Multiomics profiling of the impact of an angiotensin (1-7)-expressing probiotic combined with exercise training in aged male rats.

Angiotensin (1-7) [Ang (1-7)] is an active heptapeptide of the noncanonical arm of the renin-angiotensin system that modulates molecular signaling pathways associated with vascular and cellular inflammation, vasoconstriction, and fibrosis. Preclinical evidence suggests that Ang (1-7) is a promising therapeutic target that may ameliorate physical and cognitive function in late life. However, treatment pharmacodynamics limits its clinical applicability. Therefore, this study explored the underlying mechanisms altered by a genetically modified probiotic (GMP) that expresses Ang (1-7) combined with and without exercise training in an aging male rat model as a potential adjunct strategy to exercise training to counteract the decline of physical and cognitive function. We evaluated cross-tissue (prefrontal cortex, hippocampus, colon, liver, and skeletal muscle) multi-omics responses. After 12 wk of intervention, the 16S mRNA microbiome analysis revealed a main effect of probiotic treatment within- and between groups. The probiotic treatment enhanced α diversity (Inverse Simpson (F[2,56] = 4.44; P = 0.02); Shannon-Wiener (F[2,56] = 4.27; P = 0.02)) and ß-diversity (F[2,56] = 2.66; P = 0.01) among rats receiving our GMP. The analysis of microbes' composition revealed three genera altered by our GMP (Enterorhabdus, Muribaculaceae unclassified, and Faecalitalea). The mRNA multi-tissue data analysis showed that our combined intervention upregulated neuroremodeling pathways on prefrontal cortex (i.e., 140 genes), inflammation gene expression in the liver (i.e., 63 genes), and circadian rhythm signaling on skeletal muscle. Finally, the integrative network analysis detected different communities of tightly (|r| > 0.8 and P < 0.05) correlated metabolites, genera, and genes in these tissues.NEW & NOTEWORTHY This manuscript uses a multiomics approach (i.e., microbiome, metabolomics, and transcriptomics) to explore the underlying mechanisms driven by a genetically modified probiotic (GMP) designed to express angiotensin (1-7) combined with moderate exercise training in an aged male rat model. After 12 wk of intervention, our findings suggest that our GMP enhanced gut microbial diversity while exercise training altered the transcriptional response in relevant neuroremodeling genes, inflammation, and circadian rhythm signaling pathways in an aging animal model.

State of Knowledge on Molecular Adaptations to Exercise in Humans: Historical Perspectives and Future Directions.

For centuries, regular exercise has been acknowledged as a potent stimulus to promote, maintain, and restore healthy functioning of nearly every physiological system of the human body. With advancing understanding of the complexity of human physiology, continually evolving methodological possibilities, and an increasingly dire public health situation, the study of exercise as a preventative or therapeutic treatment has never been more interdisciplinary, or more impactful. During the early stages of the NIH Common Fund Molecular Transducers of Physical Activity Consortium (MoTrPAC) Initiative, the field is well-positioned to build substantially upon the existing understanding of the mechanisms underlying benefits associated with exercise. Thus, we present a comprehensive body of the knowledge detailing the current literature basis surrounding the molecular adaptations to exercise in humans to provide a view of the state of the field at this critical juncture, as well as a resource for scientists bringing external expertise to the field of exercise physiology. In reviewing current literature related to molecular and cellular processes underlying exercise-induced benefits and adaptations, we also draw attention to existing knowledge gaps warranting continued research effort. © 2021 American Physiological Society. Compr Physiol 12:3193-3279, 2022.

Potential Role of Chronic Physical Exercise as a Treatment in the Development of Vitiligo.

Vitiligo is an autoimmune disease characterized by progressive skin depigmentation and the appearance of white patches throughout the body caused by significant apoptosis of epidermal melanocytes. Despite not causing any physical pain, vitiligo can originate several psychosocial disorders, drastically reducing patients' quality of life. Emerging evidence has shown that vitiligo is associated with several genetic polymorphisms related to auto-reactivity from the immune system to melanocytes. Melanocytes from vitiligo patients suffer from excess reactive oxygen species (ROS) produced by defective mitochondria besides a poor endogenous antioxidant system (EAS). This redox imbalance results in dramatic melanocyte oxidative stress (OS), causing significant damage in proteins, lipid membranes, and DNA. The damaged melanocytes secret damage-associated molecular pattern (DAMPs), inducing and increasing inflammatory gene expression response that ultimately leads to melanocytes apoptosis. Vitiligo severity has been also associated with increasing the prevalence and incidence of metabolic syndrome (MetS) or associated disorders such as insulin resistance and hypercholesterolemia. Thus, suggesting that in genetically predisposed individuals, the environmental context that triggers MetS (i.e., sedentary lifestyle) may also be an important trigger for the development and severity of vitiligo disease. This paper will discuss the relationship between the immune system and epidermal melanocytes and their interplay with the redox system. Based on state-of-the-art evidence from the vitiligo research, physical exercise (PE) immunology, and redox system literature, we will also propose chronic PE as a potential therapeutic strategy to treat and prevent vitiligo disease progression. We will present evidence that chronic PE can change the balance of inflammatory to an anti-inflammatory state, improve both EAS and the mitochondrial structure and function (resulting in the decrease of OS). Finally, we will highlight clinically relevant markers that can be analyzed in a new research avenue to test the potential applicability of chronic PE in vitiligo disease.

The Effects of Concurrent Training Combining Both Resistance Exercise and High-Intensity Interval Training or Moderate-Intensity Continuous Training on Metabolic Syndrome.

To date, there are several knowledge gaps on how to properly prescribe concurrent training to achieve the best dose-response, especially regarding the optimal intensity or volume of the aerobic component. Thus, the objective of this study is to analyze the effects of different aerobic exercise modes and intensities [i.e. aerobic high-intensity interval training (HIIT) versus moderate-intensity continuous aerobic training (MICT) combined with a resistance training (RT) program] on metabolic outcomes in participants with metabolic syndrome (MetS). Thirty-nine men and women (67.0 ± 6.7 years) volunteered to a 12-weeks exercise intervention (3 week-1, 50 min/session) and were randomly assigned to one of three groups: (a) RT plus MICT (RT+MICT) (2 males; 11 females); (b) RT plus HIIT (RT+HIIT) (4 males; 9 females); and (c) control group (CON) - without formal exercise (4 males; 9 females). Intensity was established between 60 and 70% of maximum heart rate (HRmax) in RT+MICT and ranged from 55-65% to 80-90% HRmax in the RT+HIIT group. Dependent outcomes included morphological, metabolic and hemodynamic variables. Both training groups improved waist circumference (RT+MICT: P = 0.019; RT+HIIT: P = 0.003), but not body weight, fat mass or fat-free mass (P ≥ 0.114). RT+HIIT group improved fasting glucose (P = 0.014), low density lipoprotein [LDL (P = 0.022)], insulin (P = 0.034) and homeostatic model assessment (P = 0.028). RT+MICT group reduced triglycerides (P = 0.053). Both exercise interventions did not change high sensitivity C-reactive protein, glycated hemoglobin, high density lipoprotein and total cholesterol, systolic, diastolic or mean arterial blood pressure (P ≥ 0.05). The CON group reduced the LDL (P = 0.031). This trial suggests that short-term exercise mode and intensity may differently impact the metabolic profile of individuals with MetS. Further, our data suggests that both concurrent trainings promote important cardiometabolic gains, particularly in the RT+HIIT. Nonetheless, due to the small-to-moderate effect size and the short-term intervention length, our data suggests that the intervention length also has an important modulating role in these benefits in older adults with MetS. Therefore, more research is needed to confirm our results using longer exercise interventions and larger groups.

Crosstalk Between the Gut Microbiome and Bioactive Lipids: Therapeutic Targets in Cognitive Frailty.

Cognitive frailty is a geriatric condition defined by the coexistence of cognitive impairment and physical frailty. This "composite" aging phenotype is associated with a higher risk of several adverse health-related outcomes, including dementia. In the last decade, cognitive frailty has gained increased attention from the scientific community that has focused on understanding the clinical impact and the physiological and pathological mechanisms of development and on identifying preventive and/or rehabilitative therapeutic interventions. The emergence of gut microbiome in neural signaling increased the interest in targeting the gut-brain axis as a modulation strategy. Multiple studies on gastroenteric, metabolic, and neurodegenerative diseases support the existence of a wide bidirectional communication network of signaling mediators, e.g., bioactive lipids, that can modulate inflammation, gut permeability, microbiota composition, and the gut-brain axis. This crosstalk between the gut-brain axis, microbiome, and bioactive lipids may emerge as the basis of a promising therapeutic strategy to counteract cognitive frailty. In this review, we summarize the evidence in the literature regarding the link between the gut microbiome, brain, and several families of bioactive lipids. In addition, we also explore the applicability of several bioactive lipid members as a potential routes for therapeutic interventions to combat cognitive frailty.

The Gut Microbiome as a Therapeutic Target for Cognitive Impairment.

Declining cognitive functions in older individuals have enormous emotional, clinical, and public health consequences. Thus, therapeutics for preserving function and keeping older adults living independently are imperative. Aging is associated dysbiosis, defined as a loss of number and diversity in gut microbiota, which has been linked with various aspects of cognitive functions. Therefore, the gut microbiome has the potential to be an important therapeutic target for symptoms of cognitive impairment. In this review, we summarize the current literature regarding the potential for gut-targeted therapeutic strategies for prevention/treatment of the symptoms of cognitive impairment. Specifically, we discuss four primary therapeutic strategies: wild-type and genetically modified probiotics, fecal microbiota transplantation, physical exercise, and high-fiber diets and specifically link these therapies to reducing inflammation. These strategies may hold promise as treatment paradigm symptoms related to cognitive impairment.

Wearable Technology To Reduce Sedentary Behavior And CVD Risk In Older Adults: A Pilot Randomized Clinical Trial.

BACKGROUND: Physical exercise is associated with decreased cardiovascular disease (CVD) risk, but recent large-scale trials suggest that exercise alone is insufficient to reduce CVD events in high-risk older adults. PURPOSE: This pilot randomized clinical trial aimed to collect critical data on feasibility, safety, and protocol integrity necessary to design a fully powered randomized controlled trial (RCT) and evaluate the impact of combining structured exercise with an intervention designed to enhance non-exercise physical activity (EX+NEPA) compared to EX alone. METHODS: Forty participants aged ≥60 years with moderate-to-high risk of coronary heart disease events were randomly assigned to either the EX+NEPA or EX groups and followed for 20 weeks. Both groups underwent a twice-weekly, 8-week center-based exercise intervention with aerobic and resistance exercises. EX+NEPA group also received a wearable activity tracking device along with behavioral monitoring and feedback throughout the study. Study outcomes were evaluated at 8 and 20 weeks. RESULTS: Data are presented as adjusted mean change of the differences over time with 95% confidence intervals at 20 weeks. Relative to EX, the change in steps/day at 20 weeks was 1994 (-40.27, 4028) higher for EX+NEPA. For sedentary time at close-out, the EX+NEPA group was -6.8 (-45.2, 31.6) min/day relative to EX. The between-group differences for systolic and diastolic blood pressure were -9.9 (-19.6, -0.3) and -1.8 (-6.9, 3.3) mmHg, respectively. CONCLUSION: The addition of wearable technology intervention appeared to positively influence daily activity patterns and changes in blood pressure - potentially improving risk factors for CVD. A fully powered randomized trial is needed to ultimately test this hypothesis.

Multimodal Intervention to Improve Functional Status in Hypertensive Older Adults: A Pilot Randomized Controlled Trial.

This pilot randomized controlled trial (RCT) was designed to provide the preliminary data necessary to conduct a full-scale trial to compare the efficacy of differing first-line antihypertensive medications in improving functional status in older adults, when combined with exercise. The primary objectives were to assess study feasibility, safety, and protocol integrity. Dependent outcomes included gait speed, exercise capacity, body composition, and systemic cardiometabolic biomarkers. Thirty-one physically inactive older adults (70.6 ± 6.1 years) with hypertension and functional limitations were randomly assigned to 1) Perindopril (8 mg/day n = 10), 2) Losartan (100 mg/day; n = 13), or 3) Hydrochlorothiazide (HCTZ: 25 mg/day; n = 8). Participants were also assigned to a 24-week multimodal exercise intervention, separated into an aerobic and concurrent (aerobic + resistance) phase to evaluate potential mode effects. Retention was 84% (26/31), and compliance was >90% and >79% with medication and exercise, respectively. A total of 29 adverse events (Perindopril = 5; Losartan = 12; HCTZ = 11) and one unrelated serious adverse event were observed throughout the trial. Overall, this pilot RCT provided critical data and identified several challenges to ultimately designing and implementing a fully powered trial.

Angiotensin Converting Enzyme Inhibitors Combined with Exercise for Hypertensive Seniors (The ACES Trial): Study Protocol of a Randomized Controlled Trial.

Prior evidence suggests that the choice of antihypertensive medication may influence functional status among older adults with hypertension, particularly in conjunction with exercise. In particular, angiotensin converting enzyme (ACE) inhibitors have shown potential to positively influence function. However, randomized, controlled trials are needed to confirm this hypothesis. This paper outlines an RCT designed to determine if choice of first-line antihypertensive medication influences functional and cardiovascular risk factor responses to exercise among older adults with hypertension. Two hundred and thirteen inactive, community-dwelling adults ≥60 years of age with hypertension and functional limitations will be recruited to engage in a 32-week intervention study. Participants will be randomized to one of three first-line antihypertensive agents: (1) the ACE inhibitor perindopril, (2) the AT1 receptor antagonist losartan, or (3) the thiazide diuretic hydrochlorothiazide (HCTZ). Six weeks after randomization, participants will begin a 20-week structured aerobic exercise intervention. Participants will perform two 45-min center-based sessions coupled with 60 min of home-based walking per week. The primary aim is to determine if perindopril improves self-paced gait speed when compared with losartan and HCTZ. The secondary aim is to determine the relative effect of perindopril on secondary outcomes such as: (a) exercise capacity, (b) body mass and composition, and (c) circulating indices of cardiovascular risk. This RCT is expected to identify differential effects of first-line antihypertensive medications when combined with physical exercise thus have potential implications for antihypertensive prescription guidelines for older adults. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03295734.

Statin combined with exercise training is more effective to improve functional status in dyslipidemic older adults.

BACKGROUND: Exercise training (EX) and statins are first-line therapies to manage dyslipidemia. PURPOSE: This study aims to analyze the effect of EX and statins on functional status and cardiovascular risk (CVR) in dyslipidemic older adults with comorbidities. METHODS: Participants (n = 981) underwent one of 3 conditions: (a) multicomponent exercise training (EX; n = 298; 74% females); (b) statins (ST; n = 178; 65% females); (c) combined therapy-exercise plus ST therapy (ST+EX; n = 505; 79% females). Functional fitness, anthropometry, hemodynamic and lipid profiles, and were assessed at baseline and after 2-years. RESULTS: EX and ST+EX participants improved all the functional status variables, whereas ST participants aggravated all the outcomes. Triglycerides and HDL-cholesterol maintained unchanged and total cholesterol decreased in the three groups, whereas LDL-cholesterol (LDL-C) decreased in EX and ST+EX groups but not in ST group. EX and ST+EX groups decreased body mass index (BMI), systolic and diastolic blood pressure; contrarily, ST group increased these variables. CONCLUSION: Statins combined with exercise training or exercise alone are more effective to improve functional status, to manage cholesterol levels and overall cardiovascular risk factors in dyslipidemic older adults with comorbidities than ST alone. Furthermore, current results suggest that isolated statin therapy decreases functional status and other cardiovascular risk factors.

Functional status improves in hypertensive older adults: the long-term effects of antihypertensive therapy combined with multicomponent exercise intervention.

BACKGROUND: The increasing prevalence of functionally-limited hypertensive individuals highlights the need for interventions to reduce the burden of hypertension-aging-disability and to maximize the chances of healthy aging. AIM: This study aims to compare the effects of multicomponent exercise and different pharmacological treatments on functional status and cardiovascular risk outcomes in hypertensive older adults with comorbidities. METHODS: Participants (n = 96) engage in a 3 days/week multicomponent (aerobic + resistance) exercise program and for one of the following three conditions: (1) thiazide-related diuretics (TDs; n = 33, 69.9 ± 9.5 years); (2) calcium channel blockers (CCBs; n = 23, 67.0 ± 9.0 years); (3) and ß-blockers (ßBs; n = 40, 65.6 ± 7.2 years) medication. Baseline and 2-year follow-up evaluations included the Senior Fitness Test battery, anthropometrics and hemodynamic profile, health-related quality of life (HRQoL; Short-Form Health Survey 36) and health history questionnaires. RESULTS: All groups have significantly improved the physical functional status; particularly upper and lower body strength and aerobic endurance and systolic blood pressure. The TDs and ßBs groups have diminished the waist circumference and body mass. The CCBs decreased total cholesterol (P = 0.028), perceived better physical functioning, physical component score but also augmented bodily pain (P < 0.05). The ßB group decreased triglycerides (P = 0.013). No group differences were found. CONCLUSION: Multicomponent exercise training has improved functional status regardless of the antihypertensive medication options. Hypertensive older adults should add exercise training to pharmacological antihypertensive therapy to reduce the rate of physical disability.

Antihypertensive monotherapy or combined therapy: which is more effective on functional status?

BACKGROUND: This study aims to analyze the effects of anti-hypertensive monotherapy and combined therapy on functional status, and cardiovascular risk outcomes in older adults. METHODS: This longitudinal non-randomized cohort study, involved hypertensive older adults (n = 440) aged 60 or more years with comorbidities. Participants underwent a community exercise training program and one of the following 2 conditions: i) use of daily mono-dose angiotensin-converting enzyme inhibitors (ACEi; n= 232); ii) combined therapy including ACEi plus other class agent (Combined; n= 208). Baseline and 2-year follow-up evaluations included the functional fitness, health-related quality of life (HRQoL), health history questionnaires, anthropometric and hemodynamic profile. RESULTS: Both experimental groups have significantly improved physical functional status, and have significantly decreased blood pressure and waist circumference. ACEi group has significantly reduced body mass and body mass index, the Combined group significantly reduced the waist-to-hip ratio. Additionally, both groups perceived better physical HRQoL. CONCLUSIONS: Functional status has improved with ACEi medication and exercise training, regardless the ACEi medication therapy. Exercise training plus ACEi antihypertensive therapy should be recommended into the standard prescription practice to reduce the rate of physical disability among hypertensive older adults.

Exercise training improves functional status in hypertensive older adults under angiotensin converting enzymes inhibitors medication.

BACKGROUND: The study aims to analyze the effect of three types of treatment on functional status, and cardiovascular risk outcomes in hypertensive older adults with comorbidities. METHODS: Participants (n=418) underwent one of the following 3 conditions: i) multicomponent exercise training 3 times/week (MEX; n=116); ii) angiotensin converting enzyme inhibitors used mono-dose daily (ACEi; n=70); iii) combined exercise and ACEi drugs (ACEiMEX; n=232). The trial was completed by 82% of the participants (n=342): MEX (n=90); ACEi (n=66); ACEiMEX (n=186). Baseline and 2-year follow-up evaluations included the Senior Fitness Test battery, Short Form Health Survey 36 (SF-36), the health history questionnaires, anthropometric and hemodynamic profile. RESULTS: MEX and ACEiMEX groups improved all physical functional status outcomes, decreased systolic (SBP) and diastolic blood pressure (p<0.001) and augmented the physical functioning, role physical and physical component score (PCS) (p<0.05), but also bodily pain (p<0.05). The ACEi group reduced the upper body strength, upper and lower body flexibility and aerobic endurance (p<0.05); worsened the anthropometric profile, and SBP (p<0.001); and decreased general health and PCS (p<0.05). CONCLUSIONS: The improvement of the physical functioning and HRQoL in older hypertensive adults using ACEi medications only occur if they adopt an exercise training regimen, increasing also the management of the blood pressure and other cardiovascular risk factors.

Back to basics with active lifestyles: exercise is more effective than metformin to reduce cardiovascular risk in older adults with type 2 diabetes.

To establish the effect of three types of treatment - multicomponent exercise (MEX); the oral hypoglycaemic drug metformin (MET); combined therapy comprising exercise plus metformin (MEXMET) - on cardiovascular risk in older adults with type 2 diabetes (T2D) and with comorbidities in an early stage of the disease (HbA1c < 7.5%). A sample of 284 participants was evaluated for multifactorial cardiovascular risk at baseline and at 24-month intervention according to anthropometric and hemodynamic components, lipid profile, glycaemia and cardiorespiratory fitness (CRF). Participants underwent one of three conditions: MEX (n = 59), training in three sessions per week; MET (n = 30), using metformin 850 mg twice daily; MEXMET (n = 195), combining exercise and metformin. After the 24-month intervention MEX and MEXMET showed more positive results than MET therapy. MEX decreased body mass (BM; 4%), waist circumference (WC; 4%), body mass index (BMI; 3%), systolic blood pressure (SBP; 11%), diastolic blood pressure (DBP; 11%), triglycerides (21%), and glycaemia (12%), and increased cardiorespiratory fitness (CRF; 18%). Conversely, the MET group showed increased WC (2%), waist-to-hip ratio (WHR) (3%), and SBP (5%). Differences between MEX and MET groups presented large effect sizes for BM, WC, WHR, SBP, DBP and CRF, and moderate effect sizes for BMI and glycaemia. MEX was the most effective therapy in decreasing cardiovascular risk in the early stage of T2D in older adults with multimorbidity and attenuated the adverse effects of pharmacological therapy in MEXMET treatment.

Exercise but not metformin improves health-related quality of life and mood states in older adults with type 2 diabetes.

The aim of this cohort study is to analyse the effect of three types of treatment: (i) exercise training with multicomponent exercise (E); (ii) pharmacologic treatment with oral hypoglycaemic drug - metformin (M); and (iii) a combined therapy - exercise and metformin (E + M) on health-related quality of life (HRQoL) and mood states in older adults with type 2 diabetes (T2D) with comorbidity in an early stage of the disease. Participants (n = 284) underwent 1 of the following 3 conditions: (i) E (n = 59) trained three times/week; (ii) M (n = 30) used 850 mg of metformin twice daily; and (iii) E + M (n = 195) combined exercise and metformin. Furthermore, participants completed baseline and 2-year follow-up evaluations including a Shortform Health Survey 36, Profile of Mood States - Short-form, the health history questionnaires, anthropometric, and blood biochemistry. E and E + M revealed improved mood states, with large effect size on the vigour domain, and moderate effect size in the anger and total mood disturbance (TMD) domains (P < 0.05), in comparison with the M group. After 24 months' intervention, the E and E + M groups perceived better physical and mental HRQoL than the M group. The M group unchanged HRQoL domains (P > 0.05). Metformin had no significant effect on the self-referred HRQoL in T2D participants aged above 60 years, in an early stage of the disease. The E and E + M were the most effective long-term therapies to improve mood states and HRQoL in older adults with T2D.

Effects of long-term multicomponent exercise on health-related quality of life in older adults with type 2 diabetes: evidence from a cohort study.

PURPOSE: To establish the effect of a long-term multicomponent exercise (LTMEX) intervention (24 months) on health-related quality of life (HRQoL), in older adults with type 2 diabetes (T2D). METHODS: This longitudinal retrospective cohort study analyzes the effects of a supervised LTMEX program on HRQoL in older adults with T2D (n = 279). Participants underwent one of two conditions: LTMEX (n = 241) trained three times per week; and unchanged lifestyle-the control group (CO; n = 38). Participants completed baseline, and 2-year follow-up evaluations including the Short Form Health Survey 36 (SF-36), anthropometric, hemodynamic components, and cardiorespiratory fitness (VO2 peak). RESULTS: LTMEX improves HRQoL, specifically physical functioning (P < 0.001), general health (P < 0.05), vitality (P < 0.001), mental health (MH; P < 0.05), physical component score (P < 0.001), mental component score (P < 0.001), and total SF-36 (P < 0.001). LTMEX group also decreased body weight (BW; P < 0.005), waist circumference (WC; P < 0.001), waist-to-hip ratio (WHR; P < 0.001), and systolic blood pressure (SBP; P < 0.001), and increased VO2 peak (P < 0.001). CO group increased WC (P = 0.012), BMI (P = 0.024), waist-to-hip ratio (WHR; P = 0.003) and SBP (P < 0.001), and decreased vitality (P < 0.001) and MH (P < 0.05). CONCLUSIONS: A LTMEX intervention improves physical and mental HRQoL in older adults with T2D, and also anthropometric, hemodynamic profile, and cardiorespiratory fitness.