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Glutamine and aging

Glutamine and aging

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NAC, Glutathione \u0026 Aging: New Study is Impressive

Glutamine and aging -

Hatched vertical lines indicate time points for amino acid profiling. B Total amino acid concentrations in wild-type and pka1Δ cells at different aging time points as indicated.

C Heatmap showing quantitation of individual amino acids, along with known amino acid properties at right. Averages of 3 time points with 3 independent biological repeats each are shown.

The amino acid quantities, obtained from nondividing cells, differed from those previously reported for fission yeast which have been obtained from rapidly proliferating cells 20 , At the onset of stationary phase, the total amino acid concentrations were lower in pka1Δ than in wild-type cells Figure 1B.

Accordingly, the individual amino acid concentrations were lower or similar in pka1Δ than in wild-type cells at that stage Figures 1C and 2. The concentration differences were particularly pronounced for the branched chain amino acids and aromatic amino acids phenylalanine, tryptophan, tyrosine Figures 1C and 2.

Changing amino acid concentrations during aging. Normalized concentration values of 19 amino acids in wild-type cells panels A, B and pka1Δ cells panels C, D, E during aging top to bottom.

For each condition, 3 independent samples were analyzed. Boxplots were created with R boxplot and default settings.

During chronological aging, the concentration of total free amino acids declined in wild-type but less so in pka1Δ cells, even rising slightly at the last time point Figure 1B. This rise primarily reflected an increase in the most abundant amino acid, lysine, which compensated for the decline in other amino acids Figure 2.

In wild-type samples, the variation in free amino acids between experimental repeats noticeably increased during aging, in contrast to pka1Δ samples Figures 1B and 2. This result raises the possibility that increased variation of amino acid concentrations, reflecting less tight metabolic regulation, is a feature of wild-type aging cultures.

Wild-type cells showed a general decrease in amino acids during aging, apart from aspartate Figures 1C and 2. The branched chain amino acids were initially present at ~3-fold higher levels in wild-type cells before dropping to about half the level of pka1Δ cells Figures 1C and 2.

This result suggests that changes in amino acid concentrations are not driven by limitation of precursor molecules. Likewise, there was no clustering based on glucogenic amino acids, which can be converted into glucose through gluconeogenesis Figure 1C.

This result suggests that any need for gluconeogenesis under glucose depletion does not greatly affect free amino acid composition. Reassuringly, there was also no clustering based on membrane permeability Figure 1C , as this suggests that the results were not biased by amino acids leaking from nonviable cells during the aging time course.

This result suggests that similar metabolic changes occur in aging wild-type and mutant cells, but that these changes are delayed in the long-lived mutant cells.

Some amino acids, however, showed distinct patterns in wild-type and pka1Δ cells, including lysine, glutamate, glutamine, and aspartate Figures 1C and 2. Glutamine and aspartate showed particularly striking profiles during aging.

Glutamine rapidly and strongly decreased during aging, more pronounced in wild-type cells Figures 1C and 2. Aspartate, on the other hand, was the only amino acid that increased during aging in wild-type cells, and this increase was more pronounced in pka1Δ cells Figures 1C and 2.

These results pointed to glutamine and aspartate as markers for aging in S pombe and raised the possibility that these amino acids directly contribute to cellular life span. To examine the effect of glutamine on the CLS of wild-type and pka1Δ cells, we grew cultures to stationary phase in EMM2 minimal medium.

These manipulations did not affect cell numbers or total protein levels of the aging cultures Supplementary Figure 1. In wild-type cells, glutamine supplementation significantly extended the CLS, both when added on Day 1 or 5 Figure 3A and B.

Glutamine supplementation at Day 1 extended the medial CLS from 5 to 6. Although Day 5 was close to the median life span of wild-type cells, glutamine still extended the CLS even at this late stage Figure 3A and B. These results indicate that glutamine is beneficial for viability of aging wild-type cells.

In pka1Δ cells, on the other hand, glutamine supplementation at either Day 1 or 5 had no effect on life span, with the median CLS remaining ~8 days Figure 3C and D. We conclude that glutamine addition during cellular aging promotes longevity in wild-type cells, but not in the long-lived pka1Δ cells which maintain relatively higher glutamine levels during aging Figure 2.

Effects of amino acid supplementation on chronological life span CLS. A CLS assays average of 3 biological repeats with 3 technical repeats each for wild-type cells with and without glutamine supplementation at Days 1 and 5 as indicated. Median CLS in control cells indicated with vertical lines and treated cells indicated with dotted vertical lines are shown.

B Areas under curve AUCs of CLS assays in A as indicated left panel: AUCs from Day 1; right panel: AUCs from Day 5. The p -values t test indicate significance of difference in CLS triggered by glutamine supplementation.

C CLS assays as in A for pka1Δ cells with and without glutamine supplementation at Days 1 and 5. D AUC of CLS assays in C, as described in B. E CLS assays as in A for wild-type cells with and without aspartate supplementation at Days 1 and 5. F AUC of CLS assays in E, as described in B.

G CLS assays as in A for pka1Δ cells with and without aspartate supplementation at Days 1 and 5. H AUC of CLS assays in G, as described in B. To examine the effect of aspartate on the CLS of wild-type and pka1Δ cells, we performed the same experiment as with glutamine, but supplementing aspartate to chronologically aging cultures.

Again, these manipulations did not affect cell numbers or total protein levels of the aging cultures Supplementary Figure 1. In wild-type cells, aspartate supplementation at either Day 1 or 5 had no effect on the CLS Figure 3E and F.

In pka1Δ cells, on the other hand, aspartate led to a significant shorter CLS, both when applied on Day 1 or 5 median CLS shortened from 8 to 6. We conclude that aspartate addition during cellular aging has no effect in wild-type cells but shortens the CLS in pka1Δ cells where aspartate naturally strongly increases during aging Figure 2.

We report intracellular amino acid concentrations in S pombe as a function of both chronological aging and genetic background. Our results show an overall decrease in amino acids during chronological aging, especially in wild-type cells. Such a decrease has also been observed in budding yeast We cannot exclude the possibility that some dead cells contributed to these amino acid measurements, although amino acids with high membrane permeability do not increase with age and thus do not preferentially leak from dead cells.

Such amino acid signatures might therefore serve as aging biomarkers for S pombe. Glutamine and aspartate show the most distinct profiles during aging, with a strong decrease of glutamine, especially in wild-type cells, and a strong increase of aspartate, especially in pka1Δ cells.

The antagonistic changes in glutamine and aspartate are probably linked. During glucose deprivation, yeast cells turn to glutamine and glutamate for energy by making aspartate via glutaminolysis Increased aspartate levels in aging pka1Δ cells could reflect that long-lived cells feature more efficient glutaminolysis, although alanine, another product of glutaminolysis, did not show the same trend.

Induced glutaminolysis in long-lived cells could explain why aspartate did not increase life span in pka1Δ cells which naturally feature high aspartate levels. Glutamine supplementation promotes longevity of wild-type but not of long-lived pka1Δ cells.

Aspartate supplementation, on the other hand, shortens the life span of pka1Δ but not of wild-type cells. These amino acids also affect life span in worms 15 : glutamine at high doses extends life span but at a lower dose shortens life span, while aspartate shortens life span. Glutamine and aspartate both affect mitochondrial functions which might mediate their life-span effects.

Glutamine, derived from the Krebs cycle metabolite alpha-ketoglutarate, is one of the amino acids recently shown to become limited when blocking respiration in fermentatively growing S pombe cells Amino acid supplementations at a later time point Day 5 have weaker effects on longevity, likely reflecting the lower viability of the cell population at that time which diminishes any beneficial.

It is actually surprising that the late supplementations, when cells are aging, still have some effect on life span. Further experiments will provide mechanistic insights into the roles of glutamine and aspartate during aging. These findings highlight the metabolic complexity of aging and its relationship with nutrient-sensing pathways like PKA.

Interestingly, decreased glutamine levels are associated with aging also in budding yeast, rats, and humans 16 , 26 , suggesting that conserved cellular processes are involved in this phenomenon. We thank Shajahan Anver, Clara Correia-Melo, and Stephan Kamrad for critical reading and valuable comments on the manuscript.

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ASH Publications Blood Blood Advances Hematology, ASH Education Program ASH Clinical News ASH-SAP The Hematologist. American Society of Hematology ASH Home Research Education Advocacy Meetings Publications ASH Store. Copyright by American Society of Hematology. As the positive energy balance is not reversed, UPR becomes inflammatory leading to chronic activation of NLRP3 inflammasome.

Therefore, genome instability, excess energy imbalance and epigenomic alterations observed in aging lead to the persistent activation of NLRP3 inflammasomes in metabolic tissues so that an uninterrupted supply of ILs and other inflammatory cytokines SASP disseminate inflammation throughout the body.

At the same time, NLRP3-dependent caspase-1 cleaves HuR, leading to depression of HSF1 expression, thus resulting in a marked failure to resolve inflammation via the HS response, as illustrated in Fig. Glutamine is recognized as a crucial amino acid for cell survival and growth, playing an important role in intermediate metabolism for more information on the historical aspects of glutamine research and general view of metabolic regulation in metabolism, please, consult [ ].

Compared with all other amino acids in the body, glutamine is present at the highest extracellular concentration being the most abundant free amino acid in the blood. Because the organism can synthesize and release glutamine from many tissues, the amino acid is classified as nutritionally non-essential.

However, in some catabolic conditions, such as sepsis, recovery from burns or surgery, as well as after high-intensity exercise, glutamine stores particularly in the skeletal muscle and liver may fall sharply [ — ].

This effect is due to increased bodily requirement for glutamine under such conditions, especially by the muscle itself in the case of high-intensity exercise and the rapidly dividing cells of the immune system in the remaining above cases [ 50 , ].

Moreover, glutamine is released in significant quantities from skeletal muscle stores following stress and injury [ ]. Glutamine can be used as fuel for the essential production of ATP, NADPH, and CO 2 and donates 2 amide nitrogen atoms during the synthesis of macromolecules, including purines, pyrimidines, and amino sugars [ ].

In rapidly proliferating cells e. Glutamine acts as a precursor of lipids after running through the left-hand side of the Krebs cycle until the formation of citrate. Glutamine also influences the expression of a number of genes related to cell protection and survival [ ].

Inasmuch as redox imbalances are characteristic of degenerative disorders [ , ] and aggregative diseases [ — , , ], glutamine status becomes of importance in dictating a healthy condition.

In ARDS, glutamine-elicited suppression of NF-κB blocks NOS2 expression and, therefore, excess NO production [ ]. These protective effects of glutamine, however, have long been recognized to be associated with glutamine-mediated potentiation of the HS response.

In fact, glutamine attenuates endotoxin-induced lung metabolic dysfunction [ ] and reduces lung injury after sepsis, thus improving survival, by enhancing HSP70 expression [ , ]. Moreover, glutamine protects against renal ischemia-reperfusion injury [ ].

This is because glutamine protects against cellular injury by increasing HSF1 function [ ]. This was also confirmed in in vivo studies with trained rats [ 49 ]. Glutamine increases HSF1 nuclear localization and DNA binding, which is accompanied by augmented relative abundance of activating phosphorylation at Ser of HSF1 [ 56 ].

Apart from its role in facilitating HSF1 trimerization a necessary step for its nuclear migration and activity , glutamine induces HSP expression via N -acetyl- O -glycosylation O-GlcNAcylation and phosphorylation of HSF1 and Sp1 transcription factors [ 53 ].

HBP is a metabolic pathway that leads to the eventual synthesis of uridine diphosphate UDP - N -acetylglucosamine and UDP - N -acetylgalactosamine UDP-GlcNAc and UDP-GalNAc, respectively after processing through glutamine:fructosephosphate amidotransferase GFAT, the first and rate-limiting step of HBP.

UDP-GlcNAc and UDP-GalNAc, in turn, may be attached to serine or threonine hydroxyl moieties in nuclear and cytoplasmic proteins by the enzymic action of O -linked- N -acetylglucosaminyl O-GlcNAc transferase a.

OGT [ ]. The main donors for UDP-GlcNAc are glucose, glutamine and uridine triphosphate UTP from the HBP. O-GlcNAcylation is often competitive with phosphorylation at the same sites or at proximal sites on proteins.

Indeed, O-GlcNAc signaling and its crosstalk with phosphorylation reactions affects the post-translational state of hundreds of proteins in response to nutrients and stress, and is also altered in several metabolic diseases and inflammatory processes [ ]. For instance, glutamine stimulates the expression of the argininosuccinate synthetase ASS gene involved in the regulation of NO production via NOS in many cells [ ] via O-GlcNAcylation of Sp1 [ 54 , ], a key transcription factor required for full HS response [ 54 , , ].

Glutamine availability has also been identified as a limiting step for the activation of the mammalian target of rapamycin mTOR [ ]. This is of note because many initiation transcription factor complexes e.

Key intracellular proteins and transcriptional factors, such as Sp1 [ 54 , ], are known to be O-GlcNAcylated via HBP during stress, injury, or illness, while phosphorylation of the eIF2 promotes the activation of HSF1 [ 41 ], leading to the expression of HSPs under stress conditions [ 56 ]. There is another important point where glutamine metabolism intercepts HS response via HBP.

Accordingly, OGT-mediated UDP-GlcNAc addition reaction regulates HS response by blocking GSK-3β, an enzyme that constitutively inhibits HSF1 activation by phosphorylating the transcription factor at Ser [ 55 ]. Thence, glutamine-mediated increased fluxes through HBP may, on the one hand, block GSK-3β, thus liberating glycogen synthesis by glycogen synthase and, on the other, may liberate HSF1 thus allowing enhanced expression of HSP70 [ 55 , ].

HBP is a nutrient-sensing pathway [ ] that presents multiple connections with energy metabolism, not only with glycogen synthesis [ ]. AMPK, which occupies a central position in metabolic regulation in order to avoid inflammatory dysregulation, phosphorylates and inhibits GFAT1, the flux-generating step of HBP, thus allowing for the downregulation of such a shunt from the glycolysis under low glucose situations [ ].

Conversely, chronic hexosamine flux stimulates fatty acid oxidation by activating AMPK [ ]. The metabolic flux through HBP is dependent on glucose availability [ 51 ].

Therefore, in high-glucose states, HBP may act adversely as GFAT1 gene expression is enhanced by hyperglycemia contributing to an exaggerated flux through HBP that can be deleterious [ 52 ]. Indeed, exacerbated HBP activity does contribute to insulin resistance rather than being cytoprotective [ ].

In fact, overenhanced flux through HBP is an inducer of ER stress, while being associated with insulin resistance [ 52 , ], obesity [ ], and abnormal glucose disposal rate in T1DM [ ] and T2DM itself [ ].

Physiologically, glutamine-elicited increase in the flux through HBP leads to a momentary redox imbalance by depleting pentose phosphate shunt cf. Therefore, at the same time that glutamine is cytoprotective by enhancing HS response, it may induce a small redox imbalance that suffices to increase the expression of redox-protecting genes, including those involved in GSH biosynthesis [ ].

De novo GSH synthesis is primarily induced by transcriptional regulation [ — ], via a cascade of signaling events leading to nuclear factor-erythroid 2 prelated factor 2 Nrf2 binding to promoter regions of antioxidant response elements ARE in the nucleus [ — ].

Similarly to that observed for NF-κB, under basal conditions, cytoplasmic Nrf2 is bound to the Kelch-like ECH-associated protein 1 Keap1. However, when cells are exposed to oxidative stress, the oxidation of critical cysteines present in Keap1 protein liberates Nrf2 to dissociate and traverse to the nucleus see, for instance, ref.

The same is observed when cells are treated with anti-inflammatory and HS response inducers cyPGs, which are able to undergo Michael addition reactions directed to Keap1 [ 87 ].

This passingly redox challenge is believed to be produced by glutamine-evoked depletion of glucosephosphate G-6P , which is necessary for the synthesis of NADPH. In turn, NADPH is used to regenerate GSH from GSSG via a GSSG reductase-catalyzed reaction [ 49 ].

Therefore, we believe that glutamine diverts G-6P from the hexose-monophosphate shunt toward glucosephosphate isomerase to form fructosephosphate F-6P which can be further metabolized through the HBP.

As depicted in Fig. Hence, high intracellular glutamine concentrations are expected to reduce the formation of NADPH leading to a transient decrease in GSH which rapidly triggers the transcription of Nrf2-dependent genes, such as G6PDH, γ-GCS, and GS Fig.

Beside of this, N -acetylglucosamine produced by the HBP regulates the activity of HSF1 and GSK-3β, leading to increased HS response [ 55 ]. In fact, chronic glutamine supplementation to trained rats has shown to increase muscle GSH contents and GS at the same time that it has enhanced HS response [ 49 ].

Corroborating this assumption is the fact that the activation of GFAT depletes intracellular glucose stores [ ]. Oppositely, GSH depletion, per se, increases OGT gene expression leading to O-GlcNAcylation of different regulatory proteins [ ], thus strongly suggesting that HBP has a short-loop positive feedback system devoted to assist in cytoprotection via HS response soon as some redox threatening situation is ongoing.

Heat shock response interplay with glutamine metabolism via hexosamine biosynthetic pathway HBP. Depicted are the major routes of glucose utilization after its entry in cells. Soon after passing hexokinase HK bottleneck, phosphorylated glucose may be diverted to glycolysis, glycogen synthesis, or pentose phosphate shunt hexose-monophosphate shunt , in a proportion that depends on the cell type and physiological conditions.

The present artwork is a graphic illustration of experimental values obtained from soleus and gastrocnemius muscles of 8-week trained treadmill rats treated or not with l -glutamine supplementations during the last 21 days [ 49 ].

Hence, this is an example of a very metabolically active skeletal muscle. Thicknesses of arrows indicate the approximate proportion of each metabolite entering each given sub-pathway. It is noteworthy that, under normal conditions, the muscle preferentially ~ In this case, only a minor proportion ~3.

Under l -glutamine supplementations, excess intramuscular l -glutamine supply enforces fructose 6-phosphate F6P to divert from glycolysis and enter hexosamine biosynthetic pathway HBP, shaded box in the center after its conversion to glucosamine 6-phosphate by glutamine 6-phosphate amidotransferase GFAT, a.

glutamine-fructosephosphate transaminase. UDP- N -acetylglucosamine UDP-GlcNAc , the final HBP metabolite, operates to enhance the heat shock response by acting at two different points: 1 by blocking glycogen synthase kinase-3β which phosphorylates and inactivates HSF1, under basal conditions and 2 by covalent modification of HSF1, which becomes O -linked- N -acetylglucosaminylated, having more DNA-binding and transcribing activities onto heat shock genes.

Moreover, at the estimated l -glutamine concentrations for the soleus 17—18 mM, [ 49 ] and gastrocnemius ca. This empties hexose-monophosphate shunt leading to momentary deficit of NADPH which triggers Nrf2 transcription factor-dependent gene transcription that accounts for the enhanced expression glutamine synthetase EC 6.

glutamate-ammonia ligase , γ-glutamylcysteine synthetase EC 6. glutamate-cysteine ligase and more G6PDH in order to counteract this redox imbalance. HSF1, whose activity must be enhanced following high-intensity exercise training, is potentiated by O -linked N -acetylglucosamine modification [ 55 ] thus increasing cytoprotection through the production of more HSP72 protein chaperone molecules needed during the recovery phase.

The fluxes through the biochemical pathways showed here were calculated by using Michaelis-Menten function, intracellular muscle l -glutamine, and l -glutamate estimated from [ 49 ] and the following data for the rat muscle: hexokinase HK, EC 2.

phosphoglucoisomerase, EC 5. Finally, it is import to distinguish that glutamine remarkably enhances HS response but glutamine is not a HS inducer itself. Although glutamine is able to slightly increase HSF1 trimerization in non-stressful situations [ 49 , 56 ], glutamine acts physiologically as an enhancer of the HS response, which means that a pre-existent e.

In addition, iHSP70 per se participates in glutamine-induced HS response [ ]. As a whole, glutamine synthesis and availability is indispensable for full and accurate cytoprotective stress responses. Therefore, conditions likely to induce glutamine depletion in the blood stream, reducing its availability to other cells, may result in cellular dysfunction.

In response to several forms of stress, cells can rapidly increase uptake and utilization of glucose and glutamine, mainly for the maintenance of basal metabolism and cell defense response purposes [ — , , , ].

Consequently, glutamine depletion does impair cellular stress response in human leucocytes [ ]. Now, it is clear that, besides its classic metabolic roles, glutamine is key for survival and cytoprotection via HBP.

Studies suggest that inhibition of both glycolysis and HBP results in decreased cell survival [ ]. Due to its crucial position in regulating the HS response, HBP-emanated O-GlcNAc post-translational modifications mediate cell function and survival in the cardiovascular [ — ] and neuromuscular [ ] systems, while its defective function is associated with cancer [ ].

Therefore, it is not surprising that in vitro attenuation of HBP remarkably reduce maximal HS response [ 54 ], whereas genetic mutations in GFAT gene, in which HBP activity is reduced, lead to impairment of neuromuscular junction development and function [ ].

Reductions of bodily glutamine concentration may contribute to cell death due to a reduced stress response capacity [ , ]. Interestingly, upon depletion of intracellular glutamine, the uptake of some amino acids, such as leucine, declines and mTORC1 becomes inactivated.

However, mTORC1-S6K1 signal is critical for the regulation of cell cycle progression, cell size, and cell survival [ , ], so that reduction in intracellular glutamine stores may hamper cell survival. This is of note because, besides chaperone-based, eukaryotes lay hold on autophagy as a part of protein quality control, as discussed in previous sections.

Hence, by facilitating autophagy via modulation of the HS response, glutamine becomes of importance in chronic degenerative diseases of aggregative nature. Indeed, as glutamine may enhance HS response over an initiating proteostasis defect, glutamine can even avoid the triggering of autophagy in some circumstances, such as acute exercise which is capable of inducing toxic imbalances that lead to autophagy [ , ].

Glutamine deprivation reduces proliferation of lymphocytes, influences expression of surface activation markers on lymphocytes and monocytes, affects the production of cytokines, and stimulates apoptosis.

Moreover, glutamine administration seems to have a positive effect on glucose metabolism in the state of insulin resistance [ ]. This protective effect of glutamine is related to glutamine-induced stabilization of mRNA encoding HSP70 [ ], possibly via HBP.

As discussed above, fever is a protective acute-phase response to infection. However, in critically ill patients, the harmful effects of fever seem to be predominant. Critical illness is frequently but not necessarily associated with reduced plasma glutamine levels, which contribute to the immune suppression in these patients due to impaired monocyte function [ ].

In vitro studies with glutamine-depleted monocytes obtained from PBMC of health human donors have shown that glutamine deprivation dramatically reduces PBMC thermoresistance and suggests that elevated body temperature may damage monocytes in critically ill patients with reduced plasma glutamine levels, possibly via inhibition of the cytoprotective HS response [ ].

Age-related intestinal dysfunctions may also contribute to deficient passage of amino acids to the circulation, as inflamed gut mucosa utilizes glutamine in large quantities [ ]. Studies in animal models of inflammatory bowel disease IBD suggest that supplementation of total parenteral nutrition with glutamine may increase glutamine plasma concentrations, reducing intestinal damage, improving nitrogen balance and the course of the disease.

However, human data supporting this assumption are either missing or contradictory [ ]. Nevertheless, glutamine supplementation has convincingly been demonstrated to prevent exercise-induced intestinal permeability, possibly through HSF1 activation [ , ]. In conclusion, it is evident that the overall metabolism of glutamine in aging and age-associated degenerative diseases of inflammatory nature may be partially compromised and this may negatively impact the HS response in the elderly.

Hence, interventions devoted to improve glutamine turnover and metabolism are predicted to be of value in assisting the improvement of the HS response in the elderly.

Physical exercise is one of the most powerful physiological inducers of the HS response, comparable only to fever and anti-inflammatory cyPGs. Since exercise is a homeostatically threatening situation that evoke a series of physiological adjustments, it has long been thought that exercise should mandatorily induce the HS response.

Some of the conditions known to elicit cellular stress response are similar to those experienced by cells in response to physical exercise.

All of them are potent inducers of HSP expression in different cell types and tissues [ , ]. Locke and co-workers [ ] were the first to demonstrate that vigorous physical activity is associated with the induction of HSP70 in rodents.

Subsequently, increased expression of HSPs in humans following exercise was confirmed [ ]. Now, it is peaceful that HSPs, such as HSP72 iHSP70 , are induced or activated upon acute exercise bouts and after chronic exercise training regimens, whereas HSP induction and HS response are key components of exercise adaptation that could contribute to improvements in athletic performance [ ].

Although exercise has been being increasingly prescribed to elderly people in order to combat chronic inflammatory diseases [ , ], only a few studies have addressed exercise impacts on HS response in aging [ — ].

Exercise-induced transient increases of iHSP70 inhibit the generation of inflammatory mediators and vascular inflammation, metabolic disorders e.

In all these conditions, benefits of exercise on inflammation and metabolism depend on the type, intensity, and duration of physical activity [ ]. Exercise has also been shown to produce favorable effects against neurodegenerative diseases, by both preventing and avoiding the progress of age-related AD and PD [ ].

This is linked to the fact that exercise enhances hippocampal neurogenesis, thus improving learning and memory in aged people [ ]. The expression pattern of HSPs in skeletal muscles has been demonstrated to decrease in old rats compared with young ones. Interestingly, however, exercise training significantly increases HSPs in aged rats [ ].

Hence, if acute exercise-induced HS response is severely blunted in the muscle of elderly individuals [ ], exercise training regimens are emerging as more appropriate approaches for the elderly.

Although there are some discrepancies in relation to HSP70 expression in response to exercise training in young people [ ], expression of HSPs in skeletal muscles of aged individuals depends on the frequency and duration of exercise training [ ].

Exercise induces autophagy in multiple organs involved in metabolic regulation, such as skeletal muscle, liver, pancreatic β cells, adipose tissue, and brain [ 41 , , ], so that exercise influences protein quality control via HS response per se and through HS response-dependent autophagy. Indeed, exercise stress and molecular control of proteostasis provides evidence that the HS response and autophagy coordinate and undergo sequential activation and downregulation and that this is essential for proper proteostasis in eukaryotic systems [ 41 ].

A systematic analysis carried out by Dokladny and colleagues [ 41 ] on the association between exercise-induced HS response assessed by iHSP70 expression and autophagy in humans humans; 22 studies, including data from their own group supports the notion that autophagy is upregulated during the early degradation phase of exercise while iHSP70 expression tends to increase during the later building and protein synthesis phase.

Hence, HSP70 expression appears to be the main controller of protein synthesis and degradation, whereas autophagy remains under inhibitory control of the HS response. Therefore, exercise-induced autophagy represents, up to a certain point, a desirable response to avoid the formation of misfolded protein aggregates and defective organelles, provided not in excess.

This is the case of hydroxylamine derivatives, such as the compound BGP, a small molecule that has been demonstrated to activate HSP70 in skeletal muscle, inhibiting the early-phase acetylation of HSF1 and prolonging the duration of its binding to HSEs [ ].

In mouse models of muscular dystrophy, the HS response potentializer BGP decreases kyphosis, improves the dystrophic pathophysiology in limb and diaphragm muscles, and extends lifespan [ ].

The HS response inducer BGP has proven to efficiently reverse the noxious effects of HFD-induced obesity in the muscle and adipose tissue, by increasing the HS response [ 12 ]. BGP improves cardiac function and reduces arrhythmic episodes in different mouse models that progressively develop heart failure and atrial fibrillation and can provide cytoprotection and normalization of cell signaling, which are often defective in the aged and diseased heart [ ].

Therefore, if BGP was developed to simulate the beneficial effects of exercise, it is plausible to suppose that exercise itself should present better or the best accomplishment.

As a powerful exercise-related enhancer of the HS response, glutamine is a potential target for intervention in age-related conditions. In catabolic e.

However, at the same time that the body increases its demand for glutamine, several organs reduce their ability to produce the amino acid e.

Therefore, catabolic processes, which increase amino acid utilization in order to generate other necessary compounds including glucose and acute phase proteins , contribute to the diminution of glutamine stores, a situation that is aggravated in high-throughput inflammatory and oxidative stress responses, as activated immune cells dramatically increment their glutamine utilization [ , , , , ].

Although there is no single explanation for the glutamine deficit found in the above situations [ , ], this effect is clearly observed in both humans [ ] and experimental animal models [ ].

Hence, under various conditions, glutamine can become a conditionally essential amino acid [ ]. Exercise is a homeostasis-challenging situation that tends to induce, at the beginning of the session, an accelerated glutamine and alanine release from activated skeletal muscles, thus enhancing plasma concentrations of both amino acids [ ].

Additionally, alanine released by the working muscle is taken up by the liver in order to furnish glucose to the circulation glucose-alanine cycle via gluconeogenesis. Moreover, sparing bicarbonate the main physiological alkaline defense of the body is of extreme importance during exercise, in view of acid-base imbalances imposed by the contracting skeletal muscle and exercise-related metabolic adjustments that tend to increase acid production.

In different catabolic conditions, including overtraining, the overall glutamine stores may be threatened. The availability of glutamine is thought to be a major factor during critical illnesses, such as sepsis, extensive burns, pancreatitis, trauma, and surgery [ , , ].

Similar effects have also been seen in experimental animal models of sepsis, followed by severe adaptive immune system suppression low T and B lymphocyte responses [ 50 , , ]. In such conditions, plasma glutamine depletion is an independent outcome factor in critically ill patients [ ].

But even in non-ill conditions, such as during and after exhaustive exercise, glutamine metabolism may be affected in tissues, thus undoubtedly impairing the immune system, in spite of the absence of any observed change in plasma glutamine levels [ ].

Hence, numerous studies in animal models of catabolic and critical illness indicate that total parenteral nutrition TPN supplemented with glutamine may enhance protein anabolism, gut-associated barrier functions, systemic immunity, and gut mucosal repair.

This is apparently due to the potential of glutamine as an important fuel substrate for the gut itself because glutamine upregulates cytoprotective pathways [ ]. However, in a recent study with intensive care unit ICU patients, it has been encountered that TPN supplemented with glutamine dipeptide is safe, but does not alter clinical outcomes among the patients [ ], while clinical trials have not demonstrated prolonged advantages, such as reductions in mortality or risk of infections in adults [ ].

In a recent meta-analysis of randomized clinical trials [ ], no difference has been found to allow the recommendation of glutamine supplementation to generic population of critically ills. Therefore, the efficacy of glutamine supplementation is still under debate.

Aged people tend to present an array of intestinal dysfunctions, including those associated with gut mucosa transport and dysbiosis [ 31 — 33 ].

Since glutamine is of absolute requirement as a fuel substrate for the enterocyte, intestinal utilization of glutamine is important for maintaining the integrity of the intestinal barrier, with subsequent prevention of bacterial translocation and, through stimulation of the gut-associated immune system, prevention of gut barrier atrophy.

It is assumed that a derangement of the gut mucosal barrier function, which occurs during aging and critical illnesses, results in an amplification of the general inflammatory response predisposing patients to multiple organ failure [ ].

In fact, chronic glutamine supplementation reduces exercise-induced intestinal permeability while inhibiting NF-κB pro-inflammatory pathways in human PBMC, in a mechanism associated with the activation of HSP70 expression [ ].

The same was confirmed in physically active subjects acutely treated with oral doses of glutamine prior to exercise [ ]. However, all of them converge to the fact that gut mucosa cannot overcome the persistent inflammatory milieu resolving inflammation [ ] that becomes chronic.

In any way, induction of the HS response employing heat treatment, for example has been shown to protect against TNFα-induced inflammatory shock and this is associated with HSP70 expression in many organs, including small and large intestines [ ].

Additionally, intestinal malabsorption of glutamine has been referred to as causal to the ineffectiveness of oral glutamine treatment of obese insulin-resistant mice [ ]. If, on the one hand, HSP70 expression is not definitely ascribed as causal or result of chronic inflammatory bowel diseases, overexpression of HSP70 was found to prevent the development of inflammatory process in the large intestinal mucosa provoked by various damaging factors [ 32 ].

Although intestinal obstruction is not exactly a chronic inflammatory disease, glutamine supplementation decreases intestinal permeability and preserves gut mucosa integrity in experimental mouse model of intestinal obstruction [ ].

In fact, the association with aging is one of the most distinctive characteristics of protein conformational diseases. This connection is particularly striking in neurodegeneration associated with deficient protein quality control e. On the other hand, age appears to have a modifying, rather than causative, influence on disease onset, as each disease has its characteristic age of onset, with AD and PD being late onset, ALS occurring most frequently in early to mid-life, and HD exhibiting a strong positive correlation between age of onset and polyglutamine length polymorphism [ ].

In vitro studies suggest that healthy neuronal cells require both intracellular and extracellular glutamine and that the neuroprotective effects of glutamine supplementation may prove beneficial in the treatment of AD.

In fact, glutamine acts as a neuroprotectant against DNA damage and Aβ- and H 2 O 2 -induced stress [ ]. However, no clinical trial is currently being carried out as to assess the possible beneficial effects of glutamine supplementation, or combined glutamine plus exercise schedules, over HS response in neurodegenerative diseases in aging.

When and preferably orally given, glutamine may be administered as free amino acid or in its dipeptide forms. However, even though a priori safe, caution should be taken in supplementing middle-aged and elderly individuals with glutamine at the above dosage, as increases in serum urea and creatinine, paralleled by decreased in estimated glomerular filtration rate, have been reported in this specific population after glutamine supplementations [ ].

Alternatively, glutamine can be administered as a part of TPN 0. These parenteral solutions are more effective than oral or enteral solutions, when the maintenance of glutamine concentration in the body is desired [ ].

Nevertheless, TPN is very invasive and may expose the patient to increased risk of infections, so that, as far as possible, enteral alternatives should be chosen.

Moreover, enteral routes are much more physiological and provide the physiological generation of other amino acid derivatives e. Since intestinal dysfunctions are commonly found in the elderly that hamper the ability of aged people to maintain a good nutritional state [ 31 — 33 ], more efficient ways to deliver glutamine into the circulation have been permanently being investigated.

In this regard, the excellent effects of glutamine dipeptides on glutamine availability have been attributed to the fact that enterocytes have a more efficient transport mechanism for the absorption of dipeptides and tripeptides than for the absorption of free amino acids [ ].

The glycopeptide transport protein PepT-1 , which is located in the luminal membrane of the jejunum and the ileum, has a broad substrate specificity and actively transports dipeptides and tripeptides from diet into the enterocytes of humans and animals [ , ].

Through this route, it can be avoided intracellular hydrolysis of glutamine and its subsequent metabolism by enterocytes, proceeding directly into systemic circulation [ , ]. Intestinal glutamine uptake is regulated by the high-affinity glutamine transporter solute carrier family 1 member 5 SLC1A5 and its inhibition blocks glutamine entry in enterocytes leading to the inhibition of mTORC1 signaling and consequent dysregulation of autophagy [ ].

In addition, glutamine can be carried by SLC7A5, which is a bidirectional transporter that regulates the simultaneous efflux of glutamine out of cells and the transport of other amino acids into cells.

This directional control allows for excess glutamine to signal into cell growth promoting pathways, while suppressing catabolism in different tissues and cells [ , ]. Studies in experimental animal models with acute oral glutamine supplementation, in its free form or as a dipeptide, have demonstrated an increase in plasma glutamine concentrations between 30 to min after supplementation [ ].

In another study, animals submitted to exhausting physical exercise and chronic supplementation with l -alanyl- l -glutamine have demonstrated that the nutritional intervention may attenuate the reduction of glutamine concentration in the soleus and gastrocnemius muscles immediately and 1 h after the exercise session [ ].

Combined exercise training and glutamine supplementation has also been shown to increase hepatic and muscular concentrations of glutamine and glutamate [ , ].

HSP70 expression is decreased during muscle inactivity and aging, and evidence supports the loss of HSP70 and its accompanying HS response as a key mechanism that may drive muscle atrophy, contractile dysfunction, and reduced regenerative capacity associated with these conditions [ 40 ].

Glutamine and aging acid deprivation or supplementation Gljtamine affect cellular Glutamine and aging Optimizing nutritional needs life span, but we wnd little about Wrestling nutrition supplements role of concentration nad in free, intracellular amino acids during Soothe muscle soreness. Here, Gluyamine determine free amino acid levels during chronological aging of nondividing fission yeast cells. We compare wild-type with long-lived mutant cells that lack the Pka1 protein of the protein kinase A signalling pathway. In wild-type cells, total amino acid levels decrease during aging, but much less so in pka1 mutants. Two amino acids strongly change as a function of age: glutamine decreases, especially in wild-type cells, while aspartate increases, especially in pka1 mutants.

Amino Appetite control tools app deprivation or supplementation can affect anr and organismal life span, but we know little Glutxmine the role of concentration changes in free, lGutamine amino acids during aging. Here, we determine nad amino acid levels during Glutamlne aging of nondividing fission yeast cells.

Glutamien compare wild-type with Glutamine and aging mutant cells that lack the Glytamine protein of the protein kinase A Gljtamine pathway. In wild-type cells, total Anr acid agijg decrease Gluttamine aging, but much less Glutamne in pka1 mutants.

Two amino acids strongly change as a function of age: glutamine decreases, Glytamine in ane cells, while aspartate aying, especially Glutaamine pka1 mutants. Supplementation of glutamine is sufficient to Boost Cognitive Function and Alertness the chronological life span of wild-type but not of pka1Δ cells.

Supplementation of aspartate, on the other hand, shortens qnd life span of pka1Δ lGutamine not of wild-type cells. Aand results raise Respiratory health information possibility that certain amino acids are biomarkers of aging, and their concentrations during aging Soothe muscle soreness promote or Glutamkne cellular life span.

Dietary restriction extends life span and Glutamkne age-related pathologies 12. These benefits may reflect protein or amino acid restrictions rather than overall calorie intake 3Promoting even skin texture. Restriction aginh supplementation of certain amino acids affects life span from yeast to mouse 5.

In budding yeast, isoleucine, threonine, and valine Goutamine the chronological life span CLS, the time postmitotic cells Gljtamine viable aying stationary phase 6. In other yeast ajd, serine, aginng, and valine decrease the CLS 7while removal of asparagine extends agint CLS 8.

In mice, life span agingg extended by Lower cholesterol with exercise branched chain amino Glutamine and aging leucine, Gljtamine, and valine GlutaamineGluyamine in flies, Antioxidants and heart health of Glutaminne chain amino acids extends life span in a dietary-nitrogen-dependent manner Glktamine In mice, a Diabetes prevention strategies diet extends life span 11while a methionine-restricted diet extends life span and aginy age-related agibg In flies, methionine restriction extends life span Similarly, Fermented soy products budding yeast, methionine xnd prolongs the Ating while Glutamone addition shortens it A comprehensive analysis of amino acid effects on Collagen and Skin Health span has been undertaken in worms, where life span extends upon individual Soothe muscle soreness of 18 Metabolism boosting supplements acids These results indicate that amino acids can exert both pro- and Glutaamine effects.

In budding agong, intracellular amino acid content gradually decreases during chronological aging What is missing, Glutamine and aging, however, is a global Potassium and heart health analysis of intracellular Glutwmine acids in Glutxmine and long-lived cells during cellular aging.

In fission yeast Schizosaccharomyces pombe Lentils and vegetable burgers, the protein kinase Agong PKA glucose-sensing pathway Gltamine chronological aging 17 but agingg not agign involved in amino acid sensing or transport Here we perform quantitative agimg acid profiling during ahd in wild-type and agig pka1 mutant Hypertension in women of S pombewhich are deleted for the catalytic subunit of PKA.

We show ane intracellular amino acid pools Gluyamine decrease with age. This effect Glutqmine less pronounced in long-lived cells.

Glutamine is Glutaminr faster Soothe muscle soreness the other amino acids, ajd aspartate increases during ane. Notably, supplementation of these 2 amino acids is Diabetic retinopathy ophthalmology to alter Glutamind span in wild-type or G,utamine mutant cells.

Our results suggest both a correlative and causal relationship Gkutamine longevity aginf intracellular amino acids. Strains were cultured in EMM2 gaing medium for mass spectrometry Improve executive functions acquisition, Glutamije aging, and amino acid supplementation experiments.

Ans cultures xging grown at 32°C with shaking at rpm. Cell numbers were Glutamije with a Beckman Z-series coulter ahd to Oxidative stress and free radicals equal cell amounts for Glutamie.

The metabolites were nad as Glutmine Identification of 19 proteogenic amino acids was obtained Soothe muscle soreness comparison Diabetic meal suggestions retention time an fragmentation patterns with commercial standards.

Comparison against a standard G,utamine produced from serial anv of these Glutamie allowed quantification of the free amino acids. Aginv analysis was agjng using an Agilent Infinity LC system qnd ACQUITY UPLC BEH amide columns Waters Corporation, Anc, United Kingdom pore diameter Å, particle size 1.

Cysteine was excluded from analysis due to its low stability. Aging cells were incubated in media containing amino acid supplements at Days 1 and 5, by removing the supernatant after centrifugation rpm, 3 minutes followed by resuspension in EMM2, EMM2 with 20 mM glutamine, or EMM2 with 20 mM aspartate up to their original culture volume.

Amino acids were not directly added to medium because of solubility issues. Supplementation happened specifically on the designated time points and not throughout the chronological aging. Chronological life span assays were performed as described Error bars represent standard deviations of 9 measurementscalculated from 3 independent cell cultures, with each culture measured 3 times at each time point.

Areas under the curve were measured for all experimental repeats with ImageJ We compared areas under the curve for the portion of life-span curve after amino acids supplementation as before this time life-span curves were identical.

Cells were lysed using a Fastprep 6. We used liquid chromatography-selective reaction monitoring 18 to quantify the free, intracellular pools for 19 of the 20 canonical proteogenic amino acids cysteine was excluded as it is readily oxidized during chronological aging of S pombe wild-type and long-lived pka1Δ deletion mutant cells.

Cells were grown in minimal medium, because rich medium contains variable amounts of amino acids and cells accumulate intracellular amino acids when grown in rich medium Quantitative measurements of free, intracellular amino acids in chronologically aging cells.

A Chronological life span CLS assays for wild-type and pka1Δ cells, performed in triplicate with each biological replicate measured in 3 technical repeats. Average life spans are shown solid lines together with standard deviations dotted lines. Hatched vertical lines indicate time points for amino acid profiling.

B Total amino acid concentrations in wild-type and pka1Δ cells at different aging time points as indicated. C Heatmap showing quantitation of individual amino acids, along with known amino acid properties at right. Averages of 3 time points with 3 independent biological repeats each are shown.

The amino acid quantities, obtained from nondividing cells, differed from those previously reported for fission yeast which have been obtained from rapidly proliferating cells 20 At the onset of stationary phase, the total amino acid concentrations were lower in pka1Δ than in wild-type cells Figure 1B.

Accordingly, the individual amino acid concentrations were lower or similar in pka1Δ than in wild-type cells at that stage Figures 1C and 2. The concentration differences were particularly pronounced for the branched chain amino acids and aromatic amino acids phenylalanine, tryptophan, tyrosine Figures 1C and 2.

Changing amino acid concentrations during aging. Normalized concentration values of 19 amino acids in wild-type cells panels A, B and pka1Δ cells panels C, D, E during aging top to bottom.

For each condition, 3 independent samples were analyzed. Boxplots were created with R boxplot and default settings. During chronological aging, the concentration of total free amino acids declined in wild-type but less so in pka1Δ cells, even rising slightly at the last time point Figure 1B.

This rise primarily reflected an increase in the most abundant amino acid, lysine, which compensated for the decline in other amino acids Figure 2. In wild-type samples, the variation in free amino acids between experimental repeats noticeably increased during aging, in contrast to pka1Δ samples Figures 1B and 2.

This result raises the possibility that increased variation of amino acid concentrations, reflecting less tight metabolic regulation, is a feature of wild-type aging cultures. Wild-type cells showed a general decrease in amino acids during aging, apart from aspartate Figures 1C and 2.

The branched chain amino acids were initially present at ~3-fold higher levels in wild-type cells before dropping to about half the level of pka1Δ cells Figures 1C and 2. This result suggests that changes in amino acid concentrations are not driven by limitation of precursor molecules.

Likewise, there was no clustering based on glucogenic amino acids, which can be converted into glucose through gluconeogenesis Figure 1C.

This result suggests that any need for gluconeogenesis under glucose depletion does not greatly affect free amino acid composition. Reassuringly, there was also no clustering based on membrane permeability Figure 1Cas this suggests that the results were not biased by amino acids leaking from nonviable cells during the aging time course.

This result suggests that similar metabolic changes occur in aging wild-type and mutant cells, but that these changes are delayed in the long-lived mutant cells. Some amino acids, however, showed distinct patterns in wild-type and pka1Δ cells, including lysine, glutamate, glutamine, and aspartate Figures 1C and 2.

Glutamine and aspartate showed particularly striking profiles during aging. Glutamine rapidly and strongly decreased during aging, more pronounced in wild-type cells Figures 1C and 2.

Aspartate, on the other hand, was the only amino acid that increased during aging in wild-type cells, and this increase was more pronounced in pka1Δ cells Figures 1C and 2.

These results pointed to glutamine and aspartate as markers for aging in S pombe and raised the possibility that these amino acids directly contribute to cellular life span. To examine the effect of glutamine on the CLS of wild-type and pka1Δ cells, we grew cultures to stationary phase in EMM2 minimal medium.

These manipulations did not affect cell numbers or total protein levels of the aging cultures Supplementary Figure 1. In wild-type cells, glutamine supplementation significantly extended the CLS, both when added on Day 1 or 5 Figure 3A and B. Glutamine supplementation at Day 1 extended the medial CLS from 5 to 6.

Although Day 5 was close to the median life span of wild-type cells, glutamine still extended the CLS even at this late stage Figure 3A and B. These results indicate that glutamine is beneficial for viability of aging wild-type cells. In pka1Δ cells, on the other hand, glutamine supplementation at either Day 1 or 5 had no effect on life span, with the median CLS remaining ~8 days Figure 3C and D.

We conclude that glutamine addition during cellular aging promotes longevity in wild-type cells, but not in the long-lived pka1Δ cells which maintain relatively higher glutamine levels during aging Figure 2.

Effects of amino acid supplementation on chronological life span CLS. A CLS assays average of 3 biological repeats with 3 technical repeats each for wild-type cells with and without glutamine supplementation at Days 1 and 5 as indicated.

Median CLS in control cells indicated with vertical lines and treated cells indicated with dotted vertical lines are shown. B Areas under curve AUCs of CLS assays in A as indicated left panel: AUCs from Day 1; right panel: AUCs from Day 5.

The p -values t test indicate significance of difference in CLS triggered by glutamine supplementation. C CLS assays as in A for pka1Δ cells with and without glutamine supplementation at Days 1 and 5. D AUC of CLS assays in C, as described in B.

E CLS assays as in A for wild-type cells with and without aspartate supplementation at Days 1 and 5. F AUC of CLS assays in E, as described in B. G CLS assays as in A for pka1Δ cells with and without aspartate supplementation at Days 1 and 5. H AUC of CLS assays in G, as described in B.

To examine the effect of aspartate on the CLS of wild-type and pka1Δ cells, we performed the same experiment as with glutamine, but supplementing aspartate to chronologically aging cultures. Again, these manipulations did not affect cell numbers or total protein levels of the aging cultures Supplementary Figure 1.

In wild-type cells, aspartate supplementation at either Day 1 or 5 had no effect on the CLS Figure 3E and F.

: Glutamine and aging

Glutamine for Digestive Health Although there are some discrepancies in relation to HSP70 expression in response to exercise training in young people [ ], expression of HSPs in skeletal muscles of aged individuals depends on the frequency and duration of exercise training [ ]. This feature is available to Subscribers Only Sign In or Create an Account Close Modal. Linda, you are in the right place. Elderly people are sick longer, often coping with multiple chronic diseases simultaneously. Oxford University Press News Oxford Languages University of Oxford. It is assumed that a derangement of the gut mucosal barrier function, which occurs during aging and critical illnesses, results in an amplification of the general inflammatory response predisposing patients to multiple organ failure [ ].
Glutamine Supplementation in Old Age May Produce Similar Effects to mTOR Inhibition – Fight Aging!

It helps build immune cells like white blood cells, boosting their ability to fight infections. Additionally, it provides energy for these cells to grow fast and work efficiently.

It is made in our bodies from other amino acids, or we can get it from the food we eat, or glutamine can be supplemented for specific health reasons Cruzat et al. As mentioned, glutamine is important for our digestion, and helps strengthen our immune system by building immune cells like white blood cells.

As we age, our bodies do not make as much glutamine as they used to. This reduction in glutamine can influence how our digestion works and the general fitness of our belly and intestine.

Glutamine is a key player in nitrogen and carbon transport between tissues. So, for the aging population, getting enough glutamine from meals or occasionally via supplements can be effective.

It might assist with some of the demanding situations that come with getting old and keep matters running nicely.

But it is continually an excellent plan to speak to doctors to figure out the best method for you. Sheloukhova, As we get older, glutamine becomes even more important for our digestive health.

Our bodies naturally make less of it, and that can really affect how well our digestive system functions. This reduction can impact how well our stomachs work. Therefore, having sufficient glutamine is particularly important, especially for older individuals.

This lower amount of glutamine can cause problems like not getting enough nutrients, having a weaker stomach barrier, and being more prone to stomach issues.

Taking extra glutamine as a supplement for older folks can give their stomachs a boost. It provides the essential stuff to restore and strengthen the belly lining, making it simpler for everything to digest nicely.

This can help older human beings have healthier stomachs and avoid a few of the commonplace stomach problems that come with growing older. Clinical research displays the association between glutamine supplementation and decreased mortality in trauma and seriously ill individuals. Additionally, glutamine has shown promise in assisting the immune system, lowering infection risks, and aiding in preventing or treating multiple organ dysfunction after injuries Glutamine, n.

The recommended dose of glutamine varies on different needs. Consult a health care professional before starting a glutamine supplement. Dysbiosis and dysregulation of the immune system have been found to play a major role in IBD, leading to enhanced permeability to bacterial components and loss of physiological transport systems.

If, on the one hand, protein quality control is not, at present, definitely ascribed as causal or result of chronic IBD, both physiological and pharmacological maneuvers leading to the overexpression of protein chaperones, which avoid the formation of protein aggregates and consequent chronic inflammation, have been found to prevent the development of inflammatory process in the large intestinal mucosa provoked by various damaging factors [ 32 ].

In this regard, diet is an extremely important factor, since gut microbiota strongly influences the physiology of the gastrointestinal tract, being dramatically affected by what one chronically eats [ 33 ].

In total, aging is associated with impaired resolution of inflammation that perpetuates a series of degenerative diseases in many organs and physiological systems. Such inflammatory diseases have underlying basis on chronic overburden of protein quality control, which leads to the formation of protein aggregates that triggers more inflammatory signals; this eternalizes inflammation that spreads throughout the body [ 7 ].

Hence, understanding of intracellular protein quality control system the chaperone machinery and the HS response is crucial for adequately treating age-related chronic degenerative diseases. Aging is associated with increased cellular dysfunctions. Nonetheless, nature evolved a variety of cell defensive strategies aimed to combat these imbalances.

Among such cell defenses is the expression of heat shock proteins HSPs , which are a principal focus of the present article. HSPs have attracted significant attention due to its versatility and range of functions in and out of the cells [ 34 ]. The genes encoding HSPs are highly conserved and many of them, as well as their protein products, can be assigned to families on the basis of typical molecular weight [ 35 ].

In eukaryotes, different HSP families comprise multiple members that differ in inducibility, intracellular localization, and function [ 36 ]. In the context of the present discussion, a review of the diverse HSP types, location, function, and sensitivity to exercise is highly recommended [ 35 , 37 , 38 ].

In the present paper, the 70 kDa family of HSPs HSP70 will be contemplated. HSP70 is a cytoprotective and anti-inflammatory molecular chaperone primarily devoted to avoid protein misfolding and to correct unfolded proteins, thus allowing for the proteins homeostasis i.

Since proteostasis-threatening situations rapidly evoke a strong expression of HSP70, intracellularly located HSP70 iHSP70 is, as a consequence, a universal marker of stress. As further discussed, iHSP70 expression is induced by different cell stressors and signals of imminent dangerous situations, such as heat, metabolite deprivation, redox imbalances and, particularly, during and after physical exercise, due to sympathetic nervous system activation, intracellular calcium mobilization, and exercise-induced changes in intracellular pH; all of the nominated situations being powerful inducers of iHSP70 gene expression.

The activation of iHSP70 is critical for the promotion of tissue repair, since the expression of this chaperone, by virtue of avoiding misfolded protein aggregates, confers cytoprotection and also exerts anti-inflammatory effects [ 39 ]. Hence, since aging is associated with chronic low-grade inflammation and impaired skeletal muscle repair, the activation of HSP70 expression and its effective response against cellular stress play a key role against cell dysfunction observed in aging.

Consequently, any tiny impairment in the ability of cells to respond to stress via iHSP70 expression i. Unfortunately, however, aging and age-related chronic inflammatory diseases are marked up by a conspicuous depression of stress-elicited HS response [ 7 ].

Additionally, iHSP70 expression is decreased during muscle inactivity and aging, and evidence supports the loss of iHSP70 as a key mechanism which may drive muscle atrophy, contractile dysfunction, and reduced regenerative capacity associated with these conditions.

Conversely, several interventions have shown that normal and overexpression of HSP70 are associated with improvements in skeletal muscle atrophic conditions [ 40 ]. In fact, upregulation of HSP70 contributes to the maintenance of muscle fiber integrity and facilitates muscle regeneration and recovery [ 40 ].

In addition to the HS response, cells further evolved autophagy, which is a cellular strategy to sequester and deliver for degradation to lysosomes, large protein aggregates and whole damaged organelles inaccessible to smaller proteolytic systems in the cell.

Therefore, the HS response and macroautophagy represent two ends of the spectrum of cellular protein quality control, with the former being ubiquitous in all living organisms, whereas the latter is restricted to eukaryotic cells [ 41 ]. During stress, increased levels of autophagy permit cells to adapt to changing nutritional and energy demands through protein catabolism [ 42 ].

Such a self-digestion not only provides nutrients to maintain vital cellular functions during fasting but also can make the cell free of superfluous or damaged organelles, misfolded proteins, and invading microorganisms [ 43 ]. Autophagy, a process that is potently triggered by fasting, is now emerging as a central biological pathway that functions to promote health and longevity [ 43 ].

Moreover, in animal models, autophagy protects against diseases such as cancer, neurodegenerative disorders, infections, inflammatory diseases, insulin resistance, and aging [ 43 — 45 ].

In addition to that, several studies have reported that the amino acid l -glutamine thereafter referred to as glutamine strongly enhances the HS response by acting as a potentializer of iHSP70 expression [ 49 , 50 ], mainly via the hexosamine biosynthetic pathway HBP [ 51 — 56 ].

Glutamine is important for protein quality control also by stimulating autophagy, so also avoiding the formation of undesirable protein aggregates [ 57 ]. Inasmuch as glutamine is liberated into the blood by active skeletal muscle, it follows that physical exercise may warrant a healthy HS response also via glutamine metabolism.

Mammalians developed a range of adaptations to survive in the presence of acutely and chronically non-lethal stressful situations [ 58 ]. Among these adaptations, the HS response a type of stress response is striking because it is probably the most highly conserved genetic system ever known, existing in every organism in which it has been sought, from archaebacteria to eubacteria, from plants to animals [ 59 , 60 ].

The HS response evolved to adapt organisms appropriately against several stressful insults, whether from heat, cold, oxidation, free radicals, toxins, hypoxia, or metabolic stress [ 61 ]. And, however impressive as it may seem, the HS response is also recruited from other branches of metabolism very far from proteostasis, at least a priori.

This is the case of inflammation, energy preservation, and immune responses [ 7 ]. Impaired HS response, however, is a common feature in several age-related conditions associated with inflammation, such as T1DM and T2DM, aging, and obesity [ 61 — 64 ]. Members of the 70 kDa family of heat shock proteins HSP70 mediate cytoprotective stress responses [ 63 ].

Within the HSP70 family, the constitutive heat shock cognate, HSC70 or HSP73, encoded by the HSPA8 gene in humans , and its inducible form HSP72, encoded by HSPA1A have received more attention for their ubiquity and high level of expression.

Although iHSP70 had been serendipitously discovered in heat-shocked Drosophila busckii cells by Prof. Ferruccio Ritossa in [ 65 ], HSP70 expression is associated with a variety of homeostatically stressful situations, not only heat [ 66 ].

It is noteworthy that the inducible expression of HSP72 is impressively and highly conserved in nature from bacteria to humans: in order to manage on chaperone and cytoprotective intracellular functions, at least 13 genes were identified in humans that are responsible for HSP70 family coding [ 35 , 38 ].

of intracellular proteins [ 37 ], including in skeletal muscle [ 67 ]. As a molecular chaperone, the intracellular HSP72 protein referred thereafter simply as iHSP70 can interact with other proteins either unfolded, in non-native state or in stress-denatured conformations avoiding inappropriate interactions, impeding formation of protein aggregates, and leading to the degradation of damaged proteins, as well as helping the correct refolding of proteins [ 67 ].

Other functions include protein translocation [ 68 ], anti-apoptosis, [ 69 ] and anti-inflammatory responses, the latter via HS response-dependent blockade of NF-κB transcription factor downstream pathways [ 7 , 70 ].

More recently, HSP roles have been expanded to include control of cell signaling [ 71 ], modulation of immune responses [ 72 — 74 ], in chronic diseases such as diabetes, obesity, and insulin resistance [ 12 , 63 ].

Figure 1 depicts the principal known functions of HSP General heat shock protein functions. Heat shock proteins HSPs , particularly those from the 70 kDa family HSP70 are molecular chaperones whose principal function is to assist in protein folding and to correct misfolded proteins to avoid intracellular inflammatory signals elicited by protein aggregates.

As chaperones, HSP70s attach to and help in protein transport from intracellular compartments to others, which is also observed when HSP70s facilitate antigen processing and presentation by antigen-presenting cells.

Consequently, HSP70s blunt nuclear factor κB NF-κB -dependent inflammatory pathways, so that the activation of HSP70 is anti-inflammatory as a corollary. The synthesis of iHSP70 in mammalian cells is mainly controlled by the heat shock transcription factor-1 HSF1 , while the activation of HSF1, necessary for full cytoprotective HS response, involves a multistep mechanism that comprises its phosphorylation, trimerization, nuclear translocation, and DNA binding to the heat shock elements HSE located at the promoter regions of targeted heat shock genes [ 63 , 74 , 75 ].

At rest, HSF1 is inactive in a monomeric state bound to iHSP70 molecules, located in the cytosol. Under stress conditions i. Serine-phosphorylation and trimerization of HSF1 induces enhanced HSF1 DNA-binding affinity for the cis -acting regulatory domains the HSE described above in target genes, inducing the expression of more iHSP70 HSP72, indeed molecules which, in turn, enhances cellular stress responses, and defense capacity [ 37 ].

As HSF1 is the primary regulator of the anti-inflammatory HS response, low expression of HSF1 is associated with a number of human pathologies of inflammatory nature, including T2DM [ 47 ], obesity-related fatty liver disease [ 76 ], and neurodegenerative diseases [ 63 ].

Age-related chronic inflammatory diseases, such as systemic inflammatory diseases e. However, inflammation evolved to be an acute response, as physiological mechanisms to cope with ad infinitum inflammatory responses were not predicted naturally selected.

During the activation of an inflammatory response, the production of pro-inflammatory arachidonic acid-derived prostaglandins PGs , as well as other lipid mediators and vasoactive compounds, take place.

This increases vascular permeability, allowing the arrival and activation of inflammatory cells and tissue repair [ 77 ]. In fact, maximal cyclooxygenase-2 COX-2 -dependent prostaglandin E 2 PGE 2 production occurs at 2 h after challenge, whereas COX-2 expression is much higher at 48 h, but pro-inflammatory PGE 2 production is much lower [ 78 ].

This strongly suggests the existence of some metabolic deviation of arachidonic acid metabolites toward another mediator. During the entire inflammatory response including its resolution phase , there is a finely orchestrated expression of inducible proteins centered at nuclear transcription factors from the kappa light chain enhancer of activated B cells κB family NF-κB , [ 80 ], which propel inflammation during the challenging phase but, simultaneously, prepares its resolution.

At the beginning of an inflammatory response and under the control of activated NF-κB transcription factors, inducible enzymes including COX-2 drive the synthesis of PGE 2 , which induces fever by changing bodily thermoneutral range upwardly.

As a consequence of elevation in core temperature, the highly evolutionarily conserved HS response initiates the activation of a transcriptional program based on the activation of the heat shock transcription factor HSF1 [ 81 ].

The chief impact of HSF1 activation is the elevated production of HSPs whose major representative is HSP Small heat shock proteins induced by fever, such as HSP27, also contribute to cytoprotection [ 82 , 83 ]. Since heat stress faced during fever episodes stimulates HSF1-induced HSP70 expression, cells become protected against proteotoxic stress that could emerge from heat-induced protein denaturation.

Therefore, HS response supports proteostasis protein homeostasis and cytoprotection [ 75 ]. Additionally, hyperthermia enhances toll-like receptor-4 TLR4 expression and downstream signaling in vivo [ 84 ], whereas activation of TLR2, TLR3, and TLR4 acts synergistically with fever-associated hyperthermia to induce HSP70 expression and release to the extracellular space both in vivo and in vitro [ 85 ].

This means that, under microbial pathogenous attack, fever is even more protective because bacterial lipopolysaccharides LPS may signal to phagocytes via TLRs more efficiently, thus enhancing their microbicidal capacity.

Aside being a molecular chaperone which works to reduce the formation of protein aggregates and reverse protein denaturation, iHSP70 is able to associate with the complex formed by NF-κB with its inhibitor IκB thus impeding NF-κB translocation to the nucleus [ 86 ]. Therefore, the HS response is anti-inflammatory in its very nature.

Moreover, PGE 2 and other PGs produced during the onset of inflammation may be converted into their respective electrophilic dehydration products, such as PGA 2 and J-family PGs, which are α,β-unsaturated cyclopentenone prostaglandins cyPGs possessing strong anti-inflammatory activities in vitro as well as in vivo [ 87 ].

As demonstrated in the classic studies by Prof. In other words, cyPG anti-inflammatory action is maximal only if HSP70 expression is elevated [ 88 ]. Finally, HS-activated HSF1 directly controls COX-2 transcription, thus allowing for high-throughput PGE 2 production during inflammation [ 89 ], whether to exacerbate PGE 2 itself or resolve inflammation PGE 2 conversion into PGA 2 , a cyPG.

Inasmuch as cyPGs are strong electrophiles, they promptly conjugate with reactive thiols present in cysteine moieties of proteins and peptides e. Because of this, cyPGs are inflammation-derived anti-inflammatory compounds by virtue of directly inhibiting, at Cys, IκB kinase-β IKKβ , which, in turn, phosphorylates IκB leading to NF-κB activation during inflammation [ 91 ].

These eicosanoids block NF-κB activity also directly after Michael addition reaction at Cys62 of p50 and Cys38 of p65 subunits of NF-κB [ 87 ]. At the same time, the increase in cyPG intracellular contents during inflammation momentarily creates a state of redox imbalance because cyPGs briefly reduce intracellular GSH contents in every cell type and tissue so far tested [ 92 — 95 ] and react with Nrf2-transcription factor repressor Keap1 [ 96 ], thus triggering the expression of a number of redox-protective genes, such as γ-glutamylcysteine synthetase γ-GCS , glutathione S -transferases GST , glutathione disulfide GSSG reductase, glutamine synthetase, glucosephosphate dehydrogenase G6PDH , and superoxide dismutase [ 87 , 97 , 98 ].

Therefore, besides inducing HSP70 expression, cyPG, at physiological concentrations, are cytoprotective by activating redox-sensitive gene expression. Please, see Fig. Physiology of the heat shock response during inflammation and its resolution.

Injury- and pathogen-initiated acute inflammatory processes trigger a variety of signals that lead to the activation of the nuclear factor NF-κB, the master regulator of inducible production of cytokines and inflammatory enzymes, such as cyclooxygenase-2 COX At the same time, such noxious signals stimulate the liberation of arachidonic acid from cellular stores toward the cytosol where it is converted into inflammatory prostaglandins PGs , among them is PGE 2 , which induces hyperthermia.

Fever, in turn, activates heat shock factor-1 HSF1 , leading to the expression of anti-inflammatory and cytoprotective 70 kDa heat shock proteins HSP70 that turn off NF-κB downstream pathways.

At the same time, fever-activated HSF1 induces the expression of more COX-2 molecules, which in turn exacerbate PGE 2 production. As the inflammation progresses over 24 to 48 h, PGE 2 and other prostanoids may be converted into cyclopentenone PGs cyPGs , such as PGA 2. CyPGs are the strongest inducers of HSF1 activation along with heat shock, so that inflammation can be resolved within its own.

Arrows indicate stimulation of the indicated pathways while broken lines represent inhibition. This illustration was redesigned and adapted from [ 7 ].

HSP70 blocks NF-κB activation at different levels. For instance, HSP70 impedes the phosphorylation of IκBs, while heat-induced HSP70 protein molecules are able to directly bind to IκB kinase gamma IKKγ thus inhibiting TNFα-induced apoptosis [ 99 ].

The perception that HSP70 might act intracellularly as a suppressor of NF-κB pathways has been raised after a number of seminal discoveries in which HSP70 was intentionally induced, such as the inhibition of TNFα-induced activation of phospholipase A 2 in murine fibrosarcoma cells [ ], the suppression of astroglial inducible nitric oxide synthase iNOS, encoded by the NF-κB-inducible NOS2 gene expression, paralleled by decreased NF-κB activation [ ], and the protection of rat hepatocytes from TNFα-induced apoptosis by treating cells with the nitric oxide NO -donor SNAP, which reacts with intracellular GSH molecules generating S -nitrosoglutathione SNOG that induces HSP70, and, consequently, HSP70 expression [ ].

iHSP70 confers also protection against sepsis-related circulatory fatality via the inhibition of iNOS NOS2 gene expression in the rostral ventrolateral medulla through the prevention of NF-κB activation, inhibition of IκB kinase activation and consequent inhibition of IκB degradation [ ].

This may also be unequivocally demonstrated by treating cells or tissues with HSP70 antisense oligonucleotides that completely reverses the beneficial NF-κB-inhibiting effect of heat shock and inducible HSP70 expression see, for instance, ref. Hence, HSP70 is anti-inflammatory per se, when intracellularly located.

Another striking effect of HSP70 is the inhibition of apoptosis. Caspases form an apoptotic cascade by an intrinsic pathway characterized by the release of mitochondrial pro-apoptotic factors into the cytosol, while stimulation of cell surface receptors triggers the extrinsic pathway by external signaling factors that may induce the apoptotic process.

The inhibitory potential of iHSP70 over apoptosis occurs via many intracellular downstream pathways e. Together, these mechanisms are responsible for iHSP70 anti-apoptotic function in cells under stress conditions [ ].

Therefore, iHSP is both cytoprotective and anti-inflammatory by avoiding protein denaturation and excessive NF-κB activation which may be damaging to the cells [ ].

Figure 3 highlights the steps where HS response obliterates NF-κB-elicited downstream inflammatory signals. Anti-inflammatory profile of the heat shock response.

Accordingly, the above inflammatory signals activate IKKβ which phosphorylate IκB proteins leading to NF-κB-dependent production of inflammatory cytokines and related proteins. However, HS response can completely revert NF-κB-elicited pathways, as heat shock factor-1 HSF1 impedes transcription of NF-κB-dependent genes whereas HSP70 may block IKKβ activity.

Multiple studies that have imputed a role for SIRT1 to the activation of HSF1 and, consequently, the enhanced synthesis of molecular chaperones, including iHSP70, in order to regulate the stability and function of intracellular proteins.

It has been shown that activation of SIRT1 prolongs HSF1 binding to the promoter HSE regions of heat shock genes by maintaining HSF1 in a deacetylated and DNA-binding competent state [ ], so enhancing the transcription of molecular chaperones such as HSP72 and HSP25 [ , ].

The importance of SIRT1 for the chaperone machinery is clearly demonstrated by SIRT1 knockdown, which attenuates heat shock response [ ]. After both acute and chronic stressful situations, HSPs can also be found in the extracellular milieu eHSP This happens following a finely concerted secretion, mainly from lymphocytes and tissues from the hepatosplanchnic territories [ 34 , ].

In general, eHSP70 acts as an alert signal to physiological systems for the presence of homeostatically threatening situations [ ].

eHSP70 is associated with the activation of the immune system and inflammation [ ]. For example, eHSP70 has been reported to stimulate neutrophil microbicidal capacity [ ] and chemotaxis [ ] and recruitment of natural killer NK cells [ ], as well as cytokine production by immune cells [ 73 , ].

In addition, eHSP70 has been recently hypothesized to be involved in motor neuron cell protection under stress conditions and neurodegenerative diseases [ 63 , ].

However, contrarily to that which occurs when HSP70 is within the intracellular space iHSP70 , when exported to the extracellular space eHSP70 , it functions as a stress signaling and pro-inflammatory molecule possibly by acting via TLR2 and TLR4 see, for instance, ref.

eHSP70 has been reported to be negatively correlated with intramuscular HSP70 content in obesity and diabetes [ 47 ]. Indeed, elevated levels of eHSP70 are positively associated with insulin resistance in elderly volunteers and induce TLR-dependent β cell failure [ 62 ].

Because of this, detection of plasma eHSP70 when not linked to any acute stress e. Secretion of eHSP70 by non-canonical mechanisms exosomes has been documented in lymphocytes, macrophages, epithelial cells, dendritic cells, neuronal cells, and hepatocytes [ ].

The signal triggered by eHSP70 promotes typical immunoinflammatory responses directed to the combat of infections and bacterial infiltration through the production and release of nitric oxide NO and pro-inflammatory cytokines, such as TNFα and IL-1β [ 24 ].

Furthermore, eHSP70 responses are positively associated with classical inflammatory parameters such as C-reactive protein CRP , fibrinogen, and monocyte counts [ ], being commonly found in clinical situations in which danger signaling to immune system must be required [ ].

Indeed, increased serum eHSP70 has been reported in chronic and age-related diseases [ — ]. Interestingly, during conditions in which individuals are chronically exposed to elevated eHSP70 levels e. This process is inhibitable by cyPGs [ ], which, as discussed above, are powerful anti-inflammatory autacoids possessing iHSPinducing capacity [ 87 , 91 ].

eHSPelicited TLR4 expression and signaling is increased in obese and T2DM subjects, an effect that may explain the high basal rate of MAPK phosphorylation and NF-κB activation found in these patients [ — ].

On the other hand, the above findings also help to explain why inhibition or absence of TLR4 confers protection against insulin resistance in skeletal muscle [ ], adipose tissue, and liver [ , ].

Moreover, eHSP70 is positively correlated with insulin resistance and inflammation in elderly people, being ascribed as a key player in the impairment of insulin signaling in the skeletal muscle that occurs with advanced age and in T2DM [ 62 ].

In addition, chronic exposure of β cells and islets to increased concentrations of eHSP70 results in β cell death and altered cell bioenergetics, a phenomenon that, apparently, is mediated through TLR-2 and 4 activation [ 62 ]. Since, in T1DM, there is a dramatic increase in plasma eHSP70 and, in T2DM and aging, there is a slow chronic increase in the concentration of this protein in the plasma, we have deduced that chronic exposure of pancreatic β cells to eHSP70 may lead to β cell failure and loss of functional integrity in vivo [ 34 ].

Based on the above discussion, it is sensible to state that, while iHSP70 is clearly protective, anti-apoptotic, anti-inflammatory, and associated with normal insulin sensitivity, eHSP70 is related to a pro-inflammatory response, decreased expression of the anti-inflammatory iHSP70, and reduced insulin sensitivity.

Because of this, we have suggested that the ratio of compartmental distributions of HSP70 between extra and intracellular locations may determine the outcome of inflammation in chronic degenerative diseases. In a recent study, our group observed that the ratio between plasma eHSP70 and cellular iHSP70 in lymphocytes from rats submitted to different loads of acute exercise an acute stressful situation can indicate the inflammatory status [ 34 ].

Indeed, extracellular to intracellular HSP70 ratio index H-index measured in peripheral blood mononuclear cells PBMC in relation to serum values has been recently assumed as novel and overall index of immunoinflammatory status of an individual [ 34 , 39 , , ].

The rationale for this is that the higher eHSP70 amounts, the more inflammatory signals are coming into play because eHSP70 is pro-inflammatory in nature.

On the other hand, for any specific situation, the more the cells are able to respond to stressful stimuli by enhancing iHSP70, the more such cells are in a state of anti-inflammation and cytoprotection. H-index can be applied to estimate immunoinflammatory status in many different situations, such as immune responses, CVD, neurodegenerative diseases, diabetes, and immunological impacts of exercise.

For example, as previously argued [ 34 ], assuming H-index for the controls resting, unstimulated as the unity, exercise produces a shift in H-indices to up to ca. H values higher than 5 denote an exacerbated pro-inflammatory response. Conversely, H-indices between 0 and 1 indicate a predominantly anti-inflammatory status.

Thus, changes in H-index emerge as a potentially new biomarker for inflammation and as a very sensitive indicator of inflammatory status. Several studies have shown that HSP synthesis and the HS response may be negatively affected by aging [ , ].

This can be clinically assessed with ease by examining HSP70 expression in heat-treated PBMC after an appropriate time [ 34 ]. For example, Njemini and colleagues have demonstrated, in human monocytes and lymphocytes, that basal 37 °C and heat-induced 42 °C HSP70 expression is reduced with advanced age [ ], a behavior that is inversely correlated with higher pro-inflammatory cytokine levels.

Later, the same group has demonstrated the age-related increase in basal unstimulated levels of iHSP70, iHSP32, and iHSP90 in PBMC from healthy human subjects [ ]. In addition, low-grade inflamed patients have higher basal levels of iHSP70, iHSP32, and iHSP90 in PBMC that positively correlate with serum concentrations of inflammatory mediators CRP and IL-6 [ ].

However, while basal levels of iHSP70 may increase due to the effects of pro-inflammatory cytokines and the associated oxidative stress, the essential machinery which should rapidly respond to cellular stress inducing HSP70 expression i.

Apparently, basal levels of iHSP70 in metabolic tissues e. This is supposed to be related to the fact that insulin resistance, per se, is a consequence of decreased HS response [ 7 ]. In any way, compromised HS response is observed in tissues of aged subjects, thus allowing for the establishment of an unresolved inflammatory state.

In addition, during aging, cellular ROS levels can increase due to a limited capacity of antioxidant systems and repair mechanisms. Then, excessive ROS generation associated with impaired resistance to cell stress has been proposed to play an important role in accelerating aging process [ ].

However, it is difficult to determine whether ROS-induced oxidative stress is the cause or just a consequence of aging. Moreover, it is important to highlight that in neutrophils, for example, ROS are essential for pathogen destruction through phagocytosis and for robust inflammatory responses [ ].

The lack of a positive correlation between neutrophil HSP70 levels and ROS in the latter group might be associated with the longer lifespan of these specific people. In general, however, strong evidence suggests that higher iHSP70 contents represent a more protective profile against ROS effects in aging [ ].

It is a unanimity, among the studies on the underlying mechanisms of age-related chronic inflammation, that HS response capacity not necessarily iHSP70 basal levels is seriously defective in metabolic tissues of individuals bearing age-related chronic diseases, especially when associated with obesity and physical inactivity.

This scenario leads to a myriad of inflammatory disorders associated with aging. As stated above, age-associated RA is characterized by a sequence of age-dependent degenerative conditions which starts with an acute inflammatory reaction that is perpetuated into endocrinosenescence, neurosenescence, and senescence of the muscular system [ 22 ].

Beside of this, age exponentially increases CVD risk in RA patients [ 21 ]. On the other hand, HSF1 and iHSP70 play a role in protecting against both irritant-induced gastric lesions and IBD-related colitis.

This is corroborated by the fact that irritant-induced gastric lesions is aggravated in HSF1-null mice due to their inability to up-regulate HSP70, i. Conversely, the protective role of iHSP70 against colitis is associated to its suppressive effect on the expression of pro-inflammatory cytokines [ ].

In addition, overexpression of HSP70 was found to prevent the development of inflammatory processes in the large intestinal mucosa provoked by various damaging factors [ 32 ].

As preliminarily stated above, sarcopenia is a geriatric syndrome in which there is a decrease of muscle mass and strength with aging and constitute a fundamental cause of frailty, functional decline, and disability. Although its etiology is not completely understood, sarcopenia is also closely related to inflammatory processes and aggravated by the concomitant age-related changes in cytoprotective mechanisms, particularly those involving protein quality control and HS response [ 29 ].

In line with an inflammatory nature of sarcopenic disturbs is the observation that aging contributes to enhanced extracellular eHSP70 [ ], which, as discussed above, works as a pro-inflammatory cytokine worsening the picture.

Hence, elevated plasma eHSP70 is linked to sarcopenia being a potential biomarker and predictor of the illness [ ]. Known primary causes of sarcopenia include also a sedentary lifestyle and malnutrition [ ]. While resistance training could be a promising intervention [ ], elderly individuals normally fail to adequately respond to exercise stimuli.

The decrement in regenerative capacity may also be due to a dramatic reduction in postprandial anabolism as well as an increase in generation or decrease in removal of reactive oxygen species ROS [ ].

Indeed, ROS production by normal metabolism and its overproduction in inflamed states are direct causes of aging and many aging-related degenerative complications [ ]. This may be because levels of ROS during aging can increase due to a limited capacity of antioxidant systems and repair mechanisms [ ].

Thus, excessive ROS production and the impaired resistance against oxidative stress, as well as a defective HS response capacity which could alleviate ROS consequences have been proposed to play a major role to accelerate aging process [ ]. Both treatments resulted in the expected improvement in peripheral insulin response and glycemic status.

Moreover, mitochondrial protein carbonylation an indicative of oxidative stress increases moderately with age, whereas this increase may impact upon skeletal muscle function, though it is not a hallmark of sarcopenia per se [ ].

In these studies, HSP70 basal expression is not altered in sarcopenia, but nothing is known about the capability of HS response in such condition. Skeletal muscle is a key reservoir of amino acids that sustain protein synthesis in other tissues, and limited muscle mass often associates with impaired responses to both stress and critical illness [ ].

Nevertheless, loss of muscle mass is not that simple. In both sarcopenia and cancer cachexia another muscle degenerative condition frequently observed in the elderly , type IIb glycolytic, fast twitch muscle fibers are smaller and are preferentially lost, while loss of oxidative type I low twitch fibers is a common feature observed in obese individuals.

Myofiber loss can be accompanied by inflammation, the infiltration of adipose tissue, fibrosis, and decreased capillarization [ 25 ]. Although both muscle mass and strength are needed for optimal performance, loss of muscle strength is a better predictor of mortality related to any cause during aging [ ], suggesting that muscle function is a more important health parameter than muscle mass per se [ 25 ].

Extrinsic changes in innervation, stem cell function, and endocrine regulation of muscle homeostasis contribute to muscle aging. In addition, organelle dysfunction and compromised protein homeostasis are among the primary intrinsic causes.

Some of these age-related changes can, in turn, contribute to the induction of compensatory stress responses that have a protective role during muscle aging [ 25 ].

Progression of sarcopenia depends also on the intestinal absorption of dietary protein amino acids. However, it has been shown that muscle protein synthesis is blunted in elderly when protein and carbohydrate are co-ingested or when the quantity of protein is less than approximately 20 g per meal [ 27 ].

However, despite directly causal factors, the establishment of sarcopenia is closely related to inflammatory processes and aggravated by the concomitant age-related changes in cytoprotective mechanisms particularly those involving protein quality control [ 29 ].

In any way, all the above conditions surrounding sarcopenia tend to limit physical activity which, in turn, predisposes the elderly to chronic inflammatory diseases, including obesities and T2DM [ 13 , ]. Another crucial issue in aging is the development of neurodegenerative diseases [ ]. Aging and age-related neurodegenerative disorders are tightly associated with chronic oxidative stress and impaired protein quality control systems HS response and autophagy , which are the primary pathogenic mechanisms contributing to neuronal dysfunction, degeneration, death, and cognitive decline in both humans and experimental animals [ ].

Aging leads to an accumulation of disabilities and diseases that limit normal body functions and is a major risk factor for neurodegenerative diseases [ ]. In fact, recent evidence has shown that HSPs are critically involved in the progression of neurodegeneration [ , ].

Reduced expression of many iHSPs has been observed in the brain tissue of aged humans and animal models of aging, as well as in tissues from elderly patients with neurodegeneration.

This strongly suggests their involvement in the pathophysiology of age-related neurodegenerative disorders [ ]. Additionally, as observed in relation to sarcopenia, plasma levels of the pro-inflammatory eHSP70 are correlated with neurodegeneration [ ]. The bulk of currently available information converges upon the observation that chaperone-directed protein quality control and HS response are markedly hindered in neurodegenerative diseases in general.

The totality of major neurodegenerative illnesses is associated with the accumulation of unfolded proteins and the formation of toxic protein aggregates.

Interestingly, iHSP90 and iHSP70 have opposing effects on client protein stability in protein quality control: iHSP90 stabilizes the clients and inhibits their ubiquitination, whereas iHSP70 promotes ubiquitination-dependent and proteasomal degradation [ 19 ].

iHSP70, working as a chaperone over the above client proteins, protects neurons from protein aggregation and its consequent cytotoxicity in PD, AD, polyglutamine diseases, and amyotrophic lateral sclerosis ALS , thus avoiding the establishment of an inflammatory status resulting from chronically non-removed protein aggregates [ 17 ].

Inasmuch as protein aggregates are not withdrawn from the brain tissue, a state of endoplasmic reticulum ER stress is achieved that, becoming chronic, triggers inflammation invariably [ 7 ].

As a consequence, neurodegenerative diseases are characterized by an out-of-control situation of oxidative stress and inflammatory markers. An example is the pro-inflammatory eHSP70, whose plasma concentrations are correlated with cognitive decline in language and executive functions in elderly people [ , ].

It has long been recognized that all aggregative neurodegenerative disorders have in their very heart an altered capacity of cells to produce molecular chaperones particularly HSP70 at levels compatible with protein synthesis demands [ ]. AD is the most common neurodegenerative disease causing dementia and having no treatment or cure as yet [ ].

Although the exact physiopathology of AD is still unsettled, it is clear that brain dysfunctions and atrophy due to neuronal loss that accompany AD are correlated with the accumulation of unfolded proteins that tend to form neurotoxic protein aggregates, such as extracellular deposition of amyloid plaques, accumulation of intracellular neurofibrillary tangles NFTs , inflammation, and oxidative stress [ — ].

Abundant extraneuronal deposits of amyloid-beta Aβ are the major pathological hallmark of AD and play an early pathologic role in the development of the disease [ ]. Aβ is a 40 or 42 amino acid polypeptide derived from amyloid precursor protein APP after its sequential cleavage by β- and γ-secretases.

Its physiological role is likely related to the modulation of synaptic activity, although still controversial. In AD, Aβ accumulates forming intermediate soluble oligomers that are synaptotoxic as well as insoluble β-sheet pleated amyloid fibrils that are the main constituents of dense-core plaques mainly Aβ42 and cerebral amyloid angiopathy primarily Aβ40 [ ].

In fact, Aβ protein dimers are directly associated with impairment of synaptic plasticity and memory [ ].

If depressed HSP70 may be at the core of AD, in vitro and in vivo studies have shown that rising iHSP70 contents is able to prevent protein aggregates and the formation of Aβ in brain cells, thus suppressing AD conditions [ , ].

In primary neuron cultures, adenovirus-induced HSP70 has been shown to be neuroprotective against intracellular Aβ accumulation and Aβ-mediated cytotoxicity in AD [ ]. Furthermore, transgenic mice expressing HSP70 also displayed lower levels of Aβ, Aβ plaque deposition, and neuronal and synaptic loss than control mice [ ].

NFTs have a stereotypical spatiotemporal progression that correlates with the severity of the cognitive decline, while topographic staging of NFTs from stages I to VI is used for the pathological diagnosis of AD [ ].

Under physiological conditions, tau is a soluble microtubule-associated protein located to the axon, where it physiologically facilitates the axonal transport by binding and stabilizing the microtubules [ , ].

However, in AD, tau translocates to the somatodendritic compartment and dissociates from microtubules undergoing hyperphosphorylation, misfolding, and aggregation due to self-associations to form both fibrillar and prefibrillar oligomeric clumps [ ].

These aggregates give rise to NFT and neuropil threads [ ]. Not surprisingly, therefore, iHSPs inhibits tau aggregation by a mechanism that seems to involve preferential associations with soluble, monomeric, and prefibrillar oligomeric tau species [ ]. Stimulation of the HS response has conspicuously shown to block progression of virtually all neurodegenerative diseases studied [ ].

iHSP70 prevents protein aggregation by binding to the exposed hydrophobic residues of tau [ ]. Thence, at least in vitro, iHSP70 interaction with soluble tau is supposed to inhibit self-association of tau into aggregates. In addition, iHSP70 has also been found to interact with pre-existing tau aggregates, having a preferential selectivity for oligomeric versus filamentous tau tangles.

Fibromyalgia, which is a disseminated pain disorder mainly diagnosed in middle-aged women, has traditionally been classified as either a musculoskeletal disease or a psychological disorder.

However, accumulating evidence now suggests that fibromyalgia may be associated with CNS dysfunction with loss of gray matter [ 15 ], similarly to that described for classical neurodegenerative diseases of aggregative nature. It is of note, indeed, that fibromyalgia is associated with abnormal protein ubiquitination and HS response pathways [ ], at the same time, fibromyalgia predisposes the patient to an increased risk for developing age-related diseases prematurely, suffering earlier cognitive and physical decline and experiencing earlier mortality [ 16 ].

On the other hand, long-term intranasal administration of recombinant HSP70 in order for HSP70 to reach different cerebral structures intracellularly, so to enhance iHSP70 to middle-aged and old mice has convincingly demonstrated that iHSP70 enhances animal lifespan, improves learn, memory, and locomotor and exploratory activities in old mice [ ].

This suggests that pharmacological administration of tissue-directed iHSP70 may be of value in reverting aging-associated disorders in humans. Therefore, HSPs may be envisaged as potential therapeutic tools to prevent neurodegeneration by avoiding protein aggregation processes, thus reducing the toxicity of such oligomers [ ].

However, more studies are required to identify the specific signaling pathways and routes of administration of HSP70 to avoid possible harmful effects because, if HSP70 is not accurately introduced inside brain cells, it could remain within the extracellular space, where eHSP70s is a pro-inflammatory by virtue of what the binding to TLR2 and TLR4, at least in other cells, may exert [ 62 , ].

The beneficial effects of resveratrol are believed to be associated with the activation of SIRT1 [ 18 ], which, as discussed above, enhances the HS response. Unfortunately, however, the accumulation of protein aggregates in many elderly people was found to surpass the ability of neuronal tissue to cope with appropriate HS response so that the end of story is a consequent chronic inflammatory response and tissue degeneration.

Although not completely understood, the exact mechanisms by which inflammation is chronically attained in neurodegenerative as well as in other prevalent age-associated diseases, cellular senescence in metabolic tissues may shed light on the whys of persistent unresolved inflammation that lead to tissue dysfunctions.

In aged mammals, it seems that while insulin resistance is not chronically sustained or not so severe, cells are still able to compensate increasing their HSP70 levels [ , ]. After long-term insulin resistance, notwithstanding, stress response i.

Whether this scenario is also attained in other age-related chronic degenerative diseases is a matter of current dispute. As discussed above, elders are sick longer, often coping with multiple chronic diseases simultaneously [ 4 ].

Senescent cells accumulate in many tissues during aging and start to present a unique senescence-associated secretory profile SASP that includes many pro-inflammatory cytokines [ 4 , 7 ]. On the other hand, HS response, which is critical to promote the resolution of inflammation, is severely impaired in metabolic tissues during chronic inflammation.

Similar observations have been reported in obese and non-obese T2DM patients, in which a marked reduction in the protein expression of HSP70 has been noticed in comparison with obese controls [ 47 ].

Moreover, T2DM patients show decreased intramuscular expression of both HSP70 and heme-oxygenase [ ], so that HS response-associated anti-inflammatory and antioxidant defenses are impaired leading to an inflammatory state, high NOS2 -dependent NO production and impaired insulin receptor downstream signaling pathways function by S -nitrosation [ ].

We have recently observed that HSF1-HSP70 axis is progressively suppressed in adipose tissue and liver of insulin resistant obese patients, as nonalcoholic fatty liver disease NAFLD evolves from steatosis, toward more inflammatory forms of the disease, e.

Hence, adipose tissue of insulin-resistant patients is embraced in a suppressed HS response, as observed in the age-related chronic degenerative diseases discussed in the previous section.

This is a complex situation because stress-induced iHSP70 should inhibit JNK-dependent signal transduction [ , ] under physiological conditions.

The association between NF-κB-centered unresolved inflammation and chronic diseases involves the unfolded protein response UPR a cellular reaction to overnutrition and ER stress, as observed in obesity, atherosclerosis, insulin resistance, and T2DM [ — ].

In all these cases, unremitted low-grade inflammation, which follows chronic ER stress, is a consequence of impaired resolution of inflammation [ ]. Age-related chronic inflammation and HS response pathways also intercross at gene regulatory level.

Accordingly, the promoter region of TNFα gene contains an HSF1 binding site that represses TNFα transcription, and thus loss of this repressor results in sustained expression of TNFα [ ], which possibly explains why HSF1 knockout is associated with a chronic increase in TNFα levels and increased susceptibility to endotoxin challenge [ , , ].

Regulation of this network in the opposite direction also occurs: TNFα may transiently repress HSF1 activation [ ]. However, if inflammation evolved to present both an initiation and a resolution phase Fig. The answer to this question is linked to cellular senescence and SASP.

Cellular senescence and its associated SASP is an alternative mechanism to UPR, in order for the cell to avoid apoptotic death, which would be an expected result after an inoperative anti-inflammatory HS response.

In fact, a senescent-like state can emerge in fat cells from obese individuals even young obese subjects , this being an adaptation to fat cell overutilization which resembles cellular aging [ ]. High-fat diet HFD -induced obesity also leads to vascular senescence in a process involving long-term activation of Akt1 and mTOR [ ].

Conversely, H 2 O 2 -induced oxidative stress disrupts HuR-SIRT1 mRNA interaction lowering cell survival in a cycle checkpoint kinase-2 Chk2 -dependent manner [ ]. SIRT1 knockdown, on the other hand, attenuates HS response [ ] whereas SIRT1 modulators were found to also modulate HSF1 activity and HS response in HeLa cells [ ].

Following a cellular insult e. However, HuR participation in cellular homeostasis goes beyond that, as HuR is involved in the differentiation of pre-adipocytes, including translation and stability of glucose transporter GLUT1 mRNA. Therefore, experimental data support a role for HuR in muscle and adipose tissue differentiation processes [ ].

Interestingly, HS and calorie restriction which enhances SIRT1 deacetylase activity seem to act synergistically with respect to the HS response [ ].

SIRT1 attenuates saturated fatty acid-induced ER stress and insulin resistance in hepatocyte-like cells [ ]. AMPK, in turn, inhibits glycogen synthase kinase-3β GSK-3β , an enzyme that constitutively inhibits HSF1 activity [ 55 ], so that energy sensing AMPK is linked to anti-inflammation HSP70 via AMPK and SIRT1-dependent AMPK activity Fig.

Heat shock response failure in chronic inflammatory diseases: role of cellular senescence. Under normal nutrient supply i. Any excess of demand is counteracted by enhanced heat shock HS response in order supply the correct furnishing of chaperones thus avoiding or correcting endoplasmic reticulum ER stress and the resulting unfolded protein response UPR.

When circulating glucose and fatty acids especially saturated overcome energy expenditure and high amounts of surplus energetic metabolites should be stored in adipose tissue under a higher insulin command, ER stress develops.

In the case of irremediable HS response, cells may undergo apoptosis and irreversible cell death. On the other hand, if proteostasis is not attained but cells still have conditions to avoid apoptosis, an alternative metabolic pathway may be taken in which cells do not dye but activate senescence, assuming a senescence-associated secretory phenotype SASP.

This is accomplished because adipocytes chronically challenged by excess fatty acids, cholesterol, high-fat diet, and hyperglycemia prepare an inflammatory response, which becomes chronic.

Under the persistence of risk factors, the cells develop an UPR that is diverted to the inflammatory branch since continuous inflammatory stimuli do not cease to activate NLRP3 inflammasome, leading to the activation of caspase Activated caspase-1 determines, in adipocytes, a state of frank cellular senescence which culminates in SASP that can spread out to other tissues and cell types, including adipose tissue infiltrating macrophages, skeletal muscle cells, pancreatic β cells, hepatocytes, vascular cells, and brain structures.

Glutamine for Digestive Health - Canadian Digestive Health Foundation Purchase Advertise Advertising and Corporate Services Advertising Mediakit Reprints and ePrints Sponsored Supplements Journals Career Network About About The Journals of Gerontology, Series A About The Gerontological Society of America Editorial Board - Biological Sciences Editorial Board - Medical Sciences Alerts Self-Archiving Policy Dispatch Dates Terms and Conditions Contact Us GSA Journals Journals on Oxford Academic Books on Oxford Academic. Older individuals ought to talk to their medical doctors before including L-Glutamine dietary supplements in their routine to ensure it is the healthy for them. Moreover, glutamine is released in significant quantities from skeletal muscle stores following stress and injury [ ]. You are right to be concerned about the effects of calcium supplements on your cardiovascular health. In common, all the above illnesses have a progressive disturb of protein quality control leading to the accumulation of unfolded proteins and protein aggregates that trigger inflammation in brain tissues [ 19 ]. Under l -glutamine supplementations, excess intramuscular l -glutamine supply enforces fructose 6-phosphate F6P to divert from glycolysis and enter hexosamine biosynthetic pathway HBP, shaded box in the center after its conversion to glucosamine 6-phosphate by glutamine 6-phosphate amidotransferase GFAT, a. Unfortunately, however, aging and age-related chronic inflammatory diseases are marked up by a conspicuous depression of stress-elicited HS response [ 7 ].
Glutamine and aging

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