Pilot Grant Program

1. NIA R01 (Donato)
2. AHRQ K08 (LaFleur)
3. NIDCD R01 (Lucero)
4. NEI R01 (Vetter)
5. NIA R21 (Zick)
6. NIA R21 (Zimmer)
7. NIA K23 Beeson (King)
8. NHLBI R01 (Wray)
9. NHLBI R01 (Amann)
10. NHLBI R01 (Soorappan)
11. NIA R21 (Donato)
12. NIA R01 (Duff)
13. NLM R01 (del Fiol)
14. NIA R03 (Drummond)
15. NIA R01 (Rondina)

Robert Campbell, PhD

Co-I Matthew Rondina, MD, MS

Co-I Anthony Donato, PhD, MS

Inflammation in Aging Increases Platelet Hyperactivity and Thrombosis

Aging is accompanied by a decreased tolerance to physiological stress, which promotes increased susceptibility to inflammatory illnesses. Critical illnesses such as sepsis, disportionately effect people over the age of 65, leading to increased morbidity and mortality in older adults. Thrombosis is a common complication from sepsis, contributing to organ failure and death. Emerging evidence supports the concept that dysregulated platelet functions mediate the injurious host response during inflammation. Nevertheless, the molecular mechanisms and functional consequences of dysregulated platelet functions during aging and inflammation remain incompletely understood. Our proposal, entitled "Inflammation in
Aging Increases Platelet Hyperactivity and Thrombosis" will identify new pathways by which inflammatory agonists, including, interferons (IFNs) regulate gene expression in platelets and their parent cell, the megakaryocyte (MK) in aging. Our preliminary studies have identified that the expression of IFITM3 is robustly induced in human platelets during sepsis. Interestingly, MKs and platelets from aged human and mice express more IFITM3 after IFN stimulation compared to younger controls. Our data suggest that IFITM3 promotes fibrinogen endocytosis in MKs and platelets, leading to platelet hyperreactivity and thrombosis. Our findings also suggest in aging and during inflammatory stress, the mammalian target of rapamycin (mTOR) pathway is activated, triggering IFITM3 synthesis and thrombosis. The expression and function of IFITM3 in MKs and platelets and its regulation by mTOR is a pathway not previously examined. In this proposal, we will couple studies in older and younger septic patients with in vitro and in vivo murine models using aged mice. These complementary human and murine studies will allow us to establish clinical relevance, while also dissecting the mechanisms by which IFITM3 governs MK and platelet function during inflammation. These studies are translational and innovative as IFITM3 regulation of endocytosis, a process critical for cellular function has not previously been studied in MKs, platelets, or - for that matter - any primary human cells. They will also determine for the first time whether if aging alters the effect of inflammatory agonists on transcriptional and translational events in MKs and platelets. This work will test an important functional hypothesis and clarify pathophysiologic mechanisms of thrombosis aging during inflammation.

Vincent Koppelmans, PhD

Co-I Kevin Duff, PhD

Co-I Sara Weisenbach, PhD

Co-I Robert Welsh, PhD           

Ecological Assessment of Emotion Regulation in Amnestic Mild Cognitive Impairment

Emotion regulation (ER) is important for emotional well-being and partly relies on intact neurocognitive functions. Not much is known about ER in older adults with or without amnesitc Mild Cognitive Impairment (aMCI). Cognitive problems in aMCI may further hamper ER in these subjects and thus reduce emotional well-being. This study will assess differences in emotion regulation ER strategies and mood fluctuation between healthy older adults, and a group of demographically-matched subjects with aMCI. Because most ER measures have not been validated in older adults with or without aMCI, we will use ecological momentary assessment (EMA) to measure ER in everyday life and relate that to identical and similar
measures collected in a lab environment. With the EMA we will measure mood and ER at on multiple days at several time points. We will use this data to assess the ecological validity of the conventional ER measures using the EMA ER data. In a next step we will relate the conventional and EMA ER data to measures of cognitive functioning to test if executive functioning and ER are differentially related in healthy older individuals and individuals with aMCI. Within subjects with aMCI we will look if the extent of executive dysfunction relates to type and extent of use of ER strategies. Finally, we will use the EMA data to calculate an index of mood fluctuation. Mood fluctuation cannot be derived from conventional emotion self reports, but could provide new information on the differences in emotional well-being and ER between healthy older adults and individuals with aMCI.

Michelle Litchman, PhD, FNP-BC, FAANP 

Co-I Nancy Allen, PhD, ANP-BC

A Feasibility Study of Older Adults and their Care partners using RT-CGM Share

This Center on Aging Pilot Grant will examine the use of 1) real-time continuous glucose monitoring (RTCGM) in older adults with and without cognitive decline and comorbid type 1 diabetes and 2) RT-CGM data sharing with care partners via mobile app. Adults with type 1 diabetes are living longer. Age related changes, coupled with diabetes-related complications, such as hypoglycemia and cognitive decline, places older adults at risk for cardiac events, loss of consciousness, falls, seizures, and hospitalizations. There is little information about older adults with cognitive decline who use RT-CGM or older adults who share RTCGM data with care partners. The objective of this research is to determine if older adults with and without cognitive decline can effectively share RT-CGM information with care partners to improve hypoglycemia and glycemic variability. Our three aims are: 1) adapt a RT-CGM data sharing training manual for older patients and care partners that includes the technical and behavioral components of this technology, 2) evaluate the feasibility, acceptability, adherence and clinical outcomes of RT-CGM with data sharing and 3)
evaluate hypoglycemia confidence, quality of life and RT-CGM data sharing experience. This study is a critical first step in determining how older adults and care partners can use RT-CGM with data sharing to improve hypoglycemia and glucose variability. Findings from this study will be used as preliminary data to develop a fully powered randomized control trial.

Marc Porter, PhD

Co-I Phillip Kithas, MD, PhD

Sensitive Detection of Age-Related Biomarkers Using Surface-Enhanced Raman Scattering

Preventative or curable age-related diseases such as heart disease and diabetes can be successfully treated if detected early in their development via routine physician visits and preventative screening. An emerging area in geriatric medicine centers on the detection of advanced glycation end-products (AGEs), which are proteins or lipids that become glycated as a result of exposure to sugars. AGEs have been linked to the development or worsening of conditions such as diabetes, Alzheimer’s and heart disease. Currently, there is no “gold standard” method to screen for AGEs. We propose the development of a multiplexed immunosorbent assay for three abundant blood-borne AGEs – carboxymethyllysine (CML), methylglyoxal 5-hydro-5-methylimidazolone (MG-H1), and glycated hemoglobin (Hb1Ac). This platform, which is based on an extensive body of work at the University of Utah, provides a snapshot of serum AGE levels and can be used for screening or monitoring of therapeutic interventions.

Karen Schliep, PhD, MSPH 

Association Between Women's Reproductive Health and Later Dementia   

Hypertensive disorders of pregnancy (HDP), including preeclampsia, is the leading cause of fetal and maternal morbidity and mortality, complicating 3–10% of all pregnancies. Little is known regarding the association between HDP and long-term adverse maternal neurological outcomes with similar inflammatory vascular etiologies, including the two most common forms of dementia—Alzheimer’s disease (AD) and
vascular dementia (VaD). However, emerging experimental models demonstrating distinct etiologies between HDP and AD as well as HDP and VaD make a strong biological case for such an association. An estimated 5.4 million Americans currently suffer from dementia, two-thirds of whom are women. As the US aging population increases, prevalence of dementia is expected to approach 16.0 million cases by 2050. Why AD and VaD disproportionately affect women is not known. This project sets out to test our central hypothesis that women with versus without HDP will have increased risk for dementia, with four specific aims: 1) increase diagnostic accuracy of AD, VaD, and other dementias within a large population database containing routinely collected health information; 2) investigate the association, and dose-response, between HDP and AD and/or VaD; and 3) evaluate the mediating effects of depression on HDP–AD and/or VaD risk. Our study proposes to use four complementary, unique, and rich data resources. Three have notably low measurement error in regards to definitive dementia diagnoses. The fourth has low sampling error: a statewide database of over 11 million individuals with linked family history, sociodemographic, and medical/vital records. In Aim 1, we use a machine learning approach to develop AD and VaD classification models to analyze longitudinal, individual-level routinely collected health information data to maximize both the sensitivity and specificity of identifying the gold standard AD and/or VaD cases. In Aim 2 and 3, after
optimally classifying and linking AD/VaD diagnoses within UPDB, women with HDP will be identified (n ~ 65,000) and then tested for risk for AD and/or VaD, taking into account important confounding factors and mediating effects of depression. The results of the aims will inform a life-course approach to women’s health research, with a goal of contributing to our understanding of gender disparities in dementia risk. This
research will prepare the research team to design and implement a novel R01 application to explicate the mechanistic relationship between women’s reproductive health and subsequent dementia risk leading to timely interventions targeting those with a high-risk maternal health history.

Lauren Theilen, MD

Co-I Russ Richardson, PhD

Co-I Michael Varner, MD

Vascular Aging in Women with a History of Recurrent Hypertensive Disease of Pregnancy

Women with a history of hypertensive disease of pregnancy (HDP) have increased risks for chronic diseases later in life. Cardiovascular disease is the leading cause of death among women in the United States, and HDP is now recognized as an important risk factor for the later development of cardiovascular disease. Our data have shown that women who have had HDP in more than one pregnancy (recurrent HDP) have significantly increased risks for death from heart disease and stroke before the age of 50; however, an important knowledge gap remains regarding the timeline and pathophysiology of cardiovascular risk following HDP. We hypothesize that women with recurrent HDP will have an accelerated vascular aging phenotype that may be identified before the onset of clinical cardiovascular disease via noninvasive studies of vascular function. To test this hypothesis, we propose to identify a cohort of women with a history of recurrent HDP who delivered their first affected pregnancy 10-15 years ago (exposed women). We will match them to women who have also had more than one pregnancy, but who have no history of HDP (unexposed women). We will test both groups of women in order to determine if exposed women, compared to unexposed women, 1) exhibit
increased arterial stiffness, as measured by pulse wave velocity, and 2) exhibit impaired endothelial function, as measured by the hyperemic response to passive leg movement. Our pilot study will provide preliminary data to guide subsequent investigation regarding the underlying pathophysiology and prevention of cardiovascular disease among women with a history of HDP.