Dysregulated proteostasis is a hallmark of aging. We investigated how efficiently proteostatic adaptations to chronic cardiac cyclic-adenosine-monophosphate (cAMP)-dependent stress change with aging in mice harboring marked cardiac-specific over-expression of adenylyl cyclase VIII (TGAC8). We assessed protein quality control mechanisms (PQC) (ubiquitin proteasome system, autophagic flux via macroautophagy, and mitophagy) in left ventricles of TGAC8 and wild-type littermates (WT) at 3–4 and 17–21 months of age. At 3–4 months, TGAC8 exhibited markers of increased autophagic flux (microtubule-associated protein 1A/1B light chain 3B (LC3), p62, and their phospho-forms) and enhanced canonical mitophagy signaling (PARKIN, p62S405 and p62S349 receptors), confirming a more efficient proteostasis, vs WT. In aged TGAC8, however, the PQC mechanisms were overwhelmed by proteotoxic stress, manifested in insufficient proteasome activity, slower autophagic flux, and increased mitochondrial dysfunction (network fragmentation). The accumulation of protein aggregates (increased ratio of insoluble/soluble protein fractions), of lipofuscin bodies and of desmin cardiac preamyloid oligomers, and of LC3+- and p62+-inclusions of aberrant sizes was increased in aged TGAC8 compared to young TGAC8. Thus, while increased proteostatic mechanisms maintain cardiac health in TGAC8 in youth (3–4 months), long-term exposure to sustained activation of the AC/cAMP/PKA/Ca2+ signaling axis results in severe proteostasis insufficiency in aged TGAC8, leading to cardiomyopathy and accelerated cardiac aging.

Photobiomodulation (PBM) therapy, using low intensity near-infrared light is a noninvasive form of treatment with no side effects can be used to treat Alzheimer’s disease (AD). In a double-transgenic mouse model of AD (APPswe/PS1dE9), chronic PBM therapy has been shown to reduce Aβ plaques accumulation in specific regions of the brain, including the neocortex and hippocampus. The aim of this study was to analyze the effects of PBM therapy on brain cortex neuroprotective gene expression and behavior in this APPswe/PS1dE9 mouse model. Six-month old male AD (AD-PBM, n = 7) and wild type litter mate mice (WT-PBM, n = 8) were exposed to near-infrared light (wavelength 850 nm, 4.5 J/cm2, 3min/day, 5 days/week) for 6 months. Control mice (AD-CNT, n = 7; WT-CNT, n = 7) were placed under the PBM apparatus without turning the light on for 3min/day, 5 days/week. Motor function was assessed with treadmill-based gait analysis, with metrics including hind propel, hind stance and hind step angle (DigiGait), and open field test (OFT; anxiety-like behavior) following 6 months of treatment. Gene expression sampled from cortex was analyzed by qPCR. Data were analyzed by 2-way ANOVA. In the AD group, PBM therapy significantly increased the expression of neuroprotective genes TGFb1, INFG, EGFR and MMP2, but did not affect the expression of these genes in WT (Fig. 1A-D). In the gait analysis, PBM groups significantly reduced hind step angle in AD, but not WT (Fig. 1E). In the OFT, genotype had a significant effect on the amount of distance and time spent in the center of the arena (Table); non-treated WT mice exhibited lower anxiety level vs. non-treated AD mice (Fig. 1F). PBM did not have a significant effect, but the percent of distance spent in the center out of total distance had an increasing trend (Fig. 1F) indicating a trend in a reduction of anxiety in the AD group. Two-way ANOVA analysis results are presented in Table 1. PBM therapy significantly increased neuroprotective cortical gene expression and improved motor function in AD mice. It is possible that PBM treatment contributes to the upregulation of neuroprotective genes that reduced anxiety behavior and improved motor function.

Early vascular aging (EVA), manifesting as increases in central arterial stiffness and BP, is associated with cognitive impairment in humans. EVA and cognitive impairment occurs in Dahl salt-sensitive (DSS) rats consuming a normal salt (NS) diet with an advancing age. Quercetin (QRC), a flavonoid with anti-oxidant, anti-inflammatory and senolytic properties, previously shown to reduce salt-sensitive hypertension in DSS. We hypothesized that QRC will not only reduce EVA but will also improve cognitive function in DSS consuming NS diet. Six month old male DSS rats were assigned to two groups: a control group (n = 12) on a normal salt diet (0.5% NaCl) and an experimental group (n = 24) receiving the same diet supplemented with QRC (100 mg/kg BW/daily) for a 3-month period. Systolic and diastolic blood pressure (SBP, DBP), pulse wave velocity (PWV, an index of CAS), echocardiography, and visuospatial attention test were assessed before and after QRC treatment or placebo. Before treatment, no differences existed between groups. From 6 to 9 months of age in the control group, SBP, DBP, and PWV increased, while heart rate (HR) and ejection fraction (EF) showed a borderline decrease, and attention behavior showed a borderline increase for 1.0s of stimulus duration and no change for shorter visual stimulus, 0.2s (Figure and Table). QRC treatment reduced SBP, PWV, and increased EF and attention. The QRC effect was to increase the number of correct responses for 0.2s of stimulus and was negatively correlated with PWV (Pearson r = -0.420, P = 0.02) but not with BP, indicating that CAS is linked to cognitive function. QRC supplementation demonstrated the ability to reduce EVA and enhance cognition in DSS rats, as indicated by attention behavior. Despite BP and CAS reflecting EVA, the association between attention decline and PWV, but not BP, implies that CAS is linked to cognitive function through mechanisms not directly related to BP. Further exploration is required to understand the mechanistic basis of QRC effects on EVA in DSS rats. Supported by NIA/NIH/IRP

Background: It is established that cardiovascular risk factors, high blood pressure (BP) and central arterial stiffness (CAS), e.g. early vascular aging (EVA), are associated with vascular and degenerative brain damage and an increased risk of cognitive decline and dementia. EVA and cognitive impairment occur in Dahl salt-sensitive (DSS) rats consuming a normal salt (NS) diet with an advancing age. Previously we demonstrated that senolytic quercetin (QRC), a flavonoid with antioxidant and anti-inflammatory properties, reduced EVA and improved cognitive function in adult DSS male. We hypothesized that QRC will exhibit similar effect, i.e., will reduce EVA and improve cognitive function in DSS females consuming NS diet. Methods: A NS diet (0.5% NaCl), supplemented with QRC (100 mg/kg BW/day) was administered to female DSS rats at 6-mo of age (n=25) for a 3-month period. DSS rats without dietary supplementation of QRC served as a control group (n=11). Systolic BP (SBP), pulse wave velocity (PWV, an index of CAS), echocardiography, and cognitive function, assessed by a visuospatial attention test were assessed prior to and following QRC treatment or placebo. Results: At 6-mo of age none of the measured parameters differed between control and QRC treated rats. During three-month period from 6- to 9-mo of age, SBP, and PWV and relative left ventricular wall thickness (LV-RWT) significantly increased, and attention behavior did not change in the control group. QRC treatment abrogated age-related increasing of SBP, PWV, and RWT, but it did not affect cognitive function assessed by the number of correct responses to visual stimulus (Table). However, in QRC group, the number of correct attention test responses inversely correlated with LV-RWT (Pearson r=-0.543, P=0.011), and positively borderline correlated with cardiac output (Pearson r=0.385, P=0.085) and stroke volume (Pearson r=0.409, P=0.059), indicating that heart structural and functional parameters have strong link with cognitive function. Conclusions: Chronic 3-month dietary treatment with QRC, an antioxidant and anti-inflammatory compound, effectively mitigated EVA and protected heart, but did not affect cognitive function in DSS females. However, better attention was associated with the improved heart parameters in QRC group, suggesting a potential link between cardiac remodeling and attentional performance in the aged female DSS rats. Table. Effect of Quercetin (QRC) on Behavioral and Cardiovascular Parameters in a DSS Rat Model of Early Vascular Aging. [Table: see text] Values are expressed as mean ± standard deviation. Data were analyzed by 2-way ANOVA with repeated measurements followed by Sidak’s post-test. p<0.05 was considered significant. * P < 0.05 vs. 6-mo correspondent group; † p<0.05 vs. control group at correspondent age. Supported by NIA/NIH/IRP This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

INTRODUCTION:Musculoskeletal (MSK) injury can negatively affect service members by compromising job performance and readiness. These injuries can impact the service member's physical health, functional abilities, and quality of life (QoL). Rehabilitation therapies for MSK injuries can reduce these impacts. One approach is home use rehabilitative therapy, usable during deployment and at home stations. The purpose of this updated systematic review with meta-analysis was to broaden our scope of pain/symptoms, disability, and QoL as outcome measures for nonpharmaceutical MSK therapies in a military population versus controls. MATERIALS AND METHODS:An updated systematic literature search was conducted from inception to September 2022 using electronic databases. From 2790 retrievals, 22 reports were identified from 21 randomized or nonrandomized control trials. Interventions included exercise, electrotherapy, bracing, and other devices compared to a standard control treatment. Outcomes for MSK pain/symptoms, disability, and QoL were summarized as (1) standardized change from baseline for both intervention and control by time and (2) standardized mean differences (SMDs) in the time change between the intervention and control. RESULTS:Relative to baseline, pain improved during treatment and follow-up (P < .0001) with differences between intervention and control groups (P < .0001) but no significant interactions between group and time (P = .11). Overall, interventions showed modest (0.33 SMD, 95% CI, 0.11 to 0.54) improvement relative to controls across body regions and time. On average, disability exhibited an SMD of 0.12 (95% CI, -0.20 to 0.44) across all measures with substantial heterogeneity (I2 = 0.93). Time (P = .02) but not intervention (P = .87) was a significant moderator with no clear pattern of change over time and no time by group interaction (P = .84). Quality of life had an overall modest effect with an SMD of 0.10 (95% CI, -0.04 to 0.24) with no evidence supporting a difference between the intervention and control groups (P = .10) and no significant interaction between time and group (P = .41). The QoL measures were primarily derived using the Short Form Health Survey (SF12/36), which provide a mental and physical component summary score. For the mental component, there was either no change or a small decline during the study (P(time) = .80), with a difference between the intervention and control (P = .04) but no interaction between groups over time (P = .40). For the physical component scale, there was improvement during the study (P = .01), with the intervention showing better improvement than the control (P = .005), with no interaction between the time and treatment/control group (P = .80). The report considers responses by region and individual treatments. CONCLUSIONS:This analysis demonstrated modest improvement in pain and physical well-being with therapy, with low certainty across diverse military cohorts. The impact on overall health-related disability and QoL was limited, with little change in mental well-being. The substantial heterogeneity and low certainty across diverse military cohorts limit generalizability, suggesting that further research in homogeneous environments is important for guiding clinical decisions. The study's findings suggest that nonpharmacological home use interventions may offer modest improvements in pain relief, particularly early in treatment, and in strength and function, according to our previous report. These interventions could complement standard care, providing options that may benefit service members during deployment and at home.

BACKGROUND:Growth differentiation factor 15 (GDF-15) levels are emerging as a candidate biomarker of aging. The present study aimed to: (1) characterize the association of GDF-15 with the continuum of arterial stiffening, assessed as carotid-femoral pulse wave velocity, as age increases; (2) determine the predictive role of serum GDF-15 levels on mortality; and (3) identify genetic determinants of serum GDF-15 levels. METHODS AND RESULTS:Serum levels of GDF-15 and established cardiovascular risk factors, including pulse wave velocity, were assessed in a large (4736 individual) Sardinian population. Serum levels of GDF-15, which can be reliably measured repeatedly over time, increase with age; are associated with a stiffer aorta; "mediate" a large proportion of the age-associated increase in arterial stiffness; pose risks because of their association with greater mortality; and are significantly associated with the variant rs11549407, which causes thalassemia major in homozygosity. CONCLUSIONS:Because of its consistent ability to predict functional and clinical outcomes, including all-cause mortality, we conclude that GDF-15 serum levels serve as a robust biomarker for the continuum from health to the emergence of clinical disease during aging and, subsequently, to the likelihood of mortality.

The age-associated decline in aerobic exercise performance over an average of 13 yr in community-dwelling healthy individuals is more closely associated with decreased peripheral oxygen utilization rather than decreased cardiac output. This association was more evident in older than younger individuals. These findings suggest that future studies with larger samples examine whether these associations vary across the age range and whether the decline in cardiac output plays a greater role earlier in life. In addition, studies focused on determinants of peripheral oxygen uptake by exercising muscle may guide the selection of preventive strategies designed to maintain physical fitness with advancing age.

INTRODUCTION:Musculoskeletal (MSK) injury is an inherent risk for military personnel that can potentially impact job performance, productivity, and military readiness. Evidence is needed to show the efficacy of nonpharmacological, self-managed therapies to reduce MSK symptoms at common injury sites that are feasible for use during expeditionary operations and home stations. This systematic review and meta-analysis identified, summarized, and synthesized available evidence from randomized and non-randomized trials on the effectiveness of self-managed, home-use therapies to improve pain, muscle strength, and physical performance in military personnel with MSK injuries, when compared to controls. METHODS:The electronic databases of MEDLINE ALL Ovid, Embase.com, Cochrane Library, Scopus, Clinicaltrial.gov, and CINAHL Complete via EBSCO were systematically searched for relevant reports published in English. Utilizing the Covidence platform and consistent with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, multiple reviewers, using pre-determined data fields, screened for eligibility, assessed risk of bias (RoB), and performed data extraction. Evaluation of treatment effectiveness was determined using multilevel mixed-effects meta-analysis. RESULTS:The database and register search yielded 1,643 reports that were screened for eligibility. After screening of titles/abstracts and full texts, 21 reports were identified for evidence synthesis. Of these, two reports were excluded and two described the same study, resulting in a final list of 18 studies (19 reports). For quality assessment, the overall RoB for the 18 studies was categorized as 33.3% low risk, 55.6% with some concerns, and 11.1% high risk. Across the five domains of bias, 70% of the reports were classified as low risk. This systematic review found that the differences in interventions, outcome measures, and design between the studies were associated with a substantial degree of heterogeneity (I2 = 60.74%), with a small overall improvement in outcomes of the interventions relative to their specific control (standard mean difference 0.28; 95% CI, 0.12 to 0.45). There were varying degrees of heterogeneity for individual body regions. This was due, in part, to a small number of studies per bodily location and differences in the study designs. For the neck/shoulder, heterogeneity was moderate, with the clearest positive effect being for physical performance outcomes via other medical devices. For the back, there was substantial heterogeneity between studies, with modest evidence that pain was favorably improved by other medical devices and exercise interventions. For the leg, one study showed a clear large effect for other medical devices (shockwave treatment) on pain with substantial heterogeneity. The best evidence for positive effects was for the knee, with mainly negligible heterogeneity and some benefits from bracing, electrotherapy, and exercise. CONCLUSION:Evidence showed small beneficial effects in pain, strength, and physical performance by individual body regions for some interventions, compared to controls. The best evidence for a positive effect was for the knee. The findings suggest that some benefit may be obtained by including several treatments during deployment in austere environments and prolonged casualty care scenarios of military personnel with MSK injuries. Further research is warranted to better assess the potential benefits of using these treatments during deployments in austere environments as part of an individualized, multimodal approach for MSK injuries.

Objective: Quercetin (QRC), a flavonoid with anti-oxidant, anti-inflammatory and senolytic effects, reduced BP in salt-induced hypertension in Dahl salt-sensitive (DSS) rats. The increases in central arterial stiffness (CAS) and blood pressure (BP) occur, as manifestation of early vascular aging (EVA), in DSS rats even consuming a normal salt (NS) diet, moreover, EVA is associated with cognitive impairment in humans. We hypothesized that as age advances, a decline in cognitive function will accompany EVA in DSS rats consuming a NS diet, and that QRC will not only retard EVA, but also will improve cognitive function. Design and method: A NS diet (0.5% NaCl), supplemented with QRC (100 mg/kg BW/day) was administered to male DSS rats at 6-mo of age (n=24) for a 3-month period. DSS without QRC supplementation served as a control group (n=12). Systolic and diastolic BP (SBP, DBP), pulse wave velocity (PWV, an index of CAS), echocardiography, and a visuospatial attention test were assessed prior to and following QRC treatment. Results: At 6-mo of age none of the measured parameters differ between control and QRC rats. During aging from 6- to 9-mo in the control group, SBP, DBP and PWV significantly increased, ESLV.vol showed a statistically borderline trend to increase, HR and EF showed a statistically borderline trend to decrease, and attention behavior did not change. QRC treatment reduced SBP, PWV, and ESLV.vol, and increased EF and attention (Table). The QRC effect to increase the number of correct attention test responses was inversely correlated with PWV (Pearson r=-0.420, P=0.02) but not with BP or cardiac parameters, indicating that CAS but not BP is linked to cognitive function. Conclusions: QRC reduces EVA and improves cognition assessed as an attention behavior. Although both BP and CAS are manifestations of EVA, a positive association between attention decline with PWV, but not BP, suggests that CAS is linked to cognitive function via mechanisms that are not directly related to BP. Further studies are required to determine whether the effects of QRC on EVA in DSS rats, consuming a NS diet, are linked to its anti-oxidant, anti-inflammatory or senolytic properties.

Objective: To determine whether ARA290 can prevent or delay age-related declines in cardiac function and structure in the TG AC8 heart failure model. Methods: The study consists of 9 TG AC8 + mice that were randomly assigned to treatment group (n=5) or non-treatment saline group (n=4). Both groups received intraperitoneal injections of ARA290 (100 μg/kg) or saline tri-weekly. Monthly echocardiographic assessment of heart systolic function prior to, and monthly during 7 months of treatment was performed starting at 10 months of age. Two Way ANOVA was used to analyze the data. Results: At baseline, 10 months of age, prospective treatment and non-treatment group did not exhibit any statistically significant difference in their measure of ejection fraction (EF), fractional shortening (FS), and stroke volume (SV) ( P > 0.05). ARA290 treatment preserved EF, FS, and SV, (compared to a progressive, time dependent deterioration of these systolic functions in the saline treated group). Significant interaction terms for EF ( P < 0.04), FS ( P < 0.03), and SV ( P < 0.02), and time indicated that the ARA290 effect depended upon treatment time. Conclusion: The prevention of the decline in heart systolic functional by ARA290 suggests that this small peptide derivative of EPO has therapeutic potential as a novel intervention to retard declines in cardiac function that accompany chronic heart diseases.

Aims High glucose levels and Glucose-6-Phosphate Dehydrogenase deficiency (G6PDd) have both tissue inflammatory effects. Here we determined whether G6PDd accelerates arterial aging (information linked stiffening) in diabetes. Methods Plasma glucose, interleukin 6 (IL6), and arterial stiffness (indexed as carotid-femoral Pulse Wave Velocity, PWV) and red blood cell G6PD activity were assessed in a large (4448) Sardinian population. Results Although high plasma glucose in diabetics , did not differ by G6DP status (178.2 ± 55.1 vs 169.0 ± 50.1 mg/dl) in G6DPd versus non-G6PDd subjects, respectively, IL6, and PWV (adjusted for age and glucose) were significantly increased in G6PDd vs non-G6PDd subjects (PWV, 8.0 ± 0.4 vs 7.2 ± 0.2 m/sec) and (IL6, 6.9 ± 5.0 vs 4.2 ± 3.0 pg/ml). In non-diabetics , neither fasting plasma glucose, nor IL6, nor PWV were impacted by G6PDd. Conclusion G6PDd in diabetics is associated with increased inflammatory markers and accelerated arterial aging.

Background: Renin-Angiotensin Aldosterone System (RAAS) activation plays a central role in vascular aging, leading to structural and functional alterations including vascular smooth muscle cell (VSMC) proliferation, migration and secretion of extracellular matrix and inflammatory molecules. The age-associated increase in Angiotensin II (Ang II) expression enhances AT1-receptor activity and determinates a pro-fibrotic and pro-inflammatory phenotype. Further, miR-34a expression is modulated by aging and increases in different tissues, including the mouse aorta, but no direct miR-34a target has been identified in the RAAS pathway that sustains age-dependent increase of pro-inflammatory signaling. Aims: The aim of our study is to evaluate the potential interaction between miR-34a and RAAS signaling in VSMCs. Methods and Results: miR-34a expression exhibited an age-dependent increase in Rhesus Monkey (8- to 26-year-old) and rat central arteries (8- and 30-month-old). In silico analysis indicated that AT1R-associated protein (AGTRAP), a negative modulator of AT1R signaling, is a potential miR-34a target suggesting that the age-dependent increase in miR-34a in the arterial vascular wall may decrease AGTRAP expression in arterial VSMC. Ang II enhanced miR-34a expression in 30-month-old rat and in human aorta SMCs (HASMCs), whereas AGTRAP and Sirtuin-1 (SIRT1) mRNA and protein level decreased. Immunohistochemistry analysis showed a decrease of AGTRAP in 18-month-old miR-34a knock-out mice compared to 2-month-old mice. By luciferase assay, we demonstrated that AGTRAP is a direct miR-34a target. Moreover, AGTRAP and SIRT1 decreased in HASMCs infected with miR-34a-encoding lentivirus and this effect was partially rescued in AGTRAP/miR-34a co-infected cells. Finally, pro-inflammatory genes IL-6, COX-2, MCP-1 and MFG-E8 expression was upregulated in Ang II-treated and miR-34a overexpressing HASMCs, and this effect was abolished in AGTRAP/miR-34a co-transfected cells. Conclusions: Our results show cross-modulation between miR-34a and AGTRAP. MiR-34a targeting AGTRAP increases the expression of pro-inflammatory molecules in VSMCs and represents a novel mechanism that modulates RAAS signaling in vascular aging. Statement: This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging.

Aging per se is a major risk factor for cardiovascular diseases and is associated with progressive changes in cardiac structure and function. Rodent models are commonly used to study cardiac aging, but do not closely mirror differences as they occur in humans. Therefore, we performed a 2D echocardiographic study in non-human primates (NHP) to establish age- and sex-associated differences in cardiac function and morphometry in this animal model. M mode and 2D echocardiography and Doppler analyses were performed cross-sectionally in 38 healthy rhesus monkeys (20 females and 18 males), both young (age 7–12 years; n = 20) and old (age 19–30 years; n = 18). The diameters of the cardiac chambers did not differ significantly by age group, but males had larger left ventricular diameters (2.43 vs 2.06 cm in diastole and 1.91 vs 1.49 cm in systole, p = 0.0004 and p = 0.0001, respectively) and left atrial diameter (1.981 vs 1.732 cm; p = 0.0101). Left ventricular mass/body surface area did not vary significantly with age and sex. Ejection fraction did not differ by age and females presented a higher ejection fraction than males (54.0 vs 50.8

Background:Photobiomodulation (PBM) therapy, a form of low-dose light therapy, has been noted to be effective in several age-associated chronic diseases such as hypertension and atherosclerosis. Here, we examined the effects of PBM therapy on age-associated cardiovascular changes in a mouse model of accelerated cardiac aging. Methods:Fourteen months old Adenylyl cyclase type VIII (AC8) overexpressing transgenic mice (n = 8) and their wild-type (WT) littermates (n = 8) were treated with daily exposure to Near-Infrared Light (850 nm) at 25 mW/cm(2) for 2 min each weekday for a total dose of 1 Einstein (4.5 p.J/cm(2) or fluence 3 J/cm(2)) and compared to untreated controls over an 8-month period. PBM therapy was administered for 3.5 months (Early Treatment period), paused, due to Covid-19 restrictions for the following 3 months, and restarted again for 1.5 months. Serial echocardiography and gait analyses were performed at monthly intervals, and serum TGF-beta 1 levels were assessed following sacrifice. Results:During the Early Treatment period PBM treatments: reduced the age-associated increases in left ventricular (LV) mass in both genotypes (p = 0.0003), reduced the LV end-diastolic volume (EDV) in AC8 (p = 0.04); and reduced the left atrial dimension in both genotypes (p = 0.02). PBM treatments substantially increased the LV ejection fraction (p = 0.03), reduced the aortic wall stiffness (p = 0.001), and improved gait symmetry, an index of neuro-muscular coordination (p = 0.005). The effects of PBM treatments, measured following the pause, persisted. Total TGF-beta 1 levels were significantly increased in circulation (serum) in AC8 following PBM treatments (p = 0.01). We observed a striking increase in cumulative survival in PBM-treated AC8 mice (100%; p = 0.01) compared to untreated AC8 mice (43%). Conclusion:PBM treatment mitigated age-associated cardiovascular remodeling and reduced cardiac function, improved neuromuscular coordination, and increased longevity in an experimental animal model. These responses correlate with increased TGF-beta 1 in circulation. Future mechanistic and dose optimization studies are necessary to assess these anti-aging effects of PBM, and validation in future controlled human studies is required for effective clinical translation.

Average beat interval (BI) and beat interval variability (BIV) are primarily determined by mutual entrainment between the autonomic-nervous system (ANS) and intrinsic mechanisms that govern sinoatrial node (SAN) cell function. While basal heart rate is not affected by age in humans, age-dependent reductions in intrinsic heart rate have been documented even in so-called healthy individuals. The relative contributions of the ANS and intrinsic mechanisms to age-dependent deterioration of SAN function in humans are not clear. We recorded ECG on patients (n = 16 < 21 years and n = 23 41–78 years) in the basal state and after ANS blockade (propranolol and atropine) in the presence of propofol and dexmedetomidine anesthesia. Average BI and BIV were analyzed. A set of BIV features were tested to designated the “signatures” of the ANS and intrinsic mechanisms and also the anesthesia “signature”. In young patients, the intrinsic mechanisms and ANS mainly contributed to long- and short-term BIV, respectively. In adults, both ANS and intrinsic mechanisms contributed to short-term BIV, while the latter also contributed to long-term BIV. Furthermore, anesthesia affected ANS function in young patients and both mechanisms in adult. The work also showed that intrinsic mechanism features can be calculated from BIs, without intervention.

Cardiovascular diseases (CVD), including increased central arterial stiffness (CAS), accompany chronic kidney disease (CKD) development. An increase in pulse wave velocity (PWV), an index for CAS, is implicated in age-associated changes in the brain and potentiates the development of CI in CVD and CKD in humans and animal models. The aim of this study was to determine whether inducing CKD accelerates the development of CI and CAS in aged male and female rats. Ten months-old male and female Sprague-Dawley rats were fed with 0.25% adenine diet to accelerate CKD (n = 10-12; CKD-male, CKD-female) or regular diet (n = 8-10; CNT-male, CNT-female) for 8weeks. Body weight (BW), blood pressure (BP), heart rate (HR), aortic-PWV (aPWV), behavioral tests, blood urea nitrogen (BUN), creatinine and hematocrit were assessed at the endpoint. The anxiety-like behavior was tested in open field test (OFT) and elevated plus maze (EPM). Morris water maze (MWM) and cross maze (CM) were used to test spatial memory. The data were analyzed using two-way ANOVA. CKD development in both sexes was accompanied by kidneys enlargement, increase in BUN and creatinine, and reduction in hematocrit. In CKD-male the kidney function was more compromised with higher levels of BUN and creatinine vs. CKD-female (Table 1). CKD-male had lower BW and SBP vs. CNT-male (Table 1). CKD induced a reduction in HR, increase in aPWV and aortic weight in both sexes vs. respective CNT-groups (Figure 1). Both CKD-male and CKD-female demonstrated a tendency of increase in path length to find the hidden platform in MWM, e.g., both sexes had numerically impaired spatial memory. CKD-male spent less time in the center of OFT, a measure of anxiety, and loss of spatial memory, with a reduction of spontaneous alternation task assessed by CM. CKD-female exhibited higher level of anxiety spending less time in open arm of EPM vs. CNT-female (Figure 2). CKD development in old male and female Sprague-Dawley rats was accompanied by an increase in CAS, cardiovascular remodeling, and cognitive dysfunction. In CKD, CI affected different cognitive domains in the old males than in the age-matched females. Supported by NIA/NIH/IRP

ABSTRACT Introduction Low back pain (LBP) is a major cause of visits to ambulatory care, missed duty time, and disability discharge. The subacute phase of LBP presents an opportune time to prevent chronicity and lessen recurrence. The goal of this randomized controlled trial (RCT) was to determine the relative effectiveness of neuromuscular electrical stimulation (NMES) training and a progressive exercise program (PEP) on improving physical performance, pain, and torso strength in U.S. service members with subacute LBP, compared to standard primary care management (PCM) alone. Methods This is an Institutional Review Board–approved protocol for an RCT conducted with active duty military personnel (n = 128) at Fort Campbell, Kentucky, between April 2018 and March 2020. Participants were randomized to receive NMES (n = 43), PEP (n = 42), or PCM (n = 43) for 9 weeks. Outcome measures of physical performance (sit-ups, push-ups, walking, and torso endurance), torso muscle strength (flexion and extension), and pain were assessed at baseline and after 3, 6, and 9 weeks. Analysis was intent-to-treat using linear mixed effects models. A sensitivity analysis was performed to address the protocol deviations that occurred in response to coronavirus disease 2019 pandemic, which required rescheduling 17 in-person study visits to home assessments at 9-week testing. Results Evidence was found for group differences in physical performance for sit-ups and push-ups, with NMES showing greater improvement than PCM. The two groups showed similar improvements in torso muscle strength, although the NMES groups may show better improvement during early treatment. No group differences in pain levels were observed during the intervention, and all groups improved during the course of the study period. The amount of NMES muscle stimulation was directly related to the level of improvement, which was not the case for the hours reported for PEP exercise. Conclusion In an active duty population with subacute LBP, integrating NMES strength training into the rehabilitation therapy may offer a modest benefit for increasing sit-ups and push-ups and improving torso strength.

BackgroundAging is associated with increased levels of reactive oxygen species and inflammation that disrupt proteostasis and mitochondrial function and leads to organism-wide frailty later in life. ARA290 (cibinetide), an 11-aa non-hematopoietic peptide sequence within the cardioprotective domain of erythropoietin, mediates tissue protection by reducing inflammation and fibrosis. Age-associated cardiac inflammation is linked to structural and functional changes in the heart, including mitochondrial dysfunction, impaired proteostasis, hypertrophic cardiac remodeling, and contractile dysfunction. Can ARA290 ameliorate these age-associated cardiac changes and the severity of frailty in advanced age?MethodsWe conducted an integrated longitudinal (n = 48) and cross-sectional (n = 144) 15 months randomized controlled trial in which 18-month-old Fischer 344 x Brown Norway rats were randomly assigned to either receive chronic ARA290 treatment or saline. Serial echocardiography, tail blood pressure and body weight were evaluated repeatedly at 4-month intervals. A frailty index was calculated at the final timepoint (33 months of age). Tissues were harvested at 4-month intervals to define inflammatory markers and left ventricular tissue remodeling. Mitochondrial and myocardial cell health was assessed in isolated left ventricular myocytes. Kaplan–Meier survival curves were established. Mixed ANOVA tests and linear mixed regression analysis were employed to determine the effects of age, treatment, and age-treatment interactions.ResultsChronic ARA290 treatment mitigated age-related increases in the cardiac non-myocyte to myocyte ratio, infiltrating leukocytes and monocytes, pro-inflammatory cytokines, total NF-κB, and p-NF-κB. Additionally, ARA290 treatment enhanced cardiomyocyte autophagy flux and reduced cellular accumulation of lipofuscin. The cardiomyocyte mitochondrial permeability transition pore response to oxidant stress was desensitized following chronic ARA290 treatment. Concurrently, ARA290 significantly blunted the age-associated elevation in blood pressure and preserved the LV ejection fraction. Finally, ARA290 preserved body weight and significantly reduced other markers of organism-wide frailty at the end of life.ConclusionAdministration of ARA290 reduces cell and tissue inflammation, mitigates structural and functional changes within the cardiovascular system leading to amelioration of frailty and preserved healthspan.