Nutrition and Functional Foods for Healthy Aging

book.

Part I

Overview Health and Aging

Outline

Chapter 1 Impact of Nutrition on Healthy Aging

Chapter 2 Aging and the Recovery of Skin Function and Appearance

Chapter 3 Changes in Nutritional Needs With Aging

Chapter 4 Sugars, Glucocorticoids, and the Hypothalamic Controls of Appetite

Chapter 5 Appetite Regulation in Healthy Aging

Chapter 6 Human Microbiome and Aging

Chapter 7 Fibromyalgia Syndrome: Role of Obesity and Nutrients

Chapter 8 Aging and Gait

Chapter 9 Assessment of Nutritional Status in the Elderly

Chapter 10 Eating Capability Assessments in Elderly Populations

Chapter 1

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.

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Chapter 2

Aging and the Recovery of Skin Function and Appearance

Adele Sparavigna,    Clinical Research and Bioengineering Institute, Monza, Italy

Abstract

Age-related skin changes (wrinkles, atrophy, gray spots, loss of hydration, and elasticity) can be considered the result of intrinsic factors (chronological, hormonal, and genetic) and the consequence of life habits and environmental damage mainly due to ultraviolet radiation from the sun (responsible for skin photoaging). The correlation between diet and skin is well established in some skin diseases (acne, atopic dermatitis, and psoriasis are a few examples). What is not yet entirely clear is what substances can improve skin appearance and aging for a person who is well nourished. Thanks to the analysis of recent scientific literature and my experience as a dermatologist and researcher, I will try to investigate the role of diet in counteracting skin aging by focusing on the Mediterranean dietary profile, which is characterized by the regular use of abundant fruits, vegetables, wholemeal bread and cereals, legumes, nuts, seeds, and olive oil, all of them fresh, natural, seasonal, and locally sourced.

Keywords

Skin aging; Mediterranean diet; antioxidant food; nonenzymatic glycation products; phytoestrogens; telomere shortening

Introduction

Aging can be defined as a physiological process characterized by a continuous and irreversible loss of homeostasis that involves the whole body. With the progressive increase of life expectancy in developed countries, the prevalence of aging-related diseases is increasing, making it necessary to implement specific preventive strategies. The leading role of diet in maintaining health throughout the human life cycle has been well established by a multitude of scientific papers from different medical disciplines. The effects of an unbalanced diet can be detected at different levels: diets rich in saturated fats, cholesterol, and animal protein or high in salt and sugar can not only increase metabolic and cardiovascular disease risk but also contribute to the accumulation of oxidative and inflammatory responses, increasing the production of free radicals that damage all cellular constituents and lead to an acceleration in the aging process. Skin, as an integral part of the system, is affected by these responses. Wrinkles, atrophy, gray spots, and loss of hydration and elasticity are the most visible signs. To understand how diet contributes to the maintenance of skin health is particularly relevant because skin aging is determined by the combined influences of intrinsic factors (chronological, hormonal, and genetic) and extrinsic ones that can be divided in behavioral factors such as sun exposure (responsible for photoaging), cigarette smoking, diet, alcohol drinking, drug abuse, and environmental factors such as pollution, weather, and humidity.

The correlation between diet and skin health was recently well established for several skin diseases. Examples include acne (especially for milk and dairy products, which have been correlated in several studies with more severe diseases) (Melnik, 2015), atopic dermatitis (which improves with the intake of essential fatty acids and certain probiotics) (Mohajeri and Newman, 2014), and psoriasis (which is significantly correlated with metabolic syndrome) (Voiculescu et al., 2014). Correcting poor and unbalanced nutrition undoubtedly improves skin health, but what is not yet entirely clear is what substances can improve skin health and appearance and counteract skin aging in a targeted manner for a person who is well nourished. Thanks to the analysis of recent scientific literature and my personal experience as a dermatologist and researcher, I will try to investigate these issues, focusing on the traditional feeding practices of Italy, my home country, which are most famously represented by the Mediterranean diet.

Skin Aging

As far as skin is concerned, the aging phenomenon is caused by exogenous and endogenous factors. Ultraviolet (UV) radiation exposure is the main exogenous factor responsible for aging in the skin, especially in fair-skinned Caucasian subjects and exerts its effect predominantly through the accumulation of free radicals in the tegument. Smoking, pollution, sleep deprivation, and poor nutrition are other exogenous factors that promote skin aging. The difference between the two types of skin aging—exogenous and endogenous—can be observed by comparing UV-protected and UV-exposed sites. Endogenously aged skin displays epidermal and dermal atrophy, a reduced extracellular matrix (collagen, elastin fibers, and glycosaminoglicans), and marked vascular changes. Skin functions are impaired: thermoregulation, glandular function, wound healing, the epidermal barrier, and melanogenesis are all diminished. Exogenous aging also displays thickened stratum corneum, the aggregation of abnormal elastic fibers in the dermis (solar elastosis), and deep altered production and distribution of melanin, which leads to uneven pigmentation.

Diet and Skin Aging

The contribution of diet to how skin ages remains largely unclear. While skin scientists know what skin diseases and impairments can occur because of most nutritional deficiencies (e.g., vitamins E and C, carotenoids, and polyunsaturated fatty acids), we miss studies that precisely correlate the signs of aging with qualitative and quantitative nutrient intakes (Draelos, 2013) We do not know to what extent a good diet—which is hard to define—or a supplemented diet can contribute to successful skin aging. Cosgrove et al. (2007) evaluated the associations between nutrient intakes and the appearance of aging skin using data from the first National Health and Nutrition Examination Survey conducted in the United States between 1971 and 1974. Clinical dermatological examinations were conducted of 4025 women ages 40–75 years and data were gathered for their dietary habits and other variables (e.g., body mass index, race, energy intake, physical activity, and smoking). The authors found that higher intakes of vitamin C and linoleic acid and lower intakes of fats and carbohydrates were associated with better skin aging appearance (fewer wrinkles, less senile dryness, and less skin atrophy) independently of other factors known to affect skin aging. This study is different from many others in the literature because it examined nutrient intakes from food rather than from nutritional supplements or topically applied nutrients. Nevertheless, no direct conclusion about nutrients and skin aging appearance could be determined. Significant dietary changes have occurred in the past 30 years, however, and the use of facial cosmetics has seen a tremendous increase. For these reasons, studying the relationship between dietary attitudes and skin aging has become even more complicated. On one side is the structural and biochemical complexity of aging in skin and its appendages; on the other side is the extreme variability of genetic, physiological, and pathological factors as well as environment and behavior. All of these affect our knowledge in this field. Until we have at our disposal techniques to make in vivo measurements of the different nutrients in the skin (this can only be considered science fiction now), it will be almost impossible to accurately evaluate the effect of single or grouped dietary constituents on skin aging. Anyway, although science and common sense suggest that a healthy diet such as the Mediterranean diet with its emphasis on fresh fruits and vegetables, nuts, fish, olive oil, and integral cereals may improve aging in general and skin appearance in particular, many challenges remain in designing and running nutritional research (Draelos, 2013). If we look at the aging phenomenon on a biological basis, we may be able to better predict how nutritional factors can affect it. Up to now, the main mechanisms causing aging of tissue and organs are as follows:

 Oxidative stress

 Nonenzymatic glycation products

 Sex hormone imbalance

 Telomere shortening

In this chapter we will analyze each of these mechanisms and their correlations with dietary habits.

Oxidative Stress and Chronic Inflammation

Reactive oxygen species (ROS) are essential to life. We breathe oxygen, and properly generated ROS has beneficial protective and antiaging effects on cells. Nevertheless, ROS production from several sources in our everyday lives such as UV exposure, inflammation, stress, pollution, and smoking leads to an excess of free radicals that hurt the chemical stability of cellular structures. This is why cells have their own intrinsic antioxidative enzyme systems such as superoxide dismutase that are able to neutralize ROS by taking a free electron from another source. Vitamins A, C, and E and polyphenols all exert strong antioxidation effects and work synergistically. A fundamental strategy for enhancing skin protection from oxidative stress is to support the endogenous antioxidant system via the antioxidants normally present in the skin. Since these antioxidants work in a complex harmony, a permanent intake of isolated antioxidants is not physiologically as effective as consuming a diet rich in fruits and vegetables; this remains the healthiest and safest way to maintain youthful and healthy skin.

A vast literature has been produced over the past decades about the role of antioxidants in a balanced diet. Even more detailed recent studies directly correlate dietary intake of antioxidants with skin protection: resveratrol has been demonstrated to attenuate skin atrophy induced by oxidative damage (Watanabe et al., 2015), and cocoa (Karim et al., 2014) and green tea polyphenols (Roh et al., 2015) confer protective effects on skin against UV-induced acceleration of skin aging. So far, a variety of phytomolecules derived in particular from polyphenols, triterpenes, and sterol classes have demonstrated a promising activity on skin aging. Among them, carnosic acid, curcuglicoside, curcumin, glycyrrizic acid, and extracts and pure compounds from Fabaceae, Asteraceae, and Zingiberaceae appear most interesting (Tundis et al., 2015). In particular, maslinic acid found in olive oil is a natural triterpene that has protective effects against chronic inflammatory diseases through its modulation of arachidonic acid metabolism (Yap and Lim, 2015).

Nonenzymatic Glycation Products

Nonenzymatic glycation was first diagnosed and described in diabetic patients as leading to the accumulation of advanced glycation end (AGE) products in several tissues and organs. AGEs have been associated with end-stage renal disease, chronic obstructive pulmonary disease, atherosclerosis, and connective tissue impairment. The term glycation has emerged in recent years to describe one of the most important aging factors for human tissues and organs (Simm et al., 2015); it now commonly refers to the nonenzymatic process of proteins, lipids, and nucleic acids covalently bonding to the sugar molecules glucose and fructose. Glycation occurs at random molecular sites and generally results in the inhibition of the target molecule’s functions. Immunostaining has demonstrated the presence of glycation in aged skin and resulting structural, morphological, and functional impairments. Glucose and fructose play a critical role in glycation, but foods containing glycated proteins also provide further exogenous AGEs to an organism. Barbecued meats, toasted bread, dark-colored soft drinks, and donuts contain high levels of AGEs. Now we know that grilling, frying, and roasting methods produce higher levels of AGEs in cooked food. Orally consumed and endogenous AGEs are proinflammatory and accumulate on nucleic acids, proteins, and lipids. Fortunately, dietary habits can reduce AGEs in the body. First, a diet should contain low levels of monosaccharides, which are responsible for the glycation phenomenon. Water-based cooking methods such as boiling and streaming produce a logarithmically lower amount of AGEs. Several aromatic herbs and spices are believed to be able to reduce the endogenous production of AGEs: cinnamon, oregano, cloves, ginger, garlic, α-lipoic acid, carnitine, flavonoids, resveratrol, vitamins, zinc, and manganese. Furthermore, since glycation is accelerated in the presence of an ROS, the intake of antioxidants is able to limit the production of endogenous AGEs (Draelos, 2013).

Sex Hormone Imbalances

Some of the changes that affect aging skin in menopausal women occur as a consequence of estrogen deficiency. The mechanisms involved seem to originate from the dermal and epidermal reduction of cellularity, collagen quantity, and skin thinning. This mechanism is responsible for a total cumulative loss of about 30% of skin thickness in the first 5 years after menopause. Keratinocytes and dermal fibroblasts exhibit receptors for sexual hormones, which is why we observe collagen and glycosaminoglycans deficiency after menopause. The role of estrogens in maintaining dermal thickness is demonstrated by the fact that orally administrated isoflavone-rich soy extract during six consecutive months causes significant increases in epithelial and dermal thickness (Accorsi-Neto et al., 2009). Since estrogen therapy is not always feasible due to its side effects and contraindications, phytormones in the diet represent a natural and valid alternative to hormonal therapy after menopause. Although phytoestrogens are nonsteroidal substances, they have a heterocyclic phenolic composition that shows structural similarities to the estrogens. Of particular interest is their higher affinity for the β subtype of the estrogen receptor that is present in bones, skin, and the cardiovascular system (all the organs suffering from estrogen deprivation after menopause) while having reduced or even antagonist effects on the α subtype of the estrogen receptor (found in the uterus and breast, which are at higher risk of cancerization after estrogen stimulation). This is why phytoestrogens are considered selective estrogen receptor modulators and are widely used to treat menopause estrogen deficiency. Soy isoflavones—in particular, genistein—are the best studied phytoestrogens (Nagaraju et al., 2013). Anyway, while soy is very abundant in many Asian diets, it is not characteristic of the Mediterranean diet, which helps explain why not all Western women are able to tolerate it. Also allergies to soy are more frequent in Western countries (Cordle, 2004). Other vegetables contain many other natural sources of phytoestrogens (Agradi et al., 2006). Species belonging to the Leguminosae, Apiaceae, Graminaceae, Iridaceae, Chenopodiaceae, Cruciferae (or Brassicaceae), and Solanaceae families provide significant amounts of phytoestrogens. Among the species from these families are such widely consumed foods such as beans and other legumes, tomatoes, cabbage, carrots, and some cereals. When supported by proper cooking practices as in the Mediterranean tradition, vegetable foods rich in phytoestrogens can help maintain healthy and young skin.

Telomere Shortening

Telomeres are DNA–protein complexes at the end of chromosomes that protect the genetic material and promote chromosomal stability. Telomeres shorten with time because they cannot replicate completely each time the cell divides; for that reason, they may be the most powerful biological clock yet elucidated. Furthermore, it has been demonstrated that being overweight, stressed, and sedentary accelerates the shortening of telomeres (Epel, 2012). Progressive shortening of telomeres leads to senescence, apoptosis, and oncogenic transformation of somatic cells that affect an individual’s health and lifespan. Shorter telomeres have also been associated with increased skin aging (Kosmadaki and Gilchrest, 2004; Masood, 2011).

Telomere length positively correlates with the dietary intake of fiber and negatively associates with waist circumference. A diet rich in antioxidant omega-3 fatty acids and vitamins C and E, and beta-carotene is associated with a reduced rate of telomere shortening. Antioxidants are known to protect telomeric DNA from oxidative damage caused by extrinsic and intrinsic DNA damaging agents. Reduced protein intake also seems to increase cell longevity. Of notable interest is that improved nutrition, increased exercise, and better stress management might also booster the enzyme telomerase, which directs the replication of telomeres and adds telomeric repeat sequences to the chromosomal DNA ends.

The Mediterranean Diet

The Mediterranean diet was studied for the first time in a systematic and scientific way by American scientist Ancel Keys, who demonstrated the influence of diet on longevity and health. This analysis involved some Mediterranean countries in the 1950s following the austere times in the wake of World War II, which were characterized by a physically active lifestyle and a frugal diet based mostly on vegetable products (Monteagudo et al., 2015). The Mediterranean coast is characterized by great ethnic, cultural, religious, economic, and political differences that may have influenced the quantity and quality of food. Nevertheless, these countries traditionally share the availability of the same foods derived from agriculture, herding, and fishing. Some studies widely accepted by the scientific community showed that in the early 1960s in these geographical areas, life expectancy was almost the highest in the world and that the incidence of heart disease, some cancers, and other chronic diseases related to diet was among the lowest in the world. This occurred despite high smoking, low socioeconomic levels, and a shortage of health care. It is significant that this diet is common where olive trees are traditionally grown; one accepted definition of this nutritional pattern relates to diet practiced in Mediterranean areas dominated by olive trees (Keys, 1980).

The characteristics of the Mediterranean diet are abundant fruits, vegetables, wholemeal bread and cereals, legumes, nuts, and seeds, all of them fresh, natural, seasonal, and locally sourced. Olive oil is the principal source of fat, daily servings of fresh fruit are used as dessert, and refined sugars or honey are consumed only a few times a week. Dairy products (principally cheese and yogurt) are consumed daily in moderate amounts, as are fish and poultry. Only a few eggs (0–4) are consumed per week; red meat is eaten in modest amounts; and wine, generally red, is also consumed in modest amounts, generally during the meal (Pitsavos et al., 2005). Numerous studies over several decades confirmed that the Mediterranean diet can reduce the risk of cardiovascular and metabolic disease and improve cognitive health (Davis et al., 2015), but what about skin health?

Recent publications regarding the correlation between eating habits and skin cancer have demonstrated that the Mediterranean diet may contribute to lower rates of skin cancers despite high levels of solar radiation in Mediterranean countries (Fortes et al., 2008; Malagoli et al., 2015; Shapira, 2010). Taking into account what we learned from the scientific literature and what has been explained in this chapter, the correspondence between the Mediterranean diet and good dietary habits based on potentiating antiaging mechanisms in the skin is quite high (Fig. 2.1).

Figure 2.1 Skin Mediterranean diet pyramid. Adapted from Dernini, S., Berry, E.M., 2015. Mediterranean diet: from a healthy diet to a sustainable dietary pattern. Front. Nutr. 2: 1 (Dernini and Berry, 2015).

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Chapter 3

Changes in Nutritional Needs With Aging

Teresa Juarez-Cedillo¹,²,    ¹Mexican Institute of Social Security, Mexico City, Mexico,    ²National Autonomous University of Mexico, Mexico City,