Background: High‐resistance inspiratory muscle strength training (IMST) is a novel, time‐efficient physical training modality. Methods and Results: We performed a double‐blind, randomized, sham‐controlled trial to investigate whether 6 weeks of IMST (30 breaths/day, 6 days/week) improves blood pressure, endothelial function, and arterial stiffness in midlife/older adults (aged 50–79 years) with systolic blood pressure ≥120 mm Hg, while also investigating potential mechanisms and long‐lasting effects. Thirty‐six participants completed high‐resistance IMST (75% maximal inspiratory pressure, n=18) or low‐resistance sham training (15% maximal inspiratory pressure, n=18). IMST was safe, well tolerated, and had excellent adherence (≈95% of training sessions completed). Casual systolic blood pressure decreased from 135±2 mm Hg to 126±3 mm Hg ( P <0.01) with IMST, which was ≈75% sustained 6 weeks after IMST ( P 0.05). Twenty‐four hour systolic blood pressure was lower after IMST versus sham training ( P =0.01). Brachial artery flow‐mediated dilation improved ≈45% with IMST ( P <0.01) but was unchanged with sham training ( P =0.73). Human umbilical vein endothelial cells cultured with subject serum sampled after versus before IMST exhibited increased NO bioavailability, greater endothelial NO synthase activation, and lower reactive oxygen species bioactivity ( P 0.05). Conclusions: High‐resistance IMST is a safe, highly adherable lifestyle intervention for improving blood pressure and endothelial function in midlife/older adults with above‐normal initial systolic blood pressure. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03266510.

Advancing age and many disease states are associated with declines in nicotinamide adenine dinucleotide (NAD ⁺) levels. Preclinical studies suggest that boosting NAD ⁺ abundance with precursor compounds, such as nicotinamide riboside or nicotinamide mononucleotide, has profound effects on physiological function in models of aging and disease. Translation of these compounds for oral supplementation in humans has been increasingly studied within the last ten years; however, the clinical evidence that raising NAD ⁺ concentrations can improve physiological function is unclear. The goal of this review was to synthesize the published literature on the effects of chronic oral supplementation with NAD ⁺ precursors on healthy aging and age-related chronic diseases. We identified nicotinamide riboside, nicotinamide riboside co-administered with pterostilbene, and nicotinamide mononucleotide as the most common candidates in investigations of NAD ⁺-boosting compounds for improving physiological function in humans. Studies have been performed in generally healthy midlife and older adults, adults with cardiometabolic disease risk factors such as overweight and obesity, and numerous patient populations. Supplementation with these compounds is safe, tolerable, and can increase the abundance of NAD ⁺ and related metabolites in multiple tissues. Dosing regimens and study durations vary greatly across interventions, and small sample sizes limit data interpretation of physiological outcomes. Limitations are identified and future research directions are suggested to further our understanding of the potential efficacy of NAD ⁺-boosting compounds for improving physiological function and extending human healthspan.

Midlife/older adults with above-normal blood pressure are at increased risk of developing cognitive decline and dementia. Our findings suggest that high-resistance inspiratory muscle strength training (IMST), a novel, time-efficient (5–10 min/day) form of physical training, may increase cerebrovascular reactivity to CO₂ and episodic memory in midlife/older adults with initial above-normal blood pressure.

This study was designed to determine the optimal intensity for verification phase testing (VP) in healthy, young adults. Thirty one young, active participants (16 females) completed a cycle ergometer graded exercise test (GXT) VO_2max test and 4 VP tests at 80, 90, 100, and 105% of the maximum wattage achieved during the GXT. GXT and VP VO_2max values showed a significant test x sex interaction (p = 0.02). The males elicited significantly higher VO_2max values during the GXT, 80%, and 90% when compared to the 105%, (105 vs. GXT: p = 0.05; 105% vs. 80%: p < 0.01; 105% vs. 90%: p = 0.02). There were no significant differences in VO_2max across the tests in the females (p > 0.05); 80% of the males achieved their highest VP VO_2max during a submaximal VP test compared to only 37.5% of the females. A secondary study conducted showed excellent reliability (ICCs > 0.90) and low variation (CVs < 3%) for the 90% VP. Our findings show that a submaximal verification phase intensity is ideal for young healthy males to elicit the highest VO_2max during cycle ergometer testing. For females, a range of intensities (80–105%) produce similar VO_2max values. However, the 80% VP yields an unnecessarily high time to exhaustion.

Maximal aerobic exercise capacity [maximal oxygen consumption (V̇o_2max)] is one of the strongest predictors of morbidity and mortality. Aerobic exercise training can increase V̇o_2max, but inter-individual variability is marked and unexplained physiologically. The mechanisms underlying this variability have major clinical implications for extending human healthspan. Here, we report a novel transcriptome signature related to ΔV̇o_2max with exercise training detected in whole blood RNA. We used RNA-Seq to characterize transcriptomic signatures of ΔV̇o_2max in healthy women who completed a 16-wk randomized controlled trial comparing supervised, higher versus lower aerobic exercise training volume and intensity (4 training groups, fully crossed). We found significant baseline gene expression differences in subjects who responded to aerobic exercise training with robust versus little/no ΔV̇o_2max, and differentially expressed genes/transcripts were mostly related to inflammatory signaling and mitochondrial function/protein translation. Baseline gene expression signatures associated with robust versus little/no ΔV̇o_2max were also modulated by exercise training in a dose-dependent manner, and they predicted ΔV̇o_2max in this and a separate dataset. Collectively, our data demonstrate the potential utility of using whole blood transcriptomics to study the biology of inter-individual variability in responsiveness to the same exercise training stimulus.