BACKGROUND:Recent studies suggest curcumin is a promising nutraceutical for improving important clinical and physiological markers of healthy aging, including motor and cognitive function.OBJECTIVE:To determine if curcumin supplementation improves motor and cognitive function in healthy middle-aged and older adults.METHODS:39 healthy men and postmenopausal women (45–74 yrs) were randomized to 12 weeks of placebo (n = 19) or curcumin supplementation (2000 mg/day Longvida®; n = 20) with motor and cognitive function assessed at week 0 and 12.RESULTS:Using measures of the NIH Toolbox and other standardized tests, there were no changes in muscle strength and rate of torque development, dexterity, fatigability, mobility, endurance, and balance between the placebo and curcumin groups after 12 weeks (all P > 0.05). Additionally, there were no changes after 12 weeks of placebo and curcumin supplementation in measures of fluid cognitive ability, a cognitive domain that declines with age, including processing speed, executive function, working memory, and episodic memory (all P > 0.3). There were marginal changes in language, a measure of crystallized cognitive ability that is stable with age, following the intervention, wherein reading decoding increased 3% in the curcumin group (post: 2428±35 vs. pre: 2357±34, P = 0.003), but was unchanged in the placebo group (post: 2334±39 vs. pre: 2364±40, P = 0.07).CONCLUSIONS:Overall, 12 weeks of curcumin supplementation does not improve motor and cognitive functions in healthy middle-aged and older adults. It is possible that curcumin may enhance these functions in groups with greater baseline impairments than those studied here, including adults greater than 75 years of age and/or patients with clinical disorders.

To determine the efficacy of inorganic nitrite supplementation on endothelial function in humans and mechanisms of action, we performed (1) a randomized, placebo-controlled, parallel-group clinical trial with sodium nitrite (80 mg/day, 12 weeks) in older adults (N=49, 68±1 year) and (2) reverse-translation experiments in young (6 months) and old (27 months) c57BL/6 mice. In the clinical trial, sodium nitrite increased plasma nitrite ( P <0.05) and was well tolerated. Brachial artery flow-mediated dilation (endothelial function) was increased 28% versus baseline after nitrite supplementation ( P <0.05) but unchanged with placebo. Nitrotyrosine, a marker of oxidative stress, was reduced by 45% versus baseline in biopsied endothelial cells after nitrite, but not placebo, treatment. Plasma from nitrite-treated, but not placebo-treated, subjects decreased whole-cell (CellROX) and mitochondria-specific (MitoSOX) reactive oxygen species in cultured human umbilical vein endothelial cells ( P <0.05). Old mice (old [27 months] control, n=9) had ≈30% lower ex vivo carotid artery endothelium-dependent dilation (EDD) versus young mice (young [6 months] control, n=9) due to reduced NO bioavailability ( P <0.05). Nitrite supplementation (drinking water, 50 mg/L, 8 weeks) restored EDD and NO bioavailability in old mice (n=10) to (6 months) control. Mitochondrial reactive oxygen species suppression of EDD was present in old control (increased EDD with a mitochondrial-targeted antioxidant, P <0.05) but not in young control or old mice supplemented with sodium nitrite. A mitochondrial reactive oxygen species inducer (rotenone) further impaired EDD in old control ( P <0.05); young control and old mice supplemented with sodium nitrite were protected. Markers of mitochondrial health were greater in aorta of old mice supplemented with sodium nitrite versus old control ( P <0.05). Inorganic nitrite supplementation improves endothelial function with aging by increasing NO, decreasing mitochondrial reactive oxygen species/oxidative stress, and increasing mitochondrial stress resistance. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02393742.

We previously observed improvements in vascular endothelial function as well as exploratory measures of motor and cognitive function in a pilot study of sodium nitrite supplementation in middle‐aged and older (MA/O) adults. Here, we sought to establish the efficacy of sodium nitrite for improving endothelial function (primary outcome) while also taking advantage of the opportunity to confirm our motor and cognitive function findings in a larger randomized, placebo‐controlled, double‐blind, parallel group study with 12 weeks of sodium nitrite (80 mg/day) vs. placebo in healthy MA/O adults (n = 49, 68±1 yr) with impaired endothelial function (baseline brachial artery flow‐mediated dilation [FMD] <6%). Sodium nitrite increased plasma levels of nitrite acutely (10‐fold, p<0.05 vs placebo) and chronically (p<0.05) and was well‐tolerated over the 12‐week supplementation period. Vascular endothelial function, measured by brachial artery FMD, was increased by 28% vs. baseline (p<0.05) after 12 weeks of supplementation (3.9±1.2 to 5.0±1.8%, p<0.05), but unchanged with placebo (3.8±1.4 to 4.0±1.5%, p>0.05). There were no differences in secondary outcomes of motor or cognitive function assessed with measures of the NIH Toolbox and other standardized tests between the sodium nitrite and placebo group after 12 weeks (all p>0.05). There were no differences in subject characteristics, body composition or circulating markers of inflammation and oxidative stress with sodium nitrite or placebo (all p>0.05). Collectively, these results indicate that sodium nitrite supplementation for 12 weeks improves endothelial function but does not affect motor or cognitive function in healthy, high‐functioning MA/O adults. These findings suggest therapeutic strategies to enhance nitrite levels may hold promise for treating age‐related vascular endothelial dysfunction.Clinicaltrials.gov Identifier: NCT02393742Support or Funding InformationNIH R01 AG013038, K01 DK115524 and NIH/NCATS Colorado CTSA Grant Number UL1 TR002535; American Physiology Society UGREF AwardThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Aging is the primary risk factor for cardiovascular diseases, primarily due to development of vascular endothelial dysfunction. The gut microbiome is a strong influencer of host physiology, but few studies have investigated how gut microbiome composition changes with primary (healthy) aging in humans, or how such changes may influence endothelial function. PURPOSE To: 1) determine changes in gut microbiome composition and their relation to endothelial function in healthy late middle‐aged to older (MA/O) vs. young (Y) adults; and 2) investigate potential mechanisms of this link. METHODS & RESULTS N=14/group (MA/O: 60‐79 yrs; Y: 18‐29 yrs). Data are mean ± SE. Gut microbiome composition was assessed via fecal 16S rRNA sequencing. α‐diversity, phylogenetic diversity within each sample, was higher in MA/O vs Y adults (Faith’s PD: 22.2 ± 1.8 vs 15.5 ± 1.3, P = 0.02). β‐diversity, difference in overall composition between samples, was also altered with aging (PERMANOVA: P < 0.05; unweighted UniFrac). Both α‐diversity (R = ‐0.60, P = 0.04) and β‐diversity (R = ‐0.58, P = 0.04) were inversely related to age‐related impairments in endothelial function, measured by brachial artery flow‐mediated dilation (MA/O: 4.5 ± 0.4 vs Y: 7.9 ± 1.7%, P < 0.05). Potential Mechanisms: In preliminary analyses (unpaired t‐tests), changes in gut microbiome composition were accompanied by altered relative abundance of gram‐negative bacteria (e.g., Bacteroides [MA/O: 33 ± 4% vs Y: 20 ± 4%, P = 0.02]) and Enterobacteriaceae [MA/O: 1.5 ± 0.1% vs Y: 0.4 ± 0.1%, P = 0.02]), which contain pro‐inflammatory lipopolysaccharide (LPS) in their cell walls. Translocation of LPS into systemic circulation is facilitated by increased intestinal permeability, which we found was higher with aging, as measured by a lactulose‐mannitol (L:M) test (1‐hour serum L:M ratio, MA/O: 0.012 ± 0.002 vs Y: 0.007 ± 0.001, P = 0.04). As such, plasma LPS‐binding protein, a readily detectable marker of LPS in peripheral blood, was higher in MA/O vs Y adults (31.3 ± 4.1 vs 17.7 ± 2.0 ng/mL, P = 0.01). Once in circulation, LPS is recognized as a pathogen‐associated molecular pattern and can trigger an inflammatory response. Consistent with this, circulating levels of the pro‐inflammatory markers IL‐6 [MA/O: 1.56 ± 0.29 vs Y: 0.70 ± 0.13 pg/ml, P = 0.01] and CRP [MA/O: 1.65 ± 0.27 vs Y: 0.78 ± 0.11 pg/ml, P = 0.02]) were increased with aging. In biopsied venous endothelial cells from a subset of subjects (n = 4‐8/group), abundance of phosphorylated (i.e., activated) NF□B was higher in MA/O vs Y adults (0.40 ± 0.05 vs 0.31 ± 0.04 ng/ml, P = 0.24), with no difference in total NFkB, indicating potentially increased vascular inflammation. CONCLUSIONS Our findings represent initial evidence in humans that the gut microbiome changes with healthy aging and may be an important mediator of age‐related endothelial dysfunction, possibly via increasing circulating LPS and vascular inflammation.

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