Aging reduces adaptive capacity and stress protein expression in the liver after heat stress

2000 ◽  
Vol 89 (2) ◽  
pp. 749-759 ◽  
Author(s):  
D. M. Hall ◽  
L. Xu ◽  
V. J. Drake ◽  
L. W. Oberley ◽  
T. D. Oberley ◽  
...  
Keyword(s):  
Heat Stress ◽  
Protein Expression ◽  
Recovery Period ◽  
Stress Protein ◽  
Hsp70 Expression ◽  
Functional Link ◽  
Acute Response ◽  
Age Related ◽  
Old Rats ◽  
The Impact

A decline in an organism's ability to cope with stress through acute response protein expression may contribute to stress intolerance with aging. We investigated the influence of aging on stress tolerance and the capacity to synthesize the 70-kDa heat shock protein (HSP70) in young and old rats exposed to an environmental heating protocol. Livers were assessed for injury and HSP70 expression after heat stress by use of immunohistochemical and immunoblotting techniques. The inducible HSP70 response in the cytoplasm and nucleus was markedly reduced with age at several time points over a 48-h recovery period, although senescent rats were able to strongly express HSP70 early in recovery. Older animals had extensive zone-specific liver injury, which corresponded to the diminished HSP70 response observed in these regions, and a significant reduction in thermotolerance compared with their young counterparts. These data highlight the regional nature of stress-induced injury and HSP70 expression in the liver and the impact of aging on these responses. Furthermore, the results suggest a functional link between the age-related decrements in the expression of inducible HSP70 and the pathophysiological responses to heat stress.

Chronic antioxidant enzyme mimetic treatment differentially modulates hyperthermia-induced liver HSP70 expression with aging

2006 ◽  
Vol 100 (4) ◽  
pp. 1385-1391 ◽  
Author(s):  
Hannah J. Zhang ◽  
Susan R. Doctrow ◽  
Larry W. Oberley ◽  
Kevin C. Kregel
Keyword(s):  
Heat Stress ◽  
Recovery Period ◽  
Protein Accumulation ◽  
Mrna Levels ◽  
Hsp70 Mrna ◽  
Hsp70 Protein ◽  
Age Related ◽  
Wide Range ◽  
Old Rats ◽  
The Impact

One postulated mechanism for the reduction in stress tolerance with aging is a decline in the regulation of stress-responsive genes, such as inducible heat shock protein 72 (HSP70). Increased levels of oxidative stress are also associated with aging, but it is unclear what impact a prooxidant environment might have on HSP70 gene expression. This study utilized a superoxide dismutase/catalase mimetic (Eukarion-189) to evaluate the impact of a change in redox environment on age-related HSP70 responses to a physiologically relevant heat challenge. Results demonstrate that liver HSP70 mRNA and protein levels are reduced in old compared with young rats at selected time points over a 48-h recovery period following a heat-stress protocol. While chronic systemic administration of Eukarion-189 suppressed hyperthermia-induced liver HSP70 mRNA expression in both age groups, HSP70 protein accumulation was blunted in old rats but not in their young counterparts. These data suggest that a decline in HSP70 mRNA levels may be responsible for the reduction in HSP70 protein observed in old animals after heat stress. Furthermore, improvements in redox status were associated with reduced HSP70 mRNA levels in both young and old rats, but differential effects were manifested on protein expression, suggesting that HSP70 induction is differentially regulated with aging. These findings highlight the integrated mechanisms of stress protein regulation in eukaryotic organisms responding to environmental stress, which likely involve interactions between a wide range of cellular signals.

Dysregulation of hepatic iron with aging: implications for heat stress-induced oxidative liver injury

2008 ◽  
Vol 294 (4) ◽  
pp. R1165-R1174 ◽  
Author(s):  
Steven A. Bloomer ◽  
Kyle E. Brown ◽  
Garry R. Buettner ◽  
Kevin C. Kregel
Keyword(s):  
Lipid Peroxidation ◽  
Heat Stress ◽  
Liver Injury ◽  
Iron Content ◽  
Nonheme Iron ◽  
Hepatic Iron ◽  
Young Rats ◽  
Age Related ◽  
Old Rats ◽  
Labile Iron

Environmental heat stress is associated with an age-related increase in hepatic oxidative damage and an exaggerated state of oxidative stress. The purpose of this investigation was to evaluate the regulation of hepatic iron after heat stress. A secondary aim was to determine a potential role for iron in heat stress-induced liver injury. Hyperthermia-induced alterations in hepatic iron were evaluated in young (6 mo) and old (24 mo) Fischer 344 rats by exposing them to a two-heat stress protocol. Livers were harvested at several time points after the second heating and assayed for labile and nonheme iron. In the control condition, there was no difference in labile iron between age groups. Both labile iron and storage iron were not altered by hyperthermia in young rats, but both were increased immediately after heating in old rats. To evaluate a role for iron in liver injury, hepatic iron content was manipulated in young and old rats, and then both groups were exposed to heat stress. Iron administration to young rats significantly increased hepatic iron content and ferritin but did not affect markers of lipid peroxidation under control conditions or after heat stress. In old rats, iron chelation with deferoxamine prevented the increase in nonheme iron, labile iron, ferritin, and lipid peroxidation after heat stress. These results suggest that iron may play a role in hepatic injury after hyperthermia. Thus, dysregulation of iron may contribute to the gradual decline in cellular and physiological function that occurs with aging.

Adaptive stretch-shortening contractions: diminished regenerative capacity with aging

2008 ◽  
Vol 33 (6) ◽  
pp. 1181-1191 ◽  
Author(s):  
Brent A. Baker ◽  
Melinda S. Hollander ◽  
Robert R. Mercer ◽  
Michael L. Kashon ◽  
Robert G. Cutlip
Keyword(s):  
Skeletal Muscle ◽  
Tibialis Anterior Muscle ◽  
Recovery Period ◽  
Muscle Performance ◽  
Muscle Adaptation ◽  
Regenerative Capacity ◽  
Age Related ◽  
Old Rats ◽  
Shortening Contractions ◽  
Muscle Remodeling

This study determined the age-related changes in acute events responsible for initiating skeletal muscle remodeling and (or) regeneration in the tibialis anterior muscle following a bout of stretch-shortening contractions (SSCs). Changes in muscle performance and morphology were quantified in young and old rats, following an acute exposure to adaptive SSCs at 6, 24, 48, 72, and 120 h postexposure (n = 6 for each age at each recovery period). Following SSC exposure, all performance measures were decreased in old rats throughout the 120 h acute phase. Estimates of edema were increased in the old vs. young exposed muscle at 120 h recovery. Both young and old rats displayed an increase in developmental myosin heavy chain (MHCdev+) labeling in the exposed muscle, indicating muscle regeneration. However, old rats displayed diminished MHCdev+ labeling, compared with young rats, suggesting limited remodeling and (or) regenerative capacity. Based on these data, diminished local muscle remodeling and (or) regeneration with aging may limit skeletal muscle adaptation following mechanical loading.

scholarly journals Age-Related Changes in Sirtuin 7 Expression in Calorie-Restricted and Refed Rats

Gerontology ◽  
2015 ◽  
Vol 62 (3) ◽  
pp. 304-310 ◽  
Author(s):  
Agata Wronska ◽  
Aleksandra Lawniczak ◽  
Piotr M. Wierzbicki ◽  
Zbigniew Kmiec
Keyword(s):  
Gene Expression ◽  
Protein Expression ◽  
Calorie Restriction ◽  
Ribosome Biogenesis ◽  
Healthy Aging ◽  
Mrna Levels ◽  
Age Related ◽  
Mrna And Protein Expression ◽  
Old Rats ◽  
Age Related Changes

Background: Sirtuins (SIRT1-7) have been implicated to mediate the beneficial effects of calorie restriction for healthy aging. While the physiological functions of SIRT7 are still poorly understood, SIRT7 has recently been shown to affect ribosome biogenesis, mitochondrial gene expression, and hepatic lipid metabolism. Objective: To analyze the effects of age and short-term calorie restriction (SCR) and subsequent refeeding on SIRT7 expression in key metabolic tissues. Methods: Four- and 24-month-old male Wistar rats were subjected to 40% SCR for 30 days, followed by ad libitum feeding for 2 or 4 days. Liver, white adipose tissue (WAT), heart and skeletal muscle samples were analyzed by real-time PCR and Western blotting for SIRT7 mRNA and protein expression, respectively. Results: Aging had diverse effects on SIRT7 levels in lipogenic tissues: both the mRNA and protein levels increased in the retroperitoneal depot (rWAT), did not change in the epididymal depot (eWAT), and decreased in the subcutaneous depot (sWAT) and the liver of old as compared to young animals. In the heart, extensor digitorum longus muscle (EDL) and soleus muscle (SOL), Sirt7 gene but not protein expression was lower in old than in young control rats. SCR did not affect SIRT7 expression in WAT and the liver in both age groups. In the heart of young animals, SCR did not affect SIRT7 mRNA or protein level. In EDL, SIRT7 protein but not mRNA levels decreased after SCR and remained reduced upon refeeding. In SOL, both SIRT7 mRNA and protein expression were inhibited by refeeding. In old rats, cardiac Sirt7 expression increased after SCR and refeeding. In old rats' EDL and SOL muscles, SIRT7 protein expression was inhibited by refeeding. Conclusion: Age-related changes of SIRT7 gene expression in key organs of energy homeostasis are tissue dependent.

Altered response of protein synthesis to nutritional state and endurance training in old rats

1995 ◽  
Vol 268 (2) ◽  
pp. E328-E335 ◽  
Author(s):  
L. Mosoni ◽  
M. C. Valluy ◽  
B. Serrurier ◽  
J. Prugnaud ◽  
C. Obled ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Tibialis Anterior ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Marked Change ◽  
Treadmill Running ◽  
Liver Protein ◽  
Age Related ◽  
Old Rats ◽  
The Impact

This study was undertaken to determine whether the loss of muscle protein mass during aging could be explained by a reduced sensitivity of muscle protein synthesis to feeding and exercise. Male Wistar rats aged 12 and 24 mo were exercised by treadmill running for 4 mo. Protein synthesis was measured by the flooding dose method in tibialis anterior, soleus, and liver of conscious rested, trained rats and age-matched controls in the postprandial or in the postabsorptive state. No marked change with age could be detected in basal muscle protein synthesis. In contrast, protein synthesis was stimulated in adult but not in old rats by feeding in tibialis anterior and by exercise in soleus. In liver, protein synthesis was not modified by age but was stimulated by feeding and by exercise, which improved the response to feeding. We conclude that the impact of nutrition on muscle protein synthesis is blunted in old age, which could contribute to the age-related loss of nutrition-sensitive muscle proteins.

scholarly journals Aging augments mitochondrial susceptibility to heat stress

2009 ◽  
Vol 296 (3) ◽  
pp. R812-R820 ◽  
Author(s):  
Jodie L. Haak ◽  
Garry R. Buettner ◽  
Douglas R. Spitz ◽  
Kevin C. Kregel
Keyword(s):  
Heat Stress ◽  
Stress Protein ◽  
Liver Mitochondria ◽  
Significant Loss ◽  
Cellular Damage ◽  
Rat Liver Mitochondria ◽  
Heat Shock Protein 60 ◽  
Paramagnetic Resonance ◽  
Mitochondrial Stress ◽  
Old Rats

The pathophysiology of aging is accompanied by a decline in tolerance to environmental stress. While mitochondria are primary suspects in the etiology of aging, little is known about their ability to tolerate perturbations to homeostasis in older organisms. To investigate the role of mitochondria in the increased susceptibility to heat stress that accompanies aging, young and old Fischer 344 rats underwent a heat stress protocol known to elicit exaggerated cellular damage with aging. At either 2 or 24 h after heat stress, livers were removed from animals, and hepatic mitochondria were isolated. Electron microscopy revealed extensive morphological damage to mitochondria from young and, to a greater extent, old rats after heat stress. There was also a significant loss of cytochrome c from old, but not young, mitochondria and a persistent increase in 4-hydroxynonenal-modified proteins in old vs. young mitochondria exposed to heat stress. Electron paramagnetic resonance measurements of superoxide indicate greater superoxide production from mitochondria of old compared with young animals and suggest that mitochondrial integrity was altered during heat stress. The mitochondrial stress response, which functions to correct stress-induced damage to mitochondrial proteins, was also blunted in old rats. Delayed and reduced levels of heat shock protein 60 (Hsp60), the main inducible mitochondrial stress protein, were observed in old compared with young mitochondria after heat stress. Additionally, the amount of Hsp10 protein increased in young, but not old, rat liver mitochondria after hyperthermic challenge. Taken together, these data suggest that mitochondria in old animals are more vulnerable to incurring and less able to repair oxidative damage that occurs in response to a physiologically relevant heat stress.

scholarly journals A Two-Component Regulator of Universal Stress Protein Expression and Adaptation to Oxygen Starvation in Mycobacterium smegmatis

2003 ◽  
Vol 185 (5) ◽  
pp. 1543-1554 ◽  
Author(s):  
Ronan O'Toole ◽  
Marjan J. Smeulders ◽  
Marian C. Blokpoel ◽  
Emily J. Kay ◽  
Kathryn Lougheed ◽  
...  
Keyword(s):  
Heat Stress ◽  
Protein Expression ◽  
Stationary Phase ◽  
Mycobacterium Smegmatis ◽  
Stress Proteins ◽  
Response Regulator ◽  
Stress Protein ◽  
Wild Type ◽  
Two Component ◽  
Oxygen Starvation

ABSTRACT We identified a response regulator in Mycobacterium smegmatis which plays an important role in adaptation to oxygen-starved stationary phase. The regulator exhibits strong sequence similarity to DevR/Rv3133c of M. tuberculosis. The structural gene is present on a multigene locus, which also encodes a sensor kinase. A devR mutant of M. smegmatis was adept at surviving growth arrest initiated by either carbon or nitrogen starvation. However, its culturability decreased several orders of magnitude below that of the wild type under oxygen-starved stationary-phase conditions. Two-dimensional gel analysis revealed that a number of oxygen starvation-inducible proteins were not expressed in the devR mutant. Three of these proteins are universal stress proteins, one of which is encoded directly upstream of devR. Another protein closely resembles a proposed nitroreductase, while a fifth protein corresponds to the α-crystallin (HspX) orthologue of M. smegmatis. None of the three universal stress proteins or nitroreductase, and a considerably lower amount of HspX was detected in carbon-starved wild-type cultures. A fusion of the hspX promoter to gfp demonstrated that DevR directs gene expression when M. smegmatis enters stationary phase brought about, in particular, by oxygen starvation. To our knowledge, this is the first time a role for a two-component response regulator in the control of universal stress protein expression has been shown. Notably, the devR mutant was 104-fold more sensitive than wild type to heat stress. We conclude that DevR is a stationary-phase regulator required for adaptation to oxygen starvation and resistance to heat stress in M. smegmatis.

scholarly journals Expression of heat shock protein 70 is altered by age and diet at the level of transcription

1993 ◽  
Vol 13 (5) ◽  
pp. 2909-2918
Author(s):  
A R Heydari ◽  
B Wu ◽  
R Takahashi ◽  
R Strong ◽  
A Richardson
Keyword(s):  
Heat Shock ◽  
Caloric Restriction ◽  
Hsp70 Expression ◽  
Mrna Levels ◽  
Age Related ◽  
Restriction Diet ◽  
Old Rats ◽  
Ad Libitum ◽  
Shock Proteins ◽  
Hsp70 Synthesis

Because heat shock proteins have been shown to play a critical role in protecting cells from hyperthermia and other types of physiological stresses, it was of interest to determine what effect age and caloric restriction have on the ability of cells to regulate the expression of heat shock protein 70 (hsp70), the most prominent and most evolutionarily conserved of the heat shock proteins. Caloric restriction is the only experimental manipulation known to retard aging and increase survival of mammals. The ability of hepatocytes isolated from young/adult (4- to 7-month-old) and old (22- to 28-month-old) male Fischer F344 rats fed ad libitum or a caloric restriction diet (60% of the content of the ad libitum diet) to express hsp70 was determined after a mild heat shock (42.5 degrees C for 30 min). We found that the induction of hsp70 synthesis and mRNA levels by heat shock was 40 to 50% lower in hepatocytes isolated from old rats than in hepatocytes isolated from young rats. Using in situ hybridization, we found that essentially all hepatocytes from the young/adult and old rats expressed hsp70 in response to heat shock; therefore, the age-related decrease in the induction of hsp70 expression was not due to an age-related accumulation of cells that do not respond to heat shock. Measurements of hsp70 mRNA stability and hsp70 transcription demonstrated that the age-related decline in hsp70 expression arose from a decline in hsp70 transcription. Interestingly, the age-related decline in the induction of hsp70 expression was reversed by caloric restriction; e.g., the induction of hsp70 synthesis, mRNA levels, and nuclear transcription were significantly higher in hepatocytes isolated from old rats fed the caloric restricted diet than in hepatocytes isolated from old rats fed ad libitum. The levels of the heat shock transcription factor in nuclear extracts isolated from heat-shocked hepatocytes were measured in a gel shift assay. Binding of the heat shock transcription factor to the heat shock element decreased with age and was significantly higher in hepatocyte extracts isolated from old rats fed the caloric restriction diet than in those from old rats fed ad libitum. Thus, our study demonstrates that the ability of hepatocytes to respond to hyperthermia and express hsp70 decreases significantly with age and that this decrease occurs at the transcriptional level. In addition, caloric restriction, which retards aging, reversed the age-related decline in the induction of hsp70 transcription in hepatocytes.

scholarly journals Expression of heat shock protein 70 is altered by age and diet at the level of transcription.

1993 ◽  
Vol 13 (5) ◽  
pp. 2909-2918 ◽  
Author(s):  
A R Heydari ◽  
B Wu ◽  
R Takahashi ◽  
R Strong ◽  
A Richardson
Keyword(s):  
Heat Shock ◽  
Caloric Restriction ◽  
Hsp70 Expression ◽  
Mrna Levels ◽  
Age Related ◽  
Restriction Diet ◽  
Old Rats ◽  
Ad Libitum ◽  
Shock Proteins ◽  
Hsp70 Synthesis

Because heat shock proteins have been shown to play a critical role in protecting cells from hyperthermia and other types of physiological stresses, it was of interest to determine what effect age and caloric restriction have on the ability of cells to regulate the expression of heat shock protein 70 (hsp70), the most prominent and most evolutionarily conserved of the heat shock proteins. Caloric restriction is the only experimental manipulation known to retard aging and increase survival of mammals. The ability of hepatocytes isolated from young/adult (4- to 7-month-old) and old (22- to 28-month-old) male Fischer F344 rats fed ad libitum or a caloric restriction diet (60% of the content of the ad libitum diet) to express hsp70 was determined after a mild heat shock (42.5 degrees C for 30 min). We found that the induction of hsp70 synthesis and mRNA levels by heat shock was 40 to 50% lower in hepatocytes isolated from old rats than in hepatocytes isolated from young rats. Using in situ hybridization, we found that essentially all hepatocytes from the young/adult and old rats expressed hsp70 in response to heat shock; therefore, the age-related decrease in the induction of hsp70 expression was not due to an age-related accumulation of cells that do not respond to heat shock. Measurements of hsp70 mRNA stability and hsp70 transcription demonstrated that the age-related decline in hsp70 expression arose from a decline in hsp70 transcription. Interestingly, the age-related decline in the induction of hsp70 expression was reversed by caloric restriction; e.g., the induction of hsp70 synthesis, mRNA levels, and nuclear transcription were significantly higher in hepatocytes isolated from old rats fed the caloric restricted diet than in hepatocytes isolated from old rats fed ad libitum. The levels of the heat shock transcription factor in nuclear extracts isolated from heat-shocked hepatocytes were measured in a gel shift assay. Binding of the heat shock transcription factor to the heat shock element decreased with age and was significantly higher in hepatocyte extracts isolated from old rats fed the caloric restriction diet than in those from old rats fed ad libitum. Thus, our study demonstrates that the ability of hepatocytes to respond to hyperthermia and express hsp70 decreases significantly with age and that this decrease occurs at the transcriptional level. In addition, caloric restriction, which retards aging, reversed the age-related decline in the induction of hsp70 transcription in hepatocytes.

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