Impact of Nutrition on Healthy Aging
Prabhakar Vissavajjhala, Sugen Life Sciences, Pvt Ltd, Tirupati, Andhra Pradesh, India
Abstract
Aging is a unidirectional physiological phenomenon, but one can retard its detrimental consequences by healthy nutrition. It is alarming that escalating global trends of diet-induced excess weight and obesity are leading to type 2 diabetic and cardiovascular complications and inflammatory diseases among adults and adolescents. Appropriate nutritional implements and active lifestyles are recommended to help safeguard healthy aging. While many functional food ingredients may have beneficial impacts on human health, the current chapter highlights the specific roles of dietary fiber, prebiotics, and probiotics in conjunction with commensal gastrointestinal and gut microbiota, and the subsequent microbial metabolites such as short-chain fatty acids and their receptors that play critical roles in controlling a variety of molecular events. Such events influence antitumorigenicity, energy metabolism, feeding behavior, T-cell differentiation, inflammation, and immune homeostasis in preventing individuals from becoming susceptible to a variety of diseases that often come with aging. The chapter reviews the recent literature and prospective lines of further research.
Keywords
Dietary fiber; prebiotics; probiotics; gastrointestinal; gut microbiota; short-chain fatty acid; GPR41; GPR43; propionate; butyrate; antitumorigenicity; obesity; immunity; inflammation; type 2 diabetes; energy metabolism; appetite; homeostasis; healthy aging
Introduction
Aging is a continuous, unidirectional phenomenon for any system; in a real sense, it refers to all of the changes that occur during a system’s entire existence. However, biological aging is often perceived as the changes that occur toward senility, or the declining phase of an individual. Growth and development are the terms often used to denote the changes occurring from inception to an organism’s early phases, but these are also part of aging. Metaphorically, if the human body is similar to an automobile, the best performance of the body or vehicle is mostly based on maintenance through timely inputs of appropriate fuel as measured both quantitatively and qualitatively. Besides providing energy, ideally the fuel does not generate or produces only minimal harmful residues or effects and lets the body or vehicle function smoothly over a long period of time with a sense of well-being. Such a scenario for humans may be best termed healthy aging. This serves as the basis not only of healthy growth and development during an individual’s earliest phases but also for a feeling of wellness during senility, where the fuel in question is nothing but nutritious food. In practice, healthy aging for humans depends on eating right, which often also means avoiding the wrong types of foods.
Though inborn genetic defects profoundly affect an individual’s health and wellness, in general they may not be frequent. Obviously, for humans the impact of food for healthy development and survival has been of paramount interest, especially in the wake of recent alarming global trends in the numbers of overweight and obese adults and adolescents. When high caloric intake and inadequate nutrient variety and density coincide with sedentary lifestyles, the results have included diet-induced metabolic syndrome and adverse consequences on health such as insulin resistance, type 2 diabetes, cardiovascular complications, inflammation, inflammatory diseases, and some types of cancer. In addition, such situations often necessitate pharmacological intervention, which add to both social and economic burdens on countries all over the world. How a variety of foods that include diverse nutrients can address issues of metabolic syndrome has been recently reviewed (Vissavajjhala, 2014), but this chapter provides a simplified overview, highlighting the enormity of the impact of dietary fiber (DF), prebiotics, and probiotics specifically in conjunction with gastrointestinal (GI) tract and gut microbiota on humans for healthy development that continues even as individuals age.
Dietary Fiber
DF or roughage is defined as the “undigested plant material that animals/humans may ingest.” Chemically, DF consists of nonstarch polysaccharides such as arabinoxylans, cellulose, and hemicellulose and many other plant components such as resistant starch (RS), resistant dextrins, inulin, lignin, chitins, pectins, β-glucans, and oligosaccharides. Based on its physical properties, DF has both water-soluble and water-insoluble components (Slavin, 2013).
While all plant foods contain some DF, some are richer in specific ones. Soluble fiber is found in varying quantities in all plant foods, including oatmeal, rye, chia, barley, nuts, beans, lentils, some fruits (including figs, avocado, plums, prunes, berries, ripe bananas, the skin of apples, quinces, and pears), certain vegetables such as broccoli and Jerusalem artichokes, root tubers and root vegetables such as sweet potatoes and onions, psyllium seed husks, and flax seeds. Sources of insoluble fiber include whole grain foods, including whole wheat, corn bran, and brown rice; legumes such as beans and peas, nuts, and seeds; potato skins; lignans; vegetables such as cauliflower, zucchini, celery, carrots, and cucumbers; and some fruits, including avocado, unripe bananas, the skins of some fruits such as kiwis, grapes, and tomatoes (Spiller, 2001).
GI and Gut Microbiota
A plethora of microbial populations develop in humans, the distribution of which include the skin, the oral and nasal cavities, and the urogenital, respiratory, and GI tracts. They are colonized by an enormous variety of bacteria, archaea, fungi, and viruses that form a community collectively known as the human microbiome or microbiota. Among them, the key player in host health, and working in conjunction with DF, is the commensal GI or gut microbial population, which comprises more than 1000 different species contributing more than 3.3 million microbial genes to the human GI tract. In fact, the human acquisition of certain vitamins such as B and K and antibiotics is only possible because commensal bacteria are present in the digestive tract.
Mechanisms of Health Benefits
Though human food may contain a variety of carbohydrates and polysaccharides in the form of plant material (cell walls and storage polymers), animal connective tissue, food additives, and microbial and fungal products, the digestion of carbohydrates in humans is confined only to starch, lactose, and sucrose (El Kaoutari et al., 2013) because of indigenous limitations. Human gut microbiota compensate for the lack of necessary enzymatic entities in the host genetic makeup to act on DF components and generate microbial metabolites that result in health benefits for the host. While soluble components of DF are readily fermented by microbiota in the colon and result in gases and physiologically active by-products, most of the insoluble components of DF are metabolically inert (e.g., lignin), may be fermented (e.g., RS), or are incompletely fermented (e.g., cellulose) in the large intestine. Due to their physical presence and ability to absorb water, insoluble DF increases fecal mass (called bulking), eases defecation, and minimizes constipation. Bulking also aids in diluting toxins, reducing intracolonic pressure, shortening fecal transit time, and increasing defecation frequency.
Short-chain fatty acids (SCFAs) contain fewer than six carbons: in general, formate (C1), acetate (C2), propionate (C3), butyrate (C4), and valerate (C5) are produced as microbial metabolites in the colon, playing critical roles both locally (GI level) and systemically, influencing host health and immunity. These will be highlighted in later sections.
Diversity of Gut Microbiota
The complexities and variability of adult gut microbial populations have become increasingly evident in recent years and led to the establishment of the Human Microbiome Project (HMP) (http://www.hmpdacc.org/). Owing to the burgeoning technological advances in genomic DNA sequencing, the emergence of metagenomics—the study of collective genomes of the members of microbial community in the human gut—has vastly increased human awareness of gut microbiota. The study involves cloning and analyzing the genomes without culturing the organisms in the community, offering the opportunity to describe the diverse microbial inhabitants, many of which cannot be cultured (Ursell et al., 2012).
Humans may have 1014 microbes—i.e., 10 times more than the eukaryotic cells in the human body—existing as commensal colonies and often playing critical roles in human health and disease (Koboziev et al., 2014). The intricate microbiome includes mostly bacteria, which live with commensal (not harmful) or symbiotic (mutually beneficial) or dysbiotic (potentially harmful or pathogenic) characteristics in relation to the host. Hence, imbalances of gut microbiota may lead to a number of pathologies such as obesity, types 1 and 2 diabetes, inflammatory bowel disease, colorectal cancer, and chronic inflammation (inflammaging) and immunosenescence in the elderly (Brown et al., 2012).
The mammalian microbiota are highly variable with several dominant bacterial phyla: Firmicutes (e.g., Lactobacillus, Clostridium), Bacteroidetes (some commensals such as Bacteroides ovatus and some pathogenics such as Bacteriodes fragilis and Bidens vulgatus), Actinobacteria (e.g., the genera Bifidobacteria and Streptomyces), and Proteobacteria (e.g., Escherischia coli and Pseudomonas species) (Dethlefsen et al., 2007; Zoetendal et al., 2006). Firmicutes and Bacteroides account for more than 90% of the bacterial population in the colon (Ley et al., 2008), while Actinobacteria and Proteobacteria (which includes members of the family Enterobacteriaceae) are scarcely present (<1–5%) (Eckburg et al., 2005).
Factors Influencing Gut Microbiota
Apart from host genetics, numerous factors such as premature delivery, mode of delivery, antibiotic usage, and diet can play important roles in how the intestinal microbiota of infants are shaped (Conlon and Bird, 2015). Microbes colonize the human gut during or shortly after birth. The fact that babies delivered naturally have higher gut bacterial counts at 1 month of age than those delivered by cesarean section (Huurre et al., 2008) suggests that gut colonization by microbes begins during and is enhanced by natural birth. The growth and development of a robust gut microbiota is important for the development of the individual’s immune system (Kelly et al., 2007) and continues during breast-feeding, a stage that seems to be crucial for an individual’s long-term health. The microbiotic diversity of breast-fed infants has been reported to be better than infants fed on formula food (Le Huerou-Luron et al., 2010). Oligosaccharides present in breast milk promote the growth of Lactobacillus and Bifidobacterium, which dominate the infant gut (Harmsen et al., 2000), strengthen or promote the development of the immune system, and may help prevent conditions such as eczema and asthma (Arslanoglu et al., 2008).
Prebiotics
Following the pioneering effort by Gibson and Roberfroid (1995), the prebiotic concept has been refined and redefined many times. Prebiotics are defined as “selectively fermented ingredients that result in specific changes, in the composition and/or activity in the GI microbiota, thus conferring benefit/s upon host health” (Gibson et al., 2010).
Inulin-type fructans, fructooligosaccharides (FOS), and galactooligosaccharides (GOS) (nondigestible short-chain carbohydrates) are the quintessential prebiotics that typically target the Bifidobacterium and Lactobacillus groups. Inulin and FOS occur naturally in various foods, including cereals, fruits, and vegetables, so they are ubiquitous in most diets.
Probiotics
Probiotics are defined as live microorganisms that confer a health benefit to their host when administered in adequate quantities. The most commonly consumed probiotics belong to the genera Lactobacillus and Bifidobacterium. Probiotics may improve host health by augmenting immune function, which occurs through reinforcing the mucosal barrier function, reducing the mucosal transfer of luminal organisms and metabolites to the host, increasing mucosal antibody production, strengthening epithelial integrity, and empowering the antagonism of pathogenic microorganisms. However, the results of studies in humans are varied, most likely due to methodological discrepancies (such as dose and duration of probiotic administration, sampling regimens, and microbiological techniques) and differences in host cohorts (age, health status). It is clear from in vivo studies in humans and animal models that probiotic efficacy in promoting health is strain dependent rather than species or genus specific (Floch et al., 2011; Khani et al., 2012).
The Role of SCFAs in Health and Disease
The SCFAs (especially acetate, propionate, and butyrate) are the end products of gut microbial activity on DF and prebiotics and have been known for a few decades as playing a role in health and disease. Studies have been gaining momentum of late in exploring and expanding the scope and opportunity of investigation. The highest concentrations of SCFAs are in the colon following a meal. While SCFAs exert their effects locally in colon cells, they are as well transported and act systemically through their receptors. SCFAs are weak acids (pKa ~ 4.8) and help lower the pH within the colon, thereby inhibiting the growth and activity of pathogenic bacteria. SCFAs can act independently of their receptors to modulate histone acetylation and cell proliferation.
The Antitumorigenic Effects of SCFAs
SCFAs, especially butyrate, exhibit strong antitumorigenic properties, inhibit cell proliferation, and induce differentiation and apoptosis in a variety of cell lines, including human colorectal cancer cell lines HCT-116 and HT-29 (Hinnebusch et al., 2002). Indeed, SCFAs have been shown to confer protection from the development of colorectal cancer. While propionate and butyrate significantly inhibit cell proliferation, acetate has little or no effect. Both propionate and butyrate have been shown to induce apoptosis in vitro (Fung et al., 2011).
Modulation of Histone Acetylation by SCFA
Epigenetic mechanisms—histone acetylation by histone acetyl transferases (MacDonald and Howe, 2009) and deacetylation by histone deacetylases (HDACs) (Seto and Yoshida, 2014)—can regulate and modulate gene expression. SCFA metabolites produced by microbiota inhibit HDAC activity, modulating gene expression in target cells (Grunstein, 1997). Mechanistically, SCFAs function as noncompetitive inhibitors of HDACs, effectively both in vitro and in vivo (Cousens et al., 1979). Butyrate is the most potent inhibitor of HDACs, achieving 80% inhibition of calf thymus HDAC1/2 in vitro; propionate and valerate are the next most efficacious with a 60% inhibition in vitro. It has been shown that butyrate and propionate specifically inhibit HDAC1 and HDAC3 (Huber et al., 2011). Butyrate induces histone hyperacetylation in both normal and cancerous cell lines (Aoyama et al., 2010; Khan and Jena, 2014; Kim et al., 2007; Li and Li, 2006; Wu et al., 2012), not due to acetylation per se but to HDAC inhibition, which in turn increases the half-life of histone acetyl groups (Cousens et al., 1979). Though SCFAs are reported to exert HDAC inhibition directly after entering colonocytes through a transporter—SLC5A8 (Singh et al., 2010)—there is also evidence that an SCFA receptor can mediate HDAC inhibition (Wu et al., 2012).
Butyrate, while inhibiting adipogenic differentiation, may enhance osteogenic differentiation from mouse adipose-derived mesenchymal stromal cells, making it a promising alternative for autologous skeletal tissue engineering through HDAC inhibition (Xu et al., 2009).
Receptors of SCFAs
Extraintestinal or systemic effects of SCFAs involve SCFA receptors. Of the four identified, three are G protein–coupled receptors (GPRs) (−41, −43, and −109a) and an olfactory receptor (OLFR78).
GPR41 (Free Fatty Acid Receptor 3: FFAR3)
Both GPR41/FFAR3 and GPR43/FFAR2, which had previously remained orphans (their endogenous ligands were not known), were deorphanized to be receptors for SCFAs (Brown et al., 2003; Le Poul et al., 2003).
GPR41 is found coupled to the Gi of G proteins (Brown et al., 2003) and is most responsive to propionate (EC50 12 µM; Le Poul et al., 2003), although other SCFAs such as formate, acetate, butyrate, and isobutyrate also elicit varying degrees of activation. GPR41 is expressed in a variety of tissues and cell types, including the colon, kidneys, sympathetic nervous system, and blood vessels (Xiong et al., 2004; Tazoe et al., 2009), where they respond to microbiota-generated SCFAs to mediate the host’s physiological responses. GPR41 has been implicated as having a role in inhibiting cell proliferation and inducing apoptosis (Kimura et al., 2001), energy homeostasis (Inoue et al., 2014), T-cell differentiation, and immunity (Kim et al., 2014).
GPR43 (Free Fatty Acid Receptor 2: FFAR2)
Though GPR43/FFAR2 is responsive to propionate (EC50 300 µM; Le Poul et al., 2003), it can also be activated by acetate, and butyrate is found to be the strongest of the three ligands (Le Poul et al., 2003). While GPR41 couples only to Gi, GPR43 is found coupled to both the Gi and Gq of G proteins (Brown et al., 2003; Le Poul et al., 2003). GPR43 is expressed mainly in vasculature and immune cells, including lymphocytes, neutrophils, monocytes, and peripheral blood mononuclear cells (Karaki et al., 2006; Kimura et al., 2001; Tazoe et al., 2009; Xiong et al., 2004). SCFAs regulate the expression of cytokines and chemokines in both cultured intestinal epithelial cells and in mice via the activation of GPR43. GPR43-deficient mice have extensive dysregulation of inflammatory responses, showing excessive inflammation in models of colitis, arthritis, and asthma (Maslowski et al., 2009). GPR43-deficient mice exhibit obesity. GPR43 activation by SCFAs promotes glucagon-like peptide-1 (GLP-1) secretion in the gut, increasing insulin sensitivity and suppressing fat accumulation in adipose tissue (Kimura et al., 2013).
GPR109a
Initially, GPR109a was determined to be a niacin receptor and was subsequently found to be responsive to β–D-hydroxybutyrate as well as butyrate (Taggart et al., 2005) but not to acetate or propionate. GPR109a is expressed in colon epithelial cells proportionately to gut microbiota (Cresci et al., 2010). Activation of GPR109a by butyrate suppresses carcinogenesis (Singh et al., 2014).
OLFR78
OLFR78 has been deorphanized to be a receptor for SCFAs (Pluznick et al., 2013). OLFR78 responds to acetate and propionate (EC50 2.35 mM and 920 µM, respectively) but not to butyrate. While OLFR78, GPR41, and GPR43 all localize to blood vessels, OLFR78, also localizes to a specialized renal vessel (afferent arteriole) where renin is stored and secreted. Both OLFR78 and GPR41 play SCFA-activated roles to modulate blood pressure (Pluznick et al., 2013).
Systemic Effects of SCFAs
At extraintestinal level, butyrate exerts potentially useful effects on many conditions, including hemoglobinopathies, metabolic diseases, hypercholesterolemia, insulin resistance, and ischemic stroke. Majority of these are related to its potent regulatory effects on gene expression. The wide spectrum of positive effects exerted by butyrate suggests a high potential therapeutic use in human medicine (Canani et al., 2011).
SCFAs: Energy Metabolism and Feeding Behavior
SCFAs are the main energy sources for gut cells and as such play a central role in the physiology and metabolism of these cells, including proliferation, differentiation, apoptosis, mucin production, and lipid metabolism (Roy et al., 2006). Administration of butyrate decreases plasma glucose and increases insulin levels in diabetic rats as a result of cell proliferation in the pancreatic islets (Khan and Jena, 2014).
Butyrate enhances fatty acid oxidation and thermogenesis by increasing the expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and the phosphorylation of adenosine-monophosphate–activated kinase in muscle and liver tissues, and the expression of PGC-1α and mitochondrial uncoupling protein-1 in brown adipose tissues (Donohoe et al., 2011). Propionate and butyrate activate intestinal gluconeogenesis via a gut–brain neural circuit, thereby promoting metabolic benefits on body weight and glucose control (De Vadder et al., 2014). Acetate reduces appetite by changing the expression profiles of appetite-regulating neuropeptides in hypothalamus through activation of TCA cycle in mice (Frost et al., 2014).
Propionate significantly increased the release of anorectic, postprandial plasma peptide YY, and GLP-1 from colonic cells in human primary culture. In overweight human subjects, it significantly reduced the energy intake, weight gain, intraabdominal adipose tissue distribution, and intrahepatocellular lipid content and prevented deterioration in insulin sensitivity (Chambers et al., 2014). Butyrate and propionate were shown to protect against diet-induced obesity and regulated gut hormones in mice (Lin et al., 2012). The oral administration of acetate improved glucose tolerance and suppressed obesity in diabetic rat models (Yamashita et al., 2007).
As various studies point toward propionate’s hypophagic and hypocholesterolemic effects in humans, it may act as an important factor in the amelioration of obesity, a lifestyle disease arising due to energy imbalance. Thus, propionate along with acetate may also be involved in the regulation of adipogenesis, and adipokine release may depress appetite and combat the obesity epidemic (Arora et al., 2011).
SCFAs and Gut–Brain Axis Communication
The gut–brain axis is a bidirectional communication system between the central nervous system (CNS) and the GI tract. Regulation of the microbiota–brain–gut axis is essential for maintaining homeostasis, including that of the CNS. A number of approaches have been used to probe this axis, including the use of germ-free animals, probiotic agents, antibiotics, or animals exposed to pathogenic bacterial infections. Together, it is clear that the gut microbiota can be a key regulator of mood, cognition, pain, and obesity. Understanding microbiota–gut–brain communications is an exciting but challenging area of research that may contribute new insights into individual variations in cognition, personality, mood, sleep, and eating behavior and how they contribute to a range of neuropsychiatric diseases ranging from affective disorders to autism and schizophrenia. Finally the concept of psychobiotics, bacteria-based interventions with mental health benefits, is an emerging new field (Burokas et al., 2015).
SCFAs and Immunity
At the intestinal level, butyrate plays a regulatory role on transepithelial fluid transport, ameliorates mucosal inflammation and oxidative status, reinforces the epithelial defense barrier, and modulates visceral sensitivity and intestinal motility.
In mammals, besides their function as energy sources for epithelial cells, SCFAs are also potential immunostimulatory molecules (Kim et al., 2014; Shapiro et al., 2014), show improved lymphocyte function (Belkaid et al., 2013), and have immune-related effects resulting from their binding to the GPRs (Louis et al., 2014). GPR43 recognizes acetate, propionate, and butyrate and is highly expressed in neutrophils, macrophages, and monocytes. In contrast, GPR41 expression is low or undetectable in the same cells (Brestoff and Artis, 2013). GPR43 stimulation by SCFAs is necessary for the normal resolution of inflammatory responses in mice. Other immune-regulation activities of SCFAs include the inhibition of HDACs (Chang et al., 2014), regulation of autophagy (Donohoe et al., 2011), regulation of T-cell differentiation (Kim et al., 2014), and stimulation of heat shock protein production (Ren et al., 2001). Although the full spectrum of molecular mechanisms and the functioning of immune cells remains far from known, it is clear that SCFAs do play a central role in immunity of mammals.
Gut microbiota, via HDAC inhibition elicited by SCFA, affect the balance between pro- and antiinflammatory mechanisms (Arpaia et al., 2013). Propionate and butyrate inhibit production of tumor necrosis factor-α and nuclear factor-κB in neutrophils, thereby showing antiinflammatory effects (Vinolo et al., 2011).
Ongoing and Future Directions
Although most studies of SCFAs show beneficial effects, more human in vivo studies are necessary to contribute to our current understanding of SCFA-mediated effects on colonic function in health and disease (Hamer et al., 2008).
All established prebiotics to date are carbohydrates, including inulin-type fructans and GOS. While other dietary carbohydrates also qualify as prebiotics, the interindividual variability in the microbial response to RS suggests successful dietary interventions with RS need to be personalized (Tremaroli and Backhed, 2012). Similarly the relation between various indigestible carbohydrates and their catalyzing bacteria for human health benefits should be explored (Martens et al., 2014).
Other than carbohydrates, cocoa flavanols may also function as prebiotics. They increase the relative abundance of Bifidobacterium and Lactobacillus at the expense of potentially pathogenic bacteria, notably the Clostridium histolyticum group (Martin et al., 2012). The other emerging potential prebiotics are seaweeds and microalgae (De Jesus Raposo et al., 2016).
The current concept of prebiotics should be revamped and broadened beyond Bifidobacterium and Lactobacillus, as these genera alone may not include all the important contributors to host health (Conlon et al., 2012). Emerging candidates include butyrate-producing bacterial groups related to Eubacterium rectale/Roseburia spp. and Faecalibacterium prausnitzii. Populations of F. prausnitzii are reported to be decreased in Crohn’s disease, while populations of Roseburia relatives appear to be particularly sensitive to diet composition in human volunteer studies (Louis and Flint, 2009). Gut microbiota in older human subjects is reported to be least optimal for healthy aging (O’Connor et al., 2014). Cohort studies in Europe and China, despite the ethnic and dietary differences, revealed that patients with type 2 diabetes had a lower proportion of butyrate-producing and a larger proportion of nonbutyrate-producing Clostridiales (Karlsson et al., 2013; Tilg and Moschen, 2014).
While strategies for the microencapsulated delivery of bacteria (Cook et al., 2012) and the selective manipulation of microbiota (Montalban-Arques et al., 2015) have been reported, another attempt to modulate gut bacteria is fecal microbiota transplantation (Xu et al., 2015). Nevertheless, our current understanding of the intestinal ecosystem is still insufficient, as impacts of human virus and bacteriophages (virus infecting gut bacteria) also need to be taken into account for human health and disease. Further research efforts are needed to explore the scope of these potential aspects.