|Lustgarten, Michael - Jean Mayer Human Nutrition Research Center On Aging At Tufts University|
|Fielding, Roger - Jean Mayer Human Nutrition Research Center On Aging At Tufts University|
Submitted to: Experimental Gerontology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/10/2017
Publication Date: 12/15/2017
Citation: Lustgarten, M.S., Fielding, R.A. 2017. Metabolites related to renal function, immune activation, and carbamylation are associated with muscle composition in older adults. Experimental Gerontology. 100:1-10. https://doi.org/10.1016/j.exger.2017.10.003.
DOI: https://doi.org/10.1016/j.exger.2017.10.003 Interpretive Summary: Aged muscle is characterized by an increase in fat, thereby reducing overall muscle composition. Poor muscle composition in older adults is associated with insulin resistance, decreased physical function, and an increased all-cause mortality risk. To elucidate mechanisms that may underlie the maintenance of muscle composition, we analyzed associations between circulating metabolites with a marker of muscle composition and between significant muscle composition metabolites with markers of kidney function and immune activation. Sixty circulating metabolites had a statistically significant association with muscle composition. Of these 60 metabolites, 29 were associated with at least 2 markers of reduced kidney function and with immune activation. As a potential explanation for these findings, we propose the novel hypothesis that the age-related increase in fat within muscle may be a compensatory antimicrobial response to protect against an elevated systemic microbial burden.
Technical Abstract: Reduced skeletal muscle density in older adults is associated with insulin resistance, decreased physical function, and an increased all-cause mortality risk. To elucidate mechanisms that may underlie the maintenance of skeletal muscle density, we conducted a secondary analysis of previously published muscle composition and serum metabolomic data in 73 older adults (average age, 78 y). Multivariable-adjusted linear regression was used to examine associations between 321 metabolites with muscle composition, defined as the ratio between normal density (NDM) with low density (LDM) thigh muscle cross sectional area (NDM/LDM). Sixty metabolites were significantly (p </= 0.05 and q < 0.30) associated with NDM/LDM. Decreased renal function and the immune response have been previously linked with reduced muscle density, but the mechanisms underlying these connections are less clear. Metabolites that were significantly associated with muscle composition were then tested for their association with circulating markers of renal function (blood urea nitrogen, creatinine, uric acid), and with the immune response (neutrophils/lymphocytes) and activation (kynurenine/tryptophan). 43 significant NDM/LDM metabolites (including urea) were co-associated with at least 1 marker of renal function; 23 of these metabolites have been previously identified as uremic solutes. The neutrophil/lymphocyte ratio was significantly associated with NDM/LDM (beta +/- SE: - 0.3 +/- 0.1, p = 0.01, q = 0.04). 35 significant NDM/LDM metabolites were co-associated with immune activation. Carbamylation (defined as homocitrulline/lysine) was identified as a pathway that may link renal function and immune activation with muscle composition, as 29 significant NDM/LDM metabolites were co-associated with homocitrulline/lysine, with at least 2 markers of renal function, and with kynurenine/tryptophan. When considering that elevated urea and uremic metabolites have been linked with an increased systemic microbial burden, that antimicrobial defense can be reduced in the presence of carbamylation, and that adipocytes can promote host defense, we propose the novel hypothesis that the age-related increase in adipogenesis within muscle may be a compensatory antimicrobial response to protect against an elevated microbial burden.