Awards made under "Aging Biology Research to Address Health Disparities" (PA-17-164)
Read about the funding awards made under PA-17-164: Aging Biology Research to Address Health Disparities. For more information on health disparities research at NIA, visit the Office of Special Populations webpage.
3-R01-AG048021-04 – Nikolich-Zugich, Janko
Impact of CMV Upon T-Cell Aging and Immune Defense
Hispanic Americans acquire CMV and other herpesviruses earlier and at higher rate. There is evidence that Hispanic Americans also suffer disproportionally from common morbidities of aging, including cardiovascular (CVD) and metabolic diseases, including metabolic syndrome and type 2 diabetes (T2D), which are preceded by increased pericardial, intramyocellular, hepatic and visceral fat, and increased inflammation. This inflammation could be linked to CMV and to adverse health outcomes. Indeed, in elderly Hispanic Americans, increased CMV IgG antibody titers are associated with all-cause mortality even after adjusting for a number of important covariates such as age, gender, education, and baseline health conditions. Based on the data from the literature on Hispanic/non-Hispanic disparities in inflammation related to cardiovascular and metabolic diseases and in acquisition of CMV, we hypothesize that inflammation and immune homeostasis will be modulated synergistically by age and ethnicity in CMV+ subjects.
To that end, this proposal will compare parameters of hCMV virus activity and immune control in Hispanic vs. non-Hispanic aging human subjects. Our preliminary retrospective analysis of T cell phenotypic subsets in Hispanics aging with CMV indicates there are clear differences relative to non-Hispanic CMV+ subjects. Using our already collected and banked sample cohort, we will measure T cell homeostasis and CMV-specific immune function in peripheral blood cells by polychromatic flow cytometry (FCM), hCMV transcriptional activity, anti-HCMV antibody total and neutralizing titers.
Our studies proposed by this supplement will begin to address whether there are key functional differences in how Hispanic individuals are controlling hCMV infection. We will focus hCMV-specific immune function analysis using PBMC and plasma samples already banked by our research group; should we find promising associations between the immune dysregulation associated with age and hCMV-specific immune function in Hispanic individuals, vaccination studies will be planned for future applications outside of the scope of the present proposal.
3-P01-AG051428-02 – Turner, Joanne
Exploring the Impact of Inflammaging on Immune Function during M. tb Infection
The global human population over the age of 65 is forecast to increase by three-fold to about 1.5 billion by 2050. The consequence of an extended life span is increased hospitalization and mortality rates due to age-related diseases. Age is a risk factor for chronic inflammatory diseases and infections, including tuberculosis (TB) which is the focus of the parent program project grant (PPG). Aging is associated with low-grade inflammation, termed inflammaging, which is a contributing factor in age-related diseases and studies in the PPG investigate the influence of inflammaging in TB susceptibility in the elderly.
Psychological stress is also a major comorbidity in TB. The aged population is particularly susceptible to chronic psychological stress. Elderly people often experience stress due to difficulties in maintaining a daily routine, concern over increased health problems, and decreased satisfaction with life. While the influence of psychological stress on TB and chronic stress in the elderly is well-documented, studies are lacking that investigate whether psychological stress exacerbates inflammaging in the elderly and further increases susceptibility to TB. Also lacking are mouse stress models that facilitate investigation of the cellular mechanisms that are involved.
The goal of this proposal is to develop a social stress model to investigate the effect of psychological stress in aged mice on inflammaging and control of M. tuberculosis (M.tb) infection.
3-R03-AG051877-02 – Wolf, Erika
Traumatic Stress and Accelerated Aging in DNA Methylation
Our work under the Parent R03 has provided preliminary evidence for traumatic stress-related accelerated aging in DNA methylation (DNAm) as well as associations between post-traumatic stress disorder (PTSD), accelerated DNAm age, and metabolic syndrome. For the supplement, we propose to substantially expand the scope of this work by examining how environmental and demographic risk factors influence the association between traumatic stress and accelerated DNAm age. We also propose to expand our assessment of accelerated aging to new biomarkers including telomere length, and indicators of inflammation and immunosenescence.
Traumatic and social/economic stressors have previously been associated with immunological/ inflammatory biomarkers and with telomere length, but the interaction of traumatic stress and adversity has not yet been evaluated nor have the relationships among multiple biomarkers of accelerated cellular aging. Based on this, we propose to test the main and synergistic effects of traumatic stress and demographic/social adversity on multiple biomarkers of accelerated biological aging. Finally, we propose to test the hypothesis that health disparities, in the form of untreated mental and physical conditions and in the form of more pathological metabolic profiles, are associated with demographic/social adversity and accelerated cellular aging.
The exploratory aim of this supplement is to characterize genetic and epigenetic networks associated with multiple markers of accelerated biological aging in order to identify common molecular pathways implicated in accelerated aging across biological systems.
3-R03-AG051857-02 – Matsui, Reiko
Regulation of Ischemic Vascularization by Glutaredoxin-1 by Aging
Ischemia-induced angiogenic responses are blunted by aging. This is associated with decreased vascular endothelial growth factor (VEGF) and hypoxia-inducible factor (HIF)-1 activity. Low levels of oxidants are essential to transduce physiological signaling through oxidative post-translational modifications. Because of the abundance of cellular glutathione (GSH), GSH adducts on protein thiols (S-glutathionylation) are commonly formed under mild oxidative stress, and reversed by a small cytosolic thioltransferase, also known as glutaredoxin-1 (Glrx).
We found that Glrx transgenic (TG) mice showed impaired blood flow recovery after femoral artery ligation in middle-aged mice. In contrast, Glrx knockout (KO) mice improved blood flow recovery after hindlimb ischemia. Our preliminary data indicate higher protein expression of HIF-1α and VEGF in ischemic muscles of Glrx KO mice, and increased reversible thiol modification of HIF-1α in Glrx KO muscle. HIF-1α can be modified by S-nitrosylation (R-SNO) at Cys533 in the oxygen-dependent degradation domain which stabilizes HIF-1α by preventing degradation and promotes its activation. R-SNO adducts react rapidly with abundant GSH to become the more stable modification GSH adducts (R-SSG) which would be increased by lack of Glrx. Therefore, we hypothesize that Glrx KO may increase HIF-1α-GSH adducts resulting in stabilization and activation of HIF-1α and increased VEGF production.
Our findings will reveal the novel concept and mechanism that increased GSH adducts, oxidative modification, improve ischemic revascularization. These studies can be extended to generating tissue-specific Glrx KO mice and to apply to other ischemic models in aging.
3-R01-AG042504-04 – Segev, Dorry
Frailty and Risk Prediction in Older Adults Considering Kidney Transplantation
In the US, older adults and African Americans (AAs) are disproportionately burdened by end stage renal disease (ESRD), a condition that results in poor clinical outcomes, quality of life, and life expectancy for patients. Kidney transplantation (KT) offers greater survival and quality of life (versus hemodialysis) for many patients. However, little progress has been achieved in eliminating pervasive disparities in KT assessment and referral for older adults and AAs. Prior studies suggest that nephrologists’ views about the benefits of KT over dialysis for older AAs may be associated with the timing and quality of their assessments for KT suitability and discussions about KT. Provider concerns about the survival benefit of KT may also be related to historical reports of poorer graft and patient survival after KT for older adults and AAs, as well as an observed “survival paradox” in which older AAs receiving chronic hemodialysis (HD) live longer than older non-AA HD patients.
Enhanced prediction models to better determine which older AAs would benefit from KT are needed to inform clinical decision-making and address disparities in KT assessment. We hypothesize that the incorporation of novel risk metrics specific to older adults (e.g., inflammation and frailty), which are highly prevalent among older ESRD patients but not captured in national registries, will significantly improve KT risk prediction and help to address significant disparities in KT assessment and referral for older AAs with ESRD.
To maximize appropriate and minimize inappropriate referral of older AAs for KT, we will conduct new comparative analyses by race/ethnicity using our existing NIA/R01-funded study of older adults with ESRD. We will explore race as a potential effect modifier of the associations of frailty and inflammation on ESRD outcomes to test whether these aging risk predictors differentially affect AAs. This supplement will actualize personalized clinical decision making regarding KT assessment and referral for older AAs by developing a decision process model to aid in identifying appropriate older AA candidates for KT.
3-R01-AG047310-03 – Kulminski, Alexander
Life Course and Genetic and Non-genetic Factors in Health and Survival