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Unité de Nutrition et Métabolisme Protéique, Institut National de la Recherche Agronomique, Theix, 63 122 Saint-Genès-Champanelle, France
1To whom correspondence should be addressed. E-mail: papet{at}clermont.inra.fr.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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2-macroglobulin, 1-acid glycoprotein and proteins other than albumin revealed a low grade inflammation in old rats. Protein fractional synthesis rates (FSR) and protein synthesis efficiencies of thymus were 29 and 26% lower in old than in adult rats, respectively; these variables did not differ in spleen. Protein absolute synthesis rates (ASR) of the thymus and spleen were 76% lower and 67% greater in old than adult rats, respectively. The FSR and ASR of albumin and other plasma proteins were greater in old than in adult rats. Protein synthesis measurement is a valuable nonimmunological tool to assess, in vivo, immune and inflammatory variables. Alterations in secondary lymphoid organs and plasma protein synthesis may contribute to the significant repartitioning of amino acids in old compared with adult rats and may be involved in sarcopenia.
KEY WORDS: • aging • inflammation • lymphoid tissues • protein synthesis • rats
Aging is a natural, complex and multifactorial process, characterized by a progressive decline in many functions in the absence of disease and malnutrition. However, the unanimously recognized age-related dysregulation of the immune system may contribute to morbidity and mortality due to increased susceptibility to infectious diseases and possibly certain cancers in aged individuals (1
). The origin of the age-related alterations of the immune function has not been clearly established, but modifications in hematopoiesis and thymus function likely contribute to the decrease in both the humoral and cellular responses, with T-cell alterations playing a crucial role (1
–5
).
The orchestration of immune cell activities is highly dependent on the cytokine network. Aging is also associated with a dysregulation in cytokine production reflected by increased circulating levels of tumor necrosis factor-, interleukin-6 and cytokine antagonists in vivo (6
). This proinflammatory status, resulting mainly from chronic age-related stimulation of macrophages, is referred to as "inflamm-aging" (5
). It is associated with increased plasma levels of acute phase proteins. Concentrations of C-reactive protein, fibrinogen and 1-acid glycoprotein increase during aging in humans (7
–9
). On the contrary, decreased levels of plasma albumin are frequently found in older people in the absence of disease (10
,11
). Similar variations of acute phase proteins have been reported in rats (12
).
Aging is associated with a dysregulation of the immune system and a chronic low-grade inflammation that are expected to affect in vivo protein synthesis rates in lymphoid tissue and plasma protein synthesis rates. Quantification of these alterations would help clarify how protein metabolism is partitioned between tissues and organs in aged individuals. It is already known that aging is associated with sarcopenia (13
,14
) and an increased utilization of dietary amino acids by the splanchnic area (15
).
In vivo protein synthesis rates in blood lymphocytes and lymphoid tissues from various species have already been reported. Such measurements have been recognized recently as a valuable nonimmunological tool for the evaluation of the metabolic activity of immune cells in vivo (16
). Lymphocyte protein synthesis has been shown to be sensitive to stresses, such as surgery (17
), acquired immune deficiency syndrome (18
), combined stress hormone infusion (19
), lipopolysaccharide challenge (20
) and bacterial infection (21
). In addition, we recently reported that the time course of protein synthesis rates of lymphoid tissues was consistent with the known activation of the immune system after a bacterial infection (21
). To our knowledge, the effect of aging on protein synthesis of lymphoid tissues has not yet been investigated. The little information that is available on the effect of aging on the rate of synthesis of plasma proteins concerns only albumin. Measurement of the in vivo synthesis of a single protein is a powerful tool with which to analyze the importance of variations in its level (7
). An increase in albumin synthesis with age has been reported in several studies performed with isolated cells as well as in vivo in rodents (22
). However, in humans, it has been found that albumin synthesis is not modified with age (23
,24
). The relationship between aging and the synthesis of plasma proteins other than albumin, including positive acute phase proteins, has not been documented at all.
This paper describes, for the first time, basal synthesis rates of thymus, spleen, albumin and plasma proteins, including albumin and acute phase proteins, in adult and old rats as an in vivo assessment of the dysregulation of the immune system and the chronic low grade inflammation associated with aging. The potential metabolic effect of these alterations on skeletal muscle atrophy and protein synthesis rates, which have already been reported for these rats (25
), is questioned.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Nine adult (8 mo) and 10 old (22 mo) male Wistar rats were purchased from Iffa Credo (Lyon, France) and housed under controlled conditions (temperature 22°C, 12-h dark period starting at 0800 h). They were housed individually with free access to water. They also had free access to a diet containing 18.2% protein (25
) during the dark period from 0900 to 1700 h and received no food during the light period. They were acclimated for 1 mo to their surroundings. Food intake was determined on a daily basis and rats were weighed every morning. The study was performed according to the current legislation on animal experiments in France.
Measurement of in vivo protein synthesis.
Rates of protein synthesis were measured in vivo using a flooding dose of L-(1-13C)phenylalanine (50 µmol/100 g body, 99 atom% excess, 0.32 mL/100 g body, massTrace, Woburn, MA) as already described and validated (25
). The flooding dose method minimizes problems related to the precursor pool that are encountered with the constant infusion method (26
). Moreover the constant infusion would have been very difficult to carry out in old rats. A blood sample was taken from a lateral tail vein 5 min after the tracer injection. General anesthesia was induced by intraperitoneal injection of pentobarbital (6 mg/100 g body, Sanofi, Libourne, France) 5 min before killing. At 40 min after the flooding dose injection, blood was withdrawn from the abdominal aorta. Blood was collected in heparinized tubes. Plasma was separated by centrifugation and kept at –20°C until analysis. Thymus, spleen and liver were removed, weighed, and immediately frozen.
Phenylalanine enrichments.
Free and protein-bound phenylalanine were separated and their enrichments measured as described previously (25
). In the case of liver, the protein pellet was discarded. The tracer incorporation lasted too long for an accurate measurement of total liver protein synthesis because exported proteins were no longer present in the liver. Nevertheless, liver free phenylalanine 13C enrichment was needed as the precursor pool enrichment to calculate plasma protein synthesis rates. Albumin was separated from other plasma proteins as described (27
). Free phenylalanine enrichments at 40 min were 57, 38, 35 and 30 atom% excess, in plasma, liver, spleen and thymus from adult rats and 63, 46, 44 and 42 atom% excess in plasma, liver, spleen and thymus from old rats, respectively.
Protein and RNA levels.
Total plasma proteins were determined using the biuret protein assay on a Cobas Mira analyzer (ABX Diagnostics, Montpellier, France). Plasma fibrinogen was measured by nephelometry (Biodirect, Les Ulis, France). Albumin, 2-macroglobulin and 1-acid glycoprotein were measured by single radial diffusion as described previously (28
). The procedure followed to quantify phenylalanine enrichments allows the determination of tissue protein content using the bicinchoninic acid procedure (BCA Protein Assay Kit; Pierce Chemical, Rockford, IL, USA) and tissue RNA content using a spectrophotometric assay (29
).
Calculations.
Protein fractional synthesis rate (FSR, %/d)2 was calculated from the formula FSR = 100 x (Sb - Sb0)/(Sa' x t), where Sb0 is the mean basal enrichment of protein-bound phenylalanine of four additional rats fed no tracer injection (atom% excess), Sb is the enrichment of protein-bound phenylalanine at 40 min (atom% excess), Sa' is the mean free tissue phenylalanine enrichment during the incorporation period and t is the incorporation period in days (26
). For plasma proteins, which are synthesized in the liver and then exported into plasma, liver free phenylalanine was used. In addition, the duration of tracer incorporation was calculated as the time between the flooding dose injection and killing minus 20 min, which corresponds to the secretion time of liver exported proteins. Consequently, Sa' was calculated over this period as previously described (30
). To calculate Sa', the decline in tissue free phenylalanine enrichment during the labeling period was estimated to be parallel to the decrease in plasma values between 5 and 40 min after the flooding dose injection. Due to the differences between plasma and tissue free phenylalanine enrichments, we verified that the significance of differences between adult and old rats was conserved when FSR was calculated using plasma free phenylalanine enrichment values. The absolute synthesis rate (ASR; mg/d) was calculated by multiplying FSR by the total tissue protein content. For plasma proteins, intravascular absolute synthesis rates were calculated by multiplying FSR by plasma protein level and expressed as g protein synthesized/(d · L plasma). Ribosomal capacity (Cs, mg/g) of lymphoid tissues was estimated as the ratio of RNA to protein. The corresponding translational efficiency [kRNA, mg protein synthesized/(d · mg RNA)] was calculated as the ratio of FSR to Cs.
Statistical analysis.
Values are given as means ± SEM, n = 8–10. The significance of differences was analyzed using the Student’s t test for unpaired data. Differences among means were considered significant when P < 0.05. Linear regression was used to determine the relationship between variables. All statistical analyses were performed using StatView for Windows, version 5 software (SAS Institute, Cary, NC).
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Body weight and food intake did not differ between adult (8 mo) and old (22 mo) rats (Table 1
). As expected, thymus weight was 55% lower in old than in adult rats. On the contrary, a 40% hypertrophy of the spleen was observed in old compared with adult rats, whereas the liver weights did not differ. Thymus and spleen total protein contents were 67% lower and 40% greater in old than in adult rats, respectively (Table 2
). The tibialis anterior was 10% lighter in old than adult rats (Table 1)
. Gastrocnemius and soleus muscles masses and protein contents were also lower in old than in adult rats (25
). Plasma total protein concentration was 8% higher in old than in adult rats, mainly reflecting the increase in plasma proteins minus albumin, whose level was 26% higher in older rats (Table 1)
. Plasma albumin concentration was 22% lower in old than in adult rats. The acute phase proteins, 1-acid glycoprotein, fibrinogen and 2-macroglobulin, were 48 (P = 0.1), 93 and 346% greater in old than adult rats, respectively. The plasma fibrinogen concentration was inversely correlated with albumin plasma level in old, but not in adult rats (Fig. 1
).
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In adult rats, thymus FSR (76%/d), was greater than spleen FSR (39%/d, Table 2
). Thymus FSR was 29% lower, whereas spleen FSR tended to be greater (17%; P = 0.1) in old than in adult rats. Therefore, thymus FSR and spleen FSR were similar in old rats. Age-associated differences in thymus FSR was not due to a modification of the Cs but were due to a 26% lower kRNA in old than in adult rats. The thymus ASR was 76% lower and the spleen ASR 67% greater in old than adult rats.
Synthesis of plasma proteins.
In adult rats, the FSR of albumin and other plasma proteins were 63 and 40%/d, respectively; old rats had 92 and 12% greater rates, respectively (Table 3
). The ASR of albumin and other plasma proteins were 49 and 40% higher in old than in adult rats, respectively.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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). The efficiency of the immune system relies on a network of several types of highly specialized immune cells, whose activities are often tested using in vitro techniques. Such investigations do not necessarily reflect the in vivo metabolic activity of lymphoid tissues. The originality of the present study lies in the analysis of the effect of aging on the in vivo metabolic activity of lymphoid tissues by measuring protein synthesis rates in thymus and spleen from adult (8 mo) and old (22 mo) rats.
As previously observed in growing rats (21
), the FSR of the lymphoid tissues were high in adult rats, with the thymus (primary lymphoid tissue) more active than the spleen (secondary lymphoid tissue). Only the thymus FSR was much lower in old than in adult rats, suggesting that aging specifically affects immune tissues exhibiting higher turnover rates. This effect was not due to a decrease in the capacity of synthesis (RNA/protein was unchanged) but an impairment in the efficiency of protein synthesis. The direct cause of such an effect is unknown, but surely related to hormonal, neuronal and environmental factors leading to the age-associated decline in the thymus function and consequently to immunosenescence (4
). Age-induced thymus atrophy occurs with a shift from the thymic epithelial space, in which thymopoiesis occurs, to the perivascular space (31
). In the present study, a 55% weight loss occurred in the thymus between 8 and 22 mo. Thymus protein content was even lower in old than adult rats (-76%), consistent with the adipocyte proliferation and differentiation increase that occurs as the thymus ages (31
). The age-induced decrease in FSR likely reflects the failure of thymic T-cells to undergo differentiation, leading to alterations in the relative amounts of T-cells subtypes (naive/memory, mature/immature and T-helper 1/T-helper 2) responsible for the age-related immune dysfunction (32
).
In contrast to the thymus, the spleen was hypertrophied in old rats in agreement with previous observations (33
). Because the relative body weight of most other organs decreases with aging, the age-induced hypertrophy of the spleen is unique. The metabolic activity (FSR) of the spleen was not markedly affected by aging, regardless of the age-induced modification in the lymphocyte populations (34
). Part of the age-related increase in spleen ASR may reflect macrophage activation. Indeed, macrophage function, supporting innate immunity, is preserved or even increased with aging (32
). Chronic age-related stimulation of macrophages likely plays an important role in the progressive increase in proinflammatory status (5
).
High plasma levels of fibrinogen, 2-macroglobulin and 1-acid glycoprotein associated with low albumin plasma level (Fig. 1)
clearly revealed a low grade inflammatory state in old rats. This is consistent with the "inflamm-aging" concept (5
). Acute inflammation associated with sepsis or injury leads to similar modifications in albumin and fibrinogen levels (35
) but greater increases in 2-macroglobulin and 1-acid glycoprotein levels (28
,36
). Moderate inflammation induced by vaccination in humans increases fibrinogen level without affecting the albumin level (37
). Hypoalbuminemia has been reported previously in old rats (12
). In the present experiment, it was not induced by undernutrition because old rats ate the same amount of food as adults, nor was it induced by disease because old rats appeared as healthy as younger ones. This hypoalbuminemia cannot be explained by a lower synthesis rate, as already observed in patients (35
) and in rats during the early acute response to infection (36
). The increased synthesis of albumin in old rats is consistent with previous investigations (22
) and suggests that old rats have a higher demand for albumin than adult rats. This is due mainly to increased fluid phase endocytosis because gastrointestinal protein loss remains constant and urinary albumin excretion accounts for 2.4% of total albumin elimination in old rats (22
). The effect of aging on albumin metabolism deserves further investigation.
Both the level and the synthesis of plasma proteins other than albumin, mainly positive acute phase proteins and immunoglobulins, were higher in old than in adult rats. This is in agreement with the increase in fibrinogen plasma level and ASR observed in healthy humans after vaccination (37
) or in patients (35
). Fibrinogen ASR was similar in old and middle-aged humans; however, only a small increase in plasma level of fibrinogen (+12%) was observed (23
). It appears that the increase in fibrinogen ASR depends on the intensity of the inflammation. No data are available concerning the effect of aging or inflammation on the rate of synthesis of immunoglobulins (Ig). Nevertheless, high levels of serum IgA (38
,39
) and IgG (38
) have been reported in healthy elderly subjects. Such alterations could contribute to the increased synthesis rate of plasma proteins.
The present study clearly showed that the dysregulation of the immune system and the low grade inflammation associated with aging have a quantitative effect on the ASR of plasma proteins and lymphoid tissues. The age-related increase in plasma protein ASR could contribute to the increased utilization of dietary proteins by the splanchnic area (15
) and consequently to a potential decrease in the availability of amino acids for peripheral tissues in the old. Actually, liver ASR would have been more informative with that respect. No difference in liver ASR was reported in 12- and 24-mo-old rats, but their inflammatory states were unknown (40
). Thymus appears to contribute little to whole body protein synthesis irrespective of the age of the rats. On the other hand, if all secondary lymphoid tissues behave as the spleen, they may utilize large amounts of amino acids and modify the partitioning of amino acids for protein synthesis among the different tissues and organs. It is tempting to speculate that these alterations could interfere with skeletal muscle protein synthesis and have a role in sarcopenia. Indeed ASR was quantified in gastrocnemius muscle from the same rats and was 15% lower in old than adult rats (25
). In addition the proinflammatory state associated with aging is strongly suspected to have a signal effect on protein metabolism in skeletal muscle (41
). The present study emphasizes that the occurrence of an inflammatory state whose intensity is likely to differ from one experiment to another, in the old, should be considered in any investigations that involve sarcopenia.
In conclusion, aging is an inevitable process that includes a dysregulation of the immune system, low grade inflammation and sarcopenia, all of which contribute to morbidity and mortality. The present data clearly show that rates of synthesis of lymphoid tissue and plasma proteins in old rats are in agreement with immunosenescence and age-related chronic inflammation. These alterations may have important effects on interorgan amino acid utilization and participate in sarcopenia. The challenge for the future is to identify nutritional and therapeutic strategies to allow "successful aging" of our growing elderly population that would offer an increase in functional capabilities of the thymus and/or a decrease in the proinflammatory state during old age. Quantification of protein synthesis in lymphoid tissue and plasma proteins should be a useful tool in this research area.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Manuscript received 31 July 2002. Initial review completed 9 September 2002. Revision accepted 16 October 2002.
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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 M. Sheffield-Moore, D. Paddon-Jones, A. P. Sanford, J. I. Rosenblatt, A. G. Matlock, M. G. Cree, and R. R. Wolfe Mixed muscle and hepatic derived plasma protein metabolism is differentially regulated in older and younger men following resistance exercise Am J Physiol Endocrinol Metab, May 1, 2005; 288(5): E922 - E929. [Abstract] [Full Text] [PDF]
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M. Sheffield-Moore, C. W. Yeckel, E. Volpi, S. E. Wolf, B. Morio, D. L. Chinkes, D. Paddon-Jones, and R. R. Wolfe Postexercise protein metabolism in older and younger men following moderate-intensity aerobic exercise Am J Physiol Endocrinol Metab, September 1, 2004; 287(3): E513 - E522. [Abstract] [Full Text] [PDF]
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