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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 55:B329-B335 (2000)
© 2000 The Gerontological Society of America

Increase in Basal Level of Hsp70, Consisting Chiefly of Constitutively Expressed Hsp70 (Hsc70) in Aged Rat Brain

Keiko Unnoa, Hiromi Asakuraa, Yuka Shibuyaa, Masako Kaihoa, Shoji Okadaa and Naoto Okua

a Department of Radiobiochemistry, School of Pharmaceutical Sciences, University of Shizuoka, Japan.

Keiko Unno, Department of Radiobiochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan E-mail: unno{at}ys7.u-shizuoka-ken.ac.jp.

Decision Editor: Jay Roberts, PhD


   Abstract
Top
 Abstract
Materials and Methods
 Results
 Discussion
 References
 
Alteration of proteins in the function and higher structure has been observed in aged organisms. Stress proteins, which have a role to protect proteins from denaturation, may respond to the protein denaturation with aging. We found that the basal level of Hsp70, consisting chiefly of constitutively expressed Hsp70 (Hsc70), in 24-month-old Wistar rats was significantly higher in some parts of the brain than that in 6-month-old rats. On the other hand, the basal level of Hsp70 was significantly lower in 24-month-old rats after restricted feeding, which is known to suppress aging, than those fed the diet ad libitum. In the pons, medulla, striatum, and thalamus of 24-month-old rat brain, the level of Hsp70 increased and the denaturation of the cytosol proteins was suppressed. These results suggest that the expression of Hsp70, mostly Hsc70, increases with aging and may have a role to suppress protein denaturation.

IN aged animals, various denatured proteins such as enzymes with lowered activity, unfolded proteins, and proteins modified by oxidation and glycation have been detected (1)(2)(3)(4)(5). These abnormal proteins may lead to protein aggregation, cell damage, and decreased function of organs. Stress proteins (molecular chaperones) are thought to have a role in protecting cells from damages through defense against denaturation, and restoration or resolution of denatured proteins (6). Therefore, alterations of the expression and function of stress proteins are supposed to be linked to the protein denaturation with aging.

Among the Hsp70 family, which is a most abundant and important family of stress proteins, stress-inducible Hsp70 is essential for protecting cells from various denaturing stresses (e.g., 7) including oxidative stress (8)(9). In addition, constitutively expressed Hsp70 (Hsc70) is important for responding to diverse cellular signals, including serum factors, viral activation, developmental regulation, and stress induction (10). Hsc70 might have a role in protecting cells from a mild stress, because Hsc70 is induced at lower thresholds of hyperthermic and ischemic stresses than the inducible Hsp70 (11)(12). Some oxidative stresses enhanced the expression of the Hsc70 gene without affecting the inducible Hsp70 gene (13).

In spite of many reports of the reduced rate of induction of Hsp70 in cells from aged organisms (14)(15)(16)(17)(18)(19)(20), the basal expression of Hsp70, which consists chiefly of Hsc70, has not been fully examined in aged animals. The level of Hsc70 might be altered by the accumulation of oxidized and misfolded proteins with aging. Recently, it was suggested that the basal Hsp70 increased by accumulation of modified proteins in aged rat kidney (21). Accumulation of denatured proteins in long-lived cells like neurons might be related to the decreased function of the brain with aging.

In the present study, we found that the basal levels of Hsp70 in some parts of the rat brain, such as pons, striatum, and thalamus, were higher in aged than young animals. Furthermore, to confirm the effect of aging on the expression of Hsp70, we investigated whether the level of Hsp70 was altered in rats dietarily restricted, as caloric restriction is known to have a suppressive effect on aging and reduce oxidative stresses (22)(23)(24). We found that the level of Hsp70 was decreased by dietary restriction. Additionally, the amount of the heat-instable protein fraction was higher in some parts of the brain of 24-month-old rats than those of 6-month-old rats. However, the heat instability was suppressed in those parts with an increased level of Hsp70. In the aged rat brain, the increased level of Hsp70, mostly Hsc70, might have a role to protect proteins from denaturing stress.


   Materials and Methods
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 Abstract
 Materials and Methods
Results
 Discussion
 References
 
Animals, diets and treatments.
All animal protocols were approved by the University of Shizuoka Laboratory Animal Care Advisory Committee. Male Wistar rats purchased from Japan SLC Inc. (Hamamatsu, Japan) were maintained in a temperature- and humidity-controlled room with a 12-h light:dark cycle.

Rats aged 6 to 24 months old, ( per each age group) were fed a certified commercial pellet diet (MF; Oriental Yeast Co., Tokyo) ad libitum (Normal). In the dietary restriction (DR) experiment, two groups of 14-month-old rats (), which had been fed ad libitum previously, were fed MF every other weekday for 4 and 10 months, respectively; the dietary restriction resulted in a food intake of about half the normal.

Preparation of brain samples.
Eight parts of the brain (i.e., cerebellum, mesencephalon, cerebral cortex, pons and medulla, hippocampus, striatum, thalamus, and hypothalamus) were isolated. Liver was used as a control organ. Brain and liver samples were homogenized in 10 volumes of buffer containing 0.05 M Tris-HCl buffer (pH 6.8), 1% (v/v) 2-mercaptoethanol, and 10% (v/v) glycerol. The homogenate was centrifuged at 700 g for 10 min. The supernatant was used for measurement of protein contents and determination of the amount of Hsp70. The protein contents of samples were determined with a Bio-Rad protein assay kit (Bio-Rad Laboratories, Richmond, CA).

Determination of Hsp70 in brain.
The 700 g supernatant described above was heated at 90°C for 3 min in the presence of 1% sodium dodecyl sulfate (SDS) for electrophoresis. Samples of 20 µg protein were loaded on 10% SDS-polyacrylamide gel (SDS-PAG) and electrophoresed. Molecular weight markers (Prestained SDS-PAGE standard, Bio-Rad Laboratories) and a standard Hsp70 were coloaded on the gel. Two kinds of standard Hsp70 were used. One was bovine brain Hsc70 (StressGen Biotech Corp., Victoria, BC, Canada) which primarily consists of constitutively expressed Hsp70 (Hsc70) and fewer amounts (5–10%) of stress-inducible form of Hsp70 (Hsp72). The other was a recombinant human Hsp70 (Hsp72, StressGen Biotech Corp.).

Proteins in the gel were transferred to a polyvinylidene fluoride (PVDF) membrane (Immobilon-P, Millipore Corp., Bedford, MA). The membranes were mainly processed with two kinds of anti-Hsp70 monoclonal antibody preparations for a quantitative determination: MAb 7.10 reacts with both Hsc70 and Hsp72, and C92F3A-5 (StressGen Biotech) is specific for Hsp72. Hsc70-specific antibody preparations, 1B5 (StressGen Biotech) and 13D3 (Affinity Bioreagents, Golden, CO), were used for a qualitative confirmation. The membranes were further incubated with goat anti-rat IgG or goat anti-mouse IgG antibody, which were both conjugated with horseradish-peroxidase. MAb 7.10 was kindly given by Dr. S. Lindquist of the University of Chicago. Hsp70 bands were visualized with the ECLTM detection system (Amersham Pharmacia Biotech, Buckinghamshire, England).

For the quantitative analysis of Hsp70, the correlation between the amount of standard Hsp70 (0.005-0.5 µg) and the density of band was obtained. The density of Hsp70 was determined by using a densitometer (CS-9000, Shimadzu Corp., Kyoto, Japan). The amounts of Hsp70 in rat brain samples were calculated from the density of coloaded standard Hsp70.

Heat-stability of cytosol proteins of aged rat brain.
Brain samples (i.e., cerebellum, mesencephalon, cerebral cortex, pons and medulla, hippocampus, striatum, and thalamus) were homogenized with 10 volumes of Tris buffer. The buffer consisted of 20 mM Tris-acetate (pH 7.5), 20 mM NaCl, 15 mM 2-mercaptoethanol, 3 mM MgCl2, 10% (v/v) glycerol, and a cocktail of protease inhibitors: 10 mg/l leupeptin, 10 mg/l E64, 10 mg/l antipain, and 0.5 mmol/l phenylmethansulfonyl fluoride (PMSF). The cytosol fraction was obtained by centrifugation first at 700 g for 10 min and then at 12,000 g for 10 min. To determine the amount of heat-stable proteins, aliquots of the cytosol fraction were heat-treated at 42°C for 1 h and centrifuged at 12,000 g for 10 min, after which the supernatant was submitted to the protein measurement. Other aliquots were incubated at 4°C for 1 h and similarly centrifuged, and the amount of soluble cytosol proteins was measured as the control. The amounts of soluble proteins in the heated and unheated samples were compared to give the ratio of the heat-stable proteins.

Statistical analysis.
Data are presented as means ± SD. The StatView software (Abacus Concepts, Berkeley, CA) was used to evaluate differences among the multiple conditions. Statistical significances among the levels of Hsp70 in the brain of 6- to 24-month-old rats were analyzed by using the analysis of variance (ANOVA) followed by Fisher's protected least significant difference (PLSD). Differences in the level of Hsp70 in the brain regions between the same age-group rats fed ad libitum and dietarily restricted were examined by t test. Differences in the heat-stability of brain cytosol proteins between each brain part of 6- and 24-month-old rats were examined by t test.


   Results
Top
 Abstract
 Materials and Methods
 Results
Discussion
 References
 
Quantitative analysis of Hsp70.
To confirm that the anti-Hsp70 antibody was relevant for the quantitative analysis of rat brain Hsp70, bovine brain Hsc70 as a standard Hsp70 was analyzed with MAb 7.10. Because bovine brain Hsc70 primarily consisted of constitutively expressed Hsp70 (Hsc70) and a lesser amount of stress-inducible form of Hsp70 (Hsp72), MAb 7.10 was used for determination of both Hsc70 and Hsp72. A straight correlation between the amount of bovine brain Hsc70 (0.005-0.2 µg) and the density of band was obtained (Fig. 1). Similar straight correlation was obtained between the amount of a recombinant human Hsp70 (Hsp72) and the density obtained with Hsp72-specific antibody, C92F3A-5 (data not shown).



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  		Figure 1. Relationship between amount of bovine brain Hsc70 and the density. Bovine brain Hsc70 samples (0.005–0.5 µg) were electrophoresed on 10% SDS-PAG and transferred to PVDF membrane. The membrane was processed with MAb 7.10 and was further incubated with goat anti-rat IgG antibody conjugated with horseradish-peroxidase. Hsc70 bands visualized with the ECLTM detection system (inserted photo) were determined by using a CS-9000, densitometer. A straight relationship between the density and the amount of Hsc70 (0.005–0.2 µg) was obtained (r2 = .994).

 
The immunoblot bands of rat brain were of both Hsc70 and Hsp72, but not of other members of Hsp70, such as Grp75 and Grp78. The amount of Hsp70 (Hsc70 + Hsp72) was determined with MAb 7.10 on 8 parts of the brain and liver (Fig. 2 a and c). Although the density of each membrane was apt to alter, the value of Hsp70 amount in samples of each rat (lanes 2–10) was corrected by the density of 0.1 µg of bovine brain Hsc70 coloaded on the gel (lanes 1 and 11). The measurement of Hsp72 was similarly carried out in the presence of 5 ng of Hsp72 (Fig. 2 b and d). These levels of Hsp70 (Hsc70 + Hsp72) and Hsp72 were comparable among different membrane samples. The amount of Hsc70 was expressed as the difference between those of Hsp70 determined with MAb 7.10 and C92F3A-5.



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  		Figure 2. Hsp70 in 6- and 24-month-old rat brain and liver. Hsp70 (Hsc70 and Hsp72) was processed with MAb 7.10 (a and c), and Hsp72 was done with C92F3A-5 (b and d). They were further incubated with goat anti-rat IgG antibody or goat anti-mouse IgG antibody, which were both conjugated with horseradish-peroxidase. Hsp70 bands were visualized with the ECLTM detection system. The bands of Hsp70 in one of 6-month-old Wistar rats (a and b) and one of 24-month-old rats (c and d) were shown as follows. Lanes 1 and 11 were a standard Hsp70; 0.1 µg of bovine brain Hsc70 (a and c) or 5 ng Hsp72 (b and d). Lane 2, cerebellum; lane 3, mesencephalon; lane 4, cerebral cortex; lane 5, pons and medulla; lane 6, hippocampus; lane 7, striatum; lane 8, thalamus; lane 9, hypothalamus; lane 10, liver.

 
Increased expression of Hsp70 in the aged rat brain.
The effect of aging on the basal expression of Hsp70 was determined on 8 parts of the brain (i.e., cerebellum, mesencephalon, cerebral cortex, pons and medulla, hippocampus, striatum, thalamus, and hypothalamus) of 6- to 24-month-old rats (Fig. 3 a–h). The levels of Hsp70 detected with MAb 7.10 were significantly higher in 24-month-old rats than in 6-month-old rats in the pons and medulla, striatum, and thalamus (Fig. 3 d, f, and g). In the cerebral cortex, hippocampus, and hypothalamus, the levels tended to increase in 24-month-old rats (Fig. 3 c, e, and h). On the other hand, the amounts of Hsp70 cerebellum and mesencephalon were little increased (Fig. 3 a and b). In the liver, the level of Hsp70 did not increase with aging and was generally lower than that in the brain (Fig. 3 i).



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  		Figure 3. Age-related increase in Hsp70 of the rat brain and liver. The measurement of Hsp70 in the brain of 6- to 24-month-old male Wistar rats was carried out on 8 parts of the brain and the liver as shown in Fig. 2. Each bar represents the mean ± SD (n = 3). An asterisk represents a significant difference between 6-month-old and the indicated groups (*p < .05). (Striatum: F value = 8.577, p value = .003. Pons + medulla: .)

 
Hsp72 in the 24-month-old rats was detected with C92F3A-5. The amount of Hsp72 was very low in these rat brains (Fig. 2 and Fig. 4). The Hsp72 levels in the 6-month-old rat brains were similar to those in the 24-month-old rats (Fig. 2 b and d). Hsc70 was dominant and the level of Hsp72 was very low in these unstressed animals (i.e., the basal level of Hsp70 consisted mostly of Hsc70). The increased Hsp70 in the aged rat brain was thought to be of Hsc70. The immunoblots determined with anti-Hsc70, 1B5 and 13D3, were similar to that with MAb 7.10, suggesting that the basal level of Hsp70 consisted mostly of Hsc70 (data not shown).



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  		Figure 4. Amounts of constitutive (dark hatch) and inducible (open hatch) Hsp70 in the 24-month-old rat brain and liver. Hsp70 in 24-month-old rat was detected with anti-Hsp70 antibodies, MAb 7.10 and C92F3A-5. The latter is specific to the inducible Hsp70 (Hsp72), and the former reacts with both constitutive Hsp70 (Hsc70) and Hsp72. The measurements of Hsp70 (Hsc70 + Hsp72) and Hsp72 were carried out as described in Fig. 2 and Fig. 3. The amount of Hsc70 was obtained as the difference between those of Hsp70 measured with MAb 7.10 and C92F3A-5. Each bar represents the mean ± SD ().

 
Effect of dietary restriction on Hsc70 in the rat brain
Caloric restriction is known to have a suppressive effect on aging. To investigate the effect of caloric restriction on stress responses in the aged rat brain, the basal level of Hsp70 in the brain of DR aged rats was compared to rats fed ad libitum. Two groups of 14-month-old rats, which had been fed ad libitum previously, were fed every other weekday until they were 18 and 24 months old, respectively. The body weights of 10-month DR rats were 330–370 g and were about 80% of those of the same age-group rats fed ad libitum (420–460 g). In the 18-month-old rats restricted from food for 4 months, the levels of Hsp70 were slightly lowered in the striatum, hippocampus, pons and medulla, but not in the other parts (data not shown). In the 24-month-old DR rats restricted from food for 10 months, the amounts of Hsp70 were significantly lower in most brain parts compared with those of the same age-group rats fed ad libitum (Fig. 5). The basal Hsp70 levels in these parts of the 24-month-old DR rats were similar to those in the 6-month-old rats shown in Fig. 3.



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  		Figure 5. Decreased expression of Hsp70 in aged rats after dietary restriction. The amounts of Hsp70 in the brain were measured in 24-month-old male Wistar rats that underwent dietary restriction (DR) for the last 10 months in comparison with those fed ad libitum (Normal). Each bar represents the mean ± SD (). An asterisk represents a significant difference from Normal (*p < .05 t test).

 
Heat-stability of cytosol proteins of the aged rat brain.
Unfolded proteins are sensitive to heat treatment and become insoluble by aggregation. To investigate the role of the increased expression of Hsc70, the heat stability of proteins in the cytosol fraction was examined in the cerebellum, mesencephalon, cerebral cortex, hippocampus, striatum, pons and medulla, and thalamus of the 6- and 24-month-old rats. The increase in basal Hsp70 level was little in the cerebellum and mesencephalon, but it was significant in the pons + medulla, striatum, and thalamus. In cerebral cortex and hippocampus, the levels tended to increase.

The heat stability at 42°C of the proteins from the 24-month-old rats was significantly decreased in the cerebellum and mesencephalon compared with the 6-month-old rats (Fig. 6). The heat stability was a little decreased in the cerebral cortex and hippocampus of 24-month-old rats. However, the heat stability was not decreased in the pons + medulla, striatum, and thalamus of the 24-month-old rats.



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  		Figure 6. Heat-stability of cytosol proteins of the rat brain. Brain samples from the 6-month (open hatch) and 24-month-old (dark hatch) rats were homogenized in 10 volumes of buffer as described in Method. The cytosol fraction was obtained by centrifugation at 700 g for 10 min followed by 10 min at 12,000 g. Aliquots of the cytosol fraction were heat-treated at 42°C for 1 h, and centrifuged at 12,000 g for 10 min, and the supernatants subjected to protein measurement. Other aliquots were incubated at 4°C for 1 h and similarly centrifuged; the amounts of soluble cytosol proteins were measured as the control. The amounts of soluble proteins in the heated and unheated samples were compared to give the ratio of the heat-stable proteins. Each bar represents the mean ± SD (). An asterisk represents a significant difference from each value of the 6-month-old rat brain (*p < .05 t test).

 

   Discussion
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 Abstract
 Materials and Methods
 Results
 Discussion
References
 
In this study we focused on alterations in the basal level of Hsp70 in the brain, consisting mainly of Hsc70, in relation to aging. Neural tissues have been reported to exhibit higher amounts of Hsc70 than in non-neural tissues (25). In long-lived cells such as neurons, Hsc70 and other molecular chaperones might be greatly required for the functional maintenance of proteins, because long-lived cells are exposed to the danger of denaturation for a long period of time under various stresses. Hsc70 has been known to be regulated by various factors (10) and induced by mild ischemic and hyperthermic stresses (11)(12). Furthermore, the level of Hsc70 was reported to be slightly higher in neuroblastoma cells expressing the scrapie isoform of the prion protein than the cells expressing the cellular prion protein (26)(27). Hsc70 might respond more sensitively to the denaturation of proteins caused by stresses with aging, and also to unfolding events such as the formation of the scrapie isoform of the prion protein, than the inducible Hsp70.

In the 24-month-old rat brain, the basal levels of Hsp70, mostly Hsc70, significantly increased in the pons + medulla, striatum, and thalamus, and they tended to increase in the cerebral cortex, hippocampus, and hypothalamus (Fig. 3). The basal level of Hsp70 was suppressed by dietary restriction in aged rats (Fig. 5). It has been known that dietary restriction inhibits protein oxidation (23)(24) and that some oxidative stresses enhance the level of Hsc70, but not that of Hsp72 (13). These results suggest that the formation of oxidized proteins with aging is a cause of the increased level of Hsc70 in the aged rat brain. We are attempting to examine the kind and level of oxidized proteins in these parts of the aged rat brain.

It has been reported that the increase in Hsp70 by a previously given mild heat stress was effective for reducing the damage by subsequent heat and oxidative stresses in mammalian cells (7)(9). The overexpression of Hsp70 increased the life span of transgenic Drosophila melanogaster (28)(29). Furthermore, overexpressed Hsp70 protected primary hippocampal cultures from heat stress and protected cytosolic proteins from inactivation (30).

In the 24-month-old rat brain, the basal levels of Hsp70, mostly Hsc70, significantly increased in the pons, striatum, and thalamus; however, the levels were little changed in the cerebellum and mesencephalon. In the present study, an important effect of different levels of Hsc70 was observed in the protection of cytoplasmic proteins from heat stress. In the cerebellum and mesencephalon, the ratios of heat-stable proteins in the 24-month-old rat were lower than those in the 6-month-old rats. On the other hand, the ratios of heat-stable proteins did not decrease in the pons + medulla, striatum, and thalamus of the aged rats (Fig. 6). These results suggest that the protein denaturation is not drastic but certainly occurs in the aged rat brain, and that the enhanced level of Hsc70 may have significance in protecting intracellular proteins from denaturing stresses. The ratio of heat-stable proteins in the pons, striatum, and thalamus did not differ between the 6- and 24-month-old rats. This result may be interpreted to indicate that the protective effect of Hsc70 is offset by the increased amount of heat-instable protein with aging.

We suppose that a mild stress induces Hsc70 in the brain with aging, and an increased level of Hsc70 may be important for the protection of proteins from degeneration with aging.


   Acknowledgments
 
This research was supported in part by a Grant-in-Aid for Scientific Research, from the Ministry of Education, Science, Sports and Culture, Japan.

Received February 24, 1999

Accepted December 27, 1999


   References
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