preclinical Alzheimer’s disease (AD) points to the hypotheses that: (1) the Val66Met polymorphism in the gene for brain-derived neurotrophic factor (BDNF) adversely impacts both cognitive trajectory and β-amyloid burden, and this relationship is mediated by circulating BDNF expression; and (2) cardiorespiratory fitness (CRF) and sleep moderate the relationship between BNDF genotype and AD biomarkers. My research aims to test these hypotheses by assembling linear mixed models from longitudinal data on cognitive decline, AD neuroimaging/circulating biomarkers, BDNF genotype/plasma levels, CRF measures, and sleep quality. Altogether, this project will provide new knowledge on the mechanistic role of BDNF in preclinical AD and whether the deleterious impacts of the Val66Met polymorphism or differences in BDNF expression can be modified by CRF and sleep as malleable lifestyle factors.
Brandon Fico, PhD
Faculty Mentor- Jill Barnes, PhD
“Variability in Cerebrovascular Regulation with Aging”
Aging is associated with decreased global cerebral perfusion and cerebrovascular reactivity. I am interested in investigating how changes in cerebrovascular health may increase the risk of developing Alzheimer’s disease and related dementias. My current research focuses on the age-related variability in cerebrovascular regulation using a potential model of accelerated aging in humans. Preliminary data suggests that young and middle-aged adults with certain anatomical variations have lower cerebral perfusion than adults with “textbook” cerebral anatomy. Thus, investigating cerebral blood flow and cerebrovascular regulation in these adults may demonstrate the impact of cerebral hypoperfusion on brain structure and function. This information will help us understand how specific interventions could be employed to improve cerebrovascular health and cognitive function in this aging population.
Hannah Foster, PhD
Faculty Mentor- Matthew Merrins, PhD
“Pyruvate kinase activators as a therapy for Diabetes II in elderly patients”
The pancreatic islets of Langerhans are known for their ability to couple metabolic glucose sensing with appropriate insulin secretion. This coupling is crucial for the maintenance of blood glucose levels, and failure of this system leads to metabolic diseases—most notably, Type II Diabetes, which afflicts more than 25% of people over the age of 65. Current therapies to treat diabetes in seniors, such as GLP1 agonists, have limited efficacy versus in younger adults, driving us to explore new potential therapies. This led us to pyruvate kinase (PK), the protein responsible for catalyzing the final step in the glycolytic pathway, and small-molecule PK activators. I have tested PK activators on islets from both sexes and across all ages and found efficacy in increasing insulin secretion in all populations, including the elderly. My current research continues to explore the role of PK and the effects of PK activators in healthy and diseased islets using several mouse models and donated young and aged human islets with the goal of deepening our understanding of the insulin secretory system and how it changes throughout the human lifetime.
Yang Yeh, PhD
Faculty Mentor – Dudley Lamming, PhD
“Selective protein restriction as a late-life dietary intervention for healthspan, lifespan, and senescence”
I am interested in dissecting the biological mechanisms of aging in order to identify novel life-extending therapeutics. Caloric restriction (CR) remains the most robust mean of improving longevity but its compliance is difficult in humans. The dietary reduction of branch chained amino acids (BCAAs), especially isoleucine (Ile), confers many benefits of CR when fed lifelong. My research will evaluate whether the BCAA- or the Ile-restricted diets can serve as a late-life intervention in aged animals. Further, recent advances with senolytic drugs have entered the clinical stage as a new wave of life-extending treatments with potential benefits in improve dementia symptoms. My work will also evaluate whether the effects of protein-restriction share any common mechanisms with these anti-senescent drugs.
Current Predoctoral Scholars
Faculty Mentor – Miriam Shelef, MD, PhD
“Rheumatoid factor in rheumatoid arthritis and inflammaging”
Rheumatoid arthritis (RA) is a chronic, inflammatory disorder involving pain, stiffness and swelling of the synovial joints that can lead to decreased performance in activities of daily living and decreased productivity in the aging population. Most patients with RA have rheumatoid factor (RF), antibodies against the Fc portion of IgG. RF positivity is a poor prognostic marker in patients with elderly onset RA, underlining a potential pathologic role. My project involves identifying novel sites of binding by RF, which may provide insight into the currently unknown pathology of rheumatoid arthritis. Further, by evaluating RF reactivity in rheumatoid arthritis and control subjects, we will support the development of improved RF-based diagnostic tests. This will benefit the aging population as rheumatoid arthritis is among the most common inflammatory diseases in older age groups. The inflammatory pathway in rheumatoid arthritis may also provide insights into inflammation in other autoimmune and infectious diseases.
Faculty Mentor – Lingjun Li, PhD
“Mass Spectrometry-Based Metabolomics for Alzheimer’s Disease Biomarker Discovery”
Alzheimer’s Disease (AD) is the sixth leading cause of death in the United States and is the most common cause of dementia in the aging population. In order to diagnose AD prior to cognitive symptom onset, the complete metabolome and lipidome of AD must be well-characterized, and there is a need to develop better technology to allow for detection of early AD markers with greater sensitivity and accuracy. Typically, AD metabolomic studies utilize brain tissue, cerebrospinal fluid (CSF), plasma, and serum as tissue sources, but my research focuses on erythrocytes, or red blood cells. Erythrocytes are an overlooked component of blood and are a valuable source of disease biomarkers, as erythrocytes are active metabolic cells with intact biochemical pathways that are maintained throughout the cell’s lifespan. Because of this, any changes in red blood cell metabolite concentrations in AD patients could be indicative of systemic metabolic dysfunction, which could give insight into the systematic progression of AD. In my research, I use mass spectrometry to detect and quantify metabolites and lipids in AD erythrocytes.
Faculty Mentor – Luigi Puglielli, MD, PhD
“Structural and translational properties of the resident endoplasmic reticulum acetyltransferases in Alzheimer’s Disease and progeria”
Autophagy is an essential component of the cell degrading machinery. It helps dispose of large toxic protein aggregates that form within the secretory pathway and in the cytosol. Malfunction of autophagy and disruption of proteostasis contributes to the progression of many chronic diseases, including neurodegeneration, cancer, nephropathies, immune and cardiovascular diseases; and has been implicated with aging. ATase1 and ATase2 are components of the endoplasmic reticulum (ER) acetylation machinery which transfer acetyl from acetyl-coenzyme A (CoA) onto newly generated, properly folded proteins. Biochemical inhibition of the ATases has been shown to rescue both a progeria-like and an AD-like phenotype in relevant mouse models. The aim of my work is to characterize the structural and biochemical properties of ATase1 and ATase2, which will help us dissect important molecular aspects of the ER acetylation machinery and identify novel compounds for translational application in the fields aging and AD.
Taylor Schoen, MS
Faculty Mentors – Anna Huttenlocher, MD and Nancy Keller, PhD
“Lipid modulators of inflammation and wound healing”
Aspergillus fumigatus is the primary causative agent of invasive aspergillosis, a devastating fungal disease which primarily affects immunocompromised populations. Canonical regulators of eukaryote longevity such as NAD+ metabolism and sirtuins are conserved in A. fumigatus, however, the role of aging pathways in virulence of this human pathogen remains unknown. The goal of my work is to dissect how metabolic pathways important to longevity drive virulence of A. fumigatus and how those pathways can be targeted to improve antifungal therapies. This work will provide us with a better understanding of the role of aging and metabolism at the host-pathogen interface and allow identification of targetable fungal pathways to treat invasive aspergillosis.
Faculty Mentor – David Pagliarini, PhD
“Impact of respiratory chain complex I assembly on mitochondrial function”
Mitochondria lie at the heart of cellular metabolism, using the oxidative phosphorylation (OXPHOS) system to generate ATP as a cellular energy source. OXPHOS dysfunction has been linked to a wide spectrum of clinical diseases, including disease of aging (e.g. Alzheimer’s disease, type 2 diabetes mellitus). OXPHOS dysfunction is most commonly caused by defects in complex I (CI) of the respiratory chain. While the mature complex has been studied extensively, only a third of CI dysfunctions are due to mutations in its structural subunits. The remaining two thirds are caused by mutations in proteins involved in the assembly and maturation of CI, which are collectively termed “assembly factors (AFs).” To date, 16 AFs have been identified, but the biochemistry underlying their function remains poorly defined. My research interest lies in elucidating the biochemical mechanisms of CI assembly, beginning with the initial stages of assembly. A deeper understanding of this process will advance our knowledge of mitochondrial metabolism as a key player in aging and age-related disease vulnerability.