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Health Protocols

Immune Senescence

Integrative Interventions

Cistanche

The Cistanche deserticola (C. deserticola) plant has been used historically in traditional medicinal systems as a remedy for chronic infections and other illnesses. C. deserticola contains an array of bioactive compounds (Zhang 2014; Li 2008; Jiang 2009), some of which have been shown to have antiviral, antibacterial, anti-tumor, and immunomodulatory properties (Fu 2008; Zhai 2007).

In animal models of accelerated aging and immune decline, C. deserticola extract extended lifespan and reversed multiple laboratory indicators of immune senescence. Cistanche supplementation led to significant increases in naïve T cells and NK cells, reductions in memory T cells, and decreased levels of the inflammatory cytokine interleukin-6 (IL-6) (Zhang 2014; Abe 1994; Butterfield 2005).

Cistanche extract’s ability to improve immune function was examined in a 12-week trial in 25 aging individuals. Cistanche was the principal ingredient in the test product, which also included vitamin E, vitamin B6, coenzyme Q10, zinc, and fucoidan. The product conferred multiple benefits including increased helper T cells, improved relative proportions of types of T cells, and greater NK cell activity. There were also considerable improvements in tests of vascular function, and study volunteers reported decreased fatigue (Yonei 2011).

Reishi

Reishi (Ganoderma lucidum) is a medicinal mushroom that has been used in Asia for over 2000 years for immune system support. Reishi contains polysaccharides, triterpenoids, and other potentially therapeutic compounds. Laboratory and animal studies have shown reishi polysaccharides have immunomodulatory, anti-tumor, and cell-killing effects that appear to derive in part from their ability to influence T cells, NK cells, and macrophages (Batra 2013; Jin 2012; Xu 2011).

The beta-glucan portion of reishi polysaccharides has been found to stimulate both innate and adaptive immune responses (Jin 2012). Other reishi compounds have demonstrated antiviral properties, including activity against herpes simplex virus, hepatitis B virus, and Epstein-Barr virus. Reishi constituents have also been shown to inhibit the growth of yeast and E. coli bacteria (Avtonomova 2014; Li 2005; Ma 2011; Iwatsuki 2003; Li 2006; Vazirian 2014).

These immune-enhancing effects may help explain the results of an animal study in which reishi-supplemented mice outlived control mice by a significant margin (Wu 2011). In another study, a product containing green tea extract and a reishi extract high in polysaccharides and triterpenes stimulated the proliferation of immune cells, including B cells, T cells, and NK cells, and inhibited malignancy in mice (Chen, Zhang 2007).

A rigorous review of controlled clinical trials found cancer patients who used reishi along with chemotherapy and radiation were 50% more likely to respond favorably to their cancer therapy than patients who underwent these treatments without reishi. Reishi also increased the percentages of several subsets of T cells and may have slightly increased NK cell activity. The authors concluded that reishi could be considered “as an alternative adjunct to conventional treatment in consideration of its potential of enhancing tumour response and stimulating host immunity” (Jin 2012).

Pu-erh Tea Extract

Pu-erh tea, made from select leaves of Camellia sinensis, has a long history of use in ancient Chinese medicine for anti-aging and preventing infections (Lv 2014; Zhang 2012; Chu 2011). Pu-erh tea is rich in polyphenols and other bioactive molecules, including theabrownins, a unique group of compounds developed during the post-fermentation process (Lee 2013). Laboratory, animal, and clinical studies have demonstrated the ability of Pu-erh tea extract to help improve multiple features of immune senescence.

In senescence-accelerated mice (a model for aging), supplementation with Pu-erh tea extract markedly increased fractions of naïve T cells, cytotoxic T cells, and NK cells. In addition, elevated levels of the inflammatory cytokine IL-6 fell by 43%. Based on these results, the authors concluded that long-term consumption of Pu-erh tea may increase resistance to infection and cancer in aging individuals (Zhang 2012).

In a randomized controlled trial in 90 individuals with increased susceptibility to chronic low-level inflammation due to metabolic syndrome, Pu-erh tea extract supplementation plus diet and lifestyle advice was compared with diet and lifestyle advice alone. In the pu-erh tea extract group, levels of the inflammatory markers C-reactive protein, tumor necrosis factor-alpha, and IL-6 significantly decreased, while levels of IL-10, an anti-inflammatory molecule, increased; there were no significant changes in levels of these markers in the group receiving only diet and lifestyle advice (Chu 2011; Moore 2001).

In a laboratory study, Pu-erh tea inhibited proliferation and induced programmed cell death (apoptosis) in cancer cells. In an animal component of this study, mice treated with Pu-erh tea had reduced tumor volumes and fewer lymph node metastases than untreated mice. In addition, levels of IL-6, IL-12, and tumor necrosis factor-alpha were lower in Pu-erh-treated mice than in control mice. In this study, higher doses of pu-erh tea produced greater anti-cancer effects (Zhao 2014).

Enzymatically Modified Rice Bran

Enzymatically modified rice bran, a derivative of rice bran, has been shown to enhance the number and function of immune cells, particularly NK cells (Perez-Martinez 2015; Cholujova 2013; Ghoneum, Abedi 2004; Weiskopf 2009). This specially modified rice bran is a source of the immune-enhancing polysaccharide arabinoxylan (Choi 2014), which has been shown to prevent viral infections of the upper respiratory tract in individuals aged 70 to 95 (Maeda 2004). Polysaccharide fractions of enzymatically modified rice bran have also demonstrated antibacterial and anti-cancer properties (Kim 2007). In fact, several researchers have suggested enzymatically modified rice bran may be beneficial as an adjuvant cancer treatment (Perez-Martinez 2015; Ghoneum, Badr El-Din 2014; Ghoneum 2013).

A series of laboratory and animal experiments showed enzymatically modified rice bran increased the activity of several immune cells including neutrophils, monocytes, macrophages, and dendritic cells (Cholujova 2009; Ghoneum 2011; Ghoneum, Matsuura 2004; Ghoneum 2008; Ghoneum, Agrawal 2014). In a 2013 study on multiple myeloma patients, supplementation with an enzymatically modified rice bran product was shown to increase NK cell activity (Cholujova 2013). Enzymatically modified rice bran also increased susceptibility of cultured breast cancer cells to a chemotherapy agent by over 100-fold (Ghoneum, Badr El-Din 2014).

Dehydroepiandrosterone (DHEA)

Dehydroepiandrosterone (DHEA) is a steroid hormone that plays a major role in healthy immune system functioning (Buford 2008; Weksler 1993). DHEA levels decline markedly with age. By age 80, DHEA levels fall to 10‒20% of their peak values (Kroll 2015; UMMC 2014).

A clinical trial in men with an average age of 63 and low serum DHEA-sulfate (DHEA-S) levels found that DHEA status was rapidly corrected with oral supplementation. Compared with placebo, DHEA treatment resulted in improved immune parameters, including monocyte levels, B- and T-cell function, and NK-cell levels (Khorram 1997). In a small observational study of 38 participants, salivary DHEA levels were positively correlated with salivary bactericidal activity, a measure of innate immune function (Prall 2015). Another observational study noted an association between low levels of DHEA and high levels of IL-6, an inflammatory cytokine implicated in immune senescence. Furthermore, DHEA inhibited IL-6 production by immune cells taken from study participants (Straub 1998; Varadhan 2014). According to a study in aged mice, DHEA may also enhance the immune response to influenza vaccine (Danenberg 1995).

DHEA plays a critical role by serving as a counterweight to cortisol. Cortisol is an adrenal hormone with immunosuppressive properties, while DHEA may have direct immunostimulating properties: in a laboratory study of white blood cells from donors who were at least 65 years old, DHEA treatment reversed the age-related reduction of specific receptors on immune cells and increased immune cell responsiveness (Corsini 2005). Although DHEA levels decline dramatically with age, cortisol levels remain relatively constant, leading to an imbalance of these two hormones that is believed to contribute to immune senescence (Buford 2008; Buoso 2011).

Zinc

Zinc is an essential trace mineral that is critical to healthy immune function. Zinc deficiency is common in older individuals, and causes changes in immune function that resemble those seen in immune senescence (Cabrera 2015; Maywald 2015). Immunological alterations associated with zinc deficiency include diminished thymus function, decreased antibody response to vaccines, and impaired function of phagocytic and NK cells (Haase 2009; Cabrera 2015).

In a study in healthy older volunteers, daily intake of 45 mg zinc for one year resulted in a 67% reduction versus placebo in incidence of infections. Levels of tumor necrosis factor-alpha, an inflammatory cytokine, were also greatly reduced in those taking zinc (Prasad 2007). In a study of older individuals in nursing homes, residents with normal zinc levels had a significantly lower incidence of pneumonia compared with zinc-deficient individuals. Zinc-replete individuals also had shorter pneumonia duration and 50% lower usage of antibiotics, as well as lower all-cause mortality (Meydani 2007). A controlled clinical trial in aged individuals showed supplementation with 45 mg zinc per day for six months decreased plasma markers of inflammation, including IL-6 and C-reactive protein (Bao 2010).

Vitamin E

Sufficient vitamin E is critical for maintaining efficient immune function. In fact, a variety of animal studies have shown vitamin E deficiency can trigger immune suppression. Clinical evidence has shown vitamin E supplementation can increase resistance to infection, especially in older individuals (Wu 2014; Wu 2008; Han 2006).

In a study in elderly men and women, supplementation with 200 mg per day vitamin E significantly enhanced immune parameters including neutrophil, T-cell, B-cell, and NK-cell function, bringing their values close to those of younger healthy adults (De la Fuente 2008).

Increased vitamin E intake has been shown to restore the decline in T-cell function associated with aging. This improvement in T-cell function results from vitamin E’s direct impact on T cells as well as inhibition of prostaglandin E2, a mediator of inflammation and a T-cell suppressor (Wu 2014; Wu 2008; Han 2006). In a mouse model, vitamin E supplementation reversed the age-associated decline in naïve T-cell function (Adolfsson 2001).

Fucoidan

Certain Japanese populations have among the longest life expectancies in the world. Regular consumption of brown seaweed rich in a compound called fucoidan may contribute to their longevity. Studies have shown fucoidan possesses immune-enhancing, anti-inflammatory, antiviral, and anti-tumor properties (Jin 2014; Negishi 2013; Kyung 2012; Lee 2015).

Evidence from a 2014 laboratory and animal study indicates fucoidan may induce anti-tumor immune activity and increase the effectiveness of an experimental anti-tumor vaccine. Based on their findings, the study authors suggested fucoidan may be useful as a component of anti-cancer vaccines in the future (Jin 2014).

In a study in elderly Japanese volunteers, fucoidan supplementation was found to increase the immune response to the seasonal influenza vaccine. Compared with a placebo group, volunteers taking fucoidan had higher influenza virus-specific antibody levels and increased NK-cell activity five weeks after receiving the flu vaccine. These findings suggest fucoidan may reduce incidence of infection and prevent serious health problems in aging individuals with poor immune function by increasing vaccine effectiveness (Negishi 2013).

Tinospora cordifolia

Tinospora cordifolia (T. cordifolia), a medicinal herb used in traditional Ayurvedic medicine, has been the subject of considerable scientific research. Several chemical constituents that enhance immune function have been isolated from T. cordifolia (Aranha 2012; Sharma 2012; Bala, Verma 2015; Bala, Pratap 2015).

The polysaccharides from T. cordifolia are of particular interest. One of these complex carbohydrates, an arabinogalactan, has been shown to enhance dendritic cell maturation and the ability of these cells to kill cancer cells. Another T. cordifolia polysaccharide, an alpha-glucan, demonstrated the ability to activate NK cells, B cells, and T cells, eliciting a dose-dependent increase in their tumor cell-killing function (Nair 2004; Pandey 2014).

Animal and clinical studies have demonstrated T. cordifolia’s powerful immune effects in a range of conditions. In a randomized clinical trial in surgical patients with suppressed immune function, half received usual care alone while half received usual care plus T. cordifolia supplements. Neutrophil function normalized in the T. cordifolia recipients but not in controls. Septicemia, an infection in the bloodstream and a serious complication of surgery, was evident in 50% of controls but in none of those who received T. cordifolia (Rege 1993). In rats, T. cordifolia decreased arthritic inflammation and bone and cartilage damage, and also reduced levels of inflammatory cytokines, including tumor necrosis factor-alpha and IL-6 (Sannegowda 2015).

N-acetylcysteine

N-acetylcysteine (NAC) is a form of the sulfur-containing amino acid cysteine, which is a precursor of glutathione, an important facilitator in metabolic detoxification (Brosnan 2006; Santus 2014; Millea 2009). Glutathione plays a critical role in regulating inflammatory responses, particularly in the lungs. It is essential for some immune functions, including proliferation of T cells and the cell-killing activity of neutrophils and dendritic cells. Decreased cellular levels of glutathione are linked to increased susceptibility to infection (Ghezzi 2011).

In a controlled clinical trial in 262 individuals at high risk of influenza (flu) and flu-like illness, NAC supplementation at a dosage of 600 mg twice daily for six months resulted in a significant decrease in frequency and severity of flu and flu symptoms, such as cough, sore throat, headache, and muscle and joint pain. NAC’s ability to protect against flu symptoms was especially evident during the winter season. Of those who tested positive for influenza virus infection during the study, only 25% in the NAC group developed symptomatic illness compared with 79% in the placebo group (De Flora 1997). This same NAC dosage in dialysis patients, over eight weeks, resulted in marked reductions in levels of inflammatory markers, including C-reactive protein, tumor necrosis factor-alpha, and IL-6 (Purwanto 2012).

Andrographis paniculata

Andrographis paniculata is a traditional Chinese medicinal plant used to treat infection, colds, fever, and inflammation. In a 2010 study in tumor-bearing mice, Andrographis paniculata and one of its active constituents, andrographolide, enhanced the ability of NK cells and other immune cells to destroy cancer cells (Sheeja 2010; Ji 2005).

Reduced vaccine effectiveness is a prominent feature of immune senescence (Goronzy 2013; Grubeck-Loebenstein 2009; McElhaney 2012), and evidence suggests Andrographis paniculata may improve immune response to vaccines. In a study in mice, oral Andrographis paniculata extract and andrographolide both enhanced antibody production and activated immune cells in response to a Salmonella vaccine (Xu 2007).

Beta-Glucan

Beta-glucans are polysaccharides (carbohydrates) found in the cell walls of bacteria, fungi, grains including oats, and algae. Beta-glucans are among the active ingredients responsible for the immune modulating benefits of medicinal mushrooms such as reishi (Chan 2009; Karumuthil-Melethil 2014; Aleem 2013).

Beta-glucans have been found to modulate multiple aspects of immune activity, with notable anti-tumor and antimicrobial properties (Vannucci 2013; Chen, Seviour 2007; Dalonso 2015). A 2013 review of studies found plant extracts containing beta-glucans improve survival rates and quality of life in cancer patients. This review also found that beta-glucan extracts reduced side effects of chemotherapy and radiotherapy in several different forms of cancer (Aleem 2013).

Tumor cells evade the immune system through mechanisms that suppress immune function and induce immune tolerance (Liu 2009). One study showed beta-glucan may help overcome this barrier to cancer cell elimination by decreasing the suppressive function of regulatory immune cells that have been affected by tumor signaling (Ning 2016).

Lactoferrin

Lactoferrin is an iron-binding protein found in body secretions including breast milk, saliva, tears, nasal secretions, and intestinal fluids, as well as in neutrophils. Lactoferrin’s antibacterial effects include damaging microbial cell membranes and binding and isolating iron, which is needed by nearly all bacteria to grow and thrive (Siqueiros-Cendon 2014; Legrand 2008). The iron-free form of lactoferrin (apolactoferrin) is a potent iron-binding protein and has been shown to have antibacterial effects (Siqueiros-Cendon 2014; Zakharova 2012; Luna-Castro 2014; Dionysius 1993).

Lactoferrin possesses direct antimicrobial activity against a wide variety of microorganisms including bacteria, viruses, fungi, and parasites (Siqueiros-Cendon 2014; Legrand 2008; Valenti 2005; Caccavo 2002). In an animal study, 69% of mice pretreated with intravenous lactoferrin survived for 30 days after being given a lethal dose of toxic E. coli bacteria, whereas only 4% of control mice survived (Zagulski 1989).

Vitamin C

Vitamin C supports the function of both the innate and adaptive immune systems and plays an important role in the defense against bacteria and viruses. In addition to stimulating immunity, vitamin C also appears to restrain excessive immune activity, perhaps in part by interfering with the synthesis of inflammatory cytokines (Sorice 2014; Pohanka 2012; Holmannova 2012).

Emerging evidence suggests vitamin C supplementation may help maintain immune function as we age. In a mouse model of vitamin C deficiency and premature aging, a higher dose of supplemental vitamin C (equivalent to about 1300 mg per day in a 175 lb person) was compared with a lower dose (equivalent to about 130 mg per day in a 175 lb person). After one year, mice receiving the higher dose of vitamin C exhibited better thymus gland preservation and greater immune cell counts than mice receiving the lower dose (Uchio 2015).

Results from a large analysis of placebo-controlled trials indicate vitamin C supplementation reduces the duration of colds, with an 8% reduction in adults and a 14% reduction in children. In addition, the analysis found vitamin C supplements reduced the incidence of colds by half in people undergoing extreme physical exertion, such as marathon runners (Hemila 2013).

Whey Protein

Whey is the liquid separated from the curds during the cheese making process. Products derived from whey have demonstrated immune-modulating properties (Krissansen 2007; Rusu 2009). Whey protein is especially rich in precursor amino acids involved in the synthesis of glutathione, a powerful free radical scavenger with anti-inflammatory properties. Glutathione is essential for both innate and adaptive immunity (Krissansen 2007; Kloek 2011; Kent 2003; Micke 2001). (N-acetylcysteine, described earlier, is also a glutathione precursor.)

A pilot study compared the effects of whey protein and soy protein on vaccine responsiveness in 17 healthy senior citizens (Freeman 2010). The participants were randomly assigned to consume either whey protein or soy protein for four weeks. They then received the pneumococcal vaccine and continued protein supplementation for four weeks after vaccination. Compared with those who received soy protein, people who received whey protein exhibited a more robust antibody response to 12 of 14 types of pneumococcal bacteria, including the four most harmful bacterial types. The investigators concluded, “ Whey protein supplementation is a promising supplement to stimulate the immune response to vaccine in senior citizens and possibly to counteract [immune senescence] while larger studies are warranted.

In another clinical trial in 12 healthy volunteers, a single dose of a whey extract was a more effective immune activator than placebo, rapidly increasing phagocytic (microbe-engulfing) activity of certain immune cells and mobilizing new NK cells into circulation (Jensen 2012). In a study in cultured neutrophils, whey protein extract had no immediate effect but instead had a priming effect, heightening neutrophil activity 24 hours later (Rusu 2009).

Garlic Extract

Garlic, well known for its ability to improve cardiovascular risk factors, also has immune-modulating and immunostimulatory properties, as well as anti-tumor effects (Ebrahimi 2013; Purev 2012; Kyo 2001).

A detailed review of data from published clinical trials found garlic supplements significantly reduce the number, duration, and severity of upper respiratory tract infections. This review also found garlic supplements stimulate immune function by increasing macrophage activity, numbers of NK cells, and production of T and B cells (Ried 2016). In a clinical trial, 120 healthy participants, 21–50 years old, were assigned to use 2.56 g aged garlic extract or placebo daily for 90 days during cold and flu season. Garlic supplementation was associated with reduced cold and flu severity, as well as increased cytotoxic T-cell and NK-cell proliferation and activity (Percival 2016). In animal research, garlic has been shown to increase antibody production and enhance the cell-killing activity of macrophages, cytotoxic T cells, and NK cells (Ghazanfari 2000). Other animal research suggests aged garlic extract may prevent immune suppression associated with psychological stress (Kyo 1999).

Interestingly, garlic has also been demonstrated to suppress the overactive immune response associated with allergic reactions. Data from experimental studies indicate aged garlic extract may reduce histamine release and modify the function of immune cells involved in allergic reactions (Kyo 2001).


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This information (and any accompanying material) is not intended to replace the attention or advice of a physician or other qualified health care professional. Anyone who wishes to embark on any dietary, drug, exercise, or other lifestyle change intended to prevent or treat a specific disease or condition should first consult with and seek clearance from a physician or other qualified health care professional. Pregnant women in particular should seek the advice of a physician before using any protocol listed on this website. The protocols described on this website are for adults only, unless otherwise specified. Product labels may contain important safety information and the most recent product information provided by the product manufacturers should be carefully reviewed prior to use to verify the dose, administration, and contraindications. National, state, and local laws may vary regarding the use and application of many of the treatments discussed. The reader assumes the risk of any injuries. The authors and publishers, their affiliates and assigns are not liable for any injury and/or damage to persons arising from this protocol and expressly disclaim responsibility for any adverse effects resulting from the use of the information contained herein.

The protocols raise many issues that are subject to change as new data emerge. None of our suggested protocol regimens can guarantee health benefits. The publisher has not performed independent verification of the data contained herein, and expressly disclaim responsibility for any error in literature.