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Knoebel Institute for Healthy Aging

Knoebel Institute


2018 Pilot Grants

Effects of maternal and grandmaternal aging on offspring health and longevity

PIs: Tinghitella, Robin and Murphy, Shannon

Department: Biological Sciences

Abstract: Aging is associated with declines in an individual's performance and breeding success, but how advanced parental age affects offspring viability and reproductive performance is less clear. In humans and some laboratory-reared organisms, there are well-established negative relationships between maternal age and offspring fitness. Life history theory, a major tenet of evolutionary biology, predicts similar trade-offs between maternal age and offspring fitness, but paradoxically also predicts that older females allocate more resources and energy into reproduction than do younger females, suggesting that offspring of older females are more (or equally as) fit as offspring of younger females. We propose to test whether advanced maternal age influences offspring evolutionary fitness (i.e. survival and reproductive ability across multiple time points during an individual's lifespan) and immunocompetency positively, as predicted by some life-history theory, or negatively, as found in previous aging research. We use a natural insect population, rather than homozygous, lab-reared organisms because natural populations better model the complex genetic backgrounds found in nature. Further, our insect model allows us to investigate transgenerational effects of advanced maternal and grandmaternal age and to test epigenetic mechanisms. Our research will advance our understanding of how female aging affects offspring survival and reproductive success in natural populations.

Pioneering Quantitative Assessments of Disability in the Elderly after Total Knee Replacement using Wearable Devices and Machine Learning

PI: Clary, Chadd

Department: Mechanical and Materials Engineering and Center for Orthopaedic Biomechanics

Abstract: Osteoarthritis (OA) is the leading cause of disability among the aging population in the United States and is frequently treated by replacing the deteriorated joint with metal and plastic components. Developing better quantitative measures of movement quality to track patients longitudinally in their own homes would enable personalized treatment plans and hasten advancement of promising new interventions. Wearable sensors and machine learning used to quantify patient movement could revolutionize diagnosis and treatment of movement disorders are diagnosed and treated. The purpose of this proposal is to overcome technical challenges associated with the use of wearable sensors, specifically Inertial Measurement Units (IMUs), as a diagnostic tool for osteoarthritic and total joint replacement patients through a detailed biomechanical assessment and development of novel machine learning algorithms. Our hypothesis is that IMUs coupled with machine learning algorithms can accurately measure spatiotemporal movement characteristics during high demand activities and accurately predict outcomes in patients with total knee replacement. The study will result in a simple clinical tool to track the quality of a patient's movement in their own home and a method to translate those movements into diagnostic metrics that can be used by clinicians to individualize treatment plans.

Title: Brain exosomes as novel biomarkers for Alzheimer's disease: a validation study

PI: Ledreux, Aurelie

Department: KIHA

Abstract: To improve early diagnosis for Alzheimer's disease (AD), the development of blood biomarkers such as amyloid-beta (Aβ) and Tau has received a lot of attention over the last decade, but clinical studies have given inconsistent results. A novel promising technology using neuron-derived exosomes (NDE) isolated from blood has recently shown that NDE levels of P-Tau and Aβ can predict the development of AD 10 years before disease onset. However, whether these NDE reflect changes happening in the brain remains to be investigated. Moreover, as the disease progresses in the brain, Aβ plaques and neurofibrillary Tau tangles spread through the cortex in a predictable manner, from frontal cortex and temporal lobes to occipital cortex. These changes may begin 20 years before diagnosis, and some studies suggest that exosomes could play a role in spreading these pathogenic proteins. The overall hypothesis of this proposal is that the cargo of NDE isolated from blood reflect changes happening in the brain, and can be related to the spread of the pathogenic proteins Aβ and Tau. We propose to correlate Aβ and Tau levels from exosomes isolated from brain tissues and from NDE isolated from blood from these 3 cortical regions from AD and control subjects.

Establishing roles for Vps54 in motor neuron axonal transport and neurodegeneration

PI: Barbee, Scott

Department: Biological Sciences

Abstract: This grant is from a PI who is new to the area of aging research. The disruption of normal endocytic trafficking contributes to the pathology of progressive motor neuron (MN) disease in humans. This proposal focuses on Vps54, a component of a conserved tethering complex involved in the control of endosome-to-TGN (trans-Golgi network) vesicle transport. Vps54 mutations in a mouse model cause age-progressive MN degeneration very similar to that seen in human ALS. Despite much work, the precise mechanism of action remains unknown. In our preliminary data, we show that the loss of Drosophila Vps54 (called "scat") causes severe neurodevelopmental defects and scat mutant adults have a shorted lifespan with locomotor defects that are consistent with neuromuscular dysfunction. The primary objective of this proposal is to understand more about the nature of these adult phenotypes. Our central hypothesis is that MNs in scat mutants have defects in axonal transport. This causes the disruption of normal MN development in Drosophila larvae and precedes MN degeneration in scat mutant adults. If funded, data generated here will complement our existing work (not all of which is shown) and contribute significantly to a large, multiyear grant that will be submitted to the NIH.

Explaining Older Adults' Truth Bias: A Consequence of Maturational Dualism

PI: ten Brinke, Leanne

Department: Psychology

Abstract: Human societies are built on trust and cooperation, and social evaluations of strangers and known individuals are characterized by a truth bias. That is, humans are more likely to trust, than doubt, the veracity of information received from others. This is particularly true for older adults, who exhibit greater trust than young adults. While this bias may serve to protect social relationships—a goal that becomes increasingly important with age (i.e., socioemotional selectivity theory; Carstensen, 2006)—it also increases older adults' vulnerability to acts of deception aimed at financial exploitation. Building on maturational dualism hypotheses (Mendes, 2010), and recent research by the Principal Investigator (ten Brinke, Lee, & Carney, 2017), we propose that somatic reactions that alert social perceivers to the presence of risk—specifically, lies—is impaired in older adults. Without this early warning system, older adults are less likely to suspect and detect deception in others, leading to a truth bias that increases their vulnerability to financial exploitation. The proposed research will examine whether older adults' experience the same physiological reactions as young adults in response to high-stakes lies with financial repercussions.

Exosome biomarkers for TBI and Alzheimer's disease

PI: Davidson, Bradley

Department: Mechanical and Materials Engineering

Abstract: Concussion or mild traumatic brain injury (mTBI) can result in persistent disability and repeated mTBI can be especially dangerous. These injuries can be caused by high impact sports, but also by explosive blasts from improvised explosive devices in military personnel or by accidents in the general population. Recent work suggests that mTBI may lead to increased risk for Alzheimer's disease (AD), or AD-related dementias (ADRDs). Neuron- derived exosomes are small vesicles in blood that contain mRNA, proteins, and microRNA, are secreted from neurons and can be used to determine brain biomarkers, allowing direct determination of what goes on in the brain. Toxic isoforms of tau and amyloid are increased in brain following TBI, and are involved in AD pathology, but their levels are difficult to measure in blood. In addition, studies have shown that levels of brain-derived neurotrophic factor (BDNF) are reduced in brain and in circulation, after brain injuries and in AD, and can be used as a measurement of brain health. Our preliminary data demonstrate that amyloid levels are increased in athletes with a history of mTBIs, and that BDNF levels in serum are reduced post-season in ice hockey players. We propose to validate these three biomarkers in neuron-derived exosomes from blood as a potential panel of biomarkers for mTBI and future conversion to AD or ADRDs, and to correlate these biomarkers with sensitive cognitive and novel biomechanical markers in order to improve current clinical diagnosis of chronic brain disorders following mTBIs.

Impaired Financial Decision-Making in Aging Population

PI: Chess, Eric

Department: KIHA

Abstract: As our population ages, concerns regarding financial security loom large. The number one fear in people approaching retirement is running out of money. This concern is borne out by consistent evidence that a majority of US households are not financially prepared for retirement. Unfortunately, two significant factors only add to this concern. First, older people are at increased risk for financial exploitation and fraud by scams, aggressive sales techniques, and even those closes to them (family, friends, caretakers). Second, cognitive impairment increases with age and the first sign is found in financial decision making by those who are unaware of any deficits. The entire aging population is affected, but those who face the most devastating consequences of poor or impaired financial choices are vulnerable populations with least amount of support including people of color and those in lower socioeconomic brackets. The first goal of this project is to increase awareness and early identification of impaired financial decision making by creating a publically available, practical and accessible testing method that would be useful for individuals as well as financial planners. The second goal of this project is to provide education and outreach to vulnerable aging populations in Colorado. Educational outreach will be targeted toward understanding the intersection of cognitive impairment and diminished financial decision making, preventing exploitation and enhancing financial security. Our goal is to provide real life practical solutions to one of the most important concerns in our aging population. Successful identification and education programs could then be expanded to increasing numbers of vulnerable Coloradans and Americans in the future.