Intestinal Permeability

Clinical Implications

The Intestinal Epithelial Barrier

The intestinal epithelium is the largest mucosal surface and provides an interface between the external environment and the human’s internal environment. Healthy, mature gut mucosa provide an essential epithelial barrier that permits the absorption of nutrients, electrolytes, and water but restricts the passage of larger, potentially toxic compounds from the lumen into systemic circulation. The intestinal epithelium mediates selective permeability through two major routes: transcellular and paracellular pathways. Transcellular permeability is predominantly regulated by selective transporters for amino acids, electrolytes, short-chain fatty acids, and sugars (Broer 2008, Ferraris 1997, Kunzelmann 2002). The paracellular route is the dominant pathway for passive solute flow across the intestinal epithelial barrier, and its functional state depends on the regulation of intercellular tight junctions (TJ) (Yu 2009). TJ are dynamic, multiprotein complexes that function as a selective/semipermeable paracellular barrier, which facilitates the passage of ions and solutes through the intercellular space while preventing the translocation of luminal antigens, microorganisms, and their toxins.

TJ serve as barriers and selectively regulate the passive diffusion of ions and small water-soluble solutes through the paracellular pathway. They are arranged in strands and are located in the apicolateral membrane of neighbouring epithelial cells, linking cells together (Laukoetter 2006). Several transmembrane proteins located in TJ strands include zona occludens-1 (ZO-1), occludin, tricellulin, junctional adhesion molecule, and the claudin family (Bazzoni 2003, Fanning 1998, Furuse 1993, Furuse 1998, Ikenouchi 2005, Morita 1999). Within the latter group, several members have been demonstrated in detail to specifically control paracellular barrier properties. Whereas some claudins (e.g., claudin-4 and -5) increase barrier function (Amasheh 2005, Van Itallie 2001), others such as claudin-16 induce paracellular channels (Kausalya 2006). TJ are supported by a dense perijunctional ring of actin and myosin that can regulate barrier function. In the presence of an intact epithelial cell layer, the paracellular pathway between cells remains sealed.

Intestinal Permeability

An impaired TJ system compromises the epithelial barrier and leads to a phenomenon called intestinal permeability (IP). An altered barrier function is accompanied by oxidative stress, inflammation, mucosal damage, and aberrant immune responses to antigens (Cereijido 2007, Fasano 2008). When the integrity of the TJ system is compromised, antigens can pass from the intestinal lumen to the gut submucosa through the paracellular pathway. This challenges the mucosal immune system, which in turn produces an immune response that is capable of targeting any organ or tissue (Fasano 2008, Groschwitz 2009).

Diseases Associated with Leaky Gut Syndrome

A fast-growing number of diseases are recognized to involve alterations in IP related to changes in TJ competency, including:

• type 1 diabetes (Mojibian 2009, Simpson 2009, Vaarala 2006);

• celiac disease (Dubois 2008, Duerksen 2005, Pearson 1982);

• inflammatory bowel disease (Heller 2005, Zeissig 2007);

• acute colitis (Boirivant 2008);

• Clostridium difficile-associated colitis (Nusrat 2001);

• irritable bowel syndrome (IBS) (Dunlop 2006, Zhou 2009);

• multiple sclerosis (Westall 2007);

• rheumatoid arthritis (Edwards 2008);

• asthma (Benard 1996, Hijazi 2004);

• liver disease (Cariello 2010, Farhadi 2008);

• atopic dermatitis (Rosenfeldt 2004);

• food allergy and sensitivity (Kalach 2001, Ventura 2006);

• chronic heart failure (Sandek 2007);

• autism (de Magistris 2010, D’Eufemia 1996);

• multiple organ dysfunction syndrome (Doig 1998); and

• post-trauma injury severity (Faries 1998).

TJ are also thought to be involved in cancer development and allergies (Cereijido 2007, Fasano 2001, Shen 2006).

Zonulin

The discovery of Zot, an enterotoxin elaborated by Vibrio cholerae that reversibly opens TJ (Fasano 1991), has increased understanding of the intricate mechanisms that regulate the intestinal epithelial paracellular pathway. Zonulin, a novel human protein analogue to Zot induces TJ disassembly and a subsequent increase in IP (Fasano 2000). Zonulin has been observed to be upregulated in several autoimmune diseases in which TJ dysfunction seems to be the primary defect (Clemente 2003, Drago 2006).

Intestinal Permeability Urine Test

Lactulose to mannitol ratio measurement is one of the methods most widely used to diagnose IP defects (Dastych 2008). It is based on an oral challenge with lactulose and mannitol, two non-metabolized sugar molecules. Both lactulose and mannitol are absorbed as whole molecules by the human small intestine. With a radius of 0.52nm, lactulose is too large for intracellular diffusion and therefore relies on paracellular diffusion for intestinal absorption. The intestinal capacity for absorption of lactulose is a direct measure of the tightness of junctional complexes. Mannitol is much smaller than lactulose with a molecular radius of 0.4nm. It is absorbed readily through mucosal epithelial cell membranes by passive diffusion (transcellular uptake) so its absorption is less dependent on intestinal integrity. Ingestion of lactulose and mannitol simultaneously controls for fluctuations in gastric emptying, intestinal fluid volume, and intestinal transit time, allowing direct measurement of the paracellular absorptive capacity of the gut. Attaining these molecules for measurement is easily performed with a six-hour collection of urine and the ratio between them are used as indicators of IP and mucosal barrier function.

Clinical Therapeutics for the Treatment of Intestinal Permeability

Food Restriction

The relationship between food allergies and IP is unclear. Patients with atopic food allergies have baseline permeability measurements that are higher than control levels according to lactulose to mannitol ratio measurement (Andre 1987). This finding suggests that IP may be a result of food allergy or may play a role in the pathogenesis of food allergy. Therefore, patients experiencing IP may benefit from the identification of hidden food allergies and their subsequent removal from the diet. A clearer relationship has been found between IP and the consumption of gliadin, a glycoprotein within gluten that is found in wheat and some other grains, such as oats, rye, barley, and millet. Gliadin has been shown to increase IP by releasing preformed zonulin (Clemente 2003, Drago 2006). Intestinal cell lines exposed to gliadin released zonulin in the cell medium with subsequent zonulin binding to the cell surface, rearrangement of the cell cytoskeleton, loss of occludin-zonula occludens-1 (ZO1) protein–protein interaction, and increased monolayer permeability (Drago 2006). Therefore, a gliadin-free diet could be an important dietary component of an IP treatment protocol.

Glutamine

Glutamine is the primary source of amino acids for the intestinal mucosa (Windmueller 1982). It is an important energy source for cells of the intestinal mucosa and has been shown to be conditionally essential for normal mucosal structure and function (Klein 1990). Deprivation of glutamine has been shown to decrease claudin-1, occludin, and ZO-1 expression in cell studies (Li 2004) while supplementation has been shown to improve intestinal barrier function in animal models of endotoxin-induced permeability (Dugan 1995). Numerous human clinical trials support these positive findings. In a prospective, double-blind, multiple-center study conducted on 120 patients submitted to major elective abdominal surgery, the addition of alanine-glutamine dipeptide (equivalent to 0.34 grams glutamine/kg/day) for 6 days minimized the intensity of the increase in IP during the postoperative period (Jiang 1999). Similar results were obtained in 20 patients exposed to severe burns. The administration of glutamine dipeptide (equivalent to 0.34 grams glutamine/kg/day) reduced the lactulose/ mannitol ratio by the third day and normalized it by the sixth day. Normal levels were maintained through the twelfth day of treatment (Zhou 2003). Peng (2004) confirmed these results by demonstrating that the accentuated increase in IP of 25 patients exposed to severe burns was reduced by the oral administration of 0.5 grams glutamine/kg/day. Finally, the administration of glycyl-L-glutamine (equivalent to 0.23 grams glutamine/kg/ day) prevented exacerbation of the increase in IP in patients with chronic intestinal inflammatory disease or with intestinal neoplasias. All patients who received total parenteral nutrition without the addition of glutamine experienced an increase in IP (van der Hulst 1993).

Polyunsaturated Fatty Acids

The integrity of intestinal barrier function is substantially affected by the fatty acid profile of membrane phospholipids (Zhao 2008). The proportion of saturated to unsaturated fatty acids and the ratio between omega-6 and omega-3 polyunsaturated fatty acids (PUFA) exert a considerable effect on membrane fluidity, eicosanoid synthesis, mucosal health, and epithelial barrier function (Calder 2008). The effects of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and gamma-linolenic acid (GLA) on IP have been reported in a number of studies. EPA has been found to be effective in supporting barrier integrity (Willemsen 2008), while improving TJ permeability through an increased expression of occludin (Jiang 1998, Yamagata 2003). DHA has also been found to be effective in supporting barrier integrity (Willemsen 2008), while affecting TJ permeability in a concentration-dependent manner (Usami 2003), increasing intestinal absorption (Kajita 2000, Usami 2003), and protecting against increased IP caused by methotrexate administration (Horie 1998). GLA has been found to improve TJ permeability associated with an upregulation of occludin (Jiang 1998, Yamagata 2003) while also affecting TJ permeability in a concentrationdependent manner (Usami 2003). When Usami (2003) combined their results with previous results, the effects of three identical dosages of PUFA on paracellular permeability was noted to be in the order of GLA ≥ EPA ≥ DHA (Usami 2001).

Probiotics

Probiotic bacteria can directly alter epithelial barrier function by influencing the structure of TJ. A cell study found that S. thermophilus and L. acidophilus independently increased transepithelial resistance (a sensitive measure of mucosal barrier), decreased permeability, and induced activation of occludin and ZO-1 (Resta-Lenert 2003). Similarly, conditioned medium from several bacteria strains were found to independently increase transepithelial resistance. B. infantis exerted the biggest effect, decreasing claudin-2 protein expression and increasing ZO-1 and occludin total protein expression (Ewaschuk 2008). An animal in vivo study demonstrated increased ZO-1 expression upon colonization with E. coli Nissle 1917 (Ukena 2007), a probiotic sold in Europe to prevent infectious diarrhea and treat functional bowel disorders (Zyrek 2007). Pretreatment with the E. coli strain significantly reduced dextran sulfate sodium-mediated dye uptake into the colonic mucosa, which indicates reduced IP. Increased permeability of the epithelial barrier can also be caused by apoptosis (Chin 2002) and probiotics have been found to modulate apoptosis initiation by harmful stimuli. S. boulardii pretreatment prevented enterohaemorrhagic E. coli-induced apoptosis in a cell study (Dalmasso 2006) and a cell study found that two proteins (p40 and p75) secreted from L. rhamnosus inhibited cytokineinduced apoptosis (Yan 2007). Additionally, apical or basolateral pretreatment with either p40 or p75 protected several cell lines from H2O2-induced disruption of barrier function, as measured by transepithelial resistance and paracellular permeability (Seth 2008).

The ability of probiotics to improve IP has been investigated in a number of human clinical trials. A randomized singleblind, placebo-controlled study in 30 IBS patients found that a probiotic- fermented milk containing L. acidophilus, B. longum, and other lactic acid bacteria decreased small bowel permeability (Zeng 2008). In addition, a double-blind, placebo-controlled, crossover study found that six weeks of treatment with a probiotic supplement containing L. rhamnosus 19070-2 and L. reuteri DSM 12246 decreased the lactulose to mannitol ratio in 41 children with atopic dermatitis, increased IP, and gastrointestinal symptoms (Rosenfeldt 2004).

Zinc

Zinc is a trace element that is essential for the survival and function of cells as an important component of DNA polymerase and other enzymes involved in cell replication and differentiation. Dietary zinc appears to play a critical role in the maintenance of normal IP and control of inflammation. Zinc deficiency has been shown to cause ulcerations of the small intestine (Mengheri 1999) and disrupt mucosal barrier function by inducing a decrease in transepithelial resistance and alterations of TJ, specifically with delocalization of ZO-1, occludin and the transmembrane proteins, beta-catenin, and E-cadherin (Finamore 2008). There are also preliminary human data showing the benefit of zinc supplementation in helping to repair intestinal integrity. In a randomized crossover trial, 10 patients were given 37.5 mg of prophylactic zinc carnosine to determine if this would prevent the loss of intestinal integrity when administered indomethacin (Mahmood 2007). No loss of intestinal integrity was reported in those receiving zinc, while controls experienced a three to four–fold increase in IP. The zinc-treated group also had 75% reduction in gastric and small bowel injury and 50% less villous shortening.

Potential Therapeutic Agents

Quercetin (Suzuki 2009), a naturally occurring flavonoid, and phosphatidylcholine (Mitzscherling 2009), an abundant phospholipid in the plasma, have been shown to enhance intestinal barrier functions in human cells. In addition, N-acetyl- L-cysteine (NAC), an antioxidant, detoxifier, and precursor for glutathione synthesis, has been shown to prevent increased IP following intestinal ischemia and reperfusion in animals (Sun 2002).

Given the evidence, reinforcing the intestinal barrier, and more particularly the paracellular pathway, may be an excellent therapeutic strategy to treat or prevent diseases driven by luminal antigens.

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Age Related Insomnia

Nutraceutical and botanical management strategies

Insomnia represents one of the most frequent types of complaints seen in the elderly (Buysse 2008). One large epidemiological survey involving over 9000 adults aged 60 years and older found that 23 to 34% had symptoms of insomnia while a further 7 to 15% stated they did not awake feeling refreshed (Foley 1995). Most elderly report sleeping on average seven hours a night suggesting that although the total amount of sleep time does not change as we age, alterations in sleep architecture are common (Neikrug 2010). is includes a decrease in both deep sleep (stages 3 and 4 slow wave sleep) and rapid eye movement (REM sleep) as well as an increase in stage 1 (light) sleep (Fetveit 2009). Older individuals also have a reduction in endogenous melatonin production (likely due to a deterioration in the neuronal functioning of the suprachiasmatic nucleus-SCN) that in turn disrupts the normal wake sleep cycle (Pandi- Perumal 2005).

Other secondary factors leading to alterations in sleep also deserve consideration. is list includes but is not limited to medication use (i.e. beta blockers, corticosteroids, SSRI’s), painful conditions including arthritis and cancer, delirium, depression, dementia, Type 2 diabetes, obstructive sleep apnea, COPD, and restless leg syndrome (Cole 2007, McCrae 2009, Saddichha 2010). While benzodiazepines have been a prescriptive mainstay for use in older patients with insomnia, they are often fraught with potential side eff ects including drug dependence, cognitive impairment, daytime sedation, and an increased risk of falls due to a decrease in motor coordination (Wolkove 2007).

While newer generation hypnotic medications such as zopiclone may exhibit fewer side effects, it nonetheless can have a negative effect on body balance (Mets 2010), and according to the results of a recent study, chronic use of zopiclone over a 1 year time period may also increase sleep wake time, and reduce the duration of slow wave sleep (Sivertsen 2009). Integrative therapies, including melatonin, 5-HTP, L-theanine, GABA, magnesium, and several types of herbal medicines may represent a viable alternative for those with age related insomnia.

Melatonin

Melatonin (N-acetyl-5-methoxytryptamine) is a hormone that is synthesized in reply to neuronal signals arriving from the SCN of the anterior hypothalamus (Rios 2010, Wade 2008). This compound is secreted primarily by the pineal gland in response to darkness, described as the “opening of the sleep gate” (Srinivasan 2009). Research to date in older adults has supported the use of two types of melatonin: prolonged and rapid release.

Rapid release Melatonin and Age-related Insomnia

In a controlled clinical trial, 30 men and women over 50 years of age with both chronic insomnia and normal sleep patterns were randomized to receive capsules with either 0.1 mg, 0.3 mg, or 3 mg melatonin, or placebo 30 minutes before bedtime for 7 days. Treatments were separated by a 1 week washout period. Using polysomnography (PSG) on the last three nights of each treatment period, the researchers concluded that while melatonin did not improve sleep efficiency (i.e. the ratio of time spent in bed to the time spend asleep) in normal subjects, those with chronic insomnia had significant improvements in sleep efficiency at all three melatonin doses used, with the 0.3 mg dose triggering the strongest effect (p < 0.0001). The physiological dose acted primarily during the middle portion of the nights sleep and raised plasma melatonin levels to normal ranges (Zhdanova 2001).

Prolonged release (PR) melatonin: Quality of Sleep and Next Day Alertness in the Elderly

After a two week single blind run-in period, 354 elderly men and women (55 to 80 years of age) with primary insomnia were randomized to receive 2 mg of a prolonged release (PR) melatonin two hours before bedtime or placebo for three weeks. At the conclusion of the trial, those who took the melatonin had an improved percentage (26%) in the quality of sleep and morning alertness as recorded by the Leeds Sleep Evaluation Questionnaire (LSEQ) in contrast to placebo (15%) (p = 0.014). Sleep latency, as noted by the Pittsburg Sleep Quality Index (PSQI) results, improved in subjects employing the PR melatonin by 24.3 minutes compared to 12.9 minutes for the placebo group (p = 0.028). Quality of life as recorded by the WHO-5 Well Being Index was also improved in the active group (p = 0.034) (Wade 2007).

Magnesium, Melatonin, and Zinc on Insomnia in the Elderly

Magnesium along with zinc is crucial for the endogenous synthesis of melatonin according to the results of one study. Elderly men and women (n = 43; average age 78.3 years) living in a long term care facility were invited to participate in a double-blind, placebo controlled study of 60 days duration on melatonin, zinc and magnesium on primary insomnia. Each volunteer was randomized to receive a 100 g pear pulp food supplement with 5 mg melatonin, 225 mg of magnesium and 11.25 mg of zinc, or placebo 1 hour before bedtime for 2 months. At the conclusion of the trial, those employing the active supplement experienced an improvement in their overall PSQI scores compared to placebo (p < 0.001). Moreover, the LSEQ results confirmed that those employing the food-supplement mixture had better quality of sleep and greater ease getting to sleep (p < 0.001). Adverse effects were minimal with only two participants in the treatment group complaining of headache while one volunteer in the placebo group reported epigastric pain (Rondanelli 2011).

PR Melatonin, Zolpidem, and Side Effects in the Elderly

Drug-natural product interactions are always a concern to clinicians. In one study, the use of zolpidem and zolpidem with PR-melatonin significantly impaired memory and psychomotor performance 1 to 4 hours after administration in elderly volunteers (average age 59.4 years). In a simulated driving task, the number of collisions significantly increased at the 1 to 4 hour mark by 1.4 in the zolpidem (p < 0.05) group and worsened to 2.8 in the zolpidem-PR melatonin (p < 0.001) group compared to placebo respectively (Otmani 2008). Melatonin should be administered with caution among individuals already utilizing prescription medications for insomnia, regardless of whether the medication is of the benzodiazepine class or not. The results of the study also demonstrated that compared to placebo, PR melatonin on its own did not impair any of the variables tested.

5-HTP

5-hydroxy-L-tryptophan (5-HTP) is an intermediate compound in the synthesis of serotonin from the amino acid L-tryptophan. While research has shown that it is of benefit in treating depression (Byerley 1987), there have been limited studies supporting its efficacy in primary insomnia. Intravenous 5-HTP, when administered in a progressive fashion from 50 to 150 mg to one subject during the night, increased the time spent in REM sleep from 22.4 to 30.6% (Mandell 1965). In another study, eight healthy volunteers (7 women, 1 man; 17 to 21 years of age) were given 200 mg of 5-HTP at 9:15 pm and 400 mg of 5-HTP or placebo at 11:15 pm over a five day period. Those individuals using the 5-HTP had a significant improvement in their REM sleep (118 minutes) versus placebo (98 minutes) (p < 0.005) (Wyatt 1971).

GABA

GABA (γ-aminobutyric acid) is the main inhibitory neurotransmitter in the CNS (Chebib 1999). Recent reports have also suggested a role for the use of GABA derived from a naturally fermented strain of lactic acid bacteria in the treatment of general anxiety (Abdou 2006). In another study, insomnia in women with either menopause, senile dementia/depression, or autonomic ataxia were treated with GABA for two months. Using a modest amount of GABA (26.4 mg) in a defatted rice germ food 15 menopausal women (average age 49.4 years) achieved an overall significant improvement in the Kupperman symptom scale (46.2%) compared to 7.7% in placebo (p < 0.05). Moreover, 62.5% of the menopausal patients experienced an improvement in their sleeplessness (p < 0.01) (Okada 2000).

L Theanine and Insomnia

L-theanine is a naturally occurring amino acid found in Green tea (Camellia sinensis). Per 200 ml serving of green tea, the amount of L-theanine present varies from 25 to 60 mg (Cartwright 1954). Research scientists have determined that in healthy volunteers, 50 mg of L-theanine increases alpha band EEG activity relative to placebo over the 105 minute test period (Nobre 2008). In addition to promoting a relaxed mental state, L-theanine is important for sleep. One controlled study examined 22 men (12 workers and 12 students; average age 27.5 to 28 years) who were asked to consume four 50 mg tablets of L-theanine or placebo one hour prior to bedtime for six consecutive evenings. Total sleep time, as measured by actigraph, was not different between the overall active and placebo groups. However, the student sub-group demonstrated a significant improvement in both sleep efficiency and a reduction in wake after sleep onset (WASO) (p < 0.05) on actigraphic evaluation (Juneja 2004). If L-theanine affects age-related insomnia is not yet known.

Magnesium and Sleep:

A Critical Nutrient Deficiency in magnesium, whether through malabsorption, inadequate dietary intake, or multiple drug use, is common in the elderly (Barbagallo 2010). As such, poor quality sleep may be associated with magnesium status in the elderly. In a double-blind placebo-controlled crossover trial, 12 healthy volunteers (average age 68.1 years), were given an effervescent tablet containing 403 mg of magnesium oxide (10 mmol) in an increasing dose regimen from one tablet per day in the morning on the first day, one tablet in the morning and at noon on the second day, and one tablet three times a day (morning, noon, and evening) on the third day. The full dose or placebo tablets were taken for two weeks. At the conclusion of the trial, those taking the magnesium had a significant increase in the amount of slow wave sleep (16.5 minutes) compared to placebo (10.1 minutes) (p < 0.05). Delta (p < 0.05) and sigma (p < 0.01) frequency ranges, an indicator of non-REM sleep, were also improved with supplemental magnesium. Moreover, there was a significant reduction in cortisol levels by radioimmunoassay (8.3 ug/ml x min) in the first part of the night compared to placebo (11.8 ug/ml x min) (p < 0.01) (Held 2002).

Phytotherapy and Insomnia

Valerian

Valerian root (Valeriana officinalis) has a long history of successful use in humans as both a single agent and in combination with hops (Humulus lupulus) for the treatment of primary insomnia (Salter 2010). Several studies have considered its use in elderly populations greater than 60 years of age. One study involving 14 elderly women (average age 61.6 years) with poor sleep were given three tablets of 405 mg of aqueous valerian root extract (5-6:1) or placebo on the first night one hour before PSG analysis and then 1 tablet three times per day at mealtimes for seven consecutive days. PSG results concluded that those who took the valerian root had an increase in slow wave sleep from 7.7% to 12.5% (p = 0.0273) and a decrease in stage 1 sleep from 16.4% to 11.9% (p = 0.0273). As such, valerian is effective in improving non-REM sleep in older adults but there was no change in REM sleep, sleep onset time, or WASO. (Schulz 1994). However, two controlled clinical trials concluded that valerian was ineffective for acute sleep problems. One paper in five men and 11 women (55.9 years) concluded that 300 or 600 mg of valerian extract (3-6:1) given at 22:00 hours one night in six for a period of three weeks, was ineffective in improving sleep as measured by EEG and other psychometric measures (i.e. LSEQ) (Diaper 2004). In another controlled study, 16 elderly women (69.4 years) were given 300 mg of standardized valerian root extract (0.8% valerenic acid per 100 mg tablet) 30 minutes before bedtime for two weeks. Although compared to baseline, valerian did improve WASO (+ 17.7 minutes; p = 0.02) overall no change was noted in WASO, sleep efficiency, sleep latency, or self rated sleep quality compared to placebo. (Taibi 2009).

Valerian and Hops:

Better Combination for Seniors? In a pilot study, 30 patients (average age 57.6 years) with mild to moderate sleep disorders were given two tablets of valerian (250 mg per tablet) and two tablets of hops extract (60 mg per tablet) two hours before bedtime for two weeks. Using PSG as a tool to measure outcomes, researchers concluded that taking the herbal combination resulted in a significant reduction in sleep latency (36.1 to 24 minutes), total waking time (30.7 to 13.8 min) as well an increase in sleep efficiency (80.4 to 86.9%) (p < 0.05) (Fussel 2000).

Conclusion

According to Government of Canada statistics, approximately 4.8 million Canadians were 65 years of age or older in 2010. This figure is expected to reach 10.4 million by the year 2036 (Human Resources and Skills Canada 2011). With the latter increase in seniors as a population group, medical issues such as insomnia will inevitably increase. For clinicians working with elderly patients, several types of natural therapeutic options are available which can have a positive impact on the sleep architecture of seniors.

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