YI 1.4 Increases in Circulating Trimethylamine-N-Oxide Contribute to the Development of Age-Related Aortic Stiffness in Humans and Mice

Abstract

Age-related increases in aortic stiffness, assessed by pulse wave velocity (PWV), predict cardiovascular (CV)-related mortality, but the upstream drivers are incompletely understood.

Purpose

To determine if higher circulating levels of the gut microbiome-derived metabolite trimethylamine-N-oxide (TMAO) contribute to age-related aortic stiffening.

Methods and Results

Plasma TMAO concentrations were higher in healthy middle-aged-to-older (45–79 y; N = 83) vs. young (18–27 y; N = 14) humans (6.3 ± 0.6 vs. 1.8 ± 0.3 μM; p < 0.01) and positively related to carotid-femoral (c-f) PWV (r² = 0.15, p < 0.0001). To determine the role of TMAO in established age-related aortic stiffness, we supplemented old mice (27 mo; N = 12–16/group) with 1% 3,3-dimethyl-1-butanol (DMB; suppresses microbiota-dependent TMAO production) in drinking water for 8–10 weeks vs. normal drinking water (control). Relative to young mice (3 mo; N = 23), old mice had higher aortic (a) PWV (412 ± 17 vs. 349 ± 11 cm/s; p < 0.01), but DMB had no effect on aPWV (p = 0.58 vs. control) despite suppressing plasma TMAO (control: 8.7 ± 6.3 vs. DMB: 4.3 ± 1.2 µM, p = 0.07) to young levels (3.8 ± 2.6 µM). Next, to determine if TMAO contributes to the development of aortic stiffening, we initiated DMB at mid-life (18 mo; i.e., before the onset of stiffening; N = 8–21/age/treatment). aPWV was similar between young and 18 month-old mice (363 ± 5 cm/s; p = 0.58), but increased progressively with age in control mice (24 mo: 401 ± 13 cm/s, p = 0.03 vs. young; 27 mo: 442 ± 10 cm/s, p < 0.001 vs. young), whereas age-related increases in PWV were considerably attenuated by DMB (24 mo: 359 ± 9 cm/s; 27 mo: 388 ± 10 cm/s, both p < 0.01 vs. control).

Conclusions

Age-related increases in TMAO contribute to the development of aortic stiffness. TMAO-targeted interventions initiated in mid-life may prevent/delay age-related aortic stiffening and reduce CV risk.

Funding

HL134887-02S1, AG060884, HL140875, AG000279.