Vascular Health and Longevity: How Arterial Aging Determines Healthspan

The endothelium — the single-cell layer lining every blood vessel in the body — covers an area of approximately 5,000 square meters if unrolled. It regulates vascular tone, coagulation, inflammation, immune surveillance, and angiogenesis through a biochemical signaling language so sophisticated that its discoverers, Robert Furchgott, Louis Ignarro, and Ferid Murad, received the Nobel Prize in Physiology or Medicine in 1998 for identifying its primary messenger: nitric oxide (NO). When the endothelium is healthy, NO is continuously produced, arteries dilate in response to demand, platelets don’t adhere inappropriately, and leukocytes don’t transmigrate through vessel walls without cause. When the endothelium fails — as it does progressively with age, poor diet, sedentary behavior, hyperglycemia, and hypertension — the entire vascular tree begins a slow deterioration that ends, decades later, in heart attack, stroke, peripheral arterial disease, and kidney failure.

As a podiatric surgeon, I encounter the downstream consequences of vascular aging at its most dramatic endpoint: patients with diabetes and peripheral arterial disease whose feet have lost the blood supply needed to heal wounds, fight infections, or survive surgery. The ankle-brachial index (ABI) I calculate at every new patient visit is a vascular aging readout — and an ABI below 0.9 identifies peripheral arterial disease that doubles all-cause mortality risk and predicts major cardiovascular events. Understanding vascular aging biology is not academic cardiology for a podiatric practice; it is the mechanistic foundation of everything that determines whether a diabetic foot wound heals or progresses to amputation.

Endothelial Dysfunction: The Earliest Sign of Vascular Aging

Before any atherosclerotic plaque is detectable on imaging, before any symptom of cardiovascular disease is present, the endothelium is already malfunctioning in a measurable way. Endothelial dysfunction — the failure of the endothelium to produce adequate nitric oxide and to dilate in response to physiological stimuli — is detectable by flow-mediated dilation (FMD) of the brachial artery: a non-invasive ultrasound technique that measures the percentage vasodilation response to forearm ischemia-reperfusion. Healthy young adults show 8–12% FMD response; patients with established cardiovascular disease show 2–4%. Population studies demonstrate that FMD predicts future cardiovascular events independently of traditional risk factors — a 1% reduction in FMD corresponds to a 12–13% increase in cardiovascular event risk (Inaba et al., 2010, JACC).

Endothelial dysfunction is measurable by age 30–35 in individuals with metabolic risk factors, and in average Western adults by the mid-40s without overt disease. A 2004 study of 2,792 adults without cardiovascular disease in the Framingham Heart Study showed that FMD correlated inversely with age, blood pressure, BMI, fasting glucose, and smoking, and that cardiovascular risk factor burden was associated with a 25–40% impairment in endothelial-dependent dilation. The Nurses’ Health Study cohort data suggest that approximately 50% of “healthy” middle-aged Americans already have measurable endothelial dysfunction by this metric — making it a prevalent, under-recognized, and modifiable early marker of vascular aging.

Mechanisms of Endothelial Dysfunction with Aging

Four converging mechanisms drive endothelial dysfunction with aging. First, eNOS uncoupling: endothelial nitric oxide synthase (eNOS) requires the cofactor tetrahydrobiopterin (BH4) to couple electron transfer from NADPH to L-arginine for NO production. Oxidative stress depletes BH4, causing eNOS to become uncoupled — instead of producing NO, the uncoupled enzyme produces superoxide (O₂·⁻), which reacts with remaining NO to form peroxynitrite (ONOO⁻). The net result: less NO available for vasodilation, more oxidative stress, and a pro-thrombotic surface. Second, ADMA accumulation: asymmetric dimethylarginine (ADMA), an endogenous eNOS inhibitor generated by protein methylation and degraded by DDAH enzymes, accumulates with age, insulin resistance, and kidney disease — competitively inhibiting L-arginine binding to eNOS and reducing NO production. Third, reduced shear stress: sedentary behavior reduces pulsatile blood flow through peripheral vessels, removing the primary physiological stimulus for eNOS activation (Akt-mediated eNOS Ser1177 phosphorylation) — effectively putting the NO production apparatus into standby mode. Fourth, epigenetic silencing: as described in the epigenetics post, aging methylation changes accumulate at the eNOS gene promoter, reducing baseline transcription of eNOS protein.

Nitric Oxide Biology: eNOS, L-Arginine, ADMA, and the Nitrate-Nitrite Pathway

Nitric oxide is the most important vasodilator molecule in the body. Produced by eNOS in endothelial cells in response to shear stress, acetylcholine, bradykinin, and mechanical stimulation, NO diffuses into underlying smooth muscle cells, activates soluble guanylyl cyclase, increases cyclic GMP (cGMP), and activates protein kinase G — causing dephosphorylation of myosin light chains and smooth muscle relaxation. The result: vasodilation proportional to metabolic demand. Beyond vasoregulation, NO inhibits platelet aggregation (anti-thrombotic), inhibits leukocyte adhesion to the endothelial surface (anti-inflammatory), prevents smooth muscle cell proliferation (anti-atherogenic), and maintains the non-adhesive, anti-oxidant character of the endothelial glycocalyx.

The L-Arginine/L-Citrulline Cycle and ADMA Competition

L-arginine is the substrate for eNOS — its availability in endothelial cells is a rate-limiting determinant of NO production. However, supplementing L-arginine directly has shown inconsistent results in clinical trials (the “arginine paradox” — plasma arginine is adequate in most people, and eNOS operates near saturation under normal conditions). The more effective substrate supplementation strategy is L-citrulline, which is converted to L-arginine in the kidney via the urea cycle, bypassing intestinal first-pass catabolism and providing more sustained elevation of intracellular arginine than direct L-arginine supplementation. A 2010 randomized trial by Ochiai et al. in British Journal of Nutrition showed that 8 weeks of L-citrulline supplementation (5.6 g/day) improved brachial artery FMD by 1.4% and reduced arterial stiffness (PWV) by 6% in middle-aged adults with prehypertension — effects that L-arginine supplementation at equivalent doses failed to produce.

ADMA is the primary endogenous antagonist of eNOS. Plasma ADMA concentrations in the 0.4–0.5 μmol/L range seen in healthy adults rise to 0.7–1.2 μmol/L in patients with chronic kidney disease, type 2 diabetes, hypertension, hyperlipidemia, and heart failure. A meta-analysis of 13 prospective studies found that each 0.1 μmol/L increment in plasma ADMA was associated with a 22% increase in major cardiovascular events (Willeit et al., 2015, JACC). ADMA is degraded by the enzyme DDAH (dimethylarginine dimethylaminohydrolase), which is inhibited by oxidative stress — creating a vicious cycle: oxidative stress → DDAH inhibition → ADMA accumulation → eNOS inhibition → less NO → more oxidative stress.

Dietary Nitrates: The Vegetable-Based NO Pathway

A second, eNOS-independent pathway for NO production was discovered in the 2000s: the nitrate-nitrite-NO pathway. Dietary inorganic nitrate (NO₃⁻) abundant in leafy green vegetables (arugula: 480 mg/100g, beet greens: 320 mg/100g, spinach: 290 mg/100g, beets: 110 mg/100g) is absorbed in the small intestine, concentrated in saliva by salivary glands, and then converted by oral bacteria (primarily Rothia and Actinomyces species) to nitrite (NO₂⁻). Swallowed nitrite is then reduced to NO by tissue nitrite reductases in conditions of low oxygen and low pH — precisely the conditions of ischemic or exercising tissue.

The landmark clinical trial was a 2008 study by Webb and colleagues in Hypertension demonstrating that a single 500 mL glass of beet juice (containing ~400 mg nitrate) reduced systolic blood pressure by 10.4 mmHg and improved FMD by 20% within 2–3 hours. A 2013 randomized crossover trial published in Journal of the American College of Cardiology by Lansley et al. showed that dietary nitrate supplementation reduced the O₂ cost of submaximal exercise by 19%, extended time to exhaustion by 16%, and — critically — improved peripheral muscle efficiency even during ischemic conditions, suggesting particular benefit for patients with compromised vascular supply to exercising tissue.

Arterial Stiffness and Pulse Wave Velocity: The Silent Aging Clock

Arterial stiffness — the loss of the elastic compliance that allows arteries to buffer the pulsatile pressure wave of each heartbeat — is arguably the most important age-related vascular change for overall cardiovascular mortality risk. As arteries stiffen with age, the reflected pressure wave from the periphery arrives back at the aorta during systole rather than diastole: instead of augmenting diastolic coronary perfusion, the reflected wave increases cardiac afterload, elevates systolic blood pressure, and reduces coronary blood flow — creating a double hit on cardiac function with every heartbeat. Arterial stiffness also transmits the full pulsatile pressure wave into the microcirculation of organs like the brain and kidney that are designed for steady laminar flow, causing microvascular damage that underlies white matter hyperintensities, cognitive decline, and glomerulosclerosis.

Pulse wave velocity (PWV) — the speed at which the arterial pressure wave travels from the carotid to the femoral artery — is the clinical gold standard for measuring arterial stiffness. Normal carotid-femoral PWV in young adults is 5–7 m/s. In healthy 60-year-olds it is 8–10 m/s; in patients with established cardiovascular disease it reaches 12–15 m/s. A landmark meta-analysis of 17,635 subjects in 12 studies by Vlachopoulos et al. (2010, JACC) demonstrated that each 1 m/s increase in aortic PWV was associated with a 14% increase in total cardiovascular events, 15% increase in cardiovascular mortality, and 15% increase in all-cause mortality — effects independent of and additive to conventional risk factors. PWV predicts mortality better than blood pressure measurement alone and provides independent prognostic information in diabetes, chronic kidney disease, and heart failure.

Mechanisms of Arterial Stiffening

Arterial stiffness is driven by two primary structural changes in the medial layer. First, elastin fiber degradation: elastin — the protein that gives arteries their elastic recoil — has a half-life of approximately 70 years and is essentially non-renewable in adult tissues. Progressive fragmentation by matrix metalloproteinases and elastases over decades results in irreversible loss of elastic compliance. Second, collagen cross-linking: as described in the glycation and AGE (advanced glycation end-product) literature, glucose-derived Maillard reaction products form irreversible cross-links between collagen fibers, stiffening the collagen scaffolding that remains after elastin degradation. RAGE (receptor for AGE) activation in arterial smooth muscle cells and endothelial cells also drives inflammatory gene expression via NF-κB, exacerbating medial calcification and smooth muscle stiffening.

Critically, arterial stiffness is not purely structural — a significant component is functionally reversible. The smooth muscle tone contribution to large artery stiffness is significant, and interventions that reduce smooth muscle contraction (dietary nitrates, exercise, renin-angiotensin-aldosterone system blockade) can measurably reduce PWV even in older adults. A 2020 meta-analysis of 24 exercise RCTs (n = 849) showed that aerobic exercise training reduced aortic PWV by a mean of 0.54 m/s — a clinically meaningful reduction equivalent to reversing approximately 3–5 years of age-related stiffening. The magnitude of benefit was greater in interventions using higher-intensity exercise and longer duration (≥12 weeks).

Lipid Biology: LDL Particle Size, Oxidized LDL, and the Lp(a) Risk Factor

Conventional lipid panels measure LDL-cholesterol (LDL-C) — the total cholesterol mass carried by LDL particles. But cardiovascular risk correlates more precisely with LDL particle number (LDL-P) and particle size than with LDL-C mass, a discordance that becomes clinically significant in insulin-resistant and metabolic syndrome patients. Individuals with insulin resistance characteristically produce small, dense LDL particles (sdLDL, pattern B) that are more numerous per unit cholesterol, more susceptible to oxidative modification, more easily trapped in the subendothelial space, and more likely to trigger foam cell formation — all steps in early atherogenesis.

Oxidized LDL (ox-LDL) is the atherogenic form: when sdLDL particles are trapped beneath the endothelium and exposed to the oxidative environment of the vessel wall, their phospholipids are oxidized by myeloperoxidase, 15-lipoxygenase, and superoxide. Ox-LDL is recognized by scavenger receptors on macrophages (SR-A, CD36), which unlike the LDL receptor are not subject to downregulation — macrophages consume ox-LDL continuously until they become lipid-laden foam cells, the cellular building block of the atherosclerotic plaque. Circulating ox-LDL measured by ELISA correlates with carotid intima-media thickness, coronary artery calcium score, and near-term cardiovascular event risk better than standard LDL-C in several cohort studies.

Lp(a): The Underrecognized Genetic Cardiovascular Risk Factor

Lipoprotein(a) — Lp(a) — is an LDL-like particle with an additional apolipoprotein(a) protein covalently linked to apolipoprotein B via a disulfide bond. Lp(a) is genetically determined, with plasma levels set by the LPA gene and not significantly modifiable by diet, exercise, or statins. Approximately 20% of the population carries genetic variants associated with Lp(a) above 50 mg/dL, the threshold associated with markedly elevated cardiovascular risk; Lp(a) above 100 mg/dL confers risk equivalent to familial hypercholesterolemia. Lp(a) contributes to atherosclerosis through three mechanisms: it is more readily oxidized than LDL, its apolipoprotein(a) domain inhibits plasminogen and promotes thrombosis, and it promotes aortic valve calcification through phospholipid-driven inflammation.

Lp(a) has historically been untreatable — but two RNA-targeted approaches are approaching clinical approval. Inclisiran (siRNA targeting PCSK9) reduces LDL-C without affecting Lp(a), but the RNA therapeutic Olpasiran (siRNA targeting apolipoprotein(a) in the liver) reduced Lp(a) by 90–97% in Phase 2 trials (O’Donoghue et al., 2022, NEJM), with Phase 3 cardiovascular outcomes trials ongoing. Pelacarsen, an antisense oligonucleotide, similarly reduces Lp(a) by 80% in the Phase 3 Lp(a) HORIZON trial. These RNA therapeutics represent the first pharmacological agents capable of addressing Lp(a)-driven cardiovascular risk, a major advance for the substantial minority of the population with genetic elevation.

Mediterranean Diet and PREDIMED: The Gold-Standard Diet-Vascular Evidence

The PREDIMED (Prevención con Dieta Mediterránea) trial is the most rigorous dietary intervention study for cardiovascular outcomes ever conducted. The multicenter Spanish RCT randomized 7,447 adults aged 55–80 at high cardiovascular risk to three diets: Mediterranean diet supplemented with extra-virgin olive oil (EVOO, ~50g/day), Mediterranean diet supplemented with mixed nuts (30g/day), or a control low-fat diet. After a median follow-up of 4.8 years, the trial was stopped early because both Mediterranean diet groups showed dramatically lower primary endpoint rates — the olive oil group had a 30% relative risk reduction in major cardiovascular events (myocardial infarction, stroke, cardiovascular death), and the nut group showed a 28% reduction, compared to low-fat controls (Estruch et al., 2018, NEJM, corrected reanalysis).

The PREDIMED Plus extension (n = 6,874) examined a hypocaloric Mediterranean diet with physical activity in adults with metabolic syndrome, showing significant reductions in body weight, waist circumference, glycated hemoglobin, blood pressure, and triglycerides — with the cardiovascular event data still pending but biomarker improvements suggesting superior outcomes to the original PREDIMED protocol. These are not small effects from a marginal dietary tweak; a 30% relative reduction in cardiovascular events from a dietary pattern is comparable to moderate-intensity statin therapy without the drug costs, side effect profile, or compliance challenges.

Mechanisms: How Mediterranean Diet Protects the Vasculature

The vascular protection of the Mediterranean diet operates through multiple simultaneous mechanisms. Extra-virgin olive oil’s oleocanthal inhibits COX-1 and COX-2 with ibuprofen-like potency at culinary doses; oleuropein from olive leaves activates Nrf2-driven antioxidant defense and inhibits VCAM-1 expression on endothelium; oleic acid (C18:1) replaces saturated fatty acids in membrane phospholipids, reducing LDL oxidizability. The high omega-3 content from fatty fish (EPA/DHA) reduces platelet aggregation, triglycerides, and VLDL synthesis while increasing SPM (specialized pro-resolving mediator) production for inflammation resolution — as detailed in the omega-3 post. Polyphenols from red wine (resveratrol, quercetin, anthocyanins), tomatoes (lycopene), and dark leafy vegetables (lutein, zeaxanthin) activate Nrf2, SIRT1, and AMPK through xenohormetic mechanisms. The cumulative effect across multiple vascular mechanisms is measurably superior to any single-nutrient intervention.

Beyond PREDIMED, a 2023 systematic review and meta-analysis of 56 RCTs (n = 4,002) in Advances in Nutrition found that Mediterranean diet adherence reduced flow-mediated dilation impairment by 1.97% (95% CI: 1.08–2.86%), reduced carotid intima-media thickness by 0.04 mm, reduced systolic blood pressure by 2.35 mmHg, and reduced high-sensitivity CRP by 0.58 mg/L — measurable improvements in four distinct vascular aging markers simultaneously from dietary pattern rather than pharmaceutical intervention.

Exercise as Vascular Medicine: HIIT, VO2max, and Shear Stress Physiology

Exercise is the most potent lifestyle intervention for reversing endothelial dysfunction and improving vascular aging markers. The mechanism is elegantly direct: physical activity increases cardiac output and peripheral blood flow, generating pulsatile shear stress on the endothelial surface. Shear stress activates mechano-sensing ion channels (Piezo1, TRPV4) on endothelial cells, leading to Akt phosphorylation of eNOS at Ser1177, maximizing NO production. The acute NO surge from each exercise session drives vasodilation and anti-platelet effects during and immediately after exercise; the chronic adaptation to regular training is upregulation of eNOS protein expression and optimized BH4 cofactor availability — a more capable NO production system at rest.

VO2max — maximum aerobic capacity — is arguably the single strongest predictor of all-cause mortality in the medical literature. A 2018 analysis from the Cleveland Clinic of 122,007 patients who underwent treadmill exercise testing (published in JAMA Network Open by Mandsager et al.) found that the mortality hazard ratios across fitness quintiles were larger than those for smoking, hypertension, diabetes, or end-stage renal disease. The lowest VO2max quintile had a hazard ratio for all-cause mortality of 5.04 versus the highest (Elite fitness), compared to 3.12 for smoking — making extreme low fitness more lethal than smoking in this cohort. Each 1 MET (metabolic equivalent) increase in exercise capacity was associated with a 13% reduction in all-cause mortality risk.

High-Intensity Interval Training for Vascular Rejuvenation

High-intensity interval training (HIIT) produces superior vascular adaptations compared to moderate-intensity continuous training (MICT) at equivalent time commitment — a finding with significant implications for time-limited patients. A 2017 meta-analysis by Ramos and colleagues in British Journal of Sports Medicine of 14 RCTs found that HIIT improved FMD by 4.31% versus 2.15% for MICT (p=0.003 for superiority), improved VO2max by 5.5 mL/kg/min versus 3.0 mL/kg/min, and reduced resting systolic blood pressure by 4.6 vs 2.1 mmHg. The mechanistic advantage of HIIT for vascular adaptation is the higher peak shear stress generated during high-intensity intervals, producing stronger eNOS activation signals than moderate steady-state exercise.

The Ulbricht protocol (Norwegian 4×4 HIIT: 4 intervals of 4 minutes at 85–95% maximum heart rate with 3-minute active recovery) has produced the largest documented VO2max improvements in clinical populations — 7.2 mL/kg/min over 12 weeks in cardiac rehabilitation patients, compared to 3.4 mL/kg/min for MICT at equivalent duration (Wisloff et al., 2007, Circulation). Critically, this protocol was tested in patients with coronary artery disease and heart failure — conditions historically considered contraindications to high-intensity exercise — and proved safe when appropriately supervised, with superior vascular outcomes to guideline-standard moderate exercise.

Clinical Connection: PAD, ABI, Wound Healing, and the Vascular-Podiatric Interface

Peripheral arterial disease (PAD) — atherosclerotic narrowing of the infrainguinal arteries supplying the lower extremities — is the podiatric manifestation of systemic vascular aging. PAD affects approximately 8.5 million Americans over age 40, with prevalence rising to 15–25% in those over 70. In my practice, PAD is not an abstract risk category; it is the factor that determines whether a wound can heal after debridement, whether a surgical site can close, and whether a patient faces ulceration, infection, and ultimately amputation. The U.S. performs over 150,000 lower extremity amputations annually, the majority in patients with diabetes and PAD — a largely preventable catastrophe rooted in decades of untreated vascular aging.

The Ankle-Brachial Index: Vascular Aging at the Bedside

The ABI is calculated by dividing the highest systolic blood pressure at the ankle (dorsalis pedis or posterior tibial artery, measured with a hand-held Doppler) by the brachial systolic pressure. Normal ABI is 1.0–1.4; values below 0.9 indicate PAD with high sensitivity (79%) and specificity (96%) for angiographic stenosis ≥50%. An ABI below 0.5 indicates severe PAD with critical limb ischemia — the threshold below which wound healing is severely compromised without revascularization. Falsely elevated ABI (>1.4) occurs in diabetes and CKD due to medial arterial calcification and non-compressible vessels, requiring toe-brachial index (TBI) as the alternative measure (TBI <0.70 = PAD in calcified vessels).

In population studies, low ABI is as powerful a predictor of cardiovascular mortality as a prior heart attack. The ABI Collaboration meta-analysis (2008, JAMA) of 15 cohorts (48,294 participants) found that an ABI of 0.90 or below doubled 10-year cardiovascular mortality risk after adjustment for Framingham risk score, adding prognostic information equivalent to a history of prior MI. This means every patient with PAD detectable by ABI measurement has the same cardiovascular mortality risk as a post-MI patient — yet PAD is dramatically under-screened and under-treated compared to coronary artery disease.

Supervised Exercise Therapy for PAD: Vascular Hormesis at the Clinical Level

Supervised exercise therapy (SET) for PAD — a structured walking program that takes patients to claudication pain, rests, and repeats — is the most evidence-based non-surgical intervention for improving walking distance and quality of life in PAD. A 2018 Cochrane review of 32 RCTs (n = 1,835) found that SET improved maximum walking distance by 163 meters and pain-free walking distance by 82 meters over 3–12 months — effects comparable to or exceeding those of endovascular revascularization in non-limb-threatening claudication, without procedural risk. The mechanism is vascular hormesis: controlled ischemia-reperfusion during walking generates angiogenic signals (VEGF, HIF-1α) that promote collateral vessel formation, improve endothelial function in patent vessels, optimize oxygen extraction by skeletal muscle, and recruit inflammatory repair processes that remodel the ischemic tissue microenvironment. The pain of claudication is the hormetic signal; avoiding it prevents adaptation.

Frequently Asked Questions About Vascular Health and Longevity

The Bottom Line

Vascular aging is the master chronological variable in human healthspan — not because cardiovascular disease is simply common, but because every other organ system’s aging trajectory is constrained by the quality of its blood supply. The brain that degenerates, the kidney that fails, the peripheral nerve that demyelinates, the wound that won’t heal — all share the upstream determinant of endothelial dysfunction and arterial stiffening that begins decades before clinical disease.

The science is unambiguous about the reversal strategies: HIIT-driven VO2max improvement provides the largest single longevity benefit in the clinical literature; Mediterranean diet adherence reduces cardiovascular events by 30% in high-risk populations — comparable to pharmacotherapy; dietary nitrates from green leafy vegetables restore the eNOS-NO axis that underlies endothelial youth; and addressing the advanced risk factors (ApoB, Lp(a), ox-LDL, ABI) before symptomatic disease provides the most opportunity for intervention. In podiatric practice, vascular optimization is wound care — and in longevity medicine, it is the foundation on which every other healthspan intervention either succeeds or fails.

Sources & Further Reading

• Estruch R, Ros E, Salas-Salvadó J, et al. Primary prevention of cardiovascular disease with a Mediterranean diet supplemented with extra-virgin olive oil or nuts. New England Journal of Medicine. 2018;378(25):e34.
• Vlachopoulos C, Aznaouridis K, Stefanadis C. Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a systematic review and meta-analysis. Journal of the American College of Cardiology. 2010;55(13):1318-1327.
• Inaba Y, Chen JA, Bergmann SR. Prediction of future cardiovascular outcomes by flow-mediated vasodilatation of brachial artery: a meta-analysis. International Journal of Cardiovascular Imaging. 2010;26(6):631-640.
• Mandsager K, Harb S, Cremer P, et al. Association of cardiorespiratory fitness with long-term mortality among adults undergoing exercise treadmill testing. JAMA Network Open. 2018;1(6):e183605.
• Ramos JS, Dalleck LC, Tjonna AE, Beetham KS, Coombes JS. The impact of high-intensity interval training versus moderate-intensity continuous training on vascular function: a systematic review and meta-analysis. Sports Medicine. 2015;45(5):679-692.
• Webb AJ, Patel N, Loukogeorgakis S, et al. Acute blood pressure lowering, vasoprotective, and antiplatelet properties of dietary nitrate via bioconversion to nitrite. Hypertension. 2008;51(3):784-790.
• O’Donoghue ML, Rosenson RS, Gencer B, et al. Small interfering RNA to reduce lipoprotein(a) in cardiovascular disease. New England Journal of Medicine. 2022;387(20):1855-1864.
• Willeit P, Freitag DF, Laukkanen JA, et al. Asymmetric dimethylarginine and cardiovascular risk: systematic review and meta-analysis of 22 prospective studies. Journal of the American Heart Association. 2015;4(6):e001833.
• ABI Collaboration. Ankle brachial index combined with Framingham Risk Score to predict cardiovascular events and mortality. JAMA. 2008;300(2):197-208.
• Patel MR, Conte MS, Cutlip DE, et al. Evaluation and treatment of patients with lower extremity peripheral artery disease. Circulation. 2015;132(22):2110-2126.
• Wisloff U, Støylen A, Loennechen JP, et al. Superior cardiovascular effect of aerobic interval training versus moderate continuous training in heart failure patients. Circulation. 2007;115(24):3086-3094.

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