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.

Association Between Immunosenescence Phenotypes and Pre-frailty in Older Subjects: Does Cytomegalovirus Play a Role?

Frailty is highly prevalent in old age and confers an important mortality risk. Although the causes of frailty are multiple, immunosenescence (IS)-predominantly driven by cytomegalovirus (CMV)-has been implicated in its pathophysiology. Thus far, research examining the association between IS and frailty states is sparse and equivocal. On the other hand, evidence is mounting in support of the view that frailty can be reversed, especially for those in the pre-frail stage. Therefore, we aimed to clarify the impact of CMV on IS and its relevance to pre-frailty. One hundred seventy-three persons aged 80 to 99 years were enrolled. Pre-frailty was defined according to Fried's criteria. Anti-CMV IgG and serum IL-6 were measured using Architect iSystem and Luminex, respectively. T-cell phenotypes were determined using flow cytometry. The prevalence of pre-frailty was 52.6%, increased with age (p = .001), and was greater in men than women (p = .044). No relationship was found between pre-frailty and positive CMV serology. Further, CMV-seropositivity was significantly associated with less naïve cells, more memory and senescence-prone phenotypes (all p < .001). After adjusting for potential confounders, only IL-6, age and sex were predictive of pre-frailty. We conclude that the presence of pre-frailty is independent from CMV infection in very old subjects.

Sex difference in the heat shock response to high external load resistance training in older humans.

BACKGROUND: Literature reports on the effects of resistance training on heat shock protein70 (Hsp70) adaptation in older subjects are scarce. Moreover, the optimum training load required to obtain a beneficial adaptation profile is lacking. Therefore, the aim of this study was to determine the effects of resistance training at various external loads on extracellular Hsp70 (eHsp70) resting levels in older humans. METHODS: Fifty-six community-dwelling older (68±5years) volunteers were randomized to 12weeks of resistance training (3×/week) at either high-resistance (HIGH, 8 males, 10 females, 2×10-15 repetitions at 80% 1RM), low resistance (LOW, 9 Males, 10 Females, 1×80-100 repetitions at 20% 1RM), or mixed low resistance (LOW+, 9 Males, 10 Females, 1×60 repetitions at 20% 1RM followed by 1×10-20 repetitions at 40% 1RM). Serum was available from 48 out of the 56 participants at baseline and after 12weeks for determination of eHsp70. Mid-thigh muscle volume (computed tomography), muscle strength (1RM & Biodex dynamometer) and physical functioning (including 6min walk distance [6MWD]) were assessed. RESULTS: There was a sex-related dichotomy in the heat shock response to high external load training. We observed a significant decrease in eHsp70 concentration in the HIGH group for female, but not male, subjects. At baseline, men had a larger muscle volume, leg press and leg extension 1RM compared to women (all p<0.001). Also, the 6MWD was significantly higher in men compared to women at baseline. However, this difference disappeared when correcting for height. Moreover, the overall functional performance and physical activity scores were similar in men and women. None of the participants' characteristics nor any of the outcome variables differed between groups at baseline. There was a significant increase in the strength and physical performance parameters in both men and women post-exercise (all p<0.05). Females in the HIGH group clearly demonstrated a larger gain in leg press 1RM and the isometric knee extensor strength compared to females in the LOW group (p=0.036 and p=0.044, respectively). More so, we found an inverse association between the change in eHsp70 levels and improvement in isometric knee extensor strength and 6MWD (r=-0.443, p=0.002 and r=-0.428, p=0.002; respectively) post exercise. CONCLUSIONS: Our results show that resistance training at high external load decreases the resting levels of eHsp70 in older females. Whether this reflects a better health status requires further investigation.

Effects of resistance training at different loads on inflammatory markers in young adults.

PURPOSE: Suppressing inflammaging at an early stage in life via exercise might prevent chronic diseases later in life. The aim was to investigate the influence of resistance training at different external loads on inflammatory markers in healthy young adults. METHODS: Serum was collected for basal levels of cytokines (IL-1beta, IL-6, IL-8, sTNFR1, IL-1RA, IL-10 and GM-CSF) before and after 9 weeks exercise from 36 young (22 ± 2 years) healthy subjects who were randomized to three times weekly supervised resistance training at either HImax (n = 12, 1 × 10-12 repetitions at 80% 1RM), LO (n = 12, 1 × 10-12 repetitions at 40% 1RM), or LOmax (n = 12, 1 × 10-12 repetitions at 40% 1RM preceded by 60 repetitions at 20-25% 1RM) respectively. RESULTS: Overall, IL-8 increased (p < 0.001) and IL-6 decreased (p = 0.001) after training, but no significant time*group interaction was found (respectively, p = 0.283 and p = 0.058 for IL-8 and IL-6). When analyzed separately, IL-8 increased significantly in HImax (p = 0.022) and LOmax (p = 0.024); and IL-6 decreased significantly in LOmax (p = 0.009) and LO (p = 0.013). No significant overall time effect was observed for sTNFR1 and IL-1RA; however, in HImax sTNFR1 (p = 0.031) and IL-1RA (p = 0.014) increased significantly, but remained unchanged in LOmax and LO. IL-1beta, IL-10 and GM-CSF levels remained undetectable in most participants. CONCLUSIONS: Nine weeks of resistance training-irrespective of the external load-have beneficial effects on circulating IL-8 and IL-6. In addition, training at high external load increases the anti-inflammatory cytokines sTNFR1 and IL-1RA. The results of this study show that resistance training has anti-inflammatory effects in healthy young persons and that the response of the different inflammatory mediators depends on the magnitude of the external load.

Load-Specific Inflammation Mediating Effects of Resistance Training in Older Persons.

BACKGROUND: Little is known about the effects of resistance training (RT) on circulating cytokines in older adults. Also, dose-response relationships remain unclear. This study investigated the impact of RT at different external loads on circulating inflammatory mediators in older community-dwelling individuals. METHODS: Fifty-six community-dwelling older (68 ± 5 years) volunteers were randomized to 12 weeks of supervised RT (×3/week) at either high-resistance training [8 males, 10 females, 2 × 10-15 repetitions at 80% 1 repetition maximum (RM)], low-resistance training (9 males, 10 females, 1 × 80-100 repetitions at 20% 1 RM), or mixed low-resistance training (9 males, 10 females, 1 × 60 repetitions at 20% 1 RM followed by 1 × 10-20 repetitions at 40% 1 RM). Serum was available from 51 out of 56 participants at baseline and after 12 weeks for determination of interleukin (IL)-6, IL-8, IL-10, IL-1ß, soluble tumor necrosis factor receptor (sTNFR)1, granulocyte macrophage colony-stimulating factor, and IL-1 receptor antagonist (ra). RESULTS: Twelve weeks of RT significantly increased sTNFR1 from 2.48 ± 0.57 ng/mL to 2.58 ± 0.59 ng/mL (overall time-effect P = .033) and Log IL-8 from 0.38 ± 0.18 pg/mL to 0.53 ± 0.32 pg/mL (overall time-effect P = .007). No time X group interaction (P = .916) was observed. In males of the high-resistance training group, there was an increase in Log IL-8 (from 0.45 ± 0.16 pg/mL to 0.68 ± 0.19 pg/mL; P = .005) and IL-1ra (from 68.60 ± 24.12 pg/mL to 79.56 ± 29.07 pg/mL; P = .007). No significant changes were found for the other markers. CONCLUSIONS: Our results show that 12 weeks of supervised RT induced an overall significant increase of circulating IL-8 and sTNFR1, independently from the external load applied. We suggest that exercising until volitional fatigue is the main trigger for exercise-induced responses. However, training at high external load also increased anti-inflammatory IL-1ra in male participants, which might be beneficial in combating low-grade inflammation.

Shifts in subsets of CD8+ T-cells as evidence of immunosenescence in patients with cancers affecting the lungs: an observational case-control study.

BACKGROUND: Shifts in CD8+ T-cell subsets that are hallmarks of immunosenescence are observed in ageing and in conditions of chronic immune stimulation. Presently, there is limited documentation of such changes in lung cancer and other malignancies affecting the lungs. METHODS: Changes in CD8+ T-cell subsets, based on the expression of CD28 and CD57, were analysed in patients with various forms of cancer affecting the lungs, undergoing chemotherapy and in a control group over six months, using multi-colour flow cytometry. RESULTS: The differences between patients and controls, and the changes in the frequency of CD8+ T-cell subpopulations among lung cancer patients corresponded to those seen in immunosenescence: lower CD8-/CD8+ ratio, lower proportions of CD28+CD57- cells consisting of naïve and central memory cells, and higher proportions of senescent-enriched CD28-CD57+ cells among the lung cancer patients, with the stage IV lung cancer patients showing the most pronounced changes. Also observed was a tendency of chemotherapy to induce the formation of CD28+CD57+ cells, which, in line with the capacity of chemotherapy to induce the formation of senescent cells, might provide more evidence supporting CD28+CD57+ cells as senescent cells. CONCLUSION: Immunosenescence was present before the start of the treatment; it appeared to be pronounced in patients with advanced cases of malignancies affecting the lungs, and might not be averted by chemotherapy.

Aging-associated subpopulations of human CD8+ T-lymphocytes identified by their CD28 and CD57 phenotypes.

BACKGROUND: During organismal aging, human T-cells shift towards less functional phenotypes, often called senescent cells. As these cells have not been well characterized, we aimed to relate surface markers of human T-cell senescence with characteristics of in vitro cellular aging and to further characterize these cells. METHODS: We identified, by flow cytometry, subpopulations of CD8+ T-cells based on CD57 and CD28 expression, and tested them for some markers of cellular senescence, apoptosis, differentiation and homing. RESULTS: Elderly persons presented significantly higher proportions not only of CD28-CD57+, but also of CD28+CD57+ cells. CD28+CD57+ cells had the highest expression of p16, p21, Bcl-2, CD95, CD45RO, CCR5 and PD-1, thereby arguing in favor of a senescent phenotype. CONCLUSION: Among CD8+ T-lymphocytes, CD28+CD57+ cells represent a subset with some senescent features that are distinct from the CD28-CD57+ cells.

Dose-and gender-specific effects of resistance training on circulating levels of brain derived neurotrophic factor (BDNF) in community-dwelling older adults.

BACKGROUND: BDNF is known to induce neuroplasticity and low circulating levels have been related to neuronal loss in older persons. Physical exercise is thought to trigger BDNF-induced neuroplasticity, but conflicting observations have been reported regarding the effects of resistance training on circulating BDNF in the elderly. These conflicting observations might reflect dose-and gender-specific differences. METHOD: Fifty-six apparently healthy elderly (68 ± 5 years) participants were randomized to 12 weeks of resistance training (3×/week) at either high-resistance (HIGH, 8 Males, 10 Females, 2 × 10-15 repetitions at 80% 1 RM), low-resistance (LOW, 9 Males, 10 Females, 1 × 80-100 repetitions at 20% 1 RM), or mixed low-resistance (LOW+, 9 Males, 10 Females, 1 × 60 repetitions at 20% 1 RM followed by 1 × 10-20 repetitions at 40% 1 RM). Serum was collected for BDNF assay at baseline and after 12 weeks (24 h-48 h after the last training). RESULTS: 12 weeks of LOW+ exercise significantly increased BDNF levels in male (from 34.9 ± 10.7 ng/mL to 42.9 ± 11.9 ng/mL, time × group interaction p=0.013), but not in female participants. No significant change was observed in HIGH or LOW, neither in male nor female subjects. CONCLUSION: Our results show that only the mixed-low-resistance training program with a very high number of repetitions at a sufficiently high external resistance was able to increase circulating BDNF in older male participants. Training to volitional fatigue might be necessary to obtain optimal results. Additional studies are needed to unravel the underlying mechanisms, as well as to confirm the observed gender difference.

Chemotherapy-induced changes and immunosenescence of CD8+ T-cells in patients with breast cancer.

BACKGROUND: Changes in sub-populations of cytotoxic (CD8+) T-cells, which are observed in aging and in conditions of chronic immune stimulation, are not well-documented in cancer. MATERIALS AND METHODS: Using flow cytometry, CD8+ T-cell subsets were analyzed in patients with breast cancer undergoing DNA-damaging chemotherapy and in an older female control group during a six-month longitudinal study, to explore shifts in CD8+ T-cells and the effect of DNA-damaging chemotherapy on different T-cell sub-populations. RESULTS: As expected, there was a consistent decrease in absolute numbers of leukocytes, lymphocytes, T-cells and CD8+ T-cells during chemotherapy in patients with cancer. Among the T-cells, there was a lower CD8-/CD8+ ratio, persisting over the six months, in patients with cancer compared to controls. The proportion of CD28-CD57+ cells also remained higher among patients with cancer throughout the sampling duration. The number of CD28+CD57- and CD28-CD5- cells decreased faster during DNA-damaging chemotherapy than CD28+CD57+ and CD28-CD57+ cells, while only CD28-CD57- cells showed a significant reconstitutive capacity after six months. CONCLUSION: Immunosenescence appeared to be pronounced in patients with breast cancer, with senescent CD8+ T-cells playing a role. The normal condition was not restored after six months of chemotherapy.

Strength training reduces circulating interleukin-6 but not brain-derived neurotrophic factor in community-dwelling elderly individuals.

Ageing is associated with a chronic low-grade inflammatory profile (CLIP). Physical exercise could circumvent the deleterious effects of CLIP by influencing circulating inflammatory mediators and neurotrophic growth factors. This study aimed at assessing whether 12 weeks of progressive strength training (PST) influences circulating brain-derived neurotrophic factor (BDNF), interleukin (IL)-6 and IL-10 in elderly individuals. Forty community-dwelling persons aged 62-72 years participated. Twenty participants were assigned to 12-week PST (70-80 % of maximal strength, three times per week). Matched control individuals (n = 20) maintained daily activity levels. Serum was collected for BDNF, IL-6 and IL-10 assay from all participants before and after 12 weeks (for PST subjects 24-48 h after the last training). In PST, muscle strength was significantly improved (+49 % for leg extension, p = 0.039), and basal IL-6 levels significantly reduced (p = 0.001), which remained unchanged in control (p = 0.117). No significant change in BDNF was observed in PST subjects (p = 0.147) or control (p = 0.563). IL-10 was below the detection limit in most subjects. Gender and health status did not influence the results. Our results show that after 12-week PST, muscle performance improved significantly, and basal levels of IL-6 were significantly decreased in older subjects. However, serum BDNF was not altered. The lack of an observable change in BDNF might be due to a short-lived BDNF response, occurring acutely following exercise, which might have been washed out when sampling. Furthermore, blood levels of BDNF may not reflect parallel increases that occur locally in the brain and muscle. These hypotheses need confirmation by further studies.