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Journal of Science in Sport and Exercise

, Volume 1, Issue 2, pp 97–115 | Cite as

Exercise Training for the Elderly: Inflammaging and the Central Role for HSP70

  • Carlos Henrique de Lemos Muller
  • Jorge Roberto de Matos
  • Gisele Bettú Grigolo
  • Helena Trevisan Schroeder
  • Josianne Rodrigues-Krause
  • Mauricio KrauseEmail author
Review article

Abstract

Inflammation is a common feature of aging tissues, being involved in most, if not all, age-related diseases. The origin of a low-grade inflammation state in aging (inflammaging) is multifactorial and may involve changes in body composition, immunosenescence, autophagy, microbiota modification and loss of proteostasis. The heat shock response pathway (HSR, and HSP70 expression) plays an important role as a mechanism of resolution of inflammation and proteostasis control. In this review, we sought to discuss the mechanisms that may lead to inflammaging, and the importance of the HSP70 in this process. Besides, we also discuss how physical exercise, particularly resistance training, can improve the HSR and the inflammatory balance of elderly people.

Keywords

Aging Inflammation Exercise training Cytokines Heat shock response HSP70 

Introduction

Population aging is a phenomenon related to the increasing number of elderly people within a country’s overall structure [124]. People over 80 years old will represent up to 30% of the industrial countries' population and 12% of the under development ones in 2030 [124]. As such, the so called “2030 problem” represents a challenge in terms of assuring sufficient resources and effective health services by then, when elderly population will be doubled [66]. The economic and social consequences of aging are considerable, particularly regarding the burden of dependence [124].

It is widely known that aging leads to physical, biological and cognitive declines [87]. Aging is a complex process modulated by several factors such as DNA damage/repair, apoptosis, epigenetic and transcriptional changes, immune response, cellular senescence, oxidative stress, metabolic dysfunction and inflammation [59]. Inflammation, in particular, has been shown as a key player involved in the development of several aging-related diseases, such as sarcopenia, diabetes, insulin resistance, heart disease, neurodegenerative diseases (e.g. Alzheimer’s Disease, AD), among others [59].

In fact, inflammation is a consistent feature of aging tissues, being involved in most, if not all, age-related diseases [48]. In the elderly, this condition has been described as “inflamm-aging”, a low-grade, chronic, systemic inflammation (in the absence of infection), which is significantly associated to both mortality and morbidity [47, 48, 139]. Studies confirm inflammatory mediators, such as the cytokines interleukin (IL)-6, tumor necrosis factor alpha (TNF)-α, and IL-1β,  are dramatically increased in the bloodstream of healthy elderly in comparison to young people [16]. Also, in vitro studies have shown IL-1β stimulates IL-6 mRNA expression and myotubes proteolysis, which occurs partially through the activation of the nuclear transcriptional factor kappa B (NF-κB). This is a known trigger for muscle wasting, one of the major issues regarding physiological declines with aging, which is defined as the progressive loss of muscle mass and function (sarcopenia) [82, 85]. NF-κB is a key inflammatory mediator, its subunits are found abundant in muscle samples from elderly in comparison to young people [17, 133]. Upon activation, this transcription factor induces the expression of archetypal inflammatory cytokines, such as IL-1β and TNF-α, which increase the inflammatory cascade [78]. As such, NF-κB activation and associated cytokines released induce an inflammatory feed-forward that may be involved in age-related sarcopenia in elderly [130].

The origin of the low-grade inflammation is multifactorial. Evidences suggest that the inflammatory profile is directly connected with the unfavourable changes in body composition that occurs with aging [75, 107]. For example, the expansion of the adipose tissue (specially visceral) leads to increased recruitment of blood monocytes and their polarization to inflammatory cells (M1 phenotype). Simultaneously, the known loss of lean mass that occurs with aging, particularly skeletal muscle, an important source of anti-inflammatory myokines in response to contraction, may lead to an imbalance between pro vs. anti-inflammatory cytokines (Fig. 1). This cause several changes and dysfunction in many tissues, including nervous system, gut, skeletal muscle, heart, lungs blood vessels, pancreas and many others, leading to a chronic unresolved inflammation [94]. For this reason, the maintenance of optimal body composition (↓ adipose tissue and ↑ muscle mass) may be determinant to the inflammatory status. Other important triggers of inflammaging include changes in immune function (immunosenescence) [9], autophagy regulation [111], microbiota [19] and loss of proteostasis [33].
Fig. 1

Body composition and inflammaging. Body composition is determinant on the inflammatory status. The expansion of the adipose tissue (specially visceral) leads to increased recruitment of blood monocytes and their polarization to inflammatory cells (M1 phenotype). Simultaneously, the loss of lean mass that occurs with aging, particularly skeletal muscle, an important source of anti-inflammatory myokines in response to contraction (or reduced physical activity, or both), may lead to an imbalance between pro vs. anti-inflammatory cytokines that culminates in inflammaging and its propagation to all organs

Considering the central role of inflammation in aging-related conditions (sarcopenia, T2DM, AD, etc.), activation of pathways that induce the resolution of inflammation is vital to avoid these complications. Among the mechanisms of resolution of inflammation, the heat shock protein 70 kDa family (HSP70) plays a crucial role. In this review we sought to discuss the mechanisms that leads to inflammaging and the importance of the HSP70 (and the heat shock response, HSR) on the induction and resolution of inflammation in aging. We also discuss how physical exercise, particularly resistance training, can improve the HSR and the inflammatory balance of elderly people. Finally, considering the potential benefits of amino acid and protein supplementation to improve HSR in elderly people, we suggest that the combination of resistance training along with protein supplementation may result in long term maintenance of HSR, thus preventing/reducing the incidence of inflammatory-related diseases.

Immunosenescence and Inflammation in Aging

Immunosenescence, a potential inducer of inflammaging, may occurs as a consequence of immune cells exposure to antigenic overload during life, which leads to a reduction in the activity of innate and adaptive immunity [19, 26]. These changes appear to be related to reduced self-renewal capacity of hematopoietic stem cells, thereby reducing the formation of immune cells [9, 84]. In addition, reductions in the total number of dentritic cells, chemotaxis, and phagocytosis (in innate immunity), as well as decreased number of naive T cells and Th1 (T helper 1), and increased number of dysfunctional memory T cells and Th2 (in adaptative immunity), can lead to a greater release of pro-inflammatory cytokines (mainly by chronically activated macrophages and Th2 cells) resulting in a chronic maintenance of a pro-inflammatory state (inflammaging) [9, 19, 26]. Thus, the continuous antigenic stimulation of dysfunctional immune cells, gradually induces a senescence-associated secretory phenotype (SASP) that increases the pro-inflammatory mediators levels, intensifying the systemic inflammatory state.

In terms of cell signalling, senescence is characterized by increased activity of β-galactosidase and p38MAPK, both used as markers for senescence [50, 93]. Activation of p38MAPK induces a senescence-associated secretory phenotype, which initiates the release of IL-6 and IL-8 [29, 136]. SASP induction is caused by increased NF-κB activation [50] and also by NLRP3 inflammassome [2]. The NLRP3 inflammasome is a multiprotein complex that can activate procaspase-1 in response to cellular danger, resulting in processing and secretion of the pro-inflammatory cytokines IL-1β and IL-18. Generally, inflammasome activation results from oligomerization of a nucleotide-binding domain-like receptor (NLR) after sensing different pathogenic or endogenous sterile dangerous signals (pathogen- or danger-associated molecular patterns, PAMPs or DAMPs) [35].

Particularly, NLRP3 inflammation is also related to the autophagic process [115]. Activation of NLRP3 can trigger an age-related pro-inflammatory phenotype that represses autophagy [115]. In fact, there are evidences that tumor necrosis factor-α (TNF-α), an inflammatory cytokine, can induce or repress autophagy in an NF-κB-dependent manner [37]. Autophagy is an important mechanism to control cell homeostasis by assisting the removal of damaged organelles and unfolded proteins [84]. Normal autophagy activity inhibits the activation of inflammation [115]. However, it is well known that the reduction of autophagy is associated with aging [111]. Indeed, it was demonstrated that a knockout (drosophila) for Atg7 (an important protein in the autophagic machinery) allows the accumulation of damaged organelles and unfolded proteins, leading to a cellular senescence profile [61]. In addition, reduced expression/activation of SIRT-1 (a deacetylase protein) is related to reduced autophagy in aging [111]. Therefore, reduced autophagy in aging can lead to accumulation of cellular debris, such as protein aggregates and organelles (“garb-aging” process) that, when released into the circulation, may induce an inflammatory process in different tissues and organs, thus promoting the propagation of inflammation in aging [49].

To sum up, autophagy plays an important role in cell homeostasis, mainly because it facilitates the breakdown and eventual recycling of macromolecules during cellular adaptation to environmental challenges. An important organelle that is involved in this process is the endoplasmic reticulum (ER). Under cellular stress conditions, such as metabolic, heat, oxidative, or protein folding defects, the normal function of the ER in protein synthesis is disrupted, and the ER switches to a stress state [97]. As misfolded proteins accumulate, the unfolded protein response (UPR) is initiated to counter these stress effects.

Inflammation and the Unfolded Protein Response

Recent evidence attributes the participation of adaptive responses to stress within the endoplasmic reticulum, in several aging-related diseases, to a pathway known as the unfolded protein response (UPR). Failure of the ER adaptive capacity and subsequent activation of the UPR (i.e., ER stress) intersect inflammatory and other stress pathways and play a key role in age-associated diseases, such as T2DM and AD. In metabolic disorders, such as obesity and aging, inflammatory mediators and lipids can activate signalling cascades that trigger inflammatory mediators such as JNK and IKK. This, in turn, can lead to serine phosphorylation of IRS1/2 and subsequent inhibition of insulin signalling [55]. The activation of inflammatory signalling pathways can trigger ER stress, which can lead to further inhibition of insulin action, in addition to the generation of reactive oxygen species (ROS) through mitochondrial dysfunction [55].

An important player of the UPR is the molecular chaperone heat shock protein HSPA1A (or HSP72). The intracellular HSP72 is a universal marker of stress, whose expression is induced by different cell stressors, such as heat, metabolite deprivation, redox imbalances and also physical exercise [77]. The activation of the iHSP72 is sine qua non for the promotion of tissue repair, since the expression of this chaperone confers cytoprotection and also exerts anti-inflammatory effects through the inhibition of NF-κB and JNK pathways. Even though the up-regulation of the HSP is essential for any stress adaptation, the absence and/or the inhibition of HSP72 expression has been shown to result in increased vulnerability of the cells to stress [92, 112]. The ability of a cell to properly sense and initiate this response is critical for its survival. In some conditions and chronic neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), Alzheimer’s disease, and polyglutamine (polyQ) diseases, the inability to activate an appropriated heat shock response causes an abnormal accumulation and inclusions of proteins, a commonly observed characteristic. Under pathological conditions, the level of such misfolded proteins may exceed the protective machinery of the cell to either maintain them in a soluble form or degrade them, resulting in their accumulation, cell dysfunction and death [3].

Heat Shock Response (HSR, thus HSP70 expression), is activated following an oxidative insult or increased ER stress. Under normal conditions, when iHSP70 expression is normal, the chaperone supply for the appropriate folding of newly synthesised proteins is sufficient. However, due to inflammation-induced inability to express iHSP70, the UPR is induced, causing cell dysfunction, perpetuation of inflammation and increasing the risk of apoptosis [56]. Indeed, IR is associated with blunted HSR, thus, lowering the capacity of our cells to induce HSP70 [72]. Hence, age-related IR may lead to increased incidence of neurodegenerative diseases. In this regard, strategies capable of changing the HSP72 content, such as exercise training, are likely to be used as a therapeutic strategy for the prevention or treatment of IR and AD. In addition, HSP70 expression is essential not only as a chaperone for stress-denaturated proteins, but also for maintaining mitochondrial integrity, normal protein synthesis, inhibition of protein degradation (thus connected to normal muscle mass size and function), reducing inflammation and apoptosis. Considering the aforementioned information on the importance of HSP70 (and HSR) to the control of inflammation, we will now focus on the physiology of this protein.

HSP70 as an Inflammatory Modulator

As we previously discussed, HSR (thus HSP70 expression) is essential to protect the cells against any type on non-lethal stress. HSP70 family, a very conserved stress protein, is induced during cell stress, increasing its content up to 2% of the total cellular protein content [98]. HSP70 (encoded by the HSPA1A gene in humans), can act as molecular chaperones by interacting with other proteins (unfolded, in non-native state and/or stress-denatured conformations), thus avoiding inappropriate interactions, formation of protein aggregates and degradation of damaged proteins, as well as helping the correct refolding of nascent proteins [86]. In addition to its other functions (anti-apoptosis, protein translocation, metabolism, and others) [72], this protein exerts, intracellularly, a powerful anti-inflammatory effect [70].

HSP70 expression (particularly the stress-inducible form HSP72) is mediated by the HSR pathway. This response is initiated through the activation of heat shock transcription factor-1 (HSF1) [125]. The principal impact of HSF1 activation is the exacerbated production of the anti-inflammatory and cytoprotective HSP72. A full description of HSR is described elsewhere (please consult [70]). The crosstalk between HSR and inflammation occurs at several levels (gene level, posttranscriptional and protein level). For example, the promoter region of TNFα gene contains an HSF1 binding site that represses TNFα transcription, so that the loss of this repressor results in sustained expression of TNFα [126], while TNFα may transiently repress HSF1 activation [67]. In addition, JNK1 (a pro-inflammatory factor) can phosphorylate HSF1 in its regulatory domain causing its suppression, whereas HSP70 prevents Bax activation by inhibiting the JNK/Bim pathway [81, 138]. Sirtuin 1 (NAD+-dependent deacetylase sirtuin-1; SIRT1) also plays a critical role on HSR, prolonging HSF1 binding to the promoter regions of heat shock genes, by maintaining HSF1 in a deacetylated and DNA-binding competent state, therefore enhancing the transcription of HSP72 [39, 137].

The newly synthesized HSP70 (here called intracellular, iHSP70), exerts its direct anti-inflammatory effect through the interaction with NF-κB, blocking its activation [60] at several levels. For example, HSP70 avoids the phosphorylation of inhibitor of κB (IκBs) [23] and directly binding to IκB kinase gamma (IKKγ) [24], which will result in continued binding (and inactivation of NF-κB) thus inhibiting downstream inflammatory signals. In addition, stress-induced elevations in iHSP70 inhibit c-Jun N-terminal kinase (JNK)-dependent signal transduction therefore promoting cell survival [51].

Although iHSP70 has anti-inflammatory effects, when released to the extracellular environment (here called extracellular HSP70, eHSP70), this protein exerts opposite effects, inducing inflammation and immune activation [34, 107]. This antagonic effect is mediated through its biding to Toll-like receptors (TLR)2 and 4, activating innate immune responses which may lead to adaptive immune responses [128]. TLR signalling may activate NF-κB and JNK by a pathway related to IL-1 receptor-associated kinase (IRAK) family of protein kinases [140]. In fact, serum eHSP70 concentrations are positively correlated with markers of inflammation, such as C-reactive protein, monocyte count, and TNF-α [73]. Thus, the balance between intra versus extracellular HSP70s (i.e. iHSP70/eHSP70 ratio) will modulate NF-κB translocation capacity and then the inflammatory level [72]. For this reason, interventions that are capable to induce changes in the iHSP70/eHSP70 balance (↑iHSP70 and ↓eHSP70), such as physical exercise, are potential candidates to decrease inflammaging and its deleterious effects.

Inflammaging and the HSP70 Role: A Unifying Hypothesis

Aging is characterized by a progressive decline in physiological reserve of all organ systems, albeit at different rates. Several hormonal responses are reduced with aging, such as growth hormone (GH), which will influence the physiology of all target tissues. Here, we will start to discuss the chronic changes in adipose tissue (expansion) followed by modifications in other tissues, integrating some hormonal aspects, cell senescence, inflammation and the HSP70 in a unifying hypothesis on the overall effects of HSP70 in inflammaging (Fig. 2).
Fig. 2

Proposed integrative tissue crosstalk in inflammaging and the role of HSR and HSP70. This model suggests the crosstalk between main organs/tissues affected by the chronic low-grade inflammation (please consult the text for full detailed explanation). Exercise can change the inflammatory balance by its anti-inflammatory effects, improving insulin sensitivity (key for HSR maintenance), reducing adipose tissue (lipolysis) and the inflammatory profile of infiltrated macrophages, improving muscle metabolism (by increasing heat production and energy challenge), activating important molecular pathways that leads to protein synthesis, mitochondrial biogenesis and maintenance of proteostasis. Red arrows: inhibition; Blue arrows: activation

Adipose tissue expansion, especially visceral, is characterized by several morphological and biochemical changes. Adipocytes are constantly exposed to nutrients and hormones, such as glucose, fatty acids, insulin and others, at every postprandial period. In response to this physiological metabolic challenge, adipocytes are stimulated to uptake and store the available nutrients. However, all activated fat anabolic signalling, is followed by increased necessity for protein synthesis. Again, the maintenance of proteostasis is required to assist in protein folding, thus activating the unfolded protein response, autophagy, and/or HSR [59]. As previously discussed, chronic positive energy balance that may occur in aging (↑ nutrients intake and ↓ physical activity), may overcome HSR (↓HSP70), inducing an state of adipocyte cellular senescence. In this case, adipocytes acquire a pro-inflammatory profile (SASP), inducing the release of cytokines that will signalize to other tissues and spreading inflammation [94].

Diminished lipolitic hormones, such as GH, will also associate with adipose tissue expansion. Among the pro-inflammatory secreted molecules, Monocyte chemoattractant protein-1 (MCP-1), is one of the key chemokines that regulate the migration and infiltration of monocytes/macrophages that, in a pro-inflammatory microenvironment, acquire a M1 phenotype, increasing the release of cytokines and adipokines with inflammatory effects (IL-6, TNF-α, IL-1β, leptin and others) [70]. The pro-inflammatory cytokines, through its binding to specific receptors in target cells, will induce signalling activation mainly through the NF-κB activation [70]. For example, TNF-α, is a known inductor of inflammation, catabolism and insulin resistance [59]. Its signaling leads to the activation of serine threonine kinases JNKs and IKK, which phosphorylate insulin receptor (IR) substrate-1 (IRS-1) on Ser-307, leading to the inactivation of the insulin receptor downstream response [25].

Inhibition of insulin signaling (insulin resistance) plays a major role not only as an anabolic molecule [thus reducing protein synthesis, favoring sarcopenia through the release of catabolic factors activity such as FOXO3A (forkhead box O3), MuRF1 (Muscle RING-finger protein-1), MAFbx (muscle atrophy F-box) and the ubiquitin proteasome system], but also by its crosstalk with HSR [74, 120]. As shown in Fig. 2, the downstream insulin signaling can interact directly with HSF1, or indirectly, through inhibition of glycogen synthase kinase-3β (GSK-3β). This enzyme causes the suppression of HSF-1 activation and binding to HSE’s (heat shock element) [12], thus reducing HSP70 expression. Thus, the lower HSP70, an inhibitor of NF-κB activation, will culminate in increased inflammatory signaling, in a feed-forward mechanism (↑inflammation ⇒ ↓ insulin signaling ⇒ ↓ HSP70 ⇒ ↑ inflammation). In addition to its anti-inflammatory role, HSP70 can also modulate skeletal muscle metabolism.

Furthermore, HSP70 prevents disuse atrophy induced-proteolysis, through inhibiting the activation of FOXO3 and NF-kB signaling pathways [119, 120]. Another point of crosstalk between HSR and protein synthesis may occur at the level of eIF2 protein (a downstream protein of the mTOR pathway). In fact, eIF2 promotes the activation of HSF1 [38], leading to the expression of HSPs under stress conditions. Indeed, it was recently demonstrated that HSP70 inhibits FOXO3-dependent transcription in a gene-specific manner [120]. Specifically, HSP70 inhibited FOXO3a-induced promoter activation of atrogin-1(MAFbx), but not MuRF1) [120]. These two proteins are ubiquitin E3 ligases, which tag ubiquitin to specific protein substrates, marking them for recognition by the 26S proteasome, for protein degradation. In fact, although multiple proteolytic systems are involved in muscle protein breakdown, degradation through the ubiquitin proteasome system (UPS) may account for the majority of proteolysis during skeletal muscle wasting [132].

It is commonly reported in aging muscles that the reduction in individual fiber size is mainly confined to fast type II fibers, leading to a progressive decrease in the type II-to-type I fiber area ratio, indicating a selective atrophy of type II fibers [69]. Myosin isoform content is the main determinant of a fiber’s contractile properties, and the aging-related shift in muscle MHC content has been found to play an important role in the decline of rapid force capacity. This is especially important because it is directly related to decreased muscle function and increased incidence of falls in older people [15]. Muscle wasting depends on the activation of two major pathways, the proteasomal and the autophagic-lysosomal systems, both controlled by FOXO3. As discussed, other pathways, such as NF-κB, are also involved. FOXO3 activity is downregulated by several factors such as Akt, HSP70 and the transcriptional co-activator PGC-1α, with the last being more abundant in slow oxidative than in fast glycolytic muscle fibers [27]. This may explain why type I fibers are more resistant to atrophy. PGC-1α was found to prevent FOXO3 binding to the Atrogin1/MAFbx promoter and to inhibit Atrogin1/MAFbx transcription [116]. Besides that, exercise is a well known inductor of PGC-1α expression, inducing a protective effect against muscle atrophy [44]. As recently demonstrated, HS response (expression of HSP70 after stress) is higher in glycolytic fibers than in oxidative (type I) fibers. Thus, the higher content of HSP70 in fast twitch fibers may protect these fibers against atrophy (induced by FOXO3 and NF-κB activation), and higher PGC-1α expression would account for protection in slow twitch fibers [105].

Considering the activation of inflammatory pathways, the decreased insulin anabolic signaling, the lower HSR and the increased catabolic factors, the aging process will lead to muscle inflammation, impaired proteostasis, muscle atrophy, fiber type shift and cellular dysfunction. In addition, muscle repair, that is dependent of muscle microenvironment signaling, can become impaired. Muscle repair after injury, requires a precise sequence of signaling molecules to the satellite stem muscle cells in order to induce their activation, proliferation and differentiation [129]. Macrophages have a key role in this process by shifting their phenotype profile.

Recent evidence demonstrated that after acute injury, M1 (pro-inflammatory) macrophages infiltrate early in the damaged muscle to promote the clearance of necrotic debris, whereas M2 macrophages (alternative anti-inflammatory) appear later to sustain tissue healing. The initial sequence includes the activation of macrophages (local and recruited from the blood) in a M1 phenotype (pro-inflammatory), secreting several cytokines to trigger inflammation, the clearance of cell debris and the activation of stem cells. Phagocytosis of apoptotic and necrotic cells induces an M1 to M2 macrophage transition. Then, M2 macrophages initiate a regenerative stage during which stem cells differentiate, and the damage is finally resolved. In the case of aging (and the chronic low-grade inflammation), the muscle microenvironment may be inadequate to induce the proper macrophage shift, causing muscle repair impairment. Thus, in inflammaging, the maintenance of M1 activated macrophages can lead to fibrosis, fat deposition, and exhaustion of the stem cell pool [106]. Interestingly, a role for eHSP70 in this response, was suggested [114]. HSP70 is released into the extracellular environment following tissue injury and facilitates the activation of pro-inflammatory processes and the recruitment of immune cells to the injury site, being involved in the inflammatory response to muscle injury [114]. However, when elevated chronically, eHSP70 may blunt the normal repair process.

The chronic low-grade inflammation will also affect liver cells (hepatocytes and kupffer cells) [5], leading to further local inflammation. During systemic inflammation, the liver becomes unresponsive to GH, resulting in decreased plasma insulin-like growth factor-I (IGF-I), with concomitant reductions in lean body mass. This process is apparently mediated by the elevated level of IL-6 in inflammatory conditions, where IL-6 induces hepatic GH resistance thought the inhibition of GH-inducible promoter activity [5]. Other inflammatory cytokines, such as IL-1β and TNF-α (mediated by STAT5 and NF-κB activation), are also involved in GH resistance [18, 123]. On the constant presence of inflammation, along with insulin resistance, the protective anti-inflammatory role of HSP70 is diminished [36]. Thus, lower GH secretion and lower IGF-1 release from the liver can contribute to the lower anabolic signaling in elderly people.

Pancreas is also an easy target for inflammation, since pancreatic β-cells are highly vulnerable to metabolic and oxidative stress. The mechanisms involved in β-cell dysfunction include an increase in generation of reactive oxygen and nitrogen species (ROS and RNS) [95], activation of oxidative stress responses, activation of endoplasmic reticulum (ER) stress and a reduction in energy generation capacity [56]. In fact, long term inflammation in aging may induce Langerhans islets inflammation that can reduce β-cell viability and insulin secretion [70]. As discussed later, not only TNF-α and IL-1β are involved in this harmful response, but also the eHSP72 appears to have a potential role [73].

As previously mentioned, HSP70 is a versatile protein, and its function depends on its location. In contrast to its anti-inflammatory/protective role in the intracellular milieu, eHSP70 exerts pro-inflammatory actions through MyD88 and TIRAP that signal downstream to NF-κB via IRAK4, TRAF6 and IKK, and induces JNK activation via MEKK4/7 [4, 65], although high-affinity binding capacity of eHSP70 to other surface receptors has also been described [20]. This signaling promotes the production and release of NO˙ and pro-inflammatory cytokines, such as TNFα and IL1β [21]. In fact, increased serum HSP70 has been reported in chronic and age-related diseases [41, 42, 99]. Thus, eHSP70 can cause, when chronically released (that is the case of aging and other inflammatory conditions), a further increase of inflammation, helping its propagation in the body.

The source of eHSP70 in chronic inflammatory conditions is still under debate. However, as we suggested, the main source of this protein is the circulating lymphocytes [57, 58, 70], while during exercise the main source is the hepatosplanchnic tissue [46]. The increased levels of eHSP70 may be explained by: (1) increased sympathetic activity, thus catecholamine release (modulated by ↑ leptin and insulin) and (2) directly by pro-inflammatory cytokines (TNF-α). It was recently demonstrated a positive correlation between eHSP70 and the leptin/adiponectin ratio in older people with excessive abdominal fat accumulation [73]. Thus, chronically increased levels of leptin can affect many cells in the body, including those of the hypothalamus, which induce changes in the autonomic output, specifically increasing sympathetic nervous system activity (SNS) [118] and the release of eHSP70 to the circulation thereafter.

Considering the actions of eHSP70, it can affect several tissues, causing cell function impairments. Through its binding to TLR4, eHSP70 can induce: (1) persistent skeletal muscle inflammatory microenvironment, thus impairing muscle repair [106, 129]; (2) β-cell dysfunction and death [73]; (3) activation of kupffer cells and (4) induction of inflammation, insulin resistance, dysfunction and atrophy in skeletal muscle cells [72, 73].

It is important, however, to understand that eHSP70 can induce deleterious effects only when chronically released. This protein is also increased acutely, during stress conditions, such as exercise [72], acting as a “danger” signalling molecule, activating the immune response, participating on the motoneurons protection [76], and even exerting a post-exercise anti-inflammatory response [14].

General Effects of Exercise on Inflammaging

Physical exercise is a known modulator of the inflammatory status and widely recommended as a tool to prevent and treat inflammatory-related diseases [102]. Some of the main suggested mechanisms for the anti-inflammatory effects of exercise includes: (1) Reduction in visceral fat mass (with a subsequent decreased release of inflammatory adipokines and decreased chronic HPA axis activation); (2) acute activation of the hypothalamic–pituitary–adrenal axis and the sympathetic nervous system: causing inhibition of TNF-α by monocytes; (3) myokine release (such as IL-6) by skeletal muscle contraction: inducing several anti-inflammatory effects (↓TNF-α, ↑IL-1RA); (4) ↑ IL-10 release (from regulatory T cells); (5) reduced macrophage infiltration and a switch from M1 to M2 macrophage phenotype; (6) downregulation of Toll-like receptor 4 (TLR4): a receptor that causes inflammatory pathways activation; (7) increasing of antioxidant capacity (thus reducing activity of inflammatory redox-dependent nuclear factors such as NF-κB) (8) increasing HSR (thus HSP70 expression) [71] and decreasing eHSP70/iHSP70 ratio [72]. Tables 1, 2 and 3 summarize some of the anti-inflammatory effects of different exercise training modalities in elderly people.
Table 1

Effects of aerobic exercise on inflammatory/anti-inflammatory factors

Study/reference

Participants

Description of intervention

Biological sample

Main effects

Healthy subjects

 Mejías-Peña [90]

n = 29 (F, M), 69.7 y.o. Healthy subjects

8 wk, 2 d/wk, 25–30 min at 70–75% MHR (with intervals at 90–95% MHR)

Pre and Post.

PBMC

↔ TLR2 and TLR4

 Lee et al. [79]

n = 10 (F), 67 y.o.

Healthy subjects

8 wk, 5 d/wk, 40 min at 40–70% of HRR

Pre and Post.

Not informed

↓ CRP, IL-6, TNF-α

Overweight and obese subjects

 Conroy et al. [28]

n = 320 (F), 61 y.o. Healthy overweight subjects

1 year, 225 min/wk, 5 d/wk at 70–80% HRR

Baseline 6 and 12 months.

Plasma

↔ IL-4, IL‐10

 Conroy et al. [28]

n = 400 (F), 59 y.o. Moderate-volume group (MVG) and high-volume group (HVG).

Healthy overweight subjects

1 year, 5 d/wk at 70–80% HRR

MVG: 150 min/wk

HVG: 300 min/wk

Baseline 6 and 12 months.

Plasma

↔ IL-4, IL-10

 Ogawa et al. [100]

n = 20 (F), 63 y.o.

Healthy active overweight subjects

Observational. Subjects exercised regularly in the last 4 years. 3–5 km/d at 57% VO2peak for 30 min everyday

PBMC.

↑ CD8+/IL-2

↑ CD4/IFN-γ

 Santos et al. [117]

n = 22 (M), 71.27 y.o. Healthy overweight subjects

6 months, 3 d/wk, 60 min at ventilatory aerobic threshold

Pre and Post. Plasma

↓ IL-6, TNF-α, TNF-α/IL-10 ratio,

↑ IL-10,

↔ CPR, IL-1

 Beavers et al. [10]

n = 190 (F, M), 67 y.o. Overweight and obese subjects at risk for cardiovascular disease

18 months, 30 min walking per day, 150 min/wk (Borg = 13)

Pre, 6 and 18 months.

Plasma

↔ hsIL-6, IL-6sr, IL-8, sTNFrI

 Hammett et al. [53]

n = 61 (F, M), 66 y.o. Healthy overweight subjects

6 months, 4 d/wk, 45 min at 80% VO2max

Pre and Post. Serum

↔ CRP

Subjects with different conditions/diseases

 Kohut et al. [68]

n = 48 (F, M), 69.8 y.o. Subjects with prevalent diseases: hypertension, diabetes mellitus, osteoporosis

10 months. 3 d/wk, 45 min at 65–80% VO2max

Pre and Post. Serum

↓ IL-6, IL-18, CRP and TNF-α

 Fairey et al. [43]

n = 53 (F), 59 y.o. Breast cancer survivors

15 wk, 3 d/wk, 15–35 min at 70–75% VO2peak

Pre and Post.

PBMC

↑ NKCA, Unstimulated [3H] thymidine uptake by peripheral blood lymphocyte.

↔ IL-1α, TNF-α, IL-6, IL-4, IL-10, TGF-β1 (unstimulated or phytohemagglutinin -stimulated)

 Ryrso et al. [113]

n = 15 (F, M), 63 y.o. Patients with moderate to severe COPD

8 wk, 3 d/wk, 35 min (Borg = 14–15)

Pre and Post.

Plasma.

Skeletal muscle biopsy

Plasma:

↔ IL-1β, IL-6, IL-8, IL-18, CRP

↑ TNF-α,

Skeletal muscle:

↔ IL-1β, IL-6, IL-8, IL-18, TNF-α

↔ circulating leukocytes

 Karimi et al. [63]

n = 102 (F, M), 54 y.o. Type 2 diabetic patients

25 wk, 3 d/wk, 10–50 min per session, speed was calculated by 20 m distance test

Pre and Post.

Serum

↓ IL-6, COX-2

 Abd El-Kader and Al-Jiffri [1]

n = 40 (F, M), 69 y.o. Alzheimer’s disease patients

2 months, 10–30 min at 60–70% MHR, 3 d/wk

Pre and Post.

Serum

↓ TNF-α, IL-6

 Lima et al. [83]

n = 15 (F, M), 67.8 y.o. Hypertensive subjects.

10 wk, 3 d/wk, 20–30 min at 50–80% HRR

Pre and Post.

Plasma

↓ IL-6

↔ TNF-α

↑: significant increase; ↓: significant decrease; ↔: no significant change; Borg Borg scale of perceived exertion, CD cluster of differentiation, COX-2 cyclooxygenase-2, CRP C-reactive protein, HRR heart rate reserve, hsIL-6 high sensitivity interleukin-6, IL-1 interleukin 1, IL-1α interleukin 1α, IL-1β interleukin 1β, IL-4 interleukin 4, IL-6 interleukin 6, IL-6sr IL-6 soluble receptor, IL-8 interleukin 8, IL-10 interleukin 10, IL-18 interleukin 18, MHR maximum heart rate, NKCA natural killer cell cytotoxic activity, PBMC peripheral blood mononuclear cells, sTNFrI soluble tumor necrosis factor receptor 1, TGF-β1 transforming growth factor beta 1, TLR2 toll-like receptor, TLR4 toll-like receptor 4, TNF-α tumor necrosis factor alpha, y.o. years old

Table 2

Effects of resistance exercise on inflammatory/anti-inflammatory factors

Study/reference

Participants

Description of intervention

Biological sample

Main effects

Healthy subjects

 Shimizu et al. [122]

n = 48 (F, M), 68.5 y.o. Healthy subjects

12 wk, 2 d/wk.

1 × 15–2 × 15 repetitions, 30–40% 1-RM. Plus exercise at home for ≥ 3 d

Pre and Post.

PBMC

↑ CD28+ CD8+

↑ CD80+ CD14+ 

 Ogawa et al. [101]

n = 21 (F), 85 y.o. Healthy subjects

12 wk, ≥ 1 d/wk, 40 min, 1–2 × 10 repetitions

Pre and Post.

Plasma

↔ CRP, HSP70, IL-6, TNF-α, MCP-1, SAA (Serum amyloid A)

 Strandberg et al. [131]

n = 21 (F), 68 y.o. Healthy and physically active subjects

24 wk, 2 d/wk, 8–12 repetitions, 75–85% 1-RM

Pre and Post.

Serum

↔ CRP, IL-6.

 Raso et al. [104]

n = 42 (F), 67.5 y.o. Healthy subjects

12 months, 3 d/wk, 5 exercise, 3 × 12 repetitions, 55% 1-RM

Baseline 6 and 12 months.

Whole blood.

PBMC

Whole Blood:

↔ between the groups or according to the time for quantitative

CD3+ , CD3-CD19+ , CD56+ , CD4+ , CD8+, CD45RA+, CD45RO+, CD56dim, CD56bright, CD95+,CD28+, CD25+, CD69+, HLA-DR+

PBMC:

↔ functional immunological parameters (NKCA, lymphoproliferative response)

Overweight and obese subjects

 Mejias-Pena et al. [89]

n = 26 (F, M), 69.6 y.o. Healthy overweight subjects

8 wk, 2 d/wk, 3 exercises, 3 × 8–12, 60–80% 1-RM

Pre and Post.

PBMC

↓ NLRP3 protein levels.

 Rodriguez-Miguelez et al. [109]

n = 28 (F, M), 70 y.o. Healthy overweight subjects

8 wk, 2 d/wk, 3–4 × 1–2 repetitions. With whole body vibration

Pre and Post.

PBMC

↓ TLR2, TLR4, MyD88, p65, TRIF, HSP60, TNF-α,

↑ HSP70, IL-10 mRNA and proteins

↓ CRP and TNF-α (plasma)

 Tomeleri et al. [135]

n = 51 (F), 70.6 y.o. Healthy overweight subjects

12 wk, 45–50 min/d, 3 d/wk, 3 × 10 repetitions, 10–15 maximum repetitions

Pre and Post.

Plasma

↑ IL-6

↓ TNF-α, IL-6, CRP

 Rodriguez-Miguelez et al. [108]

n = 26 (F, M), 69.5 y.o. Healthy overweight subjects

8 wk, 2 d/wk, 3 exercises, 60–80% 1-RM

Pre and Post.

PBMC

↓ TLR2, TLR4, MyD88, p65, p38 phosphorylated, TRIF, IKKi/IKKε, IRF3, IRF7 phosphorylated, HSP60,

↑ ERK1/2, HSP70, IL-10 mRNA and proteins,

↔ TNF-α mRNA and proteins

↓ CRP

 Bobeuf et al. [13]

n = 29 (F, M) 66.7 y.o. Healthy overweight subjects

6 months, 1 h/d, 8 exercises, 3 d/wk, 3 × 8 repetitions at 80% of 1-RM

Pre and Post.

Plasma

↔ Leukocytes, neutrophils, lymphocytes, monocytes

 Krause [71]

n = 20 (F, M), 63 y.o. Healthy overweight subjects

12 wk, 45–60 min/d, 3 d/wk, 3 × 8–12 repetitions to 4 × 12–14 repetitions

Pre and Post.

Skeletal muscle biopsy

↓ MHC-I

↑ MHC-II

↔ HSF-1, HSP70, KLF15, PGC-1α, IL1-β, CCL2, IGF1 or myostatin

 Tomeleri et al. [134]

n = 38 (F), 68.2 y.o. Obese subjects

8 wk, 3 d/wk, 3 × 10–15 repetition maximum

Pre and Post.

Plasma.

Serum

Plasma:

↓ IL-6, TNF-α,

Serum:

CRP

Subjects with different conditions/diseases

 Martins et al. [88]

n = 45 (F, M), > 64 y.o. Subjects with prevalent diseases: hypertension, diabetes mellitus, angina pectoris

16 wk, 3 d/wk,

8 exercises,

1 × 8 to 3 × 15 repetitions

Baseline, after 16 weeks (post–training for the exercise groups) and at 32 weeks (follow–up). Serum

↓ hs-CRP 11% and 39% at 16 wk and 32 wk (follow up), respectively

 Ryrso et al. [113]

n = 15 (F, M), 63 y.o. Patients with moderate to severe COPD

8 wk, 3 d/wk, 4 exercises, 35 min/d, 4 × 30 s, 30–40% 1-RM

Pre and Post.

Plasma. Skeletal muscle biopsy

Plasma:

↔ IL-1β, IL-6, IL-8, IL-18, TNF-α, CRP

Skeletal muscle:

↔IL-1β, IL-6, IL-8, IL-18, TNF-α

↔ circulating leukocytes

 Miller et al. [91]

n = 36 (F, M), 67.6 y.o. Overweight, type 2 diabetic patients

12 months,

3 d/wk, 45 min/d, 3 × 8–10 repetitions,

6 months of supervised: 75–85% 1-RM.

6 months of home based training: 60% 1-RM

Baseline and subsequent 3–month intervals. Serum

↔ IL-6, IL-10, TNF-α (at 6 month)

↓ TNF-α (at 9 and 12 months)

↓ IL-10 (at 9 month)

 de Lemos Muller [33]

n = 12 (F, M), 68.9 y.o. Type 2 diabetic patients

12 wk, 3 d/wk, 60 min/d, 2–3 × 10–15 maximum repetitions

Pre and Post.

Plasma

↓ TNF-α, TNF-α/IL-10 ratio

↔ IL-10, CRP.

↑: significant increase; ↓: significant decrease; ↔: no significant change; 1-RM one-repetition maximum; CCL2 Chemokine (C–C motif) ligand 2, CD Cluster of Differentiation, CRP C-reactive protein, ERK1/2 extracellular signal-regulated protein kinases 1 and 2, hs-CRP high-sensitivity C-reactive Protein, HSF-1 heat shock transcription factor 1, HSP60 60 kDa heat shock protein, HSP70 70-kDa heat shock proteins, IGF-1 insulin-like growth factor 1, IKKi/IKKε inhibitor of nuclear factor kappa-B kinase subunit epsilon, IL-1β interleukin 1β, IL-6 interleukin 6, IL-8 interleukin 8, IL-10 interleukin 10, IL-18 interleukin 18, IRF3 interferon regulatory factor 3, IRF7 interferon regulatory factor 7, KLF15 Krüppel-like factor, MCP-1 monocyte chemotactic protein-1, MHC-I major histocompatibility complex class I, MHC-II major histocompatibility complex class II, MyD88 myeloid differentiation primary response 88, NKCA natural killer cell cytotoxic activity, NLRP3 Nucleotide-binding oligomerization domain-like receptor pyrin domain-containing-3, p38 p38 mitogen-activated protein kinase, p65 nuclear factor NF-kappa-B p65 subunit, PBMC peripheral blood mononuclear cells, PGC-1α peroxisome proliferator-activated receptor-γ coactivator-1α, TLR2 toll-like receptor 2, TLR4 toll-like receptor 4, TNF-α tumor necrosis factor alpha, TRIF TIR domain-containing adaptor protein inducing interferon, y.o. years old

Table 3

Effects of combined exercise (aerobic and resistance) and high intensity interval training (HIIT) on inflammatory/anti-inflammatory factors

Study/reference

Participants

Description of intervention

Biological sample

Main effects

High intensity interval training (HIIT)

 Overweight and obese subjects

  Allen et al. [6]

n = 55 (F, M) 49.2 y.o. HIIT, PIST (Prolonged intermittent sprint training). Healthy overweight subjects

9 wk, HIIT and PIST 3 d/wk,

HIIT 5–8 × 20–30 s sprints with 3–5 min (passive recovery)

PIST 10–24 × 10 s sprints with 2–3 min (active recovery at 75–80% MHR)

Pre and Post.

Plasma.

Serum

Plasma:

↔ TNF-α,

Serum:

CRP

  Andonian et al. [7]

n = 9 (F, M), 71.4 y.o. Healthy pre-diabetic overweight subjects

10 wk, 3 d/wk, 20 min at 50–90% HRR

Pre and Post. Skeletal muscle biopsy

↔ mIL-1β, mIL-6, mIL-8, mTNF-α, mIL-10

Combined exercise (aerobic and resistance)

 Healthy subjects

  Shimizu et al. [121]

n = 48 (F, M), 68.5 y.o. Healthy subjects

6 months, 5 d/wk, Cardio: 30 min at 80% work rate of the DPBP.

Resistance: Body Weight exercises 3 × 10 repetitions

Pre and Post. Whole blood

↑ CD28+ CD4+ , IFN-γ+ CD4+ and CD4+

↔ leukocytes, lymphocytes, CD3+ and IL-4+ CD4+

  de Gonzalo-Calvo et al. [32]

n = 26 (M), 74 y.o. Healthy subjects

Observational. Subjects trained for at least 60 min per session, 3 d/wk, for the previous 40 years. Still practicing

Serum.

Plasma.

Whole blood

Serum:

↓IL-1ra and sTNFrI

↔ TNF-α, IL-1β

Plasma:

↓IL-6 and IL-10

↑ MCP-1

↔ IL-6sr

Whole blood:

↓ White blood cell, neutrophils

↔ monocytes and lymphocytes

  Lee et al. [79]

n = 9 (F), 67 y.o. Healthy subjects

8 wk,

Cardio: 3 d/wk,

40–70% HRR,

Resistance: 2 d/wk.

Elastic bands 15–20 repetitions (Borg = 10–13)

Pre and Post.

Not informed

↓ CRP, IL-6, TNF-α

 Overweight and obese subjects

  Chagas et al. [22]

n = 70 (F), 60 y.o. Obese subjects

20 wk, 3 d/wk,

Cardio: 50 min at 50–60% VO2peak

Resistance: isometric (4 × 30 s), dynamic (4 × 10 repetitions)

Pre and Post.

Not informed

↔ IL-6

↓ TNF-α

↑ IL-10/IL-6, IL-10/TNF-α

↓ IL-10 (only in control group)

  Pedrinolla et al. [103]

n = 30 (F, M), 70 y.o. Normal weight individuals and overweight/obese individuals

Observational, Individuals exercised regularly: 2 d/wk, Cardio: 2 × 15 min at 70% MHR

Resistance: 3 × 8–12 repetitions at 60–75% 1-RM

Plasma

↑ CRP, IL-6, MCP-1 and TNF-α in overweight/obese group.

 Subjects with different conditions/diseases

  Kohut et al. [68]

n = 49 (F, M), 70.3 y.o. Subjects with prevalent diseases: hypertension, diabetes mellitus, osteoporosis

10 months,

45 min/d, alternative sports and resistance exercise 3 d/wk

Pre and Post.

Serum

↓ TNF-α,

↔ IL-6, IL-18, CRP

  Kapasi et al. [62]

n = 190 (F, M), 87 y.o. Frail subjects

32 wk, cardio and strength, 4 times per day, 5 d/w

Baseline, 8 and 32 wk.

Whole blood.

PBMC

↔ CD28CD8+ CD28CD4+ CD45RO+ CD8+ CD45RO+ CD4+

PBMC:

↔ Proliferative response to phytohemagglutinin.

  Nicklas et al. [96]

n = 183 (F, M), 76.4 y.o. Subjects at risk of disability

54 wk, 3 d/wk. Cardio: 150 min/wk (Borg = 12–13), Resistance: lower extremity exercises, (Borg = 15–16)

Baseline, 6–

12 months.

Plasma

↓ IL-6

↔ CRP

  Beavers et al. [11]

n = 182 (F, M), 76.4 y.o. Subjects at risk of disability

54 wk, 3 d/wk. Cardio: 150 min/wk (Borg = 12–13), Resistance: lower extremity exercises, (Borg = 15–16), balance and flexibility

Baseline, 6–12 months.

Plasma

↓ IL-8,

↔ IL-6sR, IL-1sRII, sTNFrI, sTNFrII, IL-15, IL-1ra, IL-2srα, and TNF-α

  Annibalini et al. [8]

n = 16 (M), 57 y.o. Type 2 diabetic patients

16 wk, 3 d/wk,

Cardio: 40–65% HRR, 30–60 min

Resistance: 2–4 × 20–12 repetitions at 40–60% 1-RM

Pre and Post.

Plasma.

PBMC

Plasma:

↔ hs-CRP

↓ IL-6, MCP-1, TNF-α

PBMC:

↓ IL-6 mRNA

↔ TNF-α mRNA

  Dos Anjos et al. [40]

n = 43, 69.9 y.o. Type 2 diabetic patients

10 wk, 3 d/wk, walking and calisthenics exercises, 50 min/d at 65–80% MHR

Pre and Post.

Plasma

↔ sTNFrI, sTNFrII, IL-6, IL-10.

  da Silva et al. [30]

n = 13 (F, M), 68.5 y.o. Chronic obstructive pulmonary disease individuals

8 wk, 90 min/d,

Endurance: 60% of the speed average of the six-minute walking test.

Resistance: Upper and lower limbs exercises

Pre and Post.

Plasma

↓ IL-6,IL-8

↔ IL-4, IFN-γ, TGF-β.

  Hojan et al. [54]

n = 72 (M), 66.23 y.o. Men with high and intermediate risk of prostate cancer

12 months,

During Radiation Therapy (5 d/wk):

Cardio: 30 min at 65–70% MHR

Resistance: 2 × 8 repetitions at 70–75% 1-RM,

After Radiation Therapy (3 d/wk):

Cardio: 40 min at 70–80% of HRR

Resistance: similar exercise program

Baseline, after radiation therapy (8 wk), after 10 months.

Serum

↔ IL-1β, TNF-α, IL-6.

  Lima et al. [83]

n = 15 (F, M), 67.8 y.o. Hypertensive subjects

10 wk, 3 d/wk,

Resistance: 1–2 × 15–20 repetitions at 50–60% 1-RM

Cardio: 20–30 min at 50–80% HRR

Pre and Post.

Plasma

↔ IL-6,

↓ TNF-α

  Leehey et al. [80]

n = 36 (M), 66 y.o. Type 2 diabetes mellitus, obese and chronic kidney disease patients

52 wk (12 at the lab and 40 of home exercise)

Lab: 12 wk, 3 d/wk, 30–60 min/d at 25–84% VO2peak

(interval training and elastic bands, hand-held weights

or weight machine exercises),

Home: 40 wk, 60 min 3 d/wk or 30 min 6 d/wk

Pre and Post.

Serum

↔ CRP

↑ significant increase, ↓ significant decrease, ↔ no significant change, 1-RM one-repetition maximum, Borg borg scale of perceived exertion, CD cluster of differentiation, CRP C-reactive protein, DPBP double-product break-point., hs-CRP high-sensitivity C-reactive protein, IFN-γ interferon gamma, IL-1β interleukin 1β, IL-1ra interleukin-1 receptor antagonist, IL-1srII interleukin-1 soluble receptor II, IL-2srα interleukin-2 soluble receptor α, IL-4 interleukin 4, IL-6 interleukin 6, IL-6sr interleukin 6 soluble receptor, IL-8 interleukin 8, IL-10 interleukin 10, IL-15 Interleukin 15, IL-18 interleukin 18, MCP-1 monocyte chemotactic protein-1, PBMC peripheral blood mononuclear cells, sTNFrI soluble tumor necrosis factor receptor 1, sTNFrII soluble tumor necrosis factor receptor 2, TGF-β transforming growth factor beta, TNF-α tumor necrosis factor alpha, y.o. years old

Resistance Exercise Training (RT) to Restore the Heat Shock Response and the Inflammatory Status

Considering the importance of HSR to proteostasis and inflammatory control, the accurate assessment of this response is an essential tool. There are several technical ways to test HSR in biological samples. The majority of the research performed in order to access if a particular intervention (such as exercise) is able to increase HSR, is through the quantification of gene and/or protein levels of factors involved (or their products) in this pathway, such as HSF1, SIRT1, HSP72, and other chaperones, before and after the intervention. However, by using this strategy, only baseline levels can be measured, sometimes, causing divergent results. For this reason, we use an “stress test” to determine the real chaperone machinery capacity of the cells to express HSP72 (and release, in the case of peripheral blood mononuclear cells) in response to a heat challenge [33].

For example, in our laboratory, we use human peripheral blood mononuclear cells (PBMC, a major source of circulating HSP72 and representative of immune cell stress response) as a model to test HSR in our patients. These cells, in normal and optimal conditions, are able to express and release HSP72, under heat stress conditions. Briefly, after harvesting, whole blood is immediately incubated at two different temperatures: 37 °C (control) and 42 °C (heat stressed) for 2 h in water bath (with gentle mix every 15 min). After the incubation, total blood is centrifuged to obtain plasma/serum and PBMC through density gradient separation, as previously described [31, 45]. Then, plasma can be used for the direct analysis of extracellular HSP72 while PBMC can be prepared for the measurement of iHSP72. The PMBC were washed and treated to ensure the absence of erythrocytes. PBMC were resuspended in RPMI 1640 medium (pH 7.4 supplemented with 2% NaHCO3, 10% bovine calf serum, 100 U/mL penicillin and 100 µg/mL streptomycin), seeded in a 24-well flat bottom plate (1 × 106 cells/well) and placed in an incubator for 6 h (37 °C in 5% CO2), in order to recover from the HS and reach the peak of HSP70 expression. Cells were then removed from the incubator, appropriated lysed and the total proteins were prepared for western Blot analysis. The difference between concentration at 37 °C and 42 °C is used as HSR index.

Our group was specifically working with the hypothesis that aging alone could cause an impairment of HSR. Thus, elderly people would have a lower HSR index. To test this hypothesis we recruited three groups of people: healthy middle-aged, healthy elderly and diabetic elderly people. The full data has been published elsewhere [33]. Briefly, to our surprise, HSR is not compromised in older people, as long as they maintain their insulin sensitivity in  an acceptable range. In fact, only in diabetic older people that this response is diminished, indicating that insulin sensitivity, rather than age alone, is the cause of lower HSR.

Considering the lower HSR found in the diabetic elderly group, we submit them to a 12 weeks resistance training (RT) program. Our RT intervention consisted of a combination of upper and lower body exercises using gym equipments, free weights and body weight as the primary resistance (supervised, three non-consecutive days of the week, ~ 60 min of duration) [33]. What we found was that RT improved the HSR and reduced inflammation [measured by TNF-α and TNF-α/IL-10 ratio). This data indicates that RT is an efficient intervention to restore the HSR and reduce inflammation, even without causing any perceptive change over metabolic parameters, at least during the 12 weeks of intervention. This result is an important finding since restoration of HSR may delay the appearance and the establishment of inflammatory-related conditions such as aging, diabetes, cardiovascular, neurodegenerative diseases and others. We also found that HSR was inversely correlated with the amount of visceral adipose tissue, confirming that adipose tissue expansion has a direct influence on the HSR [70, 72, 94].

Another type of intervention with potential benefits to improve HSR in elderly people is a combination of RT along with protein supplementation, as we recently suggested [71]. In this study we submited healthy elderly people to a 12-weeks intervention, allocated in one of the four groups: (1) Placebo: no training, receiving placebo sachets; (2) Nutrition: no training, receiving protein supplementation sachets; (3) Exercise placebo: training, placebo sachets and (4) Exercise nutrition: training, receiving protein sachets. The full data and detailed methodology can be found elsewhere [71]. We found that participants from both exercise groups increased their total lean body mass and improved results in physical tests. However, only the exercise nutrition group increased the expression of proteins involved in the HSR (HSF1 and HSP70) and protein synthesis cascade, along with reductions in catabolic pathways.

As we previously indicated, HSR interacts with inflammatory, anabolic and catabolic signalling pathways. The additional improvement promoted by a combination of exercise and protein supplementation may be explained through the activation of HSR by the increased levels of key regulatory amino acids, such as glutamine. Glutamine can improve HSR by enhancing HSF1 activation due to the activation of the hexosamine biosynthetic pathway (HBP) [59]. The final product of HBP (UDP-N-acetylglucosamine) is known to inhibit GSK-3β activity, an enzyme that constitutively inhibits HSF1 activation [52, 64, 127]. Therefore, glutamine-mediated increase of HBP may result in inhibition of GSK-3β, allowing HSF1 activation and, finally, enhanced HSP70 expression.

Considering that lower HSR is associated with the development of metabolic, cardiovascular and neurological diseases [72, 110], our findings suggest that resistance exercise along with increased protein intake can ameliorate the HS response, reducing the appearance of aging-associated diseases and also being beneficial for their treatment/management.

Conclusions and Perspectives

Inflammaging is a complex process induced by several changes that include body composition modifications, immunosenescence, autophagy and loss of proteostasis. Failure of HSR may lead to a pro-inflammatory profile that is spread to all cells and tissues. HSR (thus HSP70) plays a key role in the resolution of inflammation, and its maintenance can be reached by physical exercise and perhaps, a combination of exercise and protein supplementation. HSR can be easily tested in different populations and its assessment should be encouraged among exercise scientists.

Notes

Acknowledegments

We thank the Federal University of Rio Grande do Sul (UFRGS), Department of Physiology and the School of Physical Education of UFRGS, for supporting this work.

Funding

This work was supported by FAPERGS and CNPq. Mauricio Krause received grant support from FAPERGS (Edital FAPERGS/Decit/SCTIE/MS/CNPq/SESRS n. 03/2017-PPSUS #17/2551-0001424-3).

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Copyright information

© Beijing Sport University 2019

Authors and Affiliations

  • Carlos Henrique de Lemos Muller
    • 1
  • Jorge Roberto de Matos
    • 1
  • Gisele Bettú Grigolo
    • 1
  • Helena Trevisan Schroeder
    • 1
  • Josianne Rodrigues-Krause
    • 2
  • Mauricio Krause
    • 1
    Email author
  1. 1.Laboratory of Inflammation, Metabolism and Exercise Research (LAPIMEX) and Laboratory of Cellular Physiology, Department of Physiology, Institute of Basic Health SciencesFederal University of Rio Grande do SulPorto-AlegreBrazil
  2. 2.School of Physical Education, Physiotherapy and DanceFederal University of Rio Grande do SulPorto AlegreBrazil

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