Botanical and Diet-Based Biological Therapies and Their Use by Older Persons: Part II
Numerous botanical and biological agents are available for use by older persons. Some of these are increasingly being recommended by physicians and used by patients who seek an alternative or complementary way to treat specific medical problems, to produce an anti-aging effect, or to improve their feelings of “well-being.” Concerns continue, however, regarding the effectiveness of many of these products as well as interactions they may have with prescribed medications. The potential benefit must always be weighed against any possible side effect, although few studies have provided much data on which to make any definitive conclusion.
This article is the second part of this series (for Part I, see Clinical Geriatrics 2005;13: 26-34), and reviews more commonly used botanical and biological agents with potential impact on the older individual.
Soybeans have been cultivated and eaten in China and Japan for centuries. In fact, soy has been credited by some as being at least partially responsible for the Japanese having one of the longest lifespans of any population. Apart from being an excellent source of protein, soybeans contain fiber, iron, calcium, folic acid, magnesium, potassium, and B vitamins. Soy contains a number of isoflavones, also known as phytoestrogens. These weak, estrogen-like compounds are chemically similar in structure to naturally occurring estrogenic hormones. The estrogenic potency of isoflavones, however, is approximately 1/1000 to 1/100,000 that of estradiol; thus, large amounts must be consumed to have any clinically significant effect. In vitro data suggest that they may inhibit the CYP1A2 isoenzyme; thus, theoretically, they may influence the levels of certain medications including theophylline, clozapine, tacrine, haloperidol, and caffeine. There are also data to suggest that they may affect the disposition of nonsteroidal anti-inflammatory drugs (NSAIDs), phenytoin, and warfarin by influencing the CYP2C9 isoenzyme.
Soy is an excellent source of protein, with the additional benefit of lacking the saturated fat and cholesterol found in protein derived from animal sources. Receiving greater acceptance in the United States in recent years, soy protein is available as a wide variety of foods including soy milk, tofu, and tempeh. Soy protein powder is available as a food supplement and is commonly found in protein bars that serve as either a meal supplement or a source of quick energy. Edamame, the Japanese name for green soybeans, is increasingly used as a “healthy” snack, either steamed or even uncooked. Of historical note, the first soybean crop in the United States was planted in Savannah, Georgia, in the 1700s. An Englishman was the first to patent the formula for “soy sauce.” Soybeans were used during the Civil War as a substitute for coffee, and in 1904, George Washington Carver identified soybeans as an excellent source of protein and recommended their use as an oil. Dr. John Harvey Kellogg, the brother of the cereal manufacturer, was a vegetarian and developed soy as a meat substitute as early as the 1920s.
It was not until World War II, however, that soy received renewed interest as a possible protein source. At this time, various soy products were produced, including burgers, cereals, and food substitutes, and soy protein was suggested as a mixing additive and as a way of “stretching” animal protein due to its lower cost. In 1995, a research study was published in the New England Journal of Medicine that demonstrated that soy in the diet helped reduce cholesterol.1 In 1999, the U.S. Food and Drug Administration agreed to allow food labels to state that a diet rich in soy products has the potential to reduce the risk of coronary heart disease (CHD). It added that 25 g or more per day was required to achieve this effect; the diet should also be low in saturated fat and cholesterol.
The U.S. Department of Agriculture, responsible for evaluating various sources of protein, recently gave soy protein a “quality score” or protein digestibility-corrected amino acid score (PDCAAS) of 1.0, equivalent to animal protein. The Nutrition Committee of the American Heart Association has also concluded that clinical trials have found that diets containing 25-50 g per day of soy protein are a safe and effective way to reduce low-density lipoprotein (LDL) cholesterol by 4-8%. It recommends a daily consumption of at least 25 g of soy protein combined with a diet low in saturated fat and cholesterol as one way to promote heart health.2 What are the data to support using soy beyond its role as a source of protein? Soy has been demonstrated to reduce total cholesterol and LDL cholesterol, with some studies reporting an elevation in high-density lipoprotein (HDL) levels as well.
A meta-analysis evaluating 38 controlled clinical trials reported that soy protein intake averaging 47 g per day lowered total serum cholesterol by 9.3%, LDL cholesterol by 12.9%, and triglyceride levels by 10.5%; HDL cholesterol increased by 2.4%. The higher a person’s initial cholesterol, the more significant the decrease noted when soy products were added to the diet.1 This magnitude of change may not be sufficient alone as a treatment for everyone with elevated lipid levels, but clearly soy appears to be a safe source of protein and a complementary way to reduce lipid abnormalities and risk of CHD. In another study, 156 individuals with serum cholesterol levels between 140 and 200 mg/dL were randomized to eat a diet containing either casein protein without any isoflavones or one of four diets that included soy protein containing 3-62 mg of isoflavones. Diets containing 37 mg or more of isoflavones lowered total and LDL cholesterol by 6%, compared to only 4% for those on casein as the protein source. The greatest reduction in cholesterol was noted for those with serum cholesterol values of more than 164 mg/dL.3
A 1-year randomized trial in 202 postmenopausal women using dietary soy protein sufficient to provide 99 mg of isoflavones, however, reported no significant effect on lipids.4 A 3-month study of both men and postmenopausal women 50-75 years of age reported that isoflavone use (40 g soy; 118 mg isoflavones) was associated with a modest yet significant improvement in LDL/HDL ratios and triglyceride concentrations.5 Although not as well studied, soy has also been reported to have other possibly beneficial effects in select patient populations. Positive effects have been described on alleviating symptoms of hot flashes during the perimenopausal period. A controlled study of 145 postmenopausal women found that the addition of soy-containing foods and flaxseed in the diet for 12 weeks reduced the number of hot flashes and vaginal dryness compared to control subjects. No difference was noted, however, in overall menopausal symptoms.6 A double-blind, 6-week crossover study in 51 postmenopausal women reported that 20 g of soy protein added to the diet was associated with a reduction in the severity of menopausal symptoms.6
Although not well documented, data suggest that soy may strengthen bone mineral density through its estrogenic effects, possibly reducing the risk of developing osteopenia and osteoporosis for those at risk.7 Dietary soy has also been demonstrated in an animal model as being capable of decreasing testosterone levels and prostate weight.8 Although an anti-tumor effect has been postulated, this remains unproven. Possible beneficial effects must be weighed against side effects. Soy reportedly can increase serum lipoprotein(a) levels, and in men soy intake has been associated with a decline in vascular endothelial function. No clinical consequences have been found for these findings to date.
An increase in breast secretions has been described, and a proliferation of breast epithelium has been reported in women consuming high concentrations of soy in their diets. No link to breast cancer has been demonstrated, although some physicians have gone as far as to caution women who are at increased risk for breast cancer against consuming diets high in soy content. Interestingly, an opposite effect may actually exist—soy in the diet has been linked epidemiologically with a lower incidence of breast cancer.9,10 Additional studies seem to be well worth pursuing. For now, soy-based products remain an excellent source of vegetable protein and may offer benefits in terms of improving one’s lipid profile and perhaps exerting weak estrogenic effects that may prove useful in reducing hot flashes during the perimenopausal period, as well as having more long-lasting effects on bone metabolism.
OMEGA-3 FATTY ACIDS
Fat comes in several forms: saturated, monounsaturated, or polyunsaturated. This nomenclature relates to the number of hydrogen bonds that connect the carbon atoms that form the fat. Certain fats are naturally saturated, such as fats derived from animals and certain vegetables such as palm and coconut. Other fats may become saturated as part of their production process, as occurs when liquid oils are converted to semi-solid form, such as is the case with margarine. Fats from dietary sources consist of a mixture of lipids that are mostly triglycerides. In addition to being a major source of energy, fats in the diet furnish essential fatty acids, serve as a carrier for fat-soluble vitamins, and provide food flavor and consistency.
There are three essential fatty acids: linoleic acid, linolenic acid, and arachidonic acid. These fatty acids serve as precursors to substances that are essential for health, including the prostaglandins, thromboxanes, prostacyclins, and leukotrienes. Alpha-linolenic acid (ALA) is converted to an omega-3 fatty acid and is essential for the normal function of the central nervous system, brain, and membranes throughout the body. It may also provide protection against heart disease. Alpha-linolenic acid is found in plentiful amounts in canola oil, soy oil, walnuts, ground flaxseed, soybeans, and other nuts and seeds. Cold-water fish, particularly salmon, mackerel, cod, herring, sardines, swordfish, and tuna, are rich in omega-3 fatty acids; eggs are another source, although in lower amounts. Other omega-3 fatty acids are eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).
Although there is no definitive minimum requirement for omega-3 fatty acids, some have suggested that diets contain at least 650 mg per day. In order to achieve optimal benefit, diets with as high as 1000-4000 mg per day have been suggested. Although certain fish have become a less reliable and safe way to obtain these potentially beneficial oils due to possible contamination with mercury, low or no mercury levels have been found in salmon, pollock, shrimp, canned light tuna, halibut, and cod, among other fish. The Environmental Protection Agency continues to recommend that seafood be incorporated into the diet for two meals a week.
Omega-3 fatty acids are highly polyunsaturated fatty acids and may reduce blood clotting in the arteries, protect from heart disease, and even enhance cognition. Oils from fish tend to be the very long-chain fatty acids, EPA and DHA. These fatty acids specifically have been demonstrated to lower triglyceride levels, decrease platelet aggregation and clotting tendencies, and decrease inflammation. They are also believed to incorporate into phospholipids and thus alter prostaglandin production and increase prostacyclin synthesis. Men consuming between 18 g and 40 g of fish per day had a reduced mortality rate and a 25-65% reduction in coronary artery disease (CAD). Men who already had a myocardial infarction (MI) and an intake of 40 g of fish per day reduced their mortality by 29%; this same study, however, failed to demonstrate any reduction in the number of men who had a repeat MI.11 The Inuit Eskimos are a prime example of the likely benefits of eating food high in these oils. Despite their high-fat diet, in their case derived largely from cold-water fish and seal blubber, data actually suggest that they have a lower rate of CAD than expected.
Benefits from the omega-3 fatty acids may derive from their effects on reducing platelet aggregation, levels of C-reactive protein, inflammation in blood vessels due to an antioxidant property, and improved function of endothelial cells in blood vessels. In addition, they have been associated with increased levels of nitric oxide synthesis and, thus, vasodilation. Blood pressure may also be reduced, and a positive effect on the lipid profile has been described. In the 1990s, a Dutch study reported that omega-3 fatty acid consumption was inversely related to the development of dementia, particularly Alzheimer’s disease.12 Over 1600 subjects 45-70 years of age were evaluated over a 10-year period using a variety of neuropsychological testing parameters to measure cognition, including memory and psychomotor response time in relation to fat consumption. Of the nine categories of dietary fats studied, diets high in saturated fatty acids and cholesterol were associated with an increased risk of cognitive decline. Consumption of diets high in fatty fish and omega-3 fatty acids, particularly DHA and EPA, were associated with a reduced risk of cognitive decline. Monounsaturated fatty acids, polyunsaturated fatty acids, ALA (again, an omega-3 fatty acid), linoleic acid (omega-6 fatty acid), and total fat when taken separately had no significant effect. Clearly, additional research is necessary to better determine the role of these fatty acids in promoting health.
Fish oil concentrate administered at high doses of more than 6 g per day has been associated with reduced levels of triglycerides. This is believed to occur through an inhibition of the synthesis of very low-density lipoprotein triglycerides and apolipoprotein B. Studies have demonstrated that patients with high levels of triglycerides may lower these levels by as much as 50% with ingestion of 15 g of fish oil concentrate per day. Fish oil use has also been associated with a reduction of cholesteryl ester transfer activity. Whereas one study reported that 4 g of DHA per day increased overall LDL particle size, another study in 16 patients with non–insulin-dependent diabetes using 2.5 g of omega-3 fatty acids daily for 2 months failed to demonstrate any significant change.13
Omega-3 fatty acids have also been shown to be capable of reducing blood pressure and rates of arrhythmia while improving coagulability profile and endothelial function. A meta-analysis by Bucher et al14 evaluating 11 controlled studies on 16,806 patients compared a control diet to one enriched with omega-3 fatty acids or supplements to provide omega-3 oils. They reported significant reductions in fatal infarction, sudden death, and total mortality in those using omega-3 fatty acids, without any difference noted between dietary source and supplement. Another study of 1871 men 42-60 years of age without any clinical evidence of cardiac disease reported that men with the highest amount of fish oils in their diets had a 44% lower incidence of acute coronary events as compared to those with the lowest intake of omega-3 oils after 10 years of follow-up.15 A double-blind, placebo-controlled trial of 233 patients with proven CHD compared placebo to 6 g per day of fish oil for 3 months and 3 g per day for 21 months. Both groups receiving supplements of fish oil had improvements noted in their angiograms and a moderate reduction in cardiovascular events overall.15
The GISSI Prevention Study16 evaluated the effect of using fish oil supplement (1 g/day) and vitamin E (300 mg/day) used alone or in combination in 11,324 randomly assigned individuals who were within 3 months of having an MI. Those who took the fish oil had a significantly lower incidence of death, nonfatal infarction, and nonfatal stroke at 42 months. There was a 20% reduction in the risk of death, a 30% reduction in cardiovascular death, and a 45% reduction in sudden death. This latter finding reached statistical significance at 4 months with a relative risk reduction of 0.47. The other findings did not reach significance until after 6-8 months.16 This benefit from fish oil use continued for the 5-year follow-up of the study.
The Physician’s Health Study evaluated the risk of sudden death in physicians with the highest as compared to the lowest amounts of blood long-chain n-3 fatty acid levels. Those in the highest quartile had significantly lower rates of sudden death with an adjusted relative risk of 0.19, as compared to those in the lowest quartile.17 No data were available as to the source of these omega-3 oils. Lastly, a prospective study of 4815 persons enrolled in the Cardiovascular Health Study reported that diets rich in tuna or other broiled or baked fish—but not fried fish—correlated with higher levels of plasma n-3 fatty acids. Over a 12-year follow-up, those individuals who ate tuna or other broiled or baked fish five or more times a week had the lowest incidence of atrial fibrillation, with a lesser but significant benefit also noted for those who ate this type of fish at least once each week. Of note, eating fried fish had no effect on the rate of developing atrial fibrillation in this study.18
Although the benefits from consuming diets high in omega-3 oils or using supplements to provide a similar benefit appear to be strong, there are also some side effects that need to be considered. Diets rich in fish oil are associated with a higher level of lipid peroxides with a resultant decline in levels of vitamin E. This may require a vitamin E supplement to maintain normal levels. Fish oils have been associated with symptoms of nausea, belching, abdominal bloating, flatulence, diarrhea, and even weight gain. Some have described a “fishy” taste in their mouths. Although there have been reports of changes in glucose metabolism and even a worsening of glucose control in patients with diabetes, a meta-analysis evaluating 26 studies failed to demonstrate any adverse effect on hemoglobin A1c levels in patients with diabetes.19
Recently, multiple quality studies have become available regarding the use of hormones in postmenopausal women. Due to the results of studies such as the Women’s Health Initiative (WHI), which demonstrated an increased risk of CHD, cerebrovascular accidents, pulmonary embolism, and invasive breast cancer in the hormone treatment group, many women are increasingly using alternative therapies for menopausal symptoms.20 Menopausal symptoms of vasomotor instability and atrophy of the urogenital epithelium and skin lead approximately 40% of menopausal women to seek medical attention.21 For many clinicians, attempts to withdraw hormone replacement therapy secondary to the findings of these large, randomized controlled trials from women who have found relief from symptoms are met with resistance and even outright refusal. In a recent population-based telephone survey, 22.1% of women were noted to use alternative therapies for menopausal symptoms, of whom 89-100% found various alternative therapies useful.22
Hot flashes are transient subjective flushing, blushing, or warmth sensations of the face, neck, or upper extremities. They may be accompanied by palpitations, headaches, dizziness, fatigue, diaphoresis, and sleeplessness. They can be debilitating, with approximately 15% of women limiting their daily activities because of hot flashes. The pathophysiology of the hot flash is complex and incompletely understood, but is commonly ascribed to estrogen withdrawal and loss of estrogen feedback in the hypothalamus with possible effects on the thermoregulatory centers. Even 10 years after cessation of menopause, 85% of women may have hot flashes, although the majority subside.23
Black cohosh (Actaea racemosa) is purported to be beneficial for premenstrual symptoms and in relief of climacteric complaints such as hot flashes. It has been used for centuries in Chinese medicine to relieve a large variety of symptoms, and Native Americans have used it specifically for common reproductive and endocrinologic problems in women’s health, such as painful menses and childbirth. The presence or absence of an estrogenic effect has been a matter of contention in the literature. Reports range from an ability of phytoestrogens in black cohosh to bind to the estrogen receptor and suppress leutinizing hormone to no estrogenic or endocrine effect, to a primarily relaxing effect on uterine tissue. Some black cohosh preparations have been found to contain phytoestrogens and small amounts of salicylic acid, which may explain potential mild estrogenic effects and anti-inflammatory effects.24
Black cohosh preparations are standardized to contain 1 mg of terpene glycosides in each 20-mg dose. The studies to support the use of black cohosh for hot flashes suffer from being small, lack randomization, and often do not define the women’s hormonal status. A majority of the studies are German, and the German Commission E for herbal regulation has approved black cohosh for this and other purposes based on available data and reported low toxicity. The American College of Obstetricians and Gynecologists supports this use for up to 6 months.25 A 2002 review of the literature available regarding the herb concluded that it may be effective as a standardized preparation using black cohosh root, although the formulation had changed over the time of the four trials meeting stringent inclusion criteria, which spanned from 1985-2001.26 However, three of the four short-term, randomized controlled trials reported no difference versus placebo, and further commentary concluded that no consistent evidence is available showing black cohosh to benefit women with menopausal symptoms.27 A major concern identified in the review was the short study durations and safety questions about long-term use and the possible stimulation of breast and endometrial tissue. This question remains unresolved, as at least one study has shown no stimulation of breast cancer cell lines by black cohosh.28
At this time it would seem prudent not to consider black cohosh safe in women with a personal or family history of breast cancer until more definitive studies have been done. Other common side effects include gastrointestinal upset, headache, and dizziness. Women should not take the formulation for more than 3-6 months until more substantial data are available. Also, women who are pregnant or breastfeeding should avoid black cohosh, and a hypothetical risk of miscarriage does exist.29 Case reports of acute hepatitis and auto-immune hepatitis related to ingestion of black cohosh can be found in the literature, although a recent systematic review of the safety of black cohosh concluded that causality could not be determined and available evidence suggests that adverse events are rare.30 It is unclear whether black cohosh is effective, and further studies are needed. Black cohosh remains an option until well-designed studies are available, as it has little reported toxicity when limited to short-term use in the appropriate patient.
Garlic (Allium sativum) may have antimicrobial, antioxidant, anticoagulant, hypoglycemic, antihypertensive, and lipid-lowering properties, and it has been employed for each of these uses. However, its purported positive effect on lipids has been highlighted recently in the popular media, especially with the more stringent National Cholesterol Education Program (NCEP) interim guidelines on management of cholesterol. These state that an LDL goal lower than 70 mg/dL is a therapeutic option in high-risk persons.31 Much of the evidence is contradictory regarding garlic’s use for this purpose. Garlic is composed of alliins (alkylcysteine sulfoxides), which are converted to allicin on cutting; it is allicin that has the characteristic odor. This drug has been demonstrated to have antibacterial, fibrinolytic, and lipid-lowering effects, believed to result from inhibition of key enzymes in cholesterol biosynthesis. The dosage used and standardization vary between trials, but 800-900 mg of garlic powder tablets daily was used in several of the studies.
A 1993 meta-analysis of 28 studies that selected five of sufficient merit for analysis found that garlic decreased total serum cholesterol by about 9%. However, subsequent analysis found that although the studies were randomized and placebo-controlled, they were weakened by a lack of standardization of the method of cholesterol analysis, diet, and laboratory measurements.32 A 2001 systematic review identifying 45 randomized controlled trials of garlic found that it reduces LDL, triglycerides, and total cholesterol to a small degree without affecting HDL. This large systematic review also identified a significant decrease in platelet aggregation, mixed results regarding blood pressure effects, and no significant antihyperglycemic effects. Adverse effects included malodorous breath and body odor.
Of the pooled trials, only one assessed efficacy of blinding and found it to be unsuccessful, possibly related to the previously named adverse effects.33 A multicenter, randomized, placebo-controlled trial of 50 patients treated with 900 mg per day of garlic treatment for 12 weeks and placed on standardized diets found no statistically significant reduction in cholesterol in patients with hypercholesterolemia. Although this study demonstrated that only 11% of those ingesting garlic suffered from the side effect of odor, the authors concluded that garlic tablets were unlikely to be useful for hypercholesterolemia.34 A systematic review of the literature searching for herb-drug interactions found that garlic decreased blood concentrations of warfarin and produced hypoglycemia in patients taking chlorpropamide.35
Garlic inhibits CYP3A4 and has led to severe toxicity in patients with HIV taking ritonavir, and to decreased blood levels of the protease inhibitor saquinavir.36 Currently, the evidence available is not satisfactory to conclude whether or not garlic is effective for hypercholesterolemia. Adverse drug effects seem minimal, but herb-drug interactions have been reported. This becomes particularly problematic in an older population already at risk for polypharmacy. It is apparent that even in the positive studies of garlic, the effect is modest and additional quality studies are needed.
Individuals are searching for “natural” remedies for health care problems with increasing frequency. This may in part be due to recent negative publicity about adverse effects of prescription medications, including the withdrawal of rofecoxib from the marketplace. However, in the era of evidence-based medicine in which we practice, conclusions regarding these often ancient remedies lack the stringent scientific data to which we have become accustomed. Researchers have taken notice of this, and quality meta-analyses and better quality studies, such as the recently released SU.VI.MAX randomized, placebo-controlled trial of the health effects of antioxidant vitamins and minerals, are being published with increasing frequency.37 Until the results of higher quality trials become available, the risk-benefit profile should be considered on an individual basis with the knowledge that many of these “natural” remedies are not benign, and we must strive as clinicians to educate our patients about the best available evidence.