Older adults show biomarker evidence of PICS after sepsis

Abstract Background: Hospital deaths after sepsis have decreased substantially and most young adult survivors rapidly recover (RAP). However, many older survivors develop chronic critical illness (CCI) with poor long-term outcomes. The etiology of CCI is multifactorial and the relative importance remains unclear. Sepsis is caused by a dysregulated immune response and biomarkers reflecting a persistent inflammation, immunosuppression and catabolism syndrome (PICS) have been observed in CCI after sepsis. Therefore, the purpose of this study was to compare serial PICS biomarkers in a) older (versus young) adults and b) older CCI (versus older RAP) patients to gain insight into underlying pathobiology of CCI in older adults. Methods: Prospective longitudinal study with young (≤ 45 years) and older (≥ 65 years) septic adults who were characterized by a) baseline predisposition, b) hospital outcomes, c) serial SOFA organ dysfunction scores over 14 days, d) Zubrod Performance status at three, six and 12-month follow-up and e) mortality over 12 months. Serial blood samples over 14 days were analyzed for selected biomarkers reflecting PICS. Results: Compared to the young, more older adults developed CCI (20% vs 42%) and had markedly worse serial SOFA scores, performance status and mortality over 12 months. Additionally, older (versus young) and older CCI (versus older RAP) patients had more persistent aberrations in biomarkers reflecting inflammation, immunosuppression, stress metabolism, lack of anabolism and anti-angiogenesis over 14 days after sepsis. Conclusion: Older (versus young) and older CCI (versus older RAP) patient subgroups demonstrate early biomarker evidence of the underlying pathobiology of PICS.

1.4 million Americans of at least 40 years of age, collected from 2016 to 2019.We uncovered four aging dimensions that represent the following bodily functions: 1) kidney, 2) thyroid, 3) white blood cells, and 4) liver and heart.We found that fast agers along these dimensions are more likely to develop chronic diseases that are related to these bodily functions.They also had higher health care expenditures compared to the slow agers.K-means clustering of individuals based on the different aging rates revealed that clusters with higher odds of developing morbidity had the highest cost across all types of health care services.Results suggest that cross-sectional laboratory data can be leveraged as an alternative methodology to understand rates of aging along different dimensions, and analysis of their relationships with future costs can aid in the development of interventions to delay disease progression.Introduction: There is substantial literature to suggest that loneliness is a risk factor for marijuana initiation, use, and continued use into adulthood.However, these relationships have yet to be investigated among older adults.Given that recent research suggests marijuana use is increasing among older adults, the purpose of the present study was to examine loneliness and other risk factors among a national sample of older adults ages 50 years or older.Methods: A secondary data analysis was conducted on the 2018 Health and Retirement Study (HRS) was conducted (n = 1,431).The HRS is a national, biannual survey conducted in the United States to assess health, psychosocial, and demographic questions among adults ages 50 years or older.We created a loneliness scale from the available questions and assessed differences based on demographics, lifetime use, and past-year use of marijuana.Weighted analyses with cyclical tree-based hot-deck imputation were conducted.Results: A sizeable percentage (23.5%) of older adults have ever used marijuana and a considerable amount (14.8%) of adults have used marijuana in the past year.Differences were found based on sex (p <.0001), age (p <.0001), race (p <.0001), and income (p <.0001).Loneliness significantly predicted marijuana usage, with adults who reported loneliness nearly 5 times more likely to use marijuana (aOR: 4.87, 95% CI 3.89, 6.10).Discussion: The present study investigated loneliness and marijuana usage among a national sample of adults.Findings from the present study may inform behavioral health interventions, harm reduction, and gerontological health.

OLDER ADULTS SHOW BIOMARKER EVIDENCE OF PICS AFTER SEPSIS
Robert Mankowski, 1 Stephen Anton, 2 Gabriela Ghita, 2 Christiaan Leeuwenburgh, 2 Lyle Moldawer, 2 Philip Efron, 2 Scott Brakenridge, 2 and Frederick Moore, 2 1.University of Florida, Gainesville, Florida, United States, 2. University of Florida, University of Florida, Florida, United States Background: Hospital deaths after sepsis have decreased substantially and most young adult survivors rapidly recover (RAP).However, many older survivors develop chronic critical illness (CCI) with poor long-term outcomes.The etiology of CCI is multifactorial and the relative importance remains unclear.Sepsis is caused by a dysregulated immune response and biomarkers reflecting a persistent inflammation, immunosuppression and catabolism syndrome (PICS) have been observed in CCI after sepsis.Therefore, the purpose of this study was to compare serial PICS biomarkers in a) older (versus young) adults and b) older CCI (versus older RAP) patients to gain insight into underlying pathobiology of CCI in older adults.Methods: Prospective longitudinal study with young (≤ 45 years) and older (≥ 65 years) septic adults who were characterized by a) baseline predisposition, b) hospital outcomes, c) serial SOFA organ dysfunction scores over 14 days, d) Zubrod Performance status at three, six and 12-month follow-up and e) mortality over 12 months.Serial blood samples over 14 days were analyzed for selected biomarkers reflecting PICS.Results: Compared to the young, more older adults developed CCI (20% vs 42%) and had markedly worse serial SOFA scores, performance status and mortality over 12 months.Additionally, older (versus young) and older CCI (versus older RAP) patients had more persistent aberrations in biomarkers reflecting inflammation, immunosuppression, stress metabolism, lack of anabolism and anti-angiogenesis over 14 days after sepsis.Conclusion: Older (versus young) and older CCI (versus older RAP) patient subgroups demonstrate early biomarker evidence of the underlying pathobiology of PICS.

UROLITHIN A ENHANCES MUSCLE PERFORMANCE IN ELDERLY AND POSITIVELY IMPACTS BIO-MARKERS LINKED TO CELLULAR HEALTH Sophia Liu, and David Marcinek, University of Washington, seattle, Washington, United States
Background: Aging is associated with decline in mitochondrial function and reduced exercise capacity.Urolithin A (UA) is a natural gut metabolite shown to stimulate mitophagy and improve muscle function in aged animals, and induce mitochondrial gene expression in elderly.Purpose: Investigate if oral administration of UA improved walking distance (6MWT), muscle fatigue resistance in hand (FDI) and leg (TA) muscles, and had an impact on plasma biomarkers.Method: We conducted a randomized, double-blind, placebo-controlled study (NCT03283462) in elderly subjects (65-90 yrs.) supplemented daily with 1000mg UA or placebo for 4 months.128 subjects were screened and 66 randomized.6MWT and ATPmax via MRS were assessed at baseline and at 4 months.Muscle fatigue tests and plasma analysis of biomarkers were assessed at baseline, 2 and 4 months.Results: UA significantly improved muscle endurance (i.e., change in number of muscle contractions from baseline) in two different muscles (hand: PL 11.6 ±147.5,UA 95.3 ± 115.5;and leg: PL 5.7± 127.1,UA 41.4 ±65.5) compared with placebo at 2-months.Plasma levels of several acylcarnitines, ceramides and C-reactive-protein were decreased by UA at the end-of study.6MWT distance (PL 42.5 ± 73.3 m, UA 60.8± 67.2 m) and ATPmax increased in both groups from baseline (PL 13.7±31.4%,UA19.4± 56.8%) with UA supplemented group exhibiting greater improvements, although these were not statistically different between groups.Conclusion: UA supplementation improved muscle endurance, metabolic and inflammatory plasma biomarkers after 2-months, suggesting that UA can have a positive impact on muscle and cellular health in the elderly.

ANALYSIS OF DGAT2 MUTATIONS REVEALS POTEN-TIAL LINKS BETWEEN CANCER AND LIPID DROPLET DEREGULATION
Meghan Graber, and Hayley Barta, Xavier University, Cincinnati, Ohio, United States Diacylglycerol O-acyltransferase 2 is a transmembrane protein encoded by the DGAT2 gene that functions in lipid metabolism, triacylglycerol synthesis, and lipid droplet regulation.Since cancer cells exhibit altered lipid metabolism, it has been proposed that mutations in DGAT2 may contribute to this state.Using data from the Catalogue of Somatic Mutations in Cancer (COSMIC), we analyzed all reported DGAT2 mutations in human cancers.Bioinformatics analyses were performed to highlight the connections between age, pathogenicity, and cancer tissue type.Mutations are generally associated with samples from older individuals, except for those in glioblastomas which occur earlier.We also found that several DGAT2 mutations fall within the catalytic site of the enzyme and may affect enzyme function.Thus, these mutations may contribute to altered cancer metabolism.We identified D222V as a mutation hotspot neighboring a previously discovered Y223H mutation that causes Axonal Charcot-Marie-Tooth disease.Remarkably, Y223H has not been detected in cancers indicating it is inhibitory to cancer progression.Further analysis showed that most mutations do not affect DGAT2 gene expression suggesting this change is not a major contributor to cancer development.Intriguingly, although most cancers are characterized by low DGAT2 gene expression, some show high expression levels, indicating that, at least in certain cases, over-expression is not inhibitory to cellular proliferation.This work uncovers unknown roles of DGAT2 in cancers and suggests that its function may be more complex than previously appreciated.

ASSOCIATION OF GRIMAGE DNA METHYLATION COMPONENTS AND 2-YEAR MORTALITY IN THE HEALTH AND RETIREMENT STUDY
Jie Yang, 1 and Andrew Yockey, 2 1.East Carolina University, Greenville, North Carolina, United States, 2. University of North Texas Health Science Center, Denton, Texas, United States Helen Meier, 1 Colter Mitchell, 2 Eileen Crimmins, 3 Bharat Thyagarajan, 4 and Jessica Faul, 2 1.University of Michigan, Ann Arbor, Michigan, United States, 2. University of Michigan, University of Michigan, Michigan, United States, 3. University of Southern California, Los Angeles, California, United States, 4. University of Minnesota, Minneapolis, Minnesota, United States DNA methylation (DNAm) patterns related to age and aging phenotypes (i.e., epigenetic clocks) are of growing interest as indicators of biological age and risk of negative health outcomes.We investigated associations between the components of GrimAge, an epigenetic clock estimated from DNAm patterns for seven blood protein levels and smoking pack years, and 2-year mortality in the Health and