Intervention of L-Arginine in Aging-related Diseases

Aging is a multifactorial, progressive physiological process characterized by reduced cellular proliferation, accumulated oxidative stress, imbalanced inflammatory responses, declined vascular function, and impaired tissue repair capacity. These changes further induce a series of age-related diseases including cardiovascular diseases, neurodegenerative diseases, metabolic syndrome, and osteoporosis. As a semi-essential amino acid in the human body, L-arginine (L-Arg) serves as the sole substrate for endogenous nitric oxide (NO) synthesis and participates in the biosynthesis of bioactive substances such as polyamines and proline. It plays a core role in regulating vasomotor function, inhibiting oxidative stress, alleviating chronic inflammation, and promoting cellular repair. In recent years, numerous basic and clinical studies have confirmed that L-arginine can intervene in the core pathological mechanisms of aging through multiple targets, exerting significant intervention value in various age-related diseases. This article systematically analyzes the core mechanisms of L-arginine in intervening age-related diseases and its research progress in typical age-related disorders.

I. Core Mechanisms of L-Arginine in Intervening Age-Related Diseases

The core pathological features of aging include cellular senescence, a vicious cycle of oxidative stress and inflammation, vascular microcirculation dysfunction, and impaired stem cell function. L-arginine achieves the goal of delaying the aging process and preventing age-related diseases by targeted regulation of these key links.

1. Activating the NO-cGMP Pathway to Ameliorate Age-Related Vascular Function Decline

Vascular function decline, manifested as decreased vascular compliance and elevated peripheral vascular resistance, is a common pathological basis of age-related diseases such as cardiovascular diseases and cognitive decline.

NO, generated from L-arginine under the catalysis of endothelial nitric oxide synthase (eNOS), activates the downstream cyclic guanosine monophosphate (cGMP) pathway, exerting dual effects: first, it relaxes vascular smooth muscle, reduces peripheral vascular resistance, improves blood perfusion of systemic tissues and organs, and alleviates organ function decline caused by ischemia-hypoxia; second, it protects vascular endothelial cells, inhibits endothelial cell apoptosis, promotes the proliferation and differentiation of endothelial progenitor cells, repairs the damaged vascular endothelial barrier, and reduces lipid deposition and atherosclerotic plaque formation.

During the aging process, the body experiences decreased eNOS activity and reduced endogenous L-arginine content, leading to insufficient NO production. Exogenous L-arginine supplementation can restore the NO synthesis capacity of the aging body by increasing substrate concentration, thereby reversing vascular endothelial dysfunction.

2. Inhibiting the Vicious Cycle of Oxidative Stress-Inflammation to Alleviate Age-Related Chronic Low-Grade Inflammation

Chronic low-grade inflammation (*Inflammaging*) is a core feature of aging, characterized by persistently elevated levels of pro-inflammatory factors (e.g., TNF-α, IL-6). It forms a vicious cycle with oxidative stress, accelerating cellular senescence and tissue damage.

L-arginine blocks this cycle through dual mechanisms: first, it directly scavenges reactive oxygen species (ROS). NO reacts with ROS such as superoxide anions to neutralize their toxicity, reducing oxidative damage to cellular DNA and proteins; meanwhile, it promotes the synthesis of endogenous antioxidants including glutathione (GSH) and superoxide dismutase (SOD), enhancing the body’s antioxidant defense capacity. Second, it inhibits inflammatory signaling pathways. L-arginine suppresses the activation of the nuclear factor-κB (NF-κB) pathway, reduces the release of pro-inflammatory factors, and promotes the secretion of anti-inflammatory factors (e.g., IL-10), restoring the homeostatic balance of the immune system.

In addition, polyamines (spermidine, spermine) generated from L-arginine metabolism can activate the cellular autophagy pathway, clear damaged organelles and protein aggregates in senescent cells, alleviate oxidative stress and inflammatory damage, and delay the cellular senescence process.

3. Promoting Stem Cell Proliferation and Differentiation to Enhance Tissue Repair Capacity of the Aging Body

During aging, the proliferation and differentiation capacity of somatic stem cells (e.g., hematopoietic stem cells, mesenchymal stem cells) decreases significantly, leading to impaired tissue repair capacity, which is prone to induce diseases such as osteoporosis, sarcopenia, and delayed wound healing.

L-arginine regulates stem cell function through two pathways: first, polyamine-dependent promotion of stem cell proliferation. Polyamines are key regulators of the stem cell cycle, which can promote the differentiation of mesenchymal stem cells into osteoblasts and myocytes, enhancing the regenerative capacity of bones and muscles; second, NO-mediated stem cell homing. NO improves tissue microcirculation, guides stem cells to migrate to damaged sites, and increases tissue repair efficiency.

Studies have confirmed that L-arginine supplementation can significantly enhance the proliferative activity of bone marrow mesenchymal stem cells in aging mice, promote osteogenic differentiation, inhibit adipogenic differentiation, and alleviate age-related osteoporosis and sarcopenia.

4. Regulating Energy Metabolism to Ameliorate Age-Related Metabolic Disorders

Aging is accompanied by problems such as insulin resistance, abnormal glucose metabolism, and lipid metabolism disorders, which are predisposing factors for diseases such as metabolic syndrome and type 2 diabetes. L-arginine can activate the AMP-activated protein kinase (AMPK) signaling pathway via the NO-cGMP pathway, promote cellular glucose uptake and utilization, improve insulin sensitivity; meanwhile, it inhibits lipid synthesis in adipocytes, promotes fatty acid oxidation and decomposition, reduces blood triglyceride and cholesterol levels, and alleviates age-related metabolic disorders.

II. Research Progress of L-Arginine in Intervening Typical Age-Related Diseases

1. Age-Related Cardiovascular Diseases (Hypertension, Atherosclerosis)

Hypertension and atherosclerosis are the most common cardiovascular diseases in the elderly, with vascular endothelial dysfunction and chronic inflammation as their core pathologies. Basic studies have shown that L-arginine supplementation can significantly increase eNOS activity and NO levels in aging rats, improve vascular endothelial diastolic function, reduce systolic and diastolic blood pressure; meanwhile, it inhibits lipid deposition and inflammatory factor expression in the aortic wall, delaying the formation and progression of atherosclerotic plaques.

Clinical studies have found that daily oral administration of L-arginine (3–5 g) for 12 weeks can significantly improve flow-mediated dilation (FMD) of the brachial artery in elderly hypertensive patients, reduce peripheral vascular resistance, and the incidence of side effects is significantly lower than that of conventional antihypertensive drugs. For elderly patients with atherosclerosis, combined supplementation of L-arginine with folic acid and vitamin B12 can further delay plaque progression and reduce the risk of cardio-cerebrovascular events by synergistically increasing NO levels and lowering homocysteine concentrations.

2. Neurodegenerative Diseases (Alzheimer’s Disease, Parkinson’s Disease)

The pathological features of neurodegenerative diseases include neuronal apoptosis, neuroinflammation, and oxidative stress damage, and cerebral microcirculation dysfunction is an important inducer of disease progression. NO generated from L-arginine can dilate cerebral blood vessels, improve cerebral blood flow, and alleviate neuronal damage caused by cerebral ischemia-hypoxia; meanwhile, by inhibiting the release of neuroinflammatory factors (e.g., IL-1β, TNF-α), it reduces the overactivation of microglia and protects neuronal function.

Animal experiments have confirmed that L-arginine supplementation can significantly reduce β-amyloid deposition in the brain of Alzheimer’s disease model mice, inhibit excessive phosphorylation of tau protein, and improve cognitive function and learning-memory ability of the mice; in Parkinson’s disease models, L-arginine can protect dopaminergic neurons in the substantia nigra through antioxidant and anti-inflammatory effects, alleviating motor dysfunction.

Preliminary clinical studies have shown that L-arginine combined with cholinesterase inhibitors can significantly improve cognitive scores in patients with mild-to-moderate Alzheimer’s disease with good safety.

3. Age-Related Metabolic Syndrome (Type 2 Diabetes, Obesity)

The core pathologies of type 2 diabetes and obesity are insulin resistance and chronic inflammation, which are further exacerbated by aging. Basic studies have found that L-arginine can activate the AMPK pathway, promote glucose uptake in skeletal muscle cells and adipocytes of aging mice, improve insulin sensitivity; meanwhile, it inhibits inflammatory responses in adipose tissue, reduces the secretion of pro-inflammatory factors such as leptin and resistin by adipocytes, and alleviates metabolic disorders.

Clinical studies have indicated that daily oral administration of L-arginine (5 g) for 8 weeks can significantly reduce fasting blood glucose and glycated hemoglobin levels in elderly patients with type 2 diabetes, and increase insulin sensitivity index; for elderly obese patients, combined supplementation of L-arginine with ω-3 polyunsaturated fatty acids can synergistically reduce body fat rate and blood lipid levels, improving metabolic indicators.

4. Osteoporosis and Sarcopenia

Osteoporosis and sarcopenia are important causes of disability in the elderly, both closely related to the imbalance of mesenchymal stem cell differentiation and decreased tissue repair capacity. Polyamines generated from L-arginine metabolism can promote the differentiation of mesenchymal stem cells into osteoblasts, inhibit osteoclast activity, and increase bone mineral density; meanwhile, they promote the proliferation and differentiation of muscle satellite cells, increasing muscle mass and strength.

Animal experiments have shown that L-arginine supplementation can significantly increase femoral bone mineral density in aging rats, reduce trabecular bone spacing, and increase gastrocnemius muscle mass and contractility; clinical studies have found that supplementation of L-arginine (3 g/d) combined with calcium and vitamin D in elderly patients with osteoporosis can significantly increase lumbar spine and hip bone mineral density, reducing fracture risk; for patients with sarcopenia, combined intervention of L-arginine and resistance exercise can more significantly increase muscle strength and improve physical activity ability.

5. Age-Related Skin Damage and Delayed Wound Healing

Skin aging is an external manifestation of body aging, accompanied by collagen loss, microcirculation dysfunction, and weakened barrier function; delayed wound healing in the elderly is related to imbalanced inflammatory responses and decreased fibroblast activity. L-arginine can promote fibroblast proliferation and collagen synthesis, increase skin elasticity, and reduce wrinkle formation; meanwhile, it improves skin microcirculation, enhances tissue oxygen and nutrient supply, and accelerates wound healing.

Clinical studies have shown that topical dressings containing L-arginine can significantly shorten the healing time of chronic ulcers in elderly patients and reduce infection risk; oral L-arginine combined with topical vitamin C can synergistically improve the firmness and hydration of aging skin, delaying the skin aging process.

III. Application Strategies and Precautions of L-Arginine in Intervening Age-Related Diseases

1. Application Strategies

Dosage Selection: For the intervention of age-related diseases, the recommended daily oral dosage of L-arginine is 3–5 g. For chronic diseases (e.g., cardiovascular diseases, diabetes), the dosage can be appropriately increased to 5–10 g, but side effects caused by overdose should be avoided.

Combined Intervention: L-arginine combined with folic acid, B vitamins, ω-3 polyunsaturated fatty acids, etc., can enhance intervention efficacy through synergistic effects. For example, folic acid can enhance eNOS activity, synergistically increasing NO production with L-arginine; ω-3 fatty acids can enhance anti-inflammatory effects, synergistically improving metabolic disorders.

Combination with Lifestyle Intervention: L-arginine supplementation combined with regular exercise (especially resistance exercise), low-salt diet, smoking cessation, and alcohol restriction can more significantly delay the aging process and reduce the risk of age-related diseases.

2. Precautions

Contraindicated Populations: Patients with severe renal insufficiency should use it with caution to avoid increasing renal metabolic burden due to excessive L-arginine; patients with severe pulmonary arterial hypertension are prohibited from using it to prevent hypotension risk caused by excessive NO.

Side Effect Monitoring: Excessive oral L-arginine (＞10 g per day) may induce adverse effects such as gastrointestinal discomfort, headache, and hyperchloremic acidosis. Regular monitoring of blood electrolytes and renal function is required.

Consideration of Individual Differences: The intervention efficacy of L-arginine is affected by gene polymorphisms (e.g., eNOS gene rs1799983 polymorphism). Individuals carrying mutant alleles may require higher dosages or combination with other nutrients to achieve the desired effect.

Through multi-targeted effects including activating the NO-cGMP pathway, inhibiting the vicious cycle of oxidative stress-inflammation, promoting stem cell proliferation and differentiation, and regulating energy metabolism, L-arginine exhibits significant value in the intervention of age-related diseases such as cardiovascular diseases, neurodegenerative diseases, metabolic syndrome, and osteoporosis. As a natural amino acid, it has the advantages of high safety and minimal side effects, making it particularly suitable for long-term intervention in the elderly population.