Exercise-induced effects on inflammatory markers and brain-derived neurotrophic factor in patients with knee osteoarthritis. A systematic review with meta-analysis.

Background: In the pathogenesis of knee osteoarthritis (KOA), inflammatory mediators play an important role. However, the precise underlying mechanism by which regular exercise therapy (ET) exert effects on the immune system in KOA patients is unknown. Objectives: The aim of this systematic review was to investigate the basal and acute effects of ET on inflammatory biomarkers and brain derived neurotrophic factor (BDNF) in KOA patients. Methods: PubMed, Web Of Science and PEDro were systematically searched for appropriate studies. If possible, a meta-analysis was performed or an approximation of the effect size (ES) was calculated. Risk of bias was scored using the Cochrane ROB 2.0 or ROBINS-tools. Results: Twenty-one studies involving 1374 participants were included. Fifteen articles focused on basal exercise effects, four on acute effects, and two on both. Biomarker analysis (n=18) was performed in synovial fluid (n=4) or serum/plasma (n=17). A meta-analysis demonstrated that basal CRP was reduced in KOA patients 6-18 weeks weeks after ET (MD: -0.17;95%CI[-0.31;-0.03]), while IL-6 (MD: 0.21;95%CI[-0.44;0.85]), and TNF-α (MD: -0.57;95%CI[-1.47;0.32]), levels did not significantly change. Also, sTNFR1/2 did not change significantly after ET. For other biomarkers, insufficient data were available to perform a meta-analysis. Nevertheless, a low degree of evidence was found for a decrease in IL-6 (ES:-0.596 & -0.259 & -0.513), an increase in sTNFR1 (ES:2.325), a decrease in sTNFR2 (ES:-0.997) and an increase in BDNF (ES:1.412). Locally, intra-articular IL-10 (ES:9.163) increased, and IL1ß (ES:-6.199) and TNF-α decreased (ES:-2.322) after ET. An acute exercise session elicited a myokine response (ES IL-6:0.314), and an increase in BDNF (no ES-data). No inflammatory effect (ES CRP:0.052; ES TNF-α:-0.019 & 0.081) following an acute bout of training was found. However, a single bout of exercise elicited a decrease in intra-articular IL-10 (no ES-data). Conclusion: ET can induce circulatory and intra-articular anti-inflammatory effects in patients with KOA. The antiinflammatory properties have important implications for informing these patients and clinicians about the underlying effects of ET.

The effect of resistance exercise on the immune cell function in humans: A systematic review.

BACKGROUND: Resistance exercise is beneficial for the immune system, including decreased susceptibility to infections and improved effectiveness of vaccinations. This review aims to provide a systematic analysis of the literature regarding the impact of resistance exercise on immune cells in the blood circulation. MATERIALS AND METHODS: The protocol of this review followed the PRISMA guidelines and registered in PROSPERO (ID: CRD42020157834). PubMed and Web-of-Science were systematically searched for relevant articles. Outcomes were divided into two categories: 1) inflammatory gene expression or secretion of inflammation-related cytokines and 2) other aspects such as cell migration, proliferation, apoptosis, phagocytosis, and redox status. RESULTS: Thirty intervention studies were included in this review, of which 11 articles were randomized controlled trials and six non-randomized controlled trials. Although only resistance exercise interventions were included, there was a high heterogeneity regarding specific exercise modalities. The most frequently studied outcome measures were the gene and protein expression levels in peripheral blood mononuclear cells (PBMC). This review reveals that already one acute exercise bout activates the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway in PBMC. Although resistance exercise induces an acute cytosolic oxidative stress response, the antioxidant enzyme expression is improved after resistance training period. Natural killer cell activity increases in older but decreases in younger adults immediately after a resistance exercise bout. Moreover, resistance exercise improves neutrophil phagocytic activity. Finally, effects on lymphocyte proliferation remain unclear. CONCLUSIONS: The results of this systematic review demonstrate that resistance exercise has beneficial effects on several aspects of immune cell function both in young and older individuals. Acute changes in immune cell function occur already after a single bout of resistance exercise. However, regular resistance training during several weeks seems necessary to obtain beneficial adaptations that can be related to better immunity and reduced inflammation. The effects documented in this review confirm the beneficial effects of resistance exercise in young as well as older persons on the immune cell function.

Three Months of Strength Training Changes the Gene Expression of Inflammation-Related Genes in PBMC of Older Women: A Randomized Controlled Trial.

Here, we investigate changes in inflammation-related gene-expression in peripheral mononuclear blood cells (PBMC) by strength training. A total of 14 women aged ≥65 years were randomized into 3 months of either 3×/week intensive strength training (IST: 3×10 rep at 80% 1RM), strength endurance training (SET: 2×30 reps at 40% 1RM) or control (CON: 3×30 sec stretching). Differentially expressed genes (fold change ≤0.67 or ≥1.5) were identified by targeted RNA-sequencing of 407 inflammation-related genes. A total of 98 genes (n = 61 pro-inflammatory) were significantly affected. IST and SET altered 14 genes in a similar direction and 19 genes in the opposite direction. Compared to CON, IST changed the expression of 6 genes in the same direction, and 17 genes in the SET. Likewise, 18 and 13 genes were oppositely expressed for, respectively, IST and SET compared to CON. Changes in gene expression affected 33 canonical pathways related to chronic inflammation. None of the altered pathways overlapped between IST and SET. Liver X Receptor/Retinoid X Receptor Activation (LXR/RXR) and Triggering Receptor Expressed On Myeloid Cells 1 (TREM1) pathways were enriched oppositely in both training groups. We conclude that three months IST and SET can induce changes in CLIP-related gene expression in PBMC, but by affecting different genes and related pathways.

Systematic review on the effects of physical exercise on cellular immunosenescence-related markers - An update.

Immunosenescence is a remodeling of the immune system occurring with aging that leads to an increased susceptibility to auto-immunity, infections and reduced vaccination response. A growing consensus supports the view that physical exercise may counteract immunosenescence and improve the immune response. Unfortunately, evidence regarding the effects of exercise on markers of cellular immunosenescence lacked uniformity at the time of an extensive literature review in 2016. Moreover, exercise-induced effects in older adults were underrepresented compared to young adults or completely lacking, such as for senescent T-cells and apoptosis of T-lymphocytes. The aim of this systematic literature study was to collect and appraise newly available data regarding exercise-induced changes on immunosenescence-related markers of immune cells and compare this against data that was already available in 2016. Systematic reviewing of newly available data in the field of exercise immunology provides additional evidence for the effect of exercise on immunosenescence-related cellular markers. Importantly, this review provides evidence for the effect of long-term exercise on senescent T-lymphocytes in older adults. Additionally, newly retrieved evidence shows an acute exercise-induced mobilization of naïve and memory cells in older adults. In general, data regarding long-term exercise-induced effects in older adults remain scarce. Noteworthy was the high number of articles describing exercise-induced effects on regulatory T-cells. However exercise-induced effects on this cell type are still inconclusive as some articles reported an exercise-induced up- or downregulation, while others reported no effects at all. Numerous studies on Natural Killer cell counts did not provide uniformity among data that was already available. Recent data regarding dendritic cells mostly described an increase after exercise. Overall, our literature update highlights the major influence of the type and intensity of exercise on immunosenescence-related markers, especially in older adults.

Effect of Antihypertensive and Statin Medication Use on Muscle Performance in Community-Dwelling Older Adults Performing Strength Training.

OBJECTIVES: Antihypertensive drugs (AHTD) and statins have been shown to have effects beyond their primarily designed purpose; here we investigate their possible effect on muscle performance and strength in older adults following a physical exercise programme. DESIGN: The Senior PRoject INtensive Training (SPRINT) study is a randomised, controlled clinical trial designed to evaluate the effects of physical exercise on the immune system and muscle performance in older adults. PARTICIPANTS: In this secondary analysis, we included 179 independent participants (aged 65 years and above). We applied further categorisation based on medication use: AHTD (including, angiotensin-converting enzyme inhibitors [ACEI], angiotensin II receptor blockers [ARB], ß-blockers, and other AHTD) and statins. INTERVENTION: Participants were allocated randomly to one of the three exercise protocols: intensive strength training 3 times/week (3 × 10 repetitions at 80% of one-repetition maximum), strength endurance training (2 × 30 repetitions at 40% of one-repetition maximum), or control (passive stretching exercise) for 6 weeks. MEASUREMENTS: The change in maximal hand grip strength (GS), muscle fatigue resistance (FR), Muscle Strength Index (MSI), the 6-min walk test (6MWT), and Timed Up and Go Test (TUG) were assessed before and after 6 weeks of training. RESULTS: After 6 weeks, muscle strength (MSI and TUG) improved significantly in all training groups compared to baseline, independently of AHTD use. Moreover, AHTD had no effect on exercise improvements, with no significant differences between medication groups, except for TUG in ARB users, which exhibited a significantly lower performance. On the other hand, statin users presented a significantly longer FR time, indicating better performance compared to non-users. Finally, medication did not affect the participants' commitment to the training programme. CONCLUSION: Our study showed that statins and ARB usage might affect participant's response to strength training. Nevertheless, 6 weeks of training significantly improved muscle strength and performance irrespective of AHTD or statin use.

The effects of exercise interventions on the inflammatory profile of older adults: A systematic review of the recent literature.

INTRODUCTION: Inflammageing - characterized by age-related chronic low-grade inflammation is considered to be positively influenced by physical exercises. The aim of this systematic review is to provide an update of the most recent literature regarding exercise effects on the inflammatory profile in older adults. METHODS: This review is an update of an earlier published literature review and was performed according to the NICE guidelines. Databases PubMed and Web-of-Science were systematically searched by two independent authors screening for papers published since 2016. Effect sizes of outcome parameters related to the inflammatory profile were calculated where possible. RESULTS & DISCUSSION: Twenty-three articles were included. Resistance training (RT) was the most investigated type of exercise (13 articles: 8 in healthy, 1 in frail and 4 in older adults with a specific condition or disease). Aerobic training (AT) was investigated in 8 articles, including 5 studies in older adults with a specific disease or condition. Combined resistance & aerobic training (CT) was investigated in 7 articles: 3 were in healthy, 1 in frail and 3 in older adults with a specific condition or disease. 1 study investigated the effects of Tai Chi in older adults with mild cognitive impairment. In frail older subjects, IGF-1 - sole marker investigated - significantly increased after 8 weeks RT and CT, whereas AT showed no significant effects compared to control. Most consistent exercise effects consisted in lowering of circulating levels of CRP, IL-6 and TNF-α; which seemed more prominent in healthy older adults compared to those with a specific disease or condition. None of the studies reported an exacerbation of inflammation following exercise and all studied exercise protocols were feasible and safe for older adults. CONCLUSIONS: Overall, significant anti-inflammatory effects of exercise in older persons were reported. Literature remains extremely scarce regarding the exercise-induced effects in frail older persons. Therefore, there is an urgent need for more studies focusing on the frail elderly. There is growing literature data on exercise interventions in older adults with a specific condition or disease; however, it appears more challenging to reduce inflammageing through exercise in these specific patient groups. Importantly, the exercise interventions performed in all studies appeared to be feasible and safe for older patients, thus the presence of a specific condition or disease should not be considered as a contra-indication to perform physical exercise.

Six weeks of strength endurance training decreases circulating senescence-prone T-lymphocytes in cytomegalovirus seropositive but not seronegative older women.

BACKGROUND: Ageing is associated with a decline in immune function termed immunosenescence. This process is characterized amongst others by less naive T-cells and more senescent phenotypes, which have been implicated in the pathogenesis of many age-related diseases. Thus far, reports regarding the long-term adaptation effects of exercise on T-cell phenotypes are scant and largely equivocal. These inconsistencies may be due to potential contributors to immunosenescence, particularly cytomegalovirus infection, which is considered a hallmark of T-cell senescence. Therefore, we sought to investigate the impact of cytomegalovirus serostatus on the distribution of peripheral T-cell subsets following long-term exercise in older women. METHODS: One hundred women (aged 65 years and above) were randomized to 3 times/weekly training at either intensive strength training (3 × 10 repetitions at 80% of one-repetition maximum, n = 31), strength endurance training (2 × 30 repetitions at 40% of one-repetition maximum, n = 33), or control (passive stretching exercise, n = 36) for 6 weeks. All training sessions were supervised by trained instructors to minimize the risk of injury and to ensure that the participants adhered to the training protocol throughout the entire range of motion. The T-cell percentages and absolute blood counts were determined before and after 6 weeks (24 h-48 h after the last training session) using flow cytometry and a haematology analyser. Cytomegalovirus antibodies were measured in serum using Architect iSystem and cytomegalovirus serostatus was balanced in the three intervention groups. C-reactive protein was measured using immunonephelometry. RESULTS: We report for the first time that 6 weeks of strength endurance training significantly decreased senescence-prone T-cells along with a small increase in the number of CD8- naive T-cells in blood. The absolute counts of senescent-like T-cells decreased by 44% (from 26.03 ± 35.27 to 14.66 ± 21.36 cells/µL, p < 0.01) and by 51% (from 6.55 ± 12.37 to 3.18 ± 6.83 cells/µL, p < 0.05) for the CD8+ and CD8- T-cell pools, respectively. Intriguingly, these changes were observed in cytomegalovirus seropositive, but not cytomegalovirus seronegative individuals. CONCLUSIONS: In conclusion, the present study shows that strength endurance training leads to a reduction in circulating senescence-prone T-cells in cytomegalovirus seropositive older women. It remains to be established if monitoring of peripheral senescence-prone T-cells may have utility as cellular biomarkers of immunosenescence.

Thirteen weeks of supplementation of vitamin D and leucine-enriched whey protein nutritional supplement attenuates chronic low-grade inflammation in sarcopenic older adults: the PROVIDE study.

BACKGROUND: A chronic low-grade inflammatory profile (CLIP) is associated with sarcopenia in older adults. Protein and Vitamin (Vit)D have immune-modulatory potential, but evidence for effects of nutritional supplementation on CLIP is limited. AIM: To investigate whether 13 weeks of nutritional supplementation of VitD and leucine-enriched whey protein affected CLIP in subjects enrolled in the PROVIDE-study, as a secondary analysis. METHODS: Sarcopenic adults (low skeletal muscle mass) aged ≥ 65 years with mobility limitations (Short Physical Performance Battery 4-9) and a body mass index of 20-30 kg/m2 were randomly allocated to two daily servings of active (n = 137, including 20 g of whey protein, 3 g of leucine and 800 IU VitD) or isocaloric control product (n = 151) for a double-blind period of 13 weeks. At baseline and after 13 weeks, circulating interleukin (IL)-8, IL-1 receptor antagonist (RA), soluble tumor-necrosis-factor receptor (sTNFR)1, IL-6, high-sensitivity C-reactive protein, pre-albumin and 25-hydroxyvitamin(OH)D were measured. Data-analysis included repeated measures analysis of covariance (corrected for dietary VitD intake) and linear regression. RESULTS: IL-6 and IL-1Ra serum levels showed overall increases after 13 weeks (p = 0.006 and p < 0.001, respectively). For IL-6 a significant time × treatment interaction (p = 0.046) was observed, with no significant change over time in the active group (p = 0.155) compared to control (significant increase p = 0.012). IL-8 showed an overall significant decrease (p = 0.03). The change in pre-albumin was a significant predictor for changes in IL-6 after 13 weeks. CONCLUSIONS: We conclude that 13 weeks of nutritional supplementation with VitD and leucine-enriched whey protein may attenuate the progression of CLIP in older sarcopenic persons with mobility limitations.

Strength Endurance Training but Not Intensive Strength Training Reduces Senescence-Prone T Cells in Peripheral Blood in Community-Dwelling Elderly Women.

Aging is characterized by a progressive decline in immune function known as immunosenescence. Although the causes of immunosenescence are likely to be multifactorial, an age-associated accumulation of senescent T cells and decreased naive T-cell repertoire are key contributors to the phenomenon. On the other hand, there is a growing consensus that physical exercise may improve immune response in aging. However, the optimum training modality required to obtain beneficial adaptations in older subjects is lacking. Therefore, we aimed to investigate the effects of exercise modality on T-cell phenotypes in older women. A total of 100 women (aged ≥ 65 years) were randomized to either intensive strength training (80% of one-repetition maximum ), strength endurance training (40% one-repetition maximum), or control (stretching exercise) for 2-3 times per week during 6 weeks. The T-cell percentages and absolute counts were determined using flow cytometry and a hematology analyzer. C-reactive protein was measured using immunonephelometry. We report for the first time that 6 weeks of strength endurance training significantly decreased the basal percentage and absolute counts of senescence-prone T cells, which was positively related to the number of training sessions performed. Conceivably, training protocols with many repetitions-at a sufficiently high external resistance-might assist the reduction of senescence-prone T cells in older women.

The effect of nicotine patches on craving in the brain: A functional MRI study on heavy smokers.

BACKGROUND: Smoking is a common phenomenon and kills over 6 million people every year. Many smokers try to quit smoking by using nicotine replacement therapy (NRT). Most of the time, relapse occurs in less than six months after finishing the program of NRT. We performed a single blinded study in which our aim was to figure out what the effect of the nicotine patch is on craving in the brain of smokers deprived from smoking. METHODS: Five heavy smokers (Fagerström Test for Nicotine Dependence ≥4) underwent a functional magnetic resonance imaging (fMRI) in 4 random conditions: smoking (S); smoking deprivation (SD); SD combined with a NP (SD + NP); SD combined with a placebo patch (SD + PP). Visual stimulation provoked craving in block design by randomly displaying images of smoking related scenes. After image preprocessing, a fixed-effect analysis was performed to compare average group activations. The Questionnaire for Smoking Urges (QSU) was obtained before and after each scan. RESULTS: The fMRI results showed higher activation in areas involved in craving in S compared with SD + NP, SD + PP, and SD. In the SD + NP, limbic circuit and attention area were higher activated compared with SD and SD + PP. The SD + PP and SD showed higher activation in the frontal cortex and limbic system compared with S and SD + NP. Nonsmokers showed higher limbic activation compared with SD.The QSU increased significantly after the fMRI experiment in S (P = .036).The SD had higher QSU scores compared with the S before (P = .002), and also after (P = .022) the fMRI experiment. The NP showed lower scores than the SD before the experiment (P = .046). CONCLUSION: The fMRI experiment revealed lower activity in areas associated with attention when subjects were nicotine deprived (SD + PP and SD). Areas involved with craving showed less activity when nicotine is present (S and SD + NP). The QSU showed a significant difference between SD and when nicotine is present (S and SD + NP).

The effects of exercise on muscle strength, body composition, physical functioning and the inflammatory profile of older adults: a systematic review.

PURPOSE OF REVIEW: This systematic review reports the most recent literature regarding the effects of physical exercise on muscle strength, body composition, physical functioning and inflammation in older adults. All articles were assessed for methodological quality and where possible effect size was calculated. RECENT FINDINGS: Thirty-four articles were included - four involving frail, 24 healthy and five older adults with a specific disease. One reported on both frail and nonfrail patients. Several types of exercise were used: resistance training, aerobic training, combined resistance training and aerobic training and others. In frail older persons, moderate-to-large beneficial exercise effects were noted on inflammation, muscle strength and physical functioning. In healthy older persons, effects of resistance training (most frequently investigated) on inflammation or muscle strength can be influenced by the exercise modalities (intensity and rest interval between sets). Muscle strength seemed the most frequently used outcome measure, with moderate-to-large effects obtained regardless the exercise intervention studied. Similar effects were found in patients with specific diseases. SUMMARY: Exercise has moderate-to-large effects on muscle strength, body composition, physical functioning and inflammation in older adults. Future studies should focus on the influence of specific exercise modalities and target the frail population more.