Pleiotropic Effects of French Maritime Pine Bark Extract to Promote Healthy Aging

Abstract

Extension of the healthy life span is of primary importance for the aging society. Among exercise, healthy nutrition, and mental training, food supplements are widely used as preventive measures to postpone the diverse symptoms of aging. The extract from the bark of the French maritime pine, Pycnogenol, rich on flavonoids, has anti-inflammatory and antioxidative property, proven in in vivo studies. The extract reduces oxidative stress and improves endothelial health. Its antithrombotic properties are based on inhibition of platelet aggregation. In double-blind, placebo-controlled clinical studies, Pycnogenol shows diverse positive effects. With respect to cardiovascular symptoms, the extract has an antihypertensive effect, slows down the progression of atherosclerosis, and prevents venous thrombosis. As reported in studies in China and the United States, type 2 diabetes and diabetic retinopathy is improved with Pycnogenol. The extract restores mobility of seniors in case of patients suffering from osteoarthritis, Pycnogenol reduces pain and stiffness and use of analgesics. Furthermore, cognitive functions of elderly people, especially spatial memory, are significantly ameliorated. Climacteric symptoms are significantly alleviated by the pine bark extract. Urinary symptoms of benign prostatic hyperplasia are reduced by Pycnogenol. In combination with L-arginine, Pycnogenol restores erectile function in men with erectile dysfunction. The sum of these positive effects on relevant symptoms of aging suggests using Pycnogenol for a more extended period of healthy aging.

Introduction

Asurvey published 2012 by the New York Times found that American public did not generally opt for an unlimited life span, a majority of 60% preferred to live 80 years. However, under the assumption of continued health, 42% jumped at an unlimited life span.¹ In another survey,² the expectation of sustained mental and physical youthfulness in age was so attractive that 79.7% of responders wished to live until 120 years or longer. These and similar reports reflect the common expectation that aging is strongly associated with diseases and fragility.

Hence for the individual primary goal is not to extend total life span, but to extend healthy life span. This is not only the vital interest of the individual, but also of outstanding importance for health care systems worldwide.

A healthy life span, the number of years lived in good health was, according to World Health Organization,³ 62 years globally versus 71 years as total life span, so 9 healthy years are being missed. The attempts to extend the healthy life span are focused first of all on sports and nutrition. There is no doubt that physical and mental training prolongs a healthy life span. Calorie restriction and no smoking are other successful approaches to live longer and healthier. As for nutrition, the Mediterranean diet has been shown in many studies, reviewed by Martinez-Gonzalez and Martin-Calvo,⁴ to bring many benefits in reducing risk factors for cardiovascular events, cognitive decline, and disability.

Despite these well-known options, there is an ever-growing consumption of food supplements as an easier attempt to stay healthy without running, starving, or cooking unknown dishes.

Among the food supplements, some plant extracts seem to offer more benefits than just vitamins because of the manifold actions attributed to their complex composition. Plant extracts may offer nearly the same wide spectrum of benefits as the Mediterranean diet—as lipid lowering; protection against oxidative stress, inflammation, and platelet activation; and production of metabolites from gut microbiota enhancing endothelial health.

French maritime pine bark extract (Pycnogenol)

One of these plant-derived food supplements, an extract from the bark of the French maritime pine, Pinus pinaster, subsp. Atlantica de Villar, marketed as Pycnogenol^® (Horphag Research, Ltd.) demonstrated in clinical studies a wide range of health-promoting properties.^5

–9

The extract contains concentrate of polyphenols, mainly procyanidins, phenolic acids, catechin, and taxifolin.⁶

This extract is based on promotion of endothelial health and its antioxidative and anti-inflammatory effects.

Endothelial health

Improvement of endothelial health is key to prevention of cardiovascular diseases. The endothelial function is impaired by inflammatory stimuli and oxidative stress^10
–12 and declines gradually with aging.

Pycnogenol demonstrated a range of positive effects on the endothelium by increasing the production of nitric oxide (NO) from endothelial cells. This was shown in ex vivo studies on isolated aortic rings from rats where Pycnogenol induced relaxation, which could be inhibited by the NO-inhibitor N-methyl-L-arginine.¹³ In human volunteers, Pycnogenol improved flow-mediated dilation of the artery; this relaxation was also inhibited in the presence of an inhibitor of the endothelial NO synthase (e-NOS).¹⁴ Apart from the stimulation of e-NOS, Pycnogenol inhibited the release of endothelin-1¹⁵ and enhanced blood levels of prostacycline,¹⁵ thus combining inhibition of vasoconstriction and promotion of vasorelaxation.

Antioxidant effects

In addition to this vasomotoric regulation, Pycnogenol protects the endothelium against oxidative stress and inflammatory agents through several mechanisms. As antioxidative agent, it inactivates reactive oxygen species and other free radicals,¹⁶ thereby increasing plasma antioxidative capacity as shown in studies with seniors, students, athletes, smokers, and women.⁵ The stimulation activity of antioxidative enzymes such as superoxide dismutase and catalase¹⁷ contribute to this increase of antioxidative capacity. Furthermore, important risk factors for cardiovascular health such as C-reactive protein and fibrinogen were inhibited.¹⁸

Anti-inflammatory activity

The anti-inflammatory activity of Pycnogenol is based on several elements. The inhibition of nuclear factor kappa B (NF-κB) plays a central role,¹⁹ downstream in the inflammatory cascade, the cyclooxygenases (COXs) and lipooxygenases (LOXs) were inhibited too.^20,21 Furthermore, Pycnogenol inhibited the inducible NOS, thus preventing the production of deleterious peroxynitrite.^21,22 Gene expression of 5-LOX and COX-2 was inhibited, reducing leukotriene biosynthesis.²¹

Atherosclerosis prevention

The inhibition of adhesion factors²³ by Pycnogenol protects the endothelium against inflammatory stimuli. The inhibition of NF-κB and the Toll-like receptor 4 by Pycnogenol²⁴ contributes to prevention of atherosclerosis, as lipid accumulation in monocytes will be blocked and also the synthesis of the adipose differentiation-related protein and adipocyte lipid-binding protein (ALBP/aP2).²⁴ The inhibition of oxidative stress is important for prevention of atherosclerosis, as the peroxidation of cholesterol is the first step to start foam cell formation. For atherosclerosis prevention, the regulation of the lipid metabolism is also mandatory to prevent deposition of surplus of lipids in the arterial wall. Pycnogenol helps to balance lipid metabolism by increasing high-density lipoprotein cholesterol concentrations and lowering low-density lipoprotein-cholesterol and triglycerides,⁵ thus improving the atherosclerotic index. The combination of normalization of lipids together with inactivation of free radicals is fundamental for blocking the development of atherosclerosis.

A further risk factor for development of atherosclerosis is hypertension. Steady hypertension damages the endothelium, thereby promoting adhesion and invasion of inflammatory cells. Pycnogenol has significant (p < 0.05) antihypertensive properties as has been shown in several clinical studies.^25

–29 The consumption of Pycnogenol reduced the dosage of antihypertensive drugs.^15,26,30 The protection of the endothelial surface by normalizing blood pressure is another contribution of Pycnogenol to atherosclerosis prevention.

Antithrombogenic activity

Atherosclerosis is characterized by the formation of atherosclerotic plaques, starting with the activation of blood platelets. Activated platelets stimulate monocytes to initiate local vascular inflammation.³¹ Pycnogenol interferes with the process of platelet activation, as demonstrated in studies with smokers. Smoking cigarettes activates blood platelets within 30 minutes. Intake of Pycnogenol before smoking inhibited platelet activation to the same extent as aspirin, but with a lower dose,³² and it inhibits thromboxane formation.³³ Thus Pycnogenol intervenes in one of the first steps of atherosclerosis initiation.

Combination of Pycnogenol with an extract from Centella asiatica for atherosclerosis prevention

The manifold actions of Pycnogenol to promote endothelial health and his antithrombotic effects result in inhibition of atherosclerosis. Two clinical studies with >2000 patients compared the progress of formation of plaques for a period of 30 months³⁴ and 42 months³⁵ during consumption of Pycnogenol, aspirin (ASA), ticlopidine and after intake of a combination of Pycnogenol with an extract from Centella asiatica (CA). Both studies demonstrated by ultrasound a slower progression of plaque formation relative to untreated controls. The effect of Pycnogenol was dependent on dose, ASA and ticlopidine were at same doses less effective than Pycnogenol. Best results were obtained in the combination of Pycnogenol with the Centella extract.^34,35

Extracts from Centella asiatica contain triterpenes with antioxidative properties that stimulate synthesis of collagen³⁶ and promote fibroblast proliferation.³⁷

The reduced progression of plaque formation was reflected in a decrease of cardiovascular events.³⁵ The number of subjects experiencing cardiovascular events, as hospital admission or need of special care, was 16% in controls, 8% in Pycnogenol, ASA, or ticlopidine, but only 4% after intake of the combination of Pycnogenol with Centella extract.

To avoid embolism, plaques have to be stabilized by a fibrous cap. The fibrous cap gives rise to a stronger echo of ultrasound, appearing as white structure, lowering the dark plaque. The percentage of the white area to total plaque area was assessed as stability index of plaques.³⁸

In two studies, involving a total of 105 patients, plaque heights and lengths were significantly reduced after intake of a combination of Pycnogenol with a Centella extract (Centellicum^®) for 3 months³⁹ or 6 months.³⁸ The stability index of the plaques was doubled.³⁸

Finally, a long-term study of 391 subjects with stenosing arteriosclerotic plaques (stenosis 50%–60%) documented after 4 years a range of improvements with Pycnogenol and the combination of Pycnogenol with an extract from CA (Bayer AG, Basel).⁴⁰

Size of plaques increased over the study period considerably in controls. After intake of Pycnogenol, the increase was significantly smaller (Table 1). The combination of Pycnogenol with CA was able to reduce the size of the plaques significantly, thus reversing the trend of atherosclerosis progression.

Table 1.

Plaque Progression and Cardiovascular Events at 4 Years^a According to Ultrasound Investigations

Group	Controls	Pycnogenol 100 mg	Centella asiatica +Pycnogenol 100 mg
Participants	128	112	151
Age, mean (SD)	53.4 (2.2)	54.2 (2.1)	54.6 (3.4)
Max. plaque thickness at inclusion (mm)	1.86 (0.1)	1.821 (0.11)	1.824 (0.13)
End study	2.13 (0.12)	1.98 (0.1)^*	1.69 (0.1)^*
Max plaque length at inclusion (mm)	19.2 (0.2)	18.93 (0.13)	19.11 (0.1)
End study	22.31 (0.13)	19.3 (0.1)^*	18.7 (0.11)^*
Echogenicity (gray scale median) (0 = black; 100 = white) at inclusion	24.43 (2.1)	24.42 (2.2)	24.63 (0.9)
End study	25.2 (2)	29.4 (1.4)^*	39.78 (1.8)^*
Events
Angina	8 (6.25%)	3 (2.67%)^*	2 (1.32%)^*
Limited myocardial infarction	6 (4.68%)	2 (1.7%)^*	1 (0.76%)^*
Minor transient ischemic attacks	3 (2.34%)	2 (1.7%)^*	1 (0.6%)^*
Minor strokes	1 (0.78%)	1 (0.89%) ns	0 ns
Vascular disease (claudication)	3 (2.34%)	2 (1.7%) ns	1 (0.6%)^*
Total events	21 (15.4%)	10 (8.9%)^*	5 (3.3%)^*
% events per year in 4 years	4.1%	2.2%^*	0.82%^*

Reference³⁸

Values are given as mean (SD) or in events as n (%).

p < 0.05 versus control.

SD, standard deviation; ns, not significant.

The stability of plaques increased in the sequence: control–Pycnogenol–Pycnogenol+CA, the combination resulted in a nearly twofold increase of plaque stability (Table 1).

The improvement of the status of atherosclerosis is reflected in the frequency of cardiovascular events (Table 1). With just 5 events in 151 participants over 4 years, the combination of Pycnogenol+CA was far more effective than Pycnogenol (10 events) and highly significantly different from controls (21 events).

Oxidative stress, objectivated by quantification of free radicals in plasma,⁴¹ was reduced in plasma of participants in every study concerning atherosclerosis progression after supplementation with Pycnogenol. Aspirin or ticlopidine had no significant influence on free radical formation. The combination was more effective than Pycnogenol alone.^{35,38,39,42,43}

The stabilization of atherosclerotic plaques to prevent emboli, together with the slow-down or even halt of progression of atherosclerosis is doubtless an important contribution of Pycnogenol to healthy aging.

Prevention of venous thrombosis

Arterial thrombosis and venous thrombosis have common risk factors as obesity, smoking, diabetes, stress, and chronic inflammation. Chronic inflammation induces in arteries and veins endothelial dysfunction and hypercoagulability.^44,45 The biomarker c-reactive protein (CRP) provided a link between inflammation and venous thromboembolism in a study with >1000 participants over 8.3 years.⁴⁴ High CRP concentrations were associated with an increased risk of venous thrombosis.

As Pycnogenol lowers CRP levels⁴⁶ and inhibits platelet aggregation³² and formation of adhesion molecules as well,²³ it is understandable that Pycnogenol inhibits venous thromboses. This could be shown in total thrombosis prevention during long-distance flights.^47,48 An investigation among 493 passengers revealed full protection by Pycnogenol against thrombosis, whereas 5% thromboses were detected after flight travel in the untreated control groups. In patients experiencing thrombosis in the foregoing year, recurrent venous thrombosis was better prevented with Pycnogenol (p < 0.05) in comparison with aspirin, ticlopidine, and sulodexide.⁴⁹ Recurrent retinal thrombosis was also prevented in patients with foregoing retinal thrombosis.⁵⁰ These results suggest that Pycnogenol may prolong the healthy period of life by reducing the risk of thrombosis in arteries^{35,38
–40,50} and veins.^47

–50

Diabetes

Death rates attributed to diabetes exceed the death rates of subjects without diabetes globally.⁵¹ With increasing age, the prevalence of type 2 diabetes increases exponentially.⁵² In this context, the antidiabetic effects of Pycnogenol may contribute to healthier aging.

Glucose lowering

The antidiabetic effect of Pycnogenol is based on the inhibition of α-glucosidase, so that digestion of carbohydrates is partially blocked.⁵³ In a dose-finding study⁵⁴ in patients with diabetes, 200 mg Pycnogenol produced the maximum effect, reducing fasting glucose from 12.47 to 10.07 mmol/L and HbA1c from 8.02 to 7.37 (p < 0.05). Insulin levels remained unchanged. In 77 patients with diabetes, treated with antidiabetic drugs, the addition of 100 mg Pycnogenol to treatment for 12 weeks decreased plasma glucose significantly (p < 0.001) versus baseline.⁵⁵ In a double-blind, placebo-controlled, randomized study²⁶ in 48 patients, fasting glucose declined from 23.7 mg/dL with Pycnogenol to 12.5 mg/day, the decrease under placebo was just 5.7 mg/dL. In 64 patients with metabolic syndrome, fasting glucose dropped down from 123 to 106 mg/dL during treatment with 150 mg Pycnogenol for 3 months, glucose levels remained unchanged in controls.⁵⁶

According to anecdotal reports⁵ patients could spare the use of insulin while taking Pycnogenol.

Diabetic retinopathy

Diabetic retinopathy, eventually ending in blindness, is one of the serious consequences of diabetes. Oral intake of Pycnogenol stopped the progressing deterioration of eyesight after 6 months.⁵⁷ The positive effect is most probably caused by reduction of the pathologically enhanced permeability of retinal capillaries. Outflow of blood and exsudates into the retina and edema formation was prevented by intake of Pycnogenol,^58,59 so that visual acuity increased after treatment with 150 mg Pycnogenol for 3 months compared with controls.

The clinical reports seem to suggest that Pycnogenol could help to reduce the use of antidiabetic drugs and to ameliorate symptoms of type 2 diabetes. Given the high prevalence of type 2 diabetes, even a modest improvement of glucose metabolism and retinopathy could exert a remarkable contribution to healthier aging.

Mobility

Mobility is one key to healthy aging, maintaining a person's ability to move independently from one place to another.

Mobility limitations increase with advancing age, hindering the management of tasks of daily life. Mobility difficulties lead to sedentary behavior, subsequently to less social contacts and fewer nutritional options. Further functional decline prompts the need for help from others, the risk of disability increases. The loss of independency initiates depression. Finally, the lack of mobility increases the overall morbidity from several diseases and malfunctions. Therefore, it is mandatory to keep mobility as long as possible at a normal level during aging.

The most common cause of chronic immobility in persons older than 65 years is osteoarthritis, affecting ∼50% of the population in that age.

The restricted mobility is caused by progressing painful destruction of joints, initiated by inflammatory reactions. Constituents and metabolites of Pycnogenol were able to inhibit the activity of inflammatory mediators within the joint.^60,61

Three double-blind, placebo-controlled studies in 293 patients demonstrated a better physical function, less joint stiffness, and less pain. A mean improvement of 40% of these symptoms was observed in all studies.^62
–64 In the treadmill test, patients could triple their walking distance after intake of 100 mg Pycnogenol daily for 3 months. At the same point in time, patients in the placebo group could increase their walking distance just by one third.⁶⁴

The improved mobility results in sustained social contacts⁶⁴ thus contributing to an enhanced quality of life. Having less difficulties in putting on socks, rising up from sitting position, going shopping, performing domestic activities, and all such daily routines were greatly improved by Pycnogenol, but not by placebo.⁶⁴

The local treatment of pain with Pycnogenol patches^65,66 helped also to improve the quality of life without use of opioids, antidepressants, or nonsteroidal anti-inflammatory drugs (NSAIDs). One may conclude from these studies that it would be worthwhile to start supplementation with Pycnogenol at the earliest signs for mobility restrictions, keeping mobility and quality of life as long as possible at a normal level.

The reduction of pain with Pycnogenol allowed sparing the use of NSAIDs,^64,65 thereby decreasing gastric problems caused by NSAIDs.

The sparing of pain killers with Pycnogenol is an example for reducing dose-related side effects of drugs. Another example is the replacement of antihypertensive drugs such as CA antagonists by Pycnogenol.^15,26,30

Mental Fitness

There is a fundamental concern for the elderly people on how to deal with the age-related decline of memory and cognitive abilities. Cognitive aging affects mental functions such as executive functions, processing speed, or multitasking abilities, functions that are mandatory for engagement in daily activities. Many programs for mental or physical exercising are offered with an attempt to decelerate cognitive aging. Living independently in good mental health as long as possible is of outstanding importance for senior citizens.

First hints for a positive effect of Pycnogenol on mental skills were obtained from experiments with senescence-accelerated mice.⁶⁷ Pycnogenol improved learning and memory of the mice significantly (p < 0.01) and dose related.

To verify the effect of Pycnogenol on cognitive aging, a series of computer-assisted memory tests were used.

An investigation of 101 Australian elder citizen with moderate cognitive function decline⁶⁸ revealed a significant (p < 0.05) improvement of spatial memory after intake of 150 mg Pycnogenol for 3 months.

A clinical trial of 77 elderly individuals aged 55–70 years used in addition to conventional cognition tests another approach, resembling challenges of daily life. Half volunteers received 100 mg Pycnogenol daily for 12 months, the other half served as untreated group.⁶⁹ Both groups were instructed to follow a personal improvement plan for better lifestyle. The participants were investigated using questionnaires for decrease in cognitive function and evaluated for the ability to handle daily tasks.

According to the Informant Questionnaire on Cognitive Decline in the Elderly,⁷⁰ the elderly people in the Pycnogenol group could remember much better as to what happened in the recent past, where things were, and were better in learning new things. Furthermore, they were significantly better in handling complex situations. The evaluation of daily tasks in the control group revealed the expected signs of cognitive aging, the ability to perform daily tasks decreased, there was no improvement in any of the tested items (Table 2). In contrast, the participants in the Pycnogenol group improved their tasks, especially the more complex challenges such as decision making and dealing with problems. Furthermore, physical status and sleep quality changed to significantly better scores. The Pycnogenol group outperformed the controls also in the Short Blessed Test for evaluation of cognitive function deterioration.

Table 2.

Change of Scores for Daily Tasks from Informant Questionnaire on Cognitive Decline of the Elderly people After 8 Weeks of 100 mg/day Pycnogenol^a

Number of subjects	Pycnogenol^®	Control
Number of subjects	n = 43	n = 44
Getting up	1.6	−0.3
Shopping	1.4	−0.2
Dealing with money	1.5	−0.5
Dealing with people	2.5	−0.2
Simple decision making	3.1	−0.2
Coping with simple problems	2.6	−0.1
Moving around	2.8	−0.2
Psychophysical status	3.1	−0.1
Vision and hearing	2.4	−0.3
Appetite	2.4	−0.2
Strength	2.2	−0.7
Sleeping	3.0	−0.1

Reference⁷⁰

The results obtained in the elderly people are in complete agreement with the improvement of cognitive function by Pycnogenol observed in a group of students⁷¹ and healthy professionals.⁷² Thus, the daily intake of Pycnogenol seems to improve memory and learning in general, compensating for the process of cognitive aging.

The slowdown of cognitive aging by Pycnogenol is in line with results from studies reporting that polyphenols—as contained in Pycnogenol—act against cognitive decline.⁷³

Gender-Specific Age-Related Alterations

Aging exerts gender-specific malfunctions in both sexes as benign prostate hyperplasia and erectile dysfunction (ED) in men and the menopausal syndrome in women.

Menopausal Symptoms

Menopausal symptoms were significantly (p < 0.05) ameliorated by 200–60 mg/day of Pycnogenol for 2–6 months. The decrease in symptoms was dependent on dose and time of intervention in menopausal women from Taiwan,⁷⁴ Japan,⁷⁵ and Italy.⁷⁶ In all double-blind, placebo-controlled studies, vasomotoric symptoms, memory and concentration, psychological symptoms, and painful events improved during intake of Pycnogenol compared with placebo. The pine bark extract seems to offer a nonhormonal alternative treatment of climacteric symptoms, an important contribution to healthier aging.

Benign Prostatic Hyperplasia

The prevalence of benign prostatic hyperplasia increases clearly with age, so that by the age of 80, ∼80% of men have prostatic hyperplasia.⁷⁷ In a comparative, open study, 75 men with confirmed benign hyperplasia were treated in three groups with either standard management, 0.5 mg/day dutasteride or finasteride 5 mg/day or 150 mg Pycnogenol for 60 days.⁷⁸ Prostatic volume remained unchanged after treatment; however, signs and symptoms of prostate hyperplasia, evaluated by International Prostate Symptoms Score forms, decreased in all groups significantly (p < 0.05) to baseline. The Pycnogenol group achieved significantly (p < 0.05) lower scores, indicating better improvement compared with the other groups. Postvoid residual urine volume diminished from 99 to 48 mL, and emptying, frequency, intermitting, urgency, straining, nocturia were favorably improved by Pycnogenol.

Erectile dysfunction

Combinations of Pycnogenol with L-arginine aspartate (Prelox^®) restored ED to normal values according to the International Index of Erectile Function (IIEF).⁷⁹ One hundred men with confirmed ED participated in two randomized, placebo-controlled, double-blind crossover studies,^80,81 124 men were enrolled in a randomized, double-blind, placebo-controlled parallel arm study,⁸² and 23 men with ED in another double-blind parallel group study.⁸³ In all four studies, participants with ED achieved the scores of the IIEF questionnaire for normal erectile function after a treatment period of 1 month,^80,81 6 months,⁸² and 8 weeks.⁸³ No side effects were reported.

The common mechanism for improvement of ED and of symptoms of prostatic hyperplasia is based on the activation of e-NOS by Pycnogenol¹⁴ and the subsequent enhanced production of NO that stimulates guanyl cyclase in smooth muscle layers. Guanyl cyclase initiates intracellular production of cyclic guanosinemonophosphate (cGMP) that subsequently triggers muscle relaxation as a second messenger in corpus cavernosum.⁸⁴ Prostate and bladder smooth muscles are also relaxed by NO, as follows from treatment of lower urinary tract dysfunction with phosphodiesterase inhibitors.⁸⁵ The phosphodiesterase inhibitors enhance the concentration of cGMP in tissues, by blocking its degradation. Pycnogenol stimulates production of cGMP by increasing the concentration of NO, the trigger for cGMP production.

In conclusion, the common mechanism of positive effect of Pycnogenol on ED and lower urinary dysfunction symptoms of prostate hyperplasia is related to the NO–cGMP pathway.

An improvement of sexual activity and a relief from lower urinary tract symptoms will lead to better quality of life and healthier aging of men.

Safety of Pycnogenol

The risk for adverse effects of Pycnogenol, evaluated from 139 clinical studies with 12,135 subjects, is low. One hundred eight adverse effects were reported after ingestion of Pycnogenol (1.49%), under placebo 97 adverse effects were noted (1.99%). All adverse effects were mild; gastrointestinal troubles were the most frequent unwanted effects. All symptoms were transient without further consequences.

Conclusion

The food supplement Pycnogenol offers a wide range of favorable biochemical effects, resulting in clinically relevant benefits for human health. Even when the specific actions of Pycnogenol seem to be not that impressive compared with the corresponding pharmaceutical drugs, one may speculate that the sum of the health benefits of Pycnogenol will help to extend the healthy life span of seniors.

Footnotes

Author Disclosure Statement

The author works as a consultant for Research & Development at Horphag Research.

References

Duncan

. How Long Do You Want to Live?. N.Y. Times. 2012 Aug; p. SR 4.

Donner

, Fortney

, Calimport

, Pfleger

, Shah

, Betts-LaCroix

. Great desire for extended life and health amongst the American public. Front Genet, 2016; 6:353.

WHO. 2013. Healthy life expectancy (HALE) at birth. www.who.int/gho/mortality_burden_disease/life_tables/hale/en

Martinez-Gonzalez

, Martin-Calvo

. Mediterranean diet and life expectancy; beyond olive oil, fruits, and vegetables. Durr Opin Clin Nutr Metab Care, 2016; 19:401–407.

Rohdewald

, Passwater

. The Phenomenon Pycnogenol^® . Bochum, Germany: Ponte Press, 2015.

Rohdewald

Update on the clinical pharmacology of Pycnogenol^® . Med Res Arch, 2015; 3:1–11.

Maimoona

, Naeem

, Saddiqi

, Jameel

. A review on biological, nutraceutical and clinical aspects of French maritime pine bark extract. J Ethnopharmacol, 2011; 133:261–277.

Rohdewald

Review on sustained relief of osteoarthritis symptoms with a proprietary extract from pine bark extract, Pycnogenol. J Med Food, 2018; 21:1–4.

Rohdewald

Pycnogenol, a plant extract for women's health. Int J Womens Health Care, 2017; 2:1–5.

10.

Hadi

, Carr

, Al Suwaidi

. Endothelial dysfunction: Cardiovascular risk factors, therapy, and outcome. Vasc Health Risk Manag, 2005; 1:183–198.

11.

Rajendran

, Rengarajan

, Thangavel

, et al. The vascular endothelium and human disease. Int J Biol Sci, 2013; 9:1057–1069.

12.

Seals

, Kaplon

, Gioscia-Ryan

, LaRocca

. You're only as old as your arteries: Translational strategies for preserving vascular endothelial function with aging. Physiology (Bethesda), 2014; 29:250–264.

13.

Fitzpatrick

, Bing

, Rohdewald

. Endothelium-dependent vascular effects of Pycnogenol^® . J Cardiovasc Pharmacol, 1998; 32:509–515.

14.

Nishioka

, Hidaka

, Nakamura

, et al. Pycnogenol^®, French maritime pine bark extract, augments endothelium-dependent vasodilation in humans. Hypertens Res, 2007; 30:775–780.

15.

Liu

, Wei

, Tan

, Zhou

, Würthwein

, Rohdewald

. Pycnogenol^®, French maritime pine bark extract, improves endothelial function of hypertensive patients. Life Sci, 2004; 74:855–862.

16.

Rohdewald

A review of the French maritime pine bark extract (Pycnogenol^®), a herbal medication with a diverse clinical pharmacology. Int J Clin Pharmacol Ther, 2002; 40:158–168.

17.

Nelson

, Lau

BHS

, Ide

, Rong

. Research paper: Pycnogenol inhibits macrophage oxidative burst, lipoprotein oxidation and hydroxyl radical-induced DNA damage. Drug Dev Ind Pharm, 1998; 24:139–144.

18.

Belcaro

, Cesarone

, Errichi

, et al. Variations in C-reactive protein, plasma free radicals and fibrinogen values in patients with osteoarthritis treated with Pycnogenol. Redox Rep, 2008; 13:271–276.

19.

Grimm

, Chovanová

, Muchová

, et al. Inhibition of NF-kappaB activation and MMP-9 secretion by plasma of human volunteers after ingestion of maritime pine bark extract (Pycnogenol^®). J Inflamm, 2006; 3:1.

20.

Schäfer

, Chovanová

, Muchová

, et al. Inhibition of COX-1 and COX-2 activity by plasma of human volunteers after ingestion of French maritime pine bark extract (Pycnogenol). Biomed Pharmacother, 2006; 60:5–9.

21.

Canali

, Comitato

, Schönlau

, Virgili

. The anti-inflammatory pharmacology of Pycnogenol^® in humans involves COX-2 and 5-LOX mRNA expression in leukocytes. Int Immunopharmacol, 2009; 9:1145–1149.

22.

Uhlenhut

, Högger

. Facilitated cellular uptake and suppression of inducible nitric oxide synthase by a metabolite of maritime pine bark extract (Pycnogenol). Free Radic Biol Med, 2012; 53:305–313.

23.

Peng

, Wei

, Lau

BHS

. Pycnogenol inhibits tumor necrosis factor α-induced nuclear factor kappa B activation, and adhesion molecule expression in human vascular endothelial cells. Cell Mol Life Sci, 2000; 57:834–841.

24.

Luo

, Wang

, Qiao

, Ma

, Liu

, Zhang

. Pycnogenol^® attenuates atherosclerosis by regulating lipid metabolism through the TLR4-NF-κB pathway. Exp Mol Med, 2015; 47:e191.

25.

Hosseini

, Lee

, Sepulveda

, Fagan

, Rohdewald

, Watson

. A randomized, double blind, placebo controlled, prospective, 16 week crossover study to determine the role of Pycnogenol^® in modifying blood pressure in mildly hypertensive patients. Nutr Res, 2001; 21:1251–1260.

26.

Zibadi

, Rohdewald

, Park

, Watson

. Reduction of cardiovascular risk factors in subjects with type 2 diabetes by Pycnogenol supplementation. Nutr Res, 2008; 28:315–320.

27.

Cesarone

, Belcaro

, Stuard

, et al. Kidney flow and function in hypertension: Protective effects of Pycnogenol in hypertensive participants—A controlled study. J Cardiovasc Pharmacol Ther, 2010; 15:41–46.

28.

, Belcaro

, Cornelli

, et al. Effects of Pycnogenol^® on endothelial dysfunction in borderline hypertensive, hyperlipidemic, and hyperglycemic individuals: The borderline study. Int Angiol, 2015; 34:43–52.

29.

Luzzi

, Belcaro

, Hosoi

, et al. Normalization of cardiovascular risk factors in perimenopausal women with Pycnogenol^® . Minerva Ginecologica, 2017; 69:29–34.

30.

Belcaro

, Cesarone

, Ricci

, et al. Control of edema in hypertensive subjects treated with calcium antagonist (Nifedipine) or angiotensin-converting enzyme inhibitors with Pycnogenol. Clin Appl Thromb Hemost, 2006; 12:330–444.

31.

Daub

, Lindemann

, Langer

, Seizer

, Stellos

, Siegel-Alex

, Gawaz

. The evil in atherosclerosis: Adherent platelets induce foam cell formation. Semin Thromb Hemost, 2007; 33:173–178.

32.

Pütter

, Grotemeyer

KHM

, Würthwein

, et al. Inhibition of smoking-induced platelet aggregation by Aspirin and Pycnogenol^® . Thromb Res, 1999; 95:155–161.

33.

Araghi-Niknam

, Hosseini

, Larson

, Rohdewald

, Watson

. Pine bark extract reduces platelet aggregation. Integ Med, 1999; 2:73–77.

34.

Belcaro

, Dugall

, Hosoi

, et al. Pycnogenol^® and Centella asiatica for asymptomatic atherosclerosis progression. Int Angiol, 2014; 1:20–26.

35.

Belcaro

, Ippolito

, Dugall

, et al. Pycnogenol^® and Centella asiatica in the management of asymptomatic atherosclerosis progression. Int Angiol, 2015; 34:150–157.

36.

Hashim

, Sidek

, Helan

MHM

, Sabery

, Palanisamy

, Ilham

. Triterpene composition and bioactivities of Centella asiatica . Molecules, 2011; 16:1310–1322.

37.

Bylka

, Znajdek-Awizen

, Studzinska-Sroka

, Brzezinska

. Centella asiatica in cosmetology. Postepy Dermatol Alergol, 2013; 30:46–49.

38.

Belcaro

, Cornelli

. Variations in echogenicity in carotid and femoral atherosclerotic plaques with Pycnogenol+Centella asiatica supplementation. Int J Angiol, 2017; 26:95–101.

39.

Luzzi

, Belcaro

, Ippolito

. Carotid plaque stabilization induced by the supplement association Pycnogenol^® and Centella asiatica (Centellicum^®). Minerva Cardioangiol, 2016; 64:603–609.

40.

Belcaro

, Dugall

, Ippolito

, et al. Pycnogenol^® and Centella asiatica to prevent asymptomatic atherosclerosis progression in clinical events. Minerva Cardioangiol, 2017; 65:24–31.

41.

Cesarone

, Belcaro

, Carratelli

, et al. A simple test to monitor oxidative stress. Int Angiol, 1999; 18:127–130.

42.

Cesarone

, Belcaro

, Nicolaides

, et al. Increase in echogenicity of echolucent carotid plaques after treatment with total triterpenic fraction of Centella asiatica: A prospective, placebo-controlled, randomized trial. Angiology, 2001; 52(Suppl 2):19–25.

43.

Belcaro

, Nicolaides

, Laurora

, et al. Ultrasound morphology classification of the arterial wall and cardiovascular events in a 6-year follow-up study. Arterioscler Thromb Vasc Biol, 1996; 16:851–856.

44.

Piazza

, Ridker

. Is venous thromboembolism a chronic inflammatory disease?. Clin Chem, 2015; 61:313–316.

45.

Poredos

Interrelationship between venous and arterial thrombosis. Int Angiol, 2017; 36:295–298.

46.

Nikpayam

, Rouhani

, Pourmasoumi

, Roshanravan

, Ghaedi

, Mohammadi

. The effect of Pycnogenol supplementation on plasma c-reactive protein concentration: A systematic review and meta-analysis. Clin Nutr Res, 2018; 7:117–125.

47.

Belcaro

, Cesarone

, Rohdewald

, et al. Prevention of venous thrombosis and thrombophlebitis in long-haul flights with Pycnogenol^® . Clin Appl Thromb Hemost, 2004; 10:373–377.

48.

Belcaro

, Cornelli

, Dugall

, Hosoi

, Cotellese

, Feragalli

. Long-haul flights, edema and thrombotic events: Prevention with stockings and Pycnogenol^® supplementation (LONFLIT Registry Study). Minerva Cardioangiol, 2018; 66:152–159.

49.

Belcaro

, Dugall

, Hu

, et al. Prevention of recurrent venous thrombosis and post-thrombostic syndrome. Minerva Cardioangiol, 2018; 66:238–245.

50.

Rodriguez

, Belcaro

, Dugall

, et al. Recurrence of retinal vein thrombosis with Pycnogenol^® or Aspirin^® . A registry, supplement study. Panminerva Med, 2015; 57:121–125.

51.

Bennett

PH.

Diabetes mortality in the USA: Winning the battle but not the war?. Lancet, 2018; 391:2392–2393.

52.

Sinnott

, McHugh

, Whelton

, Lavte

, Barron

, Kearney

. Estimating the prevalence and incidence of type 2 diabetes using population level pharmacy claims data: A cross-sectional study. BMJ Open Diabetes Res Care, 2017; 5:e000288.

53.

Schäfer

, Högger

. Oligomeric procyanidins of French maritime pine bark extract (Pycnogenol^®) effectively inhibit alpha-glucosidase. Diabetes Res Clin Pract, 2007; 77:41–46.

54.

Liu

, Zhou

H-J

, Rohdewald

. French maritime pine bark extract Pycnogenol dose-dependently lowers glucose in type 2 diabetic patients. Diabetes Care, 2004; 27:839.

55.

Liu

, Wei

, Tan

, Zhou

, Würthwein

, Rohdewald

. Antidiabetic effect of Pycnogenol^® French maritime pine bark extract in patients with diabetes type II. Life Sci, 2004; 75:2505–2513.

56.

Belcaro

, Cornelli

, Luzzi

, et al. Pycgnogenol^® supplementation improves health risk factors in subjects with metabolic syndrome. Phytother Res, 2013; 27:1572–1578.

57.

Schönlau

, Rohdewald

. Pycnogenol^® for diabetic retinopathy: A review. Int Ophthalmol, 2002; 24:161–171.

58.

Spadea

, Balestrazzi

. Treatment of vascular retinopathies with Pycnogenol^® . Phytother Res, 2001; 15:219–223.

59.

Steigerwalt

, Belcaro

, Cesarone

, et al. Pycnogenol^® improves microcirculation, retinal edema, and visual acuity in early diabetic retinopathy. J Ocul Pharmacol Ther, 2009; 25:537–540.

60.

Mülek

, Seefried

, Genest

, Högger

. Distribution of constituents and metabolites of maritme pine bark extract (Pycnogenol^®) into serum, blood cells and synovial fluid of patients with severe osteoarthritis: A randomized controlled trial. Nutrients, 2017; 9:443.

61.

Jessberger

, Högger

, Genest

, Salter

, Seefried

. Cellular pharmacodynamic effects of Pycnogenol^® in patients with severe osteoarthritis: A randomized controlled pilot study. BMC Complement Altern Med, 2017; 17:537.

62.

Farid

, Mirfeizi

, Mirheidari

, et al. Pycnogenol supplementation reduces pain and stiffness and improves physical function in adults with knee arthritis. Nutr Res, 2007; 27:692–697.

63.

Cisar

, Jany

, Waczulikova

, et al. Effect of pine bark extract (Pycnogenol^®) on symptoms of knee osteoarthritis. Phytother Res, 2008; 22:1087–1092.

64.

Belcaro

, Cesarone

, Errichi

, et al. Treatment of osteoarthritis with Pycnogenol^® . The SVOS (San Valentino Osteoarthritis Study). Evaluation of signs, symptoms, physical performance and vascular aspects. Phytother Res, 2008; 22:518–523.

65.

Luzzi

, Belcaro

, Dugall

. Idiopathic, benign, transient neck pain: Effects of a Pycnogenol thin patch. Minerva Ortopedica E Traumatologica, 2016; 67:131–136.

66.

Luzzi

, Belcaro

, Feragalli

, Dugall

. Moderate, diffuse, somatic muscular pain: Effects of supplementation with a Pycnogenol patch. Minerva Ortopedica e Traumatologica, 2016; 67:170–176.

67.

Liu

, Zhang

, Lau

BHS

. Pycnogenol improves learning impairment and memory deficit in senescence-accelerated mice. J Antiaging Med, 1999; 2:349–355.

68.

Ryan

, Croft

, Mori

, et al. An examination of the effects of the antioxidant Pycnogenol^® on cognitive performance, serum lipid profile, endocrinological and oxidative stress biomarkers in an elderly population. J Psychopharmacol, 2008; 22:553–562.

69.

Belcaro

, Dugall

, Ippolito

, Hu

, Saggino

, Feragalli

. The COFU3 Study: Improvement in cognitive function, attention, mental performance with Pycnogenol^® in healthy subjects (55–70) with high oxidative stress. J Neurosurg Sci, 2015; 59:437–446.

70.

Diesfeldt

HF.

Discrepancies between its IQCODE (informant questionnaire on cognitive decline in the elderly) and cognitive test performance. Tijdschr Gerontol Geriatr, 2007; 38:225–236.

71.

Luzzi

, Belcaro

, Zulli

, et al. Pycnogenol^® supplementation improves cognitive function, attention and mental performance in students. Panminerva Med, 2011; 53(Suppl. 1, to N°3):75–78.

72.

Belcaro

, Luzzi

, Dugall

, Ipppolito

, Saggino

. Pycnogenol^® improves cognitive function, attention, mental performance and specific professional skills in healthy professionals aged 35–55. J Neurosurg Sci, 2014; 58:239–248.

73.

Bensalem

, Dal-Pan

, Gillard

, Calon

, Pallet

. Protective effects of berry polyphenols against age-related cognitive impairment. Nutr Aging, 2016; 3:89–106.

74.

Yang

H-M

, Liao

M-F

, Zhu

S-Y

, Liao

M-N

, Rohdewald

. A randomized, double-blind, placebo-controlled trial on the effect of Pycnogenol^® on the climacteric syndrome in peri-menopausal women. Acta Obstet Gynecol Scand, 2007; 86:978–985.

75.

Kohama

, Negami

. Effect of low-dose French maritime pine bark extract on climacteric syndrome in 170 perimenopausal women. J Reprod Med, 2013; 58:39–46.

76.

Errichi

, Bottari

, Belcaro

, et al. Supplementation with Pycnogenol^® improves signs and symptoms of menopausal transition. Panminerva Med, 2011; 53 (Suppl. 1, to N°3):65–70.

77.

Kim

, Larson

, Andriole

. Feasibility of an alternative option for the management of male lower urinary tract symptoms. J Urol, 2016; 195:125–130.

78.

Ledda

, Belcaro

, Feragalli

, et al. Benign prostatic hypertrophy: Pycnogenol^® supplementation improves prostate symptoms and residual bladder volume. Minerva Medica, 2018; 109:280–284.

79.

Rosen

, Cappeleri

, Gendrano

IIIN

. The International Index of Erectile Function (IIEF): A-state-of-the-science review. Int J Impot Res, 2002; 14:236–244.

80.

Stanislavov

, Nikolova

, Rohdewald

. Improvement of erectile function with Prelox: A randomized, double-blind, placebo-controlled, crossover trial. Int J Impot Res, 2008; 20:173–180.

81.

Stanislavov

, Rohdewald

. Improvement of erectile function by a combination of French maritime pine bark and roburins with aminoacids. Minerva Urol Nefrol, 2015; 67:27–32.

82.

Ledda

, Belcaro

, Cesarone

, Dugall

, Schönlau

. Investigations of a complex plant extract for mild to moderate erectile dysfunction in a randomized, double blind, placebo controlled, parallel armed study. BJU Int, 2010; 106:1030–1033.

83.

Aoki

, Nagao

, Ueda

, Strong

, Schonlau

, Yu

, Lu

J-Y

, Horie

. Clinical assessment of a supplement Pycnogenol^® and L-arginine in Japanese patients with mild to moderate erectile dysfunction. Phytother Res, 2012; 26:204–207.

84.

Andersson

KE.

Pharmacology of penile erection. Pharmacol Rev, 2001; 53:417–450.

85.

Uckert

, Oelke

. Phosphodiesterase (PDE) inhibition in the treatment of lower urinary tract dysfunction. Br J Clin Pharmacol, 2011; 72:197–204.