[Frontiers in Bioscience 2, e108-115, November 1, 1997]

	[Frontiers in Bioscience 2, e108-115, November 1, 1997] Reprints PubMed CAVEAT LECTOR
	EFFECT OF AGING AND CALORIC RESTRICTION ON INTESTINAL SUGAR AND AMINO ACID TRANSPORT Ronaldo P. Ferraris Dept of Pharmacology and Physiology, UMDNJ-New Jersey Medical School, 185 South Orange Ave., Newark, NJ 07103 Received 7/17/97 Accepted 10/2/97 2. INTRODUCTION Death by starvation has reached epidemic proportions among older Americans (1). Nutrition surveys found malnutrition in 6% of men and 5% of women between the ages of 70 and 80 years, and in 12% of men and 8% of women over the age of 80 (see review by Rolls (2)). Bond and Levitt (3) showed that 33% of active, clinically-well individuals over the age of 65 malabsorbed a portion of a 100 g carbohydrate meal. This indicates that the mean carbohydrate absorptive capacity fell progressively from age 65. Xylose absorption also decreases with advancing age (4, 5, 6). The elderly also malabsorb peptides and amino acids. Serum albumin concentrations are significantly lower in the elderly than in young humans even when their dietary protein intake is similar (7), suggesting that peptides and amino acids may be malabsorbed in the elderly. There are many possible causes of malnutrition, ranging from behavioral factors like decreased appetite to pathological conditions like malabsorption. One of the most neglected areas of study in elderly nutrition is the effect of aging on intestinal absorption and on the ability of the small intestine to regulate absorption of nutrients. This information is important since decreases in rates of transport may contribute to malabsorption and to malnutrition. In addition, the rate of intestinal absorption of sugars and their site of absorption largely determine postprandial plasma glucose concentrations. The effect of aging on glucose tolerance is quite evident after consumption of a meal (8). For each decade after middle age, the level of fasting plasma glucose increases by 0.05 to 0.1 mM, but the postprandial plasma glucose level increases much more, by 0.4 to 1.1 mM. Thus, older people often are considered diabetic based on postprandial plasma glucose level, and not on fasting glucose level. If aging results in adaptive mechanisms which alter the rate of intestinal sugar absorption and move the main absorptive site, then, the subsequent rise of plasma glucose will be affected. For example, adaptive mechanisms in chronic diabetes result in a dramatic increase in total intestinal absorptive capacity for glucose (9). Similar adaptive mechanisms during aging could result in an age-related change in postprandial plasma glucose tolerance. In this brief review, I will mainly focus on the effect of aging on intestinal sugar and amino acid absorption, and primarily on studies done in the last 15 years since Holt (10), Thomson and Keelan (11) and Vinardell (12) wrote reviews on aging and intestinal absorption. This review excludes studies on development (neonatal to adult). Holt and Balint (13) reviewed the effect of aging on intestinal lipid absorption. I will describe the nonspecific or specific mechanisms underlying the effects of aging on transport, and the reader is referred to a recent review by Ferraris and Diamond (14) which gives a detailed explanation of these mechanisms. Finally, I will also review studies on the effect of chronic caloric restriction on absorption of nutrients, since caloric restriction is a well accepted procedure for extending lifespan and postponing aging. I will end with suggestions for future research. 2.1 Basis for normalization. Because investigators use a variety of methods to determine rates of intestinal nutrient absorption, it is important for the reader to keep track of how absorption rates are normalized. Briefly, the intestinal transport rate of a nutrient may be normalized to the weight (or protein content) of intestinal tissue or cell or membrane, to length or surface area of intestinal tissue, or to the entire small intestine. The last expression is often referred to as intestinal absorptive capacity or SUMJ. When normalized in this manner, a change in the transport rate may mean a change in transport activity by the intestinal absorptive cell as well as a change in intestinal mass. Similarly, a change in transport per cm of intestine would mean a change in transport activity in that segment of intestine, as well as a change in the intestinal mass per cm. Because of macroscopic (folds) and microscopic (villi and microvilli) elaborations, the actual surface area of the absorptive mucosa is difficult to measure (see Ref. 15 for a detailed discussion). In almost all cases, absorption normalized to surface area refers only to serosal (the nonabsorptive side), and not mucosal, surface area. A change in transport expressed per unit weight reflects only a change in functional activity independent of a change in mass. Hence, if aging were to have no effect on transport activity per unit weight, but were to induce a two-fold increase in intestinal weight, studies normalizing to weight would report no age-related change in transport, but studies normalizing to surface area or intestinal length would report an increase. 2.2 Intestinal sugar and amino acid transporters. Monosaccharides and amino acids are transported from the intestinal lumen across the epithelial cells and into the blood, mainly through the transcellular pathway (figure 1). These nutrients are initially absorbed by carriers in the brushborder membrane facing the lumen and are subsequently transported from intracellular compartments across the basolateral membrane by a different set of carriers. Almost all nutrient transport studies in aging determined rates of absorption across the brushborder membrane into the cell, or across the epithelial layer into the blood (or serosal space). Both transport rates can be determined experimentally by radioisotope tracer techniques. Figure 1. Schematic diagram of an intestinal cell showing location of the Na⁺-dependent glucose (SGLT1) and Na⁺-independent fructose (GLUT5) transporters in the brushborder, and Na⁺-independent glucose and fructose (GLUT2) transporter in the basolateral membrane. Nutrient transport via the transcellular path entails crossing the brushborder and basolateral membranes in series, that via the paracellular path need only cross the tight junction. Paracellular transport accounts for only a small fraction of total intestinal nutrient transport. Absorption of glucose and galactose across the brushborder membrane of intestinal cells is Na⁺-dependent and is mediated by SGLT1 (16) (figure 1). The absorption of fructose by GLUT5 is Na⁺-independent (17). All three sugars cross the basolateral membrane via another member of the facilitative glucose transporter family, GLUT2 (18). There are many more transport systems for absorption of amino acids, seven (five are Na⁺-dependent) for the brushborder membrane and five (two are Na⁺-dependent) for the basolateral membrane (19).

[Frontiers in Bioscience 2, e108-115, November 1, 1997]
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EFFECT OF AGING AND CALORIC RESTRICTION ON INTESTINAL SUGAR AND AMINO ACID TRANSPORT

Ronaldo P. Ferraris

Dept of Pharmacology and Physiology, UMDNJ-New Jersey Medical School, 185 South Orange Ave., Newark, NJ 07103

Received 7/17/97 Accepted 10/2/97

2. INTRODUCTION

Death by starvation has reached epidemic proportions among older Americans (1). Nutrition surveys found malnutrition in 6% of men and 5% of women between the ages of 70 and 80 years, and in 12% of men and 8% of women over the age of 80 (see review by Rolls (2)). Bond and Levitt (3) showed that 33% of active, clinically-well individuals over the age of 65 malabsorbed a portion of a 100 g carbohydrate meal. This indicates that the mean carbohydrate absorptive capacity fell progressively from age 65. Xylose absorption also decreases with advancing age (4, 5, 6). The elderly also malabsorb peptides and amino acids. Serum albumin concentrations are significantly lower in the elderly than in young humans even when their dietary protein intake is similar (7), suggesting that peptides and amino acids may be malabsorbed in the elderly.

There are many possible causes of malnutrition, ranging from behavioral factors like decreased appetite to pathological conditions like malabsorption. One of the most neglected areas of study in elderly nutrition is the effect of aging on intestinal absorption and on the ability of the small intestine to regulate absorption of nutrients. This information is important since decreases in rates of transport may contribute to malabsorption and to malnutrition. In addition, the rate of intestinal absorption of sugars and their site of absorption largely determine postprandial plasma glucose concentrations.

The effect of aging on glucose tolerance is quite evident after consumption of a meal (8). For each decade after middle age, the level of fasting plasma glucose increases by 0.05 to 0.1 mM, but the postprandial plasma glucose level increases much more, by 0.4 to 1.1 mM. Thus, older people often are considered diabetic based on postprandial plasma glucose level, and not on fasting glucose level. If aging results in adaptive mechanisms which alter the rate of intestinal sugar absorption and move the main absorptive site, then, the subsequent rise of plasma glucose will be affected. For example, adaptive mechanisms in chronic diabetes result in a dramatic increase in total intestinal absorptive capacity for glucose (9). Similar adaptive mechanisms during aging could result in an age-related change in postprandial plasma glucose tolerance.

In this brief review, I will mainly focus on the effect of aging on intestinal sugar and amino acid absorption, and primarily on studies done in the last 15 years since Holt (10), Thomson and Keelan (11) and Vinardell (12) wrote reviews on aging and intestinal absorption. This review excludes studies on development (neonatal to adult). Holt and Balint (13) reviewed the effect of aging on intestinal lipid absorption. I will describe the nonspecific or specific mechanisms underlying the effects of aging on transport, and the reader is referred to a recent review by Ferraris and Diamond (14) which gives a detailed explanation of these mechanisms. Finally, I will also review studies on the effect of chronic caloric restriction on absorption of nutrients, since caloric restriction is a well accepted procedure for extending lifespan and postponing aging. I will end with suggestions for future research.

2.1 Basis for normalization.

Because investigators use a variety of methods to determine rates of intestinal nutrient absorption, it is important for the reader to keep track of how absorption rates are normalized. Briefly, the intestinal transport rate of a nutrient may be normalized to the weight (or protein content) of intestinal tissue or cell or membrane, to length or surface area of intestinal tissue, or to the entire small intestine. The last expression is often referred to as intestinal absorptive capacity or SUMJ. When normalized in this manner, a change in the transport rate may mean a change in transport activity by the intestinal absorptive cell as well as a change in intestinal mass. Similarly, a change in transport per cm of intestine would mean a change in transport activity in that segment of intestine, as well as a change in the intestinal mass per cm. Because of macroscopic (folds) and microscopic (villi and microvilli) elaborations, the actual surface area of the absorptive mucosa is difficult to measure (see Ref. 15 for a detailed discussion). In almost all cases, absorption normalized to surface area refers only to serosal (the nonabsorptive side), and not mucosal, surface area. A change in transport expressed per unit weight reflects only a change in functional activity independent of a change in mass. Hence, if aging were to have no effect on transport activity per unit weight, but were to induce a two-fold increase in intestinal weight, studies normalizing to weight would report no age-related change in transport, but studies normalizing to surface area or intestinal length would report an increase.

2.2 Intestinal sugar and amino acid transporters.

Monosaccharides and amino acids are transported from the intestinal lumen across the epithelial cells and into the blood, mainly through the transcellular pathway (figure 1). These nutrients are initially absorbed by carriers in the brushborder membrane facing the lumen and are subsequently transported from intracellular compartments across the basolateral membrane by a different set of carriers. Almost all nutrient transport studies in aging determined rates of absorption across the brushborder membrane into the cell, or across the epithelial layer into the blood (or serosal space). Both transport rates can be determined experimentally by radioisotope tracer techniques.

Figure 1. Schematic diagram of an intestinal cell showing location of the Na⁺-dependent glucose (SGLT1) and Na⁺-independent fructose (GLUT5) transporters in the brushborder, and Na⁺-independent glucose and fructose (GLUT2) transporter in the basolateral membrane. Nutrient transport via the transcellular path entails crossing the brushborder and basolateral membranes in series, that via the paracellular path need only cross the tight junction. Paracellular transport accounts for only a small fraction of total intestinal nutrient transport.

Absorption of glucose and galactose across the brushborder membrane of intestinal cells is Na⁺-dependent and is mediated by SGLT1 (16) (figure 1). The absorption of fructose by GLUT5 is Na⁺-independent (17). All three sugars cross the basolateral membrane via another member of the facilitative glucose transporter family, GLUT2 (18). There are many more transport systems for absorption of amino acids, seven (five are Na⁺-dependent) for the brushborder membrane and five (two are Na⁺-dependent) for the basolateral membrane (19).