Moving People to Better Health

The most influential strand of our work began with identifying plasma nitrite flux as a biomarker for exercise-induced vascular adaptation in peripheral artery disease (Allen et al., Free Radical Biology and Medicine, 2010). That led to a randomized trial showing that acute dietary nitrate raised plasma nitrite and prolonged claudication-free walking time (Kenjale et al., Journal of Applied Physiology, 2011) — the first clinical evidence that a non-pharmacological NO precursor could improve a clinically meaningful functional endpoint in any clinical population.

We then showed that chronic nitrate supplementation combined with 12 weeks of exercise rehabilitation improved pain-free and total walking distance beyond exercise alone, the current best treatment (Woessner et al., Circulation Research, 2018). This body of work forms the scientific rationale for two large multi-center clinical trials now underway.

A mechanistic puzzle emerged from our early trials: why did nitrate's vascular effects vary so much between people? We showed that increasing strengths of antibacterial mouthwash produced a stepwise reduction in plasma and salivary nitrite after an oral nitrate load (Woessner et al., Nitric Oxide, 2016) — the clearest evidence to date that oral bacteria are required to convert dietary nitrate into biologically active nitrite.

A collaboration with the Easton laboratory then showed that people carrying more oral nitrate-reducing bacteria produced more salivary nitrite from the same dose (Burleigh et al., Free Radical Biology and Medicine, 2018). Oral-hygiene controls and microbiome characterization are now standard in the field. We continue the line today — recent work found that patients with heart failure have disrupted oral nitrate-reducing capacity (Stahl et al., Am J Physiol Heart Circ Physiol, 2025), and industry and state funding now supports the same question in postmenopausal women, where our pilot data suggest a disrupted oral microbiome.

Many older, frail, and deconditioned patients gain little from traditional exercise training because they can't tolerate the central cardiovascular load. We introduced PRIME — Peripheral Remodeling via Intermittent Muscular Exercise — a low-mass, high-repetition regime that targets muscle groups sequentially while keeping central strain low (Allen et al., Medicine & Science in Sports & Exercise, 2018).

Used as an initial therapeutic step, PRIME produced clinically and statistically superior functional gains versus conventional rehabilitation in adults over 70 at risk of losing independence, with added benefits for vascular health and bone mineral density. A pilot in older heart-failure patients showed feasibility and gains in both fitness and strength (Giuliano et al., J American Geriatrics Society, 2020) — the foundation of our ongoing R01 (AG075556) asking how to deliver effective rehabilitation to the patients least likely to complete it.

Female participants have long been underrepresented in dietary nitrate research. In healthy young adults we found clear sex differences in nitrate's effects on exercise economy and endurance (Ortiz de Zevallos et al., J Applied Physiology, 2023), and showed those responses shift across the menstrual cycle (Hogwood et al., J Applied Physiology, 2023) — with parallel effects on muscular power and fatigue.

The link between estrogen and nitrate responsiveness drew us toward postmenopausal women, in whom the loss of estrogen's vascular protection meets a sharp rise in cardiovascular risk. We've shown that exercise intensity and acute nitrate interact to shape vascular health, and that nitrate attenuates the drop in myocardial perfusion during higher-intensity exercise (Derella et al., Experimental Physiology, 2026). Sex and hormonal status, in short, are central determinants of vascular function — not afterthoughts.