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2007 Center on Aging Pilot Grant Program Recipients

 

Maurine Hobbs, Ph.D.
Assistant Professor, School of Medicine, Department of Internal Medicine, Division of Infectious Diseases
MnSOD genotypes and Aging-related mtDNA mutations
Abstract
We previously hypothesized that a common polymorphism (A16V) in MnSOD - shown to impair mitochondrial import [7] - would lead to the accumulation of ROS and increase mtDNA damage; this would impact longevity in a normal population as well as the phenotypic expression of a mitochondrial disease (Charcot-Marie-Tooth type 2A (CMT2A)). The A16V genotype did seem to correlate with increased severity
of disease in CMT2A families, but did not impact MnSOD mRNA levels, mtDNA damage, or longevity in the normal population. However, a 5’ UTR MnSOD polymorphism (G/G genotype) correlated with reduced MnSOD mRNA levels and higher average mtDNA damage (A3243G assay). Additionally, the CEPH longitudinal data allowed us to demonstrate for the first time that individuals with the highest levels of
A3243G mtDNA damage had significantly reduced survival among normal individuals.
However, several observations in our study need clarification: 1) severity of phenotype in some CMT2A families correlated with both MnSOD genotype and maternal inheritance (suggesting a possible role of mtDNA genotype in these families), and 2) although MnSOD 5’-UTR G/G genotypes correlated with decreased expression and higher A3243G damage, paradoxically, they seem to have a slightly increased survival. Since only 10% of the CEPH grandparents had this genotype, this may be too few to give an accurate assessment of its effects on survival. We hypothesize that 1) mtDNA genotypes modify the effects of MnSOD genotypes; and 2) increased survival of those with lower MnSOD expression may reflect small sample size, or individuals with lower oxidative stress due to mtDNA genotype, lower inflammation, or leaner body mass. The identification of a relationship between MnSOD genotype, mtDNA haplotypes, mtDNA damage, and alterations in longevity or expression of disease has implications both for biologic mechanisms of aging and mitochondrial disease as well as for therapeutics.

 

Mary T. Lucero, Ph.D.
Professor, School of Medicine, Department of Physiology
Dysregulation of Fluid Balance and Aging-Related Loss of Regenerative Olfactory Function
Abstract
Humans lose their sense of smell as they age. Dehydration of the body occurs with aging, and may contribute to aging-related loss of olfactory sensory neurons (OSNs) and failure in OSN regeneration. Fluid balance in cells occurs through complex systems of ionic pumps, transporters, and channels that maintain osmotic gradients. Water passively follows ionic gradients via transport through water-specific channels (aquaporins) or non-specifically through other open channels. In the CF mouse, knock-out of the Cystic Fibrosis Transmembrane Conductance Regulator channel disrupts fluid balance in the olfactory epithelium (OE) and causes postnatal loss of OSNs. Normally, transmembrane potassium flow through glial cells is tightly coupled to aquaporin function. In the absence of aquaporins, extracellular potassium increases causing edema and excitotoxicity. In addition, the loss of intracellular potassium causes activation of the apoptotic cascade and cell death. The neuropeptide PACAP is neuroprotective in the OE and cultured olfactory neurons. PACAP reduces both potassium efflux and pro-apoptotic caspases in primary olfactory cultures. We propose to examine whether PACAP can suppress the molecular cascade that causes the dysregulation of OE fluid balance which leads to loss of OSNs and aging- associated anosmia. We will test if PACAP knock-outs exhibit premature OE aging by looking for alterations in cell proliferation, cell type profiles and morphology, and aquaporin expression. A model for OE dehydration, the CF mouse will be examined for potential changes in PACAP and aquaporin expression in vivo. In vitro assays will examine whether PACAP is protective to OE explants grown under hypertonic conditions. Collectively, these studies will identify dehydration-induced changes in OE physiology which lead to age-related anosmia.

 

Robin Marcus, Ph.D.
Assistant Professor, College of Health, Division of Physical Therapy
Mechanisms of Improved Glucose Utilization in Elders With Type 2 Diabetes
Abstract
The incidence of T2DM is growing at an astronomical rate, and especially hard hit are the elderly in whom the combined prevalence of T2DM and impaired glucose tolerance is nearly 45%. The elderly also suffer from age-related loss of skeletal muscle mass, strength and function, collectively termed sarcopenia. Because lean skeletal muscle is quantitatively the most important tissue involved in maintaining glucose homeostasis under insulin-stimulated conditions, and is a major site of insulin resistance, loss of lean tissue is thought to play an important role in the development of T2DM, especially in the elderly. The focus of this project is on changes in lean muscle mass and its impact on glucose utilization in an insulin resistant elderly cohort. While our overall goal is to capitalize on resistance exercise (a type of exercise that is more easily tolerated than aerobic exercise) to improve glucose utilization in elders with T2DM, we hypothesize that the exercise itself, rather than the muscle size improvement is responsible for the increase in glucose utilization. Two specific aims are proposed: 1)To determine whether increased quadriceps muscle mass will improve LMGU as measured with positron emission tomography (PET), and 2) to determine whether changes in insulin signaling occur 24 hours and 1 week following the final resistance exercise bout of a 12-week
RENEW protocol. We are proposing a repeated measures design with subjects serving as their own controls to minimize between subjects variability. We will simultaneously measure mass changes, glucose utilization, and insulin signaling in the quadriceps muscles of insulin resistant elders, something not previously done. Three sources [leg muscle glucose utilization by PET, insulin signaling by mRNA from biopsy samples, mass changes from magnetic resonance imaging (MRI)] from the tissue - the quadriceps - specifically targeted in the resistance exercise program are essential to identify the mechanisms of glucose uptake and will be employed. Outcomes will be measured serially at three times to allow us to answer the important question of whether the acute effects of exercise itself, rather than increased muscle mass is the important factor in improving glucose utilization in the elderly. The answer to this question has practical consequences in terms of the type of exercise that is prescribed for the elderly, where both sarcopenia and glucose intolerance are often important health issues.

 

Monica Vetter, Ph.D.
Professor, School of Medicine, Department of Neurobiology & Anatomy
Role of Microglia in Glaucoma Onset and Progression
Abstract
A significant health problem for our aging population is the prevalence of progressive degenerative diseases of the central nervous system. Glaucoma is a neurodegenerative disease of the retina that is the leading cause of blindness in the US, and is characterized by a progressive loss of vision due to the decline of retinal ganglion cells (RGCs). This is often due to elevated intraocular pressure (IOP), although many cases of normal tension glaucoma exist. The most consistent risk factor for developing glaucoma is aging – the risk of developing glaucoma increases 6-fold for people over 60 years old. Glaucoma shares many hallmark features with other age-related neurodegenerative diseases including progressive loss of neuronal viability, loss of axonal integrity and function, and involvement of non-neuronal populations including microglia. We have investigated retinal changes in a mouse model of glaucoma and have found significant activation of microglia that precedes other detectable changes in retinal glia or neurons. We hypothesize that microglia are directly involved in the recognition and progressive degradation of declining optic axons. We propose to: 1) determine the earliest age at which adult microglial activation, proliferation and phagocytosis start, 2) characterize the topographical distribution of microglia in relation to declining RGCs, 3) determine whether high-dose irradiation can deplete dysregulated, overactivated microglia from the retina and prevent RGC injury. This treatment has previously been shown to abrogate glaucoma-like pathology through unknown mechanisms. Together these experiments may shed light on the mechanisms underlying neurodegenerative diseases associated with aging.

 

Jason Watson, Ph.D.
Assistant Professor, College of Social and Behavioral Sciences, Department of Psychology
Localizing Impairment In Executive Function In Early Alzheimer’s Disease With Neuroimaging
Abstract
Although memory loss is well-established in early Alzheimer’s disease (AD), there is increasing evidence that executive function (EF) is also impaired. EF is defined as the ability to stay on task and to avoid distraction. EF is supported by a complex network of interconnected brain regions including a prominent role for prefrontal cortex in goal-directed, controlled cognition. Although change in EF may not be clinically evident, it can be documented with carefully designed and innovative experimental procedures. For example, functional magnetic resonance imaging (fMRI) could be used to localize the neural correlates of EF. However, few fMRI studies have addressed the integrity of the EF network in early AD with most of the research emphasis concentrated on the neuroimaging of memory. Hence, the primary goal of the current study is to use fMRI to determine the neural mechanisms underlying the breakdown in EF in early AD. To
achieve this goal, twenty-five healthy older adults and 25 age-matched early AD patients will receive wholebrain fMRI, white matter diffusion tensor imaging (DTI), and neuropsychological testing. Compared to controls, early AD patients will have (1) reduced neural activity in prefrontal cortex as measured by fMRI due to increased presence of frontal plaques, (2) impaired white matter functional connectivity with prefrontal cortex as measured by DTI, and (3) poorer performance on neuropsychological tests of frontal-executive function. To summarize, the current study represents an application of fMRI to the identification and localization of subtle but clinically important deficits in executive function in early AD.

2006 Center on Aging Pilot Grant Program Recipients

 

Maurine Hobbs, Ph.D.
Assistant Professor of Internal Medicine; Division of Infectious Diseases

Abstract
Reactive oxygen species (ROS) generated by the mitochondria have been implicated as a common feature linking age-related diseases and the aging of organisms.  One of the enzymes involved in the scavenging of damaging ROS is mitochondrial manganese superoxide dismutase (MnSOD).  MnSOD converts superoxide (O2.-) to hydrogen peroxide (H2O2), which is then converted to H2O and O2 by catalase.  While increased levels of MnSOD have been associated with increased longevity in drosophila [1,2], a 50% reduction in activity in heterozygous MnSOD (+/-) mice produced no detectable reduction in lifespan [3].  MnSOD (-/-) mice however die within 8 days of birth with dilated cardiomyopathy due to increased superoxide damage to mitochondrial DNA (mtDNA) and enzymes [4].  
    In humans, the A16V common (49%) polymorphism in MnSOD disrupts the mitochondrial targeting signal (MTS).  This polymorphism impairs the transport of the protein across the inner mitochondrial membrane, resulting in 80% lower activity in Val-MnSOD cells [5].  We hypothesize that this reduced activity leads not only to the accumulation of damaging ROS, but also impairs mtDNA replication, maintenance and repair, with accumulation of mtDNA deletions.  The resulting accumulation of mtDNA deletions may impact longevity as well as the phenotypic expression of mitochondrial disease.  We propose therefore to study the incidence of MnSOD polymorphisms in aged individuals from a well-defined healthy population (CEPH families) and from a population with a variably expressive mitochondrial disorder due to defects in a mitochondrial fusion protein.  As part of our proposal we will develop assays to quantitatively measure mitochondrial DNA deletion.  We will apply these assays to both healthy, aged individuals and to disease individuals that differ in severity, regardless of MnSOD genotype.  The identification of a relationship between MnSOD genotype, mtDNA defects, and alterations in expression of longevity or disease has implications both for biologic mechanisms of aging and mitochondrial disease as well as for therapeutics.

 

Petr Trvdik, Ph.D. and Scott Rogers, Ph.D.
Research Associate; Department of Human Genetics and Professor; Department of Neurobiology and Anatomy

Abstract
Alzheimer’s disease (AD) is the most common neurogenerative disease affecting the elderly, often associated with a marked decline in the cholinergic system in various brain regions. We will use the mouse model to investigate the protective role of the cholinergic system during brain aging. Our initial focus will be on the cholinergic nicotinic receptor alpha 7 (Chrna7), the role of which in AD is poorly understood. We will take advantage of two lines of mice, in which we have altered the endogenous Chrna7 gene: The control line, which co-expresses the green fluorescent protein (GFP); and a mutant line, which in addition to GFP also harbors two amino acid changes that genetically mimic the effect of nicotine by desensitization of the alpha7 receptor channel. Both lines will be crossed to the transgenic mouse model of AD and the development of plaques of amyloid-beta protein in disease-relevant regions will be measured. The outcome will elucidate the relevance of Chrna7 in the early onset and progress of the plaque formation. Next, we will generate targeting vectors allowing us to introduce the Cre recombinase in the Chrna7 and Chrna4 loci. This work will provide foundation for future research that will use the Cre/lox technology to identify cell lineages expressing these two receptors, addressing the question as to whether the decline in the cholinergic system is due to a decrease in gene expression or an increase in specific cell death. The proposed project has a high relevance for assessing the role of smoking in Alzheimer’s disease.