@article {9485, title = {Elevated Plasma Levels of Ketone Bodies Are Associated With All-Cause Mortality and Incidence of Heart Failure in Older Adults: The CHS.}, journal = {J Am Heart Assoc}, volume = {12}, year = {2023}, month = {2023 Sep 05}, pages = {e029960}, abstract = {

Background Chronic disease, such as heart failure, influences cellular metabolism and shapes circulating metabolites. The relationships between key energy metabolites and chronic diseases in aging are not well understood. This study aims to determine the relationship between main components of energy metabolism with all-cause mortality and incident heart failure. Methods and Results We analyzed the association between plasma metabolite levels with all-cause mortality and incident heart failure among US older adults in the CHS (Cardiovascular Health Study). We followed 1758 participants without heart failure at baseline with hazard ratios (HRs) of analyte levels and metabolic profiles characterized by high levels of ketone bodies for all-cause mortality and incident heart failure. Multivariable Cox analyses revealed a dose-response relationship of 50\% increase in all-cause mortality between lowest and highest quintiles of ketone body concentrations (HR, 1.5 [95\% CI, 1.0-1.9]; =0.007). Ketone body levels remained associated with incident heart failure after adjusting for cardiovascular disease confounders (HR, 1.2 [95\% CI, 1.0-1.3]; =0.02). Using K-means cluster analysis, we identified a cluster with higher levels of ketone bodies, citrate, interleukin-6, and B-type natriuretic peptide but lower levels of pyruvate, body mass index, and estimated glomerular filtration rate. The cluster with elevated ketone body levels was associated with higher all-cause mortality (HR, 1.7 [95\% CI, 1.1-2.7]; =0.01). Conclusions Higher concentrations of ketone bodies predict incident heart failure and all-cause mortality in an older US population, independent of metabolic and cardiovascular confounders. This association suggests a potentially important relationship between ketone body metabolism and aging.

}, keywords = {Aged, Aging, Cardiovascular Diseases, Heart Failure, Humans, Incidence, Ketone Bodies}, issn = {2047-9980}, doi = {10.1161/JAHA.123.029960}, author = {Niezen, Sebastian and Connelly, Margery A and Hirsch, Calvin and Kizer, Jorge R and Benitez, Maria E and Minchenberg, Scott and Perez-Matos, Maria Camila and Jiang, Zhenghui Gordon and Mukamal, Kenneth J} } @article {9375, title = {Plasma Levels of Branched Chain Amino Acids, Incident Hip Fractures and Bone Mineral Density of the Hip and Spine.}, journal = {J Clin Endocrinol Metab}, year = {2023}, month = {2023 May 18}, abstract = {

OBJECTIVE: Branched chain amino acids (BCAA) are building blocks for protein, an essential component of bone. However, the association of plasma levels of BCAA with fractures in populations outside of Hong Kong or with hip fractures in particular is not known. The purpose of these analyses was to determine the relationship of BCAA including valine, leucine and isoleucine and total BCAA (standard deviation of the sum of Z-scores for each BCAA) with incident hip fractures and bone mineral density (BMD) of the hip and lumbar spine in older African American and Caucasian men and women in the Cardiovascular Health Study (CHS).

DESIGN: Longitudinal analyses of association of plasma levels of BCAA with incident hip fractures and cross-sectional BMD of the hip and lumbar spine from the CHS.

SETTING: Community.

PARTICIPANTS: 1850 men (38\% of cohort) and women; mean age 73.

MAIN OUTCOME MEASURES: Incident hip fractures and cross-sectional BMD of the total hip, femoral neck and lumbar spine.

RESULTS: In fully adjusted models, over 12 years of follow-up, we observed no significant association between incident hip fracture and plasma values of valine, leucine, isoleucine or total BCAA per 1 standard deviation higher of each BCAA. Plasma values of leucine but not valine, isoleucine or total BCAA, were positively and significantly associated with BMD of the total hip (p = 0.03) and femoral neck (p = 0.02), but not the lumbar spine (p = 0.07).

CONCLUSIONS: Plasma levels of the BCAA leucine may be associated with higher BMD in older men and women. However, given lack of a significant association with hip fracture risk, further information is needed to determine whether BCAAs would be novel targets for osteoporosis therapies.

}, issn = {1945-7197}, doi = {10.1210/clinem/dgad275}, author = {Carbone, Laura and B{\r u}zkov{\'a}, Petra and Fink, Howard A and Robbins, John A and Barzilay, Joshua I and Elam, Rachel E and Isales, Carlos and Connelly, Margery A and Mukamal, Kenneth J} } @article {9850, title = {Circulating Ketone Bodies, Pyruvate, and Citrate and Risk of Cognitive Decline, Structural Brain Abnormalities, and Dementia.}, journal = {Aging Dis}, year = {2024}, month = {2024 Nov 08}, abstract = {

The relationship between key energy metabolites and brain health is not well understood. We investigated the association between circulating ketone bodies, pyruvate, and citrate with cognitive decline, structural brain characteristics, and risk of dementia. We measured ketone bodies (acetoacetate, β-hydroxybutyrate, and acetone), pyruvate, and citrate species using NMR in plasma samples from 1,850 older adults in the Cardiovascular Health Study collected in 1989-90 or 1992-93. Cognitive decline was assessed using the modified Mini-Mental State Examination and the Digit Symbol Substitution Test. Dementia was adjudicated by a committee of experts through comprehensive evaluations including cognitive tests, medical records, and interviews with the next of kin. Dementia-related mortality was confirmed by a committee using death certificates and other clinical data from hospitalization. Multivariable linear mixed models were used to assess 9-year cognitive decline, while multivariable Cox regression models evaluated 6-year dementia incidence and 22-year dementia-related mortality. White matter lesions and ventricular size were measured using MRI in 1992-94 and were analyzed using multivariable linear regression models. Higher plasma levels of ketones, particularly β-hydroxybutyrate, were associated with faster cognitive decline (β, -0.10; 95\% CI, -0.15 to -0.05; P\&;lt.001) and dementia-related mortality (HR per SD, 1.29; 95\% CI, 1.07 to 1.56; P=0.023). Higher pyruvate concentrations were associated with slower cognitive decline, smaller ventricular size, lower dementia risk (HR per SD, 0.87; 95\% CI, 0.77 to 0.97; P=0.013; P=0.073), and lower dementia mortality. Higher citrate levels were associated with less cognitive decline and lower dementia risk. In adults aged 65 years and older, circulating ketone bodies are associated with faster cognitive decline and higher dementia mortality, while pyruvate and citrate are associated with lower dementia risk.

}, issn = {2152-5250}, doi = {10.14336/AD.2024.0754}, author = {Gutierrez-Tordera, Laia and Moseholm, Kristine F and Trius-Soler, Marta and Bull{\'o}, M{\`o}nica and Fitzpatrick, Annette and Connelly, Margery A and Lopez, Oscar L and Jensen, Majken K and Guasch-Ferr{\'e}, Marta and Mukamal, Kenneth J} }