The mechanisms of gastrointestinal tract aging

Highlights:

• Aging causes many physiologic changes to every gastrointestinal tract part, influencing its motor function, histology, acid and enzyme secretion, as well as microbiome
• The gastric infection with Helicobacter pylori bacteria harms the gastrointestinal tract of elderly patients
• Aging is connected with patients weight changes, both malnutrition, and obesity

Introduction

Gastrointestinal (GI) diseases are a significant cause of morbidity in the elders. The GI tract is one of the most complex organ systems. Its diverse cells perform various crucial functions: secretion, digestion, absorption, excretion, and defense. The GI tract is a barrier to harmful components and pathogens and a harbor for many beneficial bacterial populations. Age-related physiological changes in the gut are individual and likely influenced by external factors. Aging causes many physiological changes to every GI tract element. These changes and other comorbidities associated with age increase the risk of gastroesophageal reflux disease, medicine-induced esophagitis, peptic ulcers, etc.

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The aging gastrointestinal tract

The gastrointestinal (GI) tract is one of the biggest interfaces (250–400 m2) between the host, environment, and antigens in the human body. During an average lifetime, 60 tons of food pass through the human digestive tract, together with countless microorganisms from the environment, which significantly threaten gut integrity (1). Its regular functioning keeps the body healthy due to the absorption of nutrients and drugs and protection against external pathogens. The GI tract is a multi-organ system with a large reserve capacity due to its length (2, 3). Thus, there are few GI function changes due to aging in healthy elders.

Nevertheless, some older people show reduced GI functions, including immune function, and more frequent bacterial and viral GI infections than younger people (4, 5). Aging is linked with structural and functional changes of mucosal defense, higher susceptibility to oxidative stress, lower ability to fight infections, and higher incidence of autoimmunity and inflammation. The gastrointestinal mucosal layer represents the first line of defense against external pathogens. Aged GI mucosa is susceptible to lesions that appear to be receptive to differential levels of sex hormones (6-9). Aging seems to be associated with an increase in function and motility GI disorders. Elders more often suffer from GI motor disorders such as dysphagia, dyspepsia, anorexia, and constipation. Nevertheless, aging per se appears to have only a minor influence on gastrointestinal functions, primarily due to the large reserve capacity of the GI tract (10).

Age-related changes in the gastrointestinal motor function

In elders aged 80-90, a significant decrease in the amplitude of peristaltic pressures is reported but not in duration and velocity. Elders also have an increased frequency of non-propulsive, often repetitive contractions. Morphological human studies have shown an age-related loss of enteric neurons in the esophagus. After 70 years of age, the number of neurons decreases while the neurons' sizes in the esophagus increase. The amplitude of peristaltic contractions in the lower esophagus of the elderly is reduced, and esophageal clearance after gastroesophageal reflux is impaired. Duration of gastroesophageal reflux episodes is longer in older persons, although the frequency of reflux episodes does not vary with age. Age also correlates inversely with lower and upper esophageal sphincter pressure and length and peristaltic wave amplitude and velocity (10, 11).

Research of gastric emptying of radiolabeled liquids or digestible solids showed that emptying is slower from the stomach in elders, even though the changes' magnitude was relatively small compared with younger patients (12). Peristalsis and gastric contractile force after eating meals are reduced in the elderly as well. Mechanisms leading to slower gastric emptying in elders are still not understood. Research in the aging enteric nervous system reported the phenomenon of age-related neurodegeneration of this system in rodents, where significant numbers of neurons in the myenteric plexus of the gastrointestinal tract are lost (10). It is suggested that chronic constipation problems or changes in the colon function are expected consequences of the aging process. Studies reported a tendency towards a longer mean colonic transit time in elders. Aging is linked with a reduction in the propulsive efficacy of the colon. Age-related changes in both the neurons and the receptors of the enteric nervous system might be one of the explanations (10).

Age influenced GI histological changes and the impact of H.pylori infection

The GI tract is an organ system characterized by dynamic cell proliferation. Aging GI tissues show visibly different phenomena from aged post-mitotic cells. In regularly fed elder rodents compared to young adult rodents, a state of hyperproliferation (a state of an abnormal, very high rate of cell proliferation, by rapid division) occurs in the stomach's epithelial cells, the small and large intestine. Interestingly, the number of apoptotic gastric and colonic mucosal cells was lower in older animals (13). Nutritional factors regulate cell proliferation of the GI mucosa layer, and restriction of calorie intake in aging rats is connected with a much higher apoptotic index in the jejunum and colon. The apoptotic index measures the number of apoptotic events/cell deaths expressed as a ratio or percentage of all cells population of interest (14). It suggests that nutritional modulation of mucosal cell proliferation is affected by aging (10).

Often observed pathological condition in older animals is the increased incidence of malignancies, such as gastric and colorectal cancers. The occurrence of digestive cancers in humans increases with age, and the peak incidence is in the seventh decade. The reasons behind these malignancies might be altered carcinogen metabolism and long-term exposure to cancer-causing agents causing mutation accumulation. For example, in colon cancer, initiation of genomic instability is caused by the loss or inactivation of the tumor suppressor gene – adenomatous polyposis coli (APC). It leads to the phenotypic appearance of an adenoma. This, in turn, sometimes leads to the accumulation of alterations in tumor suppressors (p53, DCC) and oncogenes, causing adenomatous polyps and later carcinoma (10, 15).

Helicobacter pylori infection significantly influences the state of the GI tract in elders. Studies including patients above 80 years of age without gastric atrophic lesions showed that gastric acid secretion remained normal with age in up to 90% of the patients. Advancing age did not influence gastric acid secretion in Helicobacter pylori-negative patients, while it was worse with age in H. pylori-positive patients (4, 16). There is also an increased prevalence of atrophic gastritis in elders, especially those above 80. It is known that both atrophic gastritis and intestinal metaplasia are strongly associated with H. pylori infection but not with aging itself. Atrophic gastritis results in decreased acid secretion, leading to bacterial overgrowth in the proximal intestinal tract and gastrointestinal malabsorption.

Reactive oxygen species (ROS) may cause DNA damage and mutations in the aging stomach and cancerogenesis. Chronic inflammation in the gastric mucosa can affect the expression of peptides such as leptin or ghrelin, involved in the regulation of food intake. Gastric inflammation induced by H. pylori infection raised gastric leptin expression, which caused satiety and led to lower body mass index (BMI). Ghrelin is a peptide responsible for controlling food intake and energy homeostasis in both humans and rodents. Curing the H. pylori infection increases plasma ghrelin levels, increasing appetite and weight gain. Chronic gastric inflammation and dysregulation in leptin and ghrelin expression are suggested to play a role in anorexia in older patients (10, 17).

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Impact of healthy aging on GI microbiome

The largest population of bacteria in the human body resides in the colon (more than 1011 organisms/g of wet weight). This microbiome consists of mostly anaerobic bacteria (18). Gut microbiota adapts to human life in a continuous, dynamic process essential for maintaining health by procuring nutrients and protecting against pathogens. In early childhood, the gut microbiota composition is highly vulnerable. It stabilizes in adulthood and returns to vulnerability after the sixth decade of life (19). Gut microbiota is constantly exposed to numerous influencing factors: diet, lifestyle, medications, comorbidities, and the process of aging itself. For example, a study of the fecal microbiota in 161 elders showed substantial variability in subjects' microbiota composition. Nevertheless, in general, a larger proportion of phylum Bacteroidetes and a lower proportion of phylum Firmicutes compared to younger adults was observed (20).

In the elderly, gut microbiota composition shifts may also contribute to gastrointestinal and systemic morbidities. The adaption of gut microbiota throughout a human life is a key factor in maintaining health, so interventions to restore a healthy gut microbiota composition may potentially improve health and disease outcomes in the elderly (21). Visible changes in the GI tract microbiota composition were shown in relation to nutrition, medicine intake, living conditions, ongoing immunosenescence, and inflammatory processes (19). Older people also may have reduced dentition and reduced chewing strength, which impacts their diet which becomes less various. It can thus lead to a limited range of nutrient intake to support microbial growth. Moreover, as mentioned above,  the intestinal motility may decrease with age, leading to longer colonic transit times, thus altering the dynamics of nutrient turn-over and consequently the microbiota composition (19).

Age-related weight changes

Increased body weight and body mass index with age are observed in developed countries. It happens until around 60 years of age, when BMI drops. The proportion of intra-abdominal fat, related to increased morbidity and mortality, increases with age. A gradual decline in energy intake and total daily energy expenditure is apparent, mostly due to decreased physical activity and basal metabolic rate. In the more fragile elderly population, the rapid globalization of society has resulted in multiple forms of malnutrition. The World Health Organization defines it as a "double burden of malnutrition", because of the coexistence of undernutrition, along with overweight, obesity or diet-related diseases (8). Healthy older people may have lower appetites due to a decreased stomach capacity and reduced gastric emptying. Furthermore, aging can reduce the number of taste buds, resulting in deterioration of the sense of smell (8).

Weight loss in older adults is able to reduce morbidity from arthritis, diabetes, reduce cardiovascular risk factors and improve well-being. In contrast, encouraging weight loss in extreme old age, may have little benefit, especially when there are no obesity-related conditions or biochemical risk factors observed. BMI also predicts morbidity in those without the disease. Furthermore, increased physical activity in the elderly, an essential component of weight management, can benefit muscle strength, endurance, and well-being (22).

Conclusions

Understanding the aging of the digestive tract is a crucially important area of biogerontology because of the many varied and vital functions of this organ system. The research slowly begins to unravel the complex processes and interactions of different cells of the GI system, including the microbiota. The effects of diet, the microbiota, and exercise on the aging GI system physiology are also essential for future analysis. Complex cellular interactions in the GI tract and the influences of the microbiota and diet on gut cells means that new approaches are needed to fully understand how aging influences GI functions. GI tract biogerontology requires extensive multi-center studies to understand how to improve health and well-being in old age (5).

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