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
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-
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 catalase 17 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 factors 23 by Pycnogenol protects the endothelium against inflammatory stimuli. The inhibition of NF-κB and the Toll-like receptor 4 by Pycnogenol 24 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 months 34 and 42 months 35 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 collagen 36 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 months 39 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.
Plaque Progression and Cardiovascular Events at 4 Yearsa According to Ultrasound Investigations
Reference 38
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 levels 46 and inhibits platelet aggregation 32 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 study 54 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 study 26 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 reports 5 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 contacts 64 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 decline 68 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.
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
Reference 70
The results obtained in the elderly people are in complete agreement with the improvement of cognitive function by Pycnogenol observed in a group of students 71 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
The common mechanism for improvement of ED and of symptoms of prostatic hyperplasia is based on the activation of e-NOS by Pycnogenol 14 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.
