Dietary protein intake affects albumin fractional synthesis rate in younger and older adults equally

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1 Emerging Science Dietary protein intake affects albumin fractional synthesis rate in younger and older adults equally Anna E Thalacker-Mercer and Wayne W Campbell Inclusion of dietary protein in meals and beverages affects the hepatic synthesis of the protein albumin. Besides dietary protein, several factors can influence albumin metabolism and affect plasma albumin. The role of aging in albumin synthesis is unclear. Recent research documents that albumin synthesis rate is influenced comparably in younger and older adults by dietary protein ingestion and changes in dietary protein quantity. This emphasizes the importance for all adults to consume an adequate amount of dietary protein International Life Sciences Institute INTRODUCTION Albumin is an essential plasma protein synthesized by the liver, which has many functions including transport and binding of physiologically important compounds (e.g., fatty acids, bilirubin, tryptophan, calcium, steroid hormones) and maintenance of osmotic pressure. 1,2 Healthy individuals maintain plasma albumin concentration between 3.5 and 5.0 g/dl through the rate of albumin synthesis, degradation, release from liver cells, distribution in the body, and exogenous loss. 1 In malnutrition, plasma albumin concentration can be reduced and is often used clinically as a biomarker of the general adequacy of protein nutrition. In addition, several biological and environmental factors (e.g., sepsis, inflammation, illness, smoking) influence the factors that maintain plasma albumin concentration. 3 However, the effects of advancing age on plasma albumin concentration has yet to be clearly established due to inconclusive results from studies. 4 6 AGING, DIETARY PROTEIN, AND ALBUMIN METABOLISM Some studies suggest that albumin concentration declines with advancing age, independent of illness or disease, in both institutionalized geriatric patients 7 and free-living older individuals, 4,6 while other studies suggest that plasma albumin concentration does not change with age. 5,8 There is also uncertainty about the effects of inadequate dietary protein intake on plasma albumin concentration: one study suggested there is a positive correlation between protein intake and plasma albumin concentration, 7 while another study showed no changes in plasma albumin concentration following 12 weeks of inadequate protein intake (0.45 g kg -1 d-1 ). 9 Due to the relatively long (~19 day) half-life of the albumin protein, determining the fractional synthesis rate (FSR) of albumin is an alternative approach to measuring the effects of relatively short-term environmental changes (e.g., transient changes in daily dietary intake and nutrient ingestion) and differences in these effects with advancing age on albumin metabolism. Evidence by Fu and Nair 5 suggests that independent of dietary intake, young, middle-aged, and older adults (total age range y) in good health have similar fasting-state albumin FSRs. Other studies show that ingestion of dietary protein positively influences albumin synthesis independent of age However, some research indicates there is an age-related sensitivity of albumin synthesis to changes in dietary protein intake: younger, but not older, adults have a decrease in albumin synthesis rate with decreased dietary protein intake. 4 Recent evidence by Thalacker-Mercer et al. 8 suggests that albumin FSR is comparable between younger and older adults during Affiliations: AE Thalacker-Mercer and WW Campbell are with the Department of Foods and Nutrition, Purdue University, West Lafayette, Indiana, USA. Correspondence: WW Campbell, Department of Foods and Nutrition, Purdue University, 700 West State Street, West Lafayette, IN 47907, USA. campbellw@purdue.edu, Phone: , Fax: Key words: aging, albumin, dietary protein, fractional synthesis rate doi: /j x Nutrition Reviews Vol. 66(2):

2 short-term changes in dietary protein intake and the response to acute changes in the quantity of dietary protein ingested is also similar between the two age groups. The finding that younger and older adults have a comparable response to protein ingestion is supported by a recent study by Caso et al., 10 which demonstrated that younger and older adults have similar albumin FSR responses to ingestion of beverages containing mixed macronutrients and isonitrogenous protein-only beverages. Determining if dietary protein has a differential effect on albumin synthesis rate in older adults compared to younger adults is important because approximately 38% of adults aged 60 years and older consume less than the recommended dietary allowance (0.8 g kg -1 d -1,RDA) for protein. Reduced albumin synthesis with inadequate protein intake could lead to decreased plasma albumin concentration. CHANGING DIETARY PROTEIN INTAKE AFFECTS ALBUMIN FRACTIONAL SYNTHESIS RATE In 1980 Gersovitz et al. 4 suggested there is an age-related difference in the sensitivity of albumin synthesis rate to changes in dietary protein intake. The albumin FSR during seven days of adequate protein intake (190% of the RDA) was compared to the FSR of albumin during 14 days of inadequate protein intake (50% of the RDA) in younger and older males (Table 1). While the albumin FSR was comparable between younger and older males, they found that only the younger adults had a significant decrease in albumin FSR with inadequate protein intake. The response to changes in dietary protein intake in younger adults was also seen by Jackson et al. 13 who studied younger males and females who consumed a diet containing approximately 92 g/d of dietary protein for seven days followed by a diet containing approximately 40 g/d of protein for seven days (Table 1): the fasting-state albumin FSR decreased by approximately 40% from the higher to the lower protein diet. The studies by Gersovitz et al. 4 and Jackson et al. 13 suggest that the albumin FSR in younger adults responds to changes in dietary protein intake. However, the study by Gersovitz et al. 4 was the only study to compare the albumin synthesis responses between younger and older adults. Recently, however, Thalacker-Mercer et al. 8 have presented contradicting evidence concerning the effects of aging on the response to differences in dietary protein intake. Thalacker-Mercer et al. 8 studied 36 healthy younger and older adults during three, 18-day controlled feeding periods with protein intakes of 63%, 94%, and 125% of the RDA (Table 1). The fasting and fed states of albumin FSR were estimated using L-[1-13 C] leucine during an eighthour infusion on day 12 of each trial. They hypothesized, based on the findings previously reported by Gersovitz et al., 4 that younger adults (males and females) would respond to different quantities of dietary protein intake with changes in the albumin FSR, but that the older adults would not respond. Contrary to their hypothesis, this comprehensive study demonstrated that changes in dietary protein intake consumed over a two-week period did not influence the albumin FSR differentially between younger and older adults. The fasting-state albumin FSR did not change with different quantities of protein intake during the short-term dietary period, suggesting that short-term changes in daily dietary protein intake do not influence fasting albumin synthesis rates in either younger or older adults in good health.also, there was no difference in the fed-state albumin FSR between young and older subjects, nor was a difference detected with different quantities of dietary protein ingestion. As expected, albumin FSR was higher during the fed state versus the fasting state. The change in albumin FSR from the fasting to the fed state (DFSR) was assessed: DFSR increased as dietary protein ingestion increased from 63% and 94% of the RDA to 125% of the RDA. DFSR did not differ with age. The greater DFSR when 125% of the RDA for protein was ingested, compared to the DFSR at the lower levels of protein intake, suggests that the quantity of dietary protein intake consumed in a meal or beverage acutely affects albumin synthesis in both younger and older healthy adults. So, does aging affect the response of albumin synthesis to changes in dietary protein intake? To date, Gersovitz el al. 4 and Thalacker-Mercer et al. 8 are the only groups that have assessed and compared the effects of different quantities of dietary protein intake on albumin FSR in younger and older adults. A possible explanation for the differential outcomes of the two studies is chronic inflammation. In the study by Gersovitz et al. 4 all older men reported having chronic inflammation. It has been noted previously that chronic inflammation could be an uncontrolled factor in the Gersovitz et al. 4 study, causing the albumin FSR to remain elevated following a reduction in dietary protein intake in the older males. 14 Another factor that possibly explains the difference between the two studies is the isotope that was used. Due to the extensive dosing period required to obtain equilibrium using the 15 N-glycine isotope, which is the isotope used by Gersovitz et al., 4 only the composite effects (i.e., fasting- and fed-states combined, not separate) of dietary protein on albumin FSR could be determined; therefore, it is unknown if the stimulation of albumin FSR with nutrient ingestion (i.e., fed-state vs. fasting-state) was comparable between younger and older adults. It is also unknown if the differences observed between younger and older men regarding albumin FSR with inadequate dietary protein, as noted by Gersovitz et al., 4 were due to differences in habitual protein intake between the two groups or to 92 Nutrition Reviews Vol. 66(2):91 95

3 Table 1 Summary of studies observing the effects of the quantity of dietary protein intake on the FSR of albumin. Study Age Sex Dietary protein intake (g kg -1 d -1 ) Duration of protein intake Gersovitz et al. (1980) 4 Y (19-25 y) 5 M d Fasting and fed states combined Metabolic state Albumin FSR (%/d) * ac d bc O (64-78 y) 5 M d c d c Jackson et al. (2001) 13 Y (33 6 y) 3 M, 3 F 1.40 Habitual Fasting a d b Thalacker-Mercer et al. Y (21-43 y) 10 M, 8 F d randomized (2007) 8 crossover (albumin FSR assessed on d-12 of each trial) Fasting O (63-79 y) 9 M, 9 F Y (21-43 y) 10 M, 8 F 1.00 Fed O (63-79 y) 9 M, 9 F * Values are means SEM. Within study, means in column without a common superscript differ, p < Mean fasting state FSR of albumin across the three dietary protein trials and two ages is significantly lower than the mean for the fed state FSR of albumin. Abbreviations: Y, younger; O, older; M, male; F, female; FSR, fractional synthesis rate. Nutrition Reviews Vol. 66(2):

4 Figure 1 Acute differences in the fractional synthesis rate (FSR) of albumin between protein-free beverages (-P) and beverages containing protein (+P) in younger males and acute differences in FSR following consumption of beverages containing mixed macronutrients (Mixed) and protein-only (P-O; isonitrogenous to the mixed-macronutrient beverage) in younger (Y) and older (O) males. Values are mean SEM. Data from Cayol et al (-P and +P) and Caso et al. (2007) 10 (Mixed and P-O). differences in the stimulation of protein synthesis with nutrient ingestion, since fasting- and fed-state albumin FSR were not determined. Results from the short-term study conducted by Jackson et al. 13 suggest that inadequate daily intake of protein leads to a decrease in albumin FSR. However, the results from Thalacker- Mercer et al. 8 contradict this and suggest the quantity of acutely ingested protein causes the change in albumin FSR. Future research is needed to address the discrepancy between the acute and habitual effects of dietary protein intake on albumin FSR. Findings from a recent study by Caso et al. 10 parallel those of Thalacker-Mercer et al., 8 showing that younger and older adults respond comparably to nutrient ingestion. Caso et al. 10 identified ingestion of dietary protein alone as the important factor, compared to inclusion of carbohydrates and fat, for the stimulation of albumin synthesis. The synthesis rate of albumin was assessed acutely in younger (25 1 y) and older (68 2 y) adults during the fasting and fed states using a randomized crossover design and three different beverages. The fasting state was assessed with a water-only trial. The two fed states were induced using isonitrogenous, but not isocaloric, beverages containing either mixed macronutrients (55, 30, and 15% of total energy from carbohydrate, fat, and protein, respectively) or protein alone (isonitrogenous to the mixed-macronutrient beverages). The results showed no difference between the younger and older adults during the fasting state (water-only) for albumin FSR (7.7 and 6.2%/d, respectively), and the younger and older adults responded comparably with increased albumin FSR during consumption of beverages containing mixed macronutrients and protein alone. As shown in Figure 1, there were no differences in albumin FSR between the beverages for the younger and older adults (younger: 10.0 and 9.9%/d, respectively; older: 9.2 and 9.5%/d, respectively). Similar outcomes were documented by Cayol et al., 11,12 who reported that the albumin FSR was significantly lower when protein-free beverages were consumed during a 10-h infusion compared to beverages containing 190% of the RDA for protein (6.4 and 10.0%/d, respectively) (Figure 1). Collectively, these studies demonstrate that nutrient ingestion stimulates albumin FSR and that dietary protein intake, compared to carbohydrate and fat intake, is essential for the stimulation of albumin synthesis (Figure 1). While the study by Thalacker-Mercer et al. 8 did not demonstrate a differential response between the younger and older adults to nutrient ingestion and changes in dietary protein intake, a trend was noted for DFSR over the three protein trials as protein intake increased from 63 to 94 to 125% of the RDA for protein, the DFSR became less different between the younger and older adults (Figure 2). This trend was not statistically significant, but it does demonstrate a pattern similar to changes in skeletal muscle protein synthesis between younger and older adults during ingestion of different quantities of amino acids To determine if the pattern presented in Figure 2 is not just a coincidence, future studies including a larger sample size and a wider range and larger number of dietary protein intakes are needed. Overall, a smaller DFSR of albumin with inadequate protein intake may be problematic for older adults who routinely consume less than the RDA for protein because a decrease in albumin concentration may eventually occur. 94 Nutrition Reviews Vol. 66(2):91 95

5 Figure 2 Change in fractional synthesis rate of albumin with nutrient ingestion in younger and older adults. Change in FSR of albumin from the fasting to the fed state (DFSR) in older (O) and younger (Y) adults with changes in dietary protein intake (P63 = 63%, P94 = 94%, and P125 = 125% of the recommended dietary allowance for protein). Values are mean SEM. Data from Thalacker-Mercer et al. (2007). 8 CONCLUSIONS Collectively, these studies suggest that albumin synthesis rate is influenced by dietary protein quantity and ingestion in both younger and older adults and that the responses are comparable in the two groups. The results reiterate that it is important for adults of all ages to consume adequate quantities of dietary protein. REFERENCES 1. Doweiko JP, Nompleggi DJ. Role of albumin in human physiology and pathophysiology. JPEN J Parenter Enteral Nutr 1991;15: Spector AA. Fatty acid binding to plasma albumin. J Lipid Res 1975;16: Doweiko JP, Nompleggi DJ. Role of albumin in human physiology and pathophysiology. Part III: albumin and disease states. JPEN J Parenter Enteral Nutr 1991;15: Gersovitz M, Munro HN, Udall J, Young VR. Albumin synthesis in young and elderly subjects using a new stable isotope methodology: response to level of protein intake. Metabolism 1980;29: Fu A, Sreekumaran Nair K. Age effect on fibrinogen and albumin synthesis in humans. Am J Physiol 1998;275:E Hostmark AT, Tomten SE, Berg JE. Serum albumin and blood pressure: a population-based, cross-sectional study. J Hypertens 2005;23: MacLennan WJ, Martin P, Mason BJ. Protein intake and serum albumin levels in the elderly. Gerontology 1977;23: Thalacker-Mercer AE, Johnson CA, Yarasheski KE, Carnell NS, Campbell WW. Nutrient ingestion, protein intake, and sex, but not age, affect the albumin synthesis rate in humans. J Nutr 2007;137: Castaneda C, Charnley JM, Evans WJ, Crim MC. Elderly women accommodate to a low-protein diet with losses of body cell mass, muscle function, and immune response. Am J Clin Nutr 1995;62: Caso G, Feiner J, Mileva I, et al. Response of albumin synthesis to oral nutrients in young and elderly subjects. Am J Clin Nutr 2007;85: Cayol M, Boirie Y, Prugnaud J, Gachon P, Beaufrere B, Obled C. Precursor pool for hepatic protein synthesis in humans: effects of tracer route infusion and dietary proteins. Am J Physiol 1996;270:E Cayol M, Boirie Y, Rambourdin F, et al. Influence of protein intake on whole body and splanchnic leucine kinetics in humans. Am J Physiol 1997;272:E Jackson AA, Phillips G, McClelland I, Jahoor F. Synthesis of hepatic secretory proteins in normal adults consuming a diet marginally adequate in protein. Am J Physiol Gastrointest Liver Physiol 2001;281:G Don BR, Kaysen G. Serum albumin: relationship to inflammation and nutrition. Semin Dial 2004;17: Katsanos CS, Kobayashi H, Sheffield-Moore M, Aarsland A, Wolfe RR. A high proportion of leucine is required for optimal stimulation of the rate of muscle protein synthesis by essential amino acids in the elderly. Am J Physiol Endocrinol Metab 2006;291:E Katsanos CS, Kobayashi H, Sheffield-Moore M, Aarsland A, Wolfe RR. Aging is associated with diminished accretion of muscle proteins after the ingestion of a small bolus of essential amino acids. Am J Clin Nutr 2005;82: Volpi E, Mittendorfer B, Rasmussen BB, Wolfe RR. The response of muscle protein anabolism to combined hyperaminoacidemia and glucose-induced hyperinsulinemia is impaired in the elderly. J Clin Endocrinol Metab 2000;85: Nutrition Reviews Vol. 66(2):