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Principal Investigator: michele k evans
Organization: NATIONAL INSTITUTE ON AGING
Fiscal Year: 2024
Award: $718,611
Funding agency: National Institute on Aging
The biological and behavioral health disparities research focuses on the HANDLS study. Our work has focused on biological aging and weathering, frailty, biomarkers of aging, mortality, and inflammation. However, our most important recent work has identified Early onset frailty as a surrogate for weathering. Frailty is a risk factor for disability and mortality and more prevalent among African American than White elderly. In middle-aged racially and economically diverse HANDLS adults, frail participants had lower survival probability that was independent of race, sex and poverty status, but frailty prevalence was higher among White participants at younger ages. We focused on frailty not only because we identified Early Onset Frailty in the HANDLS cohort, but also because we believe that Early Onset Frailty may be an excellent surrogate for weathering or accelerated aging. Hence, we used this surrogate for weathering to pursue different biologic transduction pathways that would allow us to identify pathways important in frailty overall and in health disparities.
We investigated whether transcriptomic differences between African American and White partici-pants were associated with frailty status, in the context of race and younger age groups. Frailty altered gene expression patterns and biological pathways differently in African American and White participants, particularly in pathways related to inflammation and immunity. These results suggested that there may be other demographic-dependent, divergent biological pathways underlying frailty in middle-aged adults. Since this investigation of global transcriptome changes demonstrated inflammatory genes and pathways were significantly altered by frailty status and race, we pursued the hypothesis that transcriptomic differences may also be driven by sex. To discover novel genes and pathways associated with sex and frailty, we employed RNA-Sequencing, Parametric Analysis of Gene Set Enrichment (PAGE) and Ingenuity Pathway Analysis (IPA). Differential gene expression and pathway analyses were performed in peripheral blood mononuclear cells for 1) frail females (FRAF) vs non-frail females (NORF) 2) frail males (FRAM) vs non-frail males (NORM), 3) FRAM vs FRAF, and 4) NORM vs NORF.
While some of the uniquely identified significant genes from each respective comparison group have been previously described, many of the genes appear to be novel and may serve important roles in frailty-associated pathological mechanisms. For example, TSC22D3, a gene uniquely identified in the FRAF vs NORF comparison, codes for the glucocorticoid-induced leucine zipper (GILZ) protein, in which de-creased expression has been associated with inflammaging in mice.15 IER3, uniquely identified in the FRAM vs FRAF comparison group, was previously associated with mortality16 and can inhibit NF-κB sig-naling in response to TNF-α activation. Therefore, several of the novel frailty-associated genes identified in our analysis may have physiological relevance in frailty.
Notably, we also observed over a third of the novel genes exclusively found in the FRAM vs FRAF comparison were noncoding RNAs (ncRNAs). Some of the novel ncRNAs exclusively identified in this comparison group have been previously associated with inflammatory processes. For example, LINC00936 and LINC00528 were recently predicted to interact with TLR2 and the Toll-like receptor signaling pathway in acute myocardial infarction.18 Another study showed overexpression of LINC00936 in cardiomyocytes resulted in significantly reduced levels of IL-10 and higher levels of IL-6, IL-1β, and TNFα. Collectively, our results suggest that ncRNAs could potentially contribute to sex-specific differences associated with chronic inflammation in aging and frailty.
In addition, we found cell cycle-related pathways were downregulated in FRAM relative to FRAF, suggesting that cell cycle progression could be inhibited in FRAM. Cell cycle arrest is one of the key features of cellular senescence, which has been considered one of the mechanisms contributing to chronic inflammation in frailty. We observed significantly increased gene expression for IL1A (IL-1α), CXCL8 (IL-8), TNF (TNF-α), and other pro-inflammatory genes related to the senescence-associated secretory phenotype in FRAM relative to FRAF. Surprisingly, we observed the Coronavirus pathogenesis pathway was predicted to be upregulated in FRAM compared to FRAF and was uniquely identified in this respective comparison group. Frailty was linked to Coronavirus disease 2019 (COVID-19) severity risk and mortality. It is well demonstrated in the literature that men have greater risk for severe COVID-19 and COVID-related mortality.22 Many of the upregulated genes in the Coronavirus pathogenesis pathway, including IL and CCL2, are associated with cytokine storm associated with severe COVID-19 disease.22 It is plausible that increased susceptibility to viral infections and cytokine storm in frail men could begin to manifest in mid-life.
Our transcriptomic studies in frailty identified altered gene expression patterns and biological path-ways associated with inflammation in frailty. Evidence suggests DNA oxidation damage related to inflammation accumulates with age, and that DNA repair capacity (DRC) declines with age and age-related conditions. Using the CometChip assay, we assessed baseline single-strand breaks and hydrogen peroxide (H2O2)-induced DNA oxidation damage and DRC in peripheral blood mononuclear cells from non-frail and frail middle-aged African American and White individuals with household incomes above and below poverty.4 We also assayed serum cytokine levels. We found that baseline DNA damage levels do not differ across frailty status, poverty status, race, or sex. There were differences in H2O2-induced DNA damage and DRC. Among those living above poverty, non-frail adults displayed higher amounts of H2O2-induced DNA damage compared to frail adults. There were two interactions for DRC: for frailty status and sex, women who were non-frail displayed lower DRC than women who were frail; for poverty status and sex, men who were below poverty displayed higher DRC than men above poverty. The serum cytokine as-says revealed that levels of the anti-inflammatory cytokine IL-10 were inversely related with both baseline DNA damage and H2O2-induced DNA damage. Finally, we found an inverse relationship with DRC and IL-4 levels in men but a positive relationship in women. We also observed men and women living above poverty had opposite relationships between DRC and TNF-α levels, while men and women living below poverty were similar.
The effect of frailty and poverty on DNA damage and DRC is complex. Our results showing that individuals living below poverty displayed smaller differences between frail or non-frail status in H2O2-induced DNA damage and that men below poverty displayed higher DRC than men above poverty, could be interpreted as poverty inducing an adaptive response to reduce DNA damage and increase DNA repair mechanisms. Chronic inflammation associated with poverty could lead to oxidative stress and thus an increase in DRC. Similarly, our finding that frail women displayed higher DRC than non-frail women points towards an adaptive response increasing DRC because of frailty-associated inflammation. Importantly, our study captures a snapshot of disparities in repair and inflammation at an earlier age than the more commonly studied inflammaging in elderly individuals. Our results point toward an interaction between frailty status and SDOH, such as sex and poverty status, to influence DNA damage and repair at midlife. Differences in DNA damage and repair observed at midlife may contribute to health disparities in the elderly. This is the first evidence that DRC may be influenced by poverty.
Terms: <(TNF)-α><21+ years old><3-10C><AMCF-I><Acceleration><Acute myocardial infarct><Acute myocardial infarction><Adult><Adult Human><African American><African American group><African American individual><African American people><African American population><African Americans><Afro American><Afroamerican><Age><Aging><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Appearance><Assay><Automobile Driving><B cell differentiation factor><B cell growth factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-1><B-Cell Differentiation Factor-2><B-Cell Growth Factor-1><B-Cell Growth Factor-I><B-Cell Proliferating Factor><B-Cell Stimulating Factor><B-Cell Stimulating Factor-1><B-Cell Stimulation Factor-1><B-Cell Stimulatory Factor-1><B-Cell Stimulatory Factor-2><BCDF><BCDF-1><BCGF><BCGF-1><BCSF 1><BSF-1><BSF-2><BSF1><BSF2><Basic Research><Basic Science><Behavioral><Beta Proprotein Interleukin 1><Binetrakin><Bioassay><Biologic Factor><Biological><Biological Aging><Biological Assay><Biological Factors><Biology><Blood Serum><CCL2><CCL2 gene><COVID disease severity><COVID severity><COVID-19 associated death><COVID-19 associated fatality><COVID-19 associated mortality><COVID-19 death><COVID-19 disease severity><COVID-19 fatality><COVID-19 induced death><COVID-19 induced fatality><COVID-19 induced mortality><COVID-19 mortality><COVID-19 related death><COVID-19 related fatality><COVID-19 related mortality><COVID-19 severity><COVID19 associated death><COVID19 associated fatality><COVID19 associated mortality><COVID19 death><COVID19 disease severity><COVID19 fatality><COVID19 induced death><COVID19 induced fatality><COVID19 induced mortality><COVID19 mortality><COVID19 related death><COVID19 related fatality><COVID19 related mortality><COVID19 severity><CSIF><CSIF-10><CXCL8><Cachectin><Cardiac Muscle Cells><Cardiac Myocytes><Cardiocyte><Causality><Cell Aging><Cell Communication and Signaling><Cell Cycle><Cell Cycle Arrest><Cell Cycle Progression><Cell Division Cycle><Cell Senescence><Cell Signaling><Cell to Cell Communication and Signaling><Cell-Cell Signaling><Cellular Aging><Cellular Senescence><Chemokine, CC Motif, Ligand 2><Chronic><Clinical Research><Clinical Study><Code><Coding System><Cognition><Cognitive Discrimination><Complex><Coronaviridae><Coronavirus><Cytokine Synthesis Inhibitory Factor><DNA><DNA Damage><DNA Damage Repair><DNA Injury><DNA Repair><Deoxyribonucleic Acid><Diathesis><Differences between sexes><Differential Gene Expression><Differs between sexes><Discrimination><Disease><Disease susceptibility><Disorder><Disparate><Disparities><Disparity><Dissection><Early identification><Economic Income><Economical Income><Elderly><Environmental Factor><Environmental Risk Factor><Epidemiologic Research><Epidemiologic Studies><Epidemiological Studies><Epidemiology Research><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Etiology><Expression Signature><Female><Functional RNA><GCP1><Gene Expression><Gene Expression Profile><Gene set enrichment analysis><Genes><Genetic><Glucocorticoids><Goals><H2O2><HPGF><Health><Health Disparities Research><Health Status><Health disparities related research><Heart Muscle Cells><Heart myocyte><Hematopoietin-1 Gene><Hepatocyte-Stimulating Factor><Household><Hybridoma Growth Factor><Hydrogen Peroxide><Hydroperoxide><IFN-beta 2><IFNB2><IL-1 beta><IL-1 β><IL-1-b><IL-10><IL-1A Gene><IL-1β><IL-4><IL-6><IL-8><IL1 Gene><IL1-Alpha Gene><IL1-Beta><IL1-β><IL10><IL10A><IL1A><IL1A gene><IL1B Protein><IL1F1 Gene><IL1F2><IL1β><IL4 Protein><IL6 Protein><IL8><IL8 gene><Immunity><Impoverished><Income><Individual><Inflammaging><Inflammation><Inflammatory><Interdisciplinary Research><Interdisciplinary Study><Interleukin 10 Precursor><Interleukin 1beta><Interleukin-1 beta><Interleukin-1-Alpha Gene><Interleukin-10><Interleukin-1β><Interleukin-4><Interleukin-4 Precursor><Interleukin-6><Intracellular Communication and Signaling><Investigation><K60><Laboratories><Leucine Zippers><Level of Health><Life Expectancy><Link><Literature><Lymphocyte Stimulatory Factor 1><MCAF><MCGF-2><MCP-1><MCP1><MGI-2><Macrophage-Derived TNF><Mast Cell Growth Factor-2><Medical><Mice><Mice Mammals><Minority><Molecular><Monocyte Chemoattractant Protein-1><Monocyte Chemotactic Protein-1><Monocyte Chemotactic and Activating Factor><Monocyte Chemotactic and Activating Protein><Monocyte Chemotactive and Activating Factor><Monocyte Secretory Protein JE><Monocyte-Derived TNF><Morbidity><Morbidity - disease rate><Multidisciplinary Collaboration><Multidisciplinary Research><Murine><Mus><Myeloid Differentiation-Inducing Protein><Neighborhoods><Network Analysis><Non-Coding><Non-Coding RNA><Non-translated RNA><Noncoding RNA><Nontranslated RNA><Outcome><Oxidative Stress><PBMC><Participant><Pathogenesis><Pathologic><Pathway Analysis><Pathway interactions><Peripheral Blood Mononuclear Cell><Phenotype><Physiologic><Physiological><Plasmacytoma Growth Factor><Population><Poverty><Predisposition><Preinterleukin 1 Alpha Gene><Preinterleukin 1 Beta><Prevalence><Probability><Process><Proteins><Psychosocial Factor><RNA Seq><RNA sequencing><RNAseq><Race><Races><Replicative Senescence><Research><Risk><Risk Factors><Role><SARS-CoV-2 associated death><SARS-CoV-2 associated fatality><SARS-CoV-2 associated mortality><SARS-CoV-2 death><SARS-CoV-2 disease severity><SARS-CoV-2 fatality><SARS-CoV-2 induced death><SARS-CoV-2 induced fatality><SARS-CoV-2 induced mortality><SARS-CoV-2 mortality><SARS-CoV-2 related death><SARS-CoV-2 related fatality><SARS-CoV-2 related mortality><SARS-CoV-2 severity><SCYA2><SCYB8><Scientist><Serum><Severities><Sex Differences><Sexual differences><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Small Inducible Cytokine A2><Socioeconomic Factors><Structural Racism><Susceptibility><T-Cell Growth Factor 2><TIL4><TLR protein><TLR2><TLR2 gene><TLR2 receptor><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><TSG-1><Telomere Shortening><Time><Tissue-Specific Differential Gene Expression><Tissue-Specific Gene Expression><Toll-Like Receptor 2><Toll-Like Receptor Family Gene><Toll-like receptors><Toll/Interleukin 1 Receptor-Like 4><Toll/Interleukin 1 Receptor-Like 4 Gene><Toll/Interleukin 1 Receptor-Like Protein 4><Translational Research><Translational Science><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Unscheduled DNA Synthesis><Untranslated RNA><Viral Diseases><Virus Diseases><Woman><Work><accelerated aging><accelerated biological age><accelerated biological aging><adulthood><advanced age><age acceleration><age associated><age associated chronic condition><age associated chronic disease><age associated chronic disorder><age associated chronic health condition><age associated chronic illness><age associated decline><age correlated><age dependent><age dependent decline><age group><age linked><age related><age related chronic condition><age related chronic disease><age related chronic disorder><age related chronic health condition><age related chronic illness><age related decline><age specific><age-related inflammation><ages><aging biological marker><aging biomarker><aging marker><b-ENAP><behavioral health><biologic><biological process of age><biological signal transduction><brain health><cardiomyocyte><causation><cohort><comparator group><comparison group><corona virus><coronavirus disease 2019 associated death><coronavirus disease 2019 associated fatality><coronavirus disease 2019 associated mortality><coronavirus disease 2019 death><coronavirus disease 2019 disease severity><coronavirus disease 2019 fatality><coronavirus disease 2019 induced death><coronavirus disease 2019 induced fatality><coronavirus disease 2019 induced mortality><coronavirus disease 2019 mortality><coronavirus disease 2019 related death><coronavirus disease 2019 related fatality><coronavirus disease 2019 related mortality><coronavirus disease 2019 severity><coronavirus disease severity><coronavirus disease-19 mortality><cytokine><cytokine release syndrome><cytokine storm><death due to COVID-19><death due to COVID19><death due to SARS-CoV-2><death due to coronavirus disease 2019><death due to severe acute respiratory syndrome coronavirus 2><death in COVID><death in COVID-19><death in SARS-CoV-2><death in coronavirus disease><death in coronavirus disease 2019><death in severe acute respiratory syndrome coronavirus 2><decline with age><disability><disease causation><disparity in health><driving><early onset><environmental risk><epidemiologic investigation><epidemiology study><epigenetically><fatality due to COVID-19><fatality due to COVID19><fatality due to SARS-CoV-2><fatality due to coronavirus disease 2019><fatality due to severe acute respiratory syndrome coronavirus 2><frailty><gene expression pattern><gene expression signature><geriatric><global gene expression><global transcription profile><health disparities science><health disparity><health level><healthy aging><healthy human aging><high risk><incomes><inflamm-ageing><inflamm-aging><intercellular communication><interferon beta 2><liability to disease><life span><life-threatening COVID><life-threatening COVID-19><life-threatening SARS-CoV-2><life-threatening coronavirus disease><life-threatening coronavirus disease 2019><life-threatening severe acute respiratory syndrome coronavirus 2><lifespan><literacy><low SES><low socio-economic position><low socio-economic status><low socioeconomic position><low socioeconomic status><male><men><mid life><mid-life><middle age><middle aged><midlife><mortality><mortality due to COVID-19><mortality due to COVID19><mortality due to SARS-CoV-2><mortality due to coronavirus disease 2019><mortality due to severe acute respiratory syndrome coronavirus 2><noncoding><novel><nutrition><overexpress><overexpression><oxidation><pathway><population based><psychosocial variables><racial><racial background><racial origin><repair><repaired><response><senescence associated secretome><senescence associated secretory phenotype><senior citizen><serious COVID><serious COVID-19><serious SARS-CoV-2><serious coronavirus disease><serious coronavirus disease 2019><serious severe acute respiratory syndrome coronavirus 2><severe COVID><severe COVID-19><severe COVID19><severe SARS-CoV-2><severe acute respiratory syndrome coronavirus 2 associated death><severe acute respiratory syndrome coronavirus 2 associated fatality><severe acute respiratory syndrome coronavirus 2 associated mortality><severe acute respiratory syndrome coronavirus 2 death><severe acute respiratory syndrome coronavirus 2 disease severity><severe acute respiratory syndrome coronavirus 2 fatality><severe acute respiratory syndrome coronavirus 2 induced death><severe acute respiratory syndrome coronavirus 2 induced fatality><severe acute respiratory syndrome coronavirus 2 induced mortality><severe acute respiratory syndrome coronavirus 2 mortality><severe acute respiratory syndrome coronavirus 2 related death><severe acute respiratory syndrome coronavirus 2 related fatality><severe acute respiratory syndrome coronavirus 2 related mortality><severe acute respiratory syndrome coronavirus 2 severity><severe coronavirus disease><severe coronavirus disease 19><severe coronavirus disease 2019><severe severe acute respiratory syndrome coronavirus 2><sex><sex based differences><sex-dependent differences><sex-related differences><sex-specific differences><social cultural factor><social culture determinant><social role><socio-economic><socio-economic factors><socio-economically><sociocultural determinant><sociocultural factor><socioeconomically><socioeconomics><telomere attrition><transcriptional profile><transcriptional signature><transcriptome><transcriptome sequencing><transcriptomic sequencing><transcriptomics><translation research><translational investigation><viral infection><virus infection><virus-induced disease>