The age-associated increase in arterial stiffness has long been considered to parallel or to cause the age-associated increase in blood pressure (BP). Yet, the rates at which pulse wave velocity ...(PWV), a measure of arterial stiffness, and BP trajectories change over time within individuals who differ by age and sex have not been assessed and compared. This study determined the evolution of BP and aortic PWV trajectories during a 9.4-year follow-up in >4000 community-dwelling men and women of 20 to 100 years of age at entry into the SardiNIA Study. Linear mixed effects model analyses revealed that PWV accelerates with time during the observation period, at about the same rate over the entire age range in both men and women. In men, the longitudinal rate at which BP changed over time, however, did not generally parallel that of PWV accelerationat ages >40 years the rates of change in systolic BP (SBP) and pulse pressure (PP) increase plateaued and then declined so that SBP, itself, also declined at older ages, whereas PP plateaued. In women, SBP, diastolic BP, and mean BP increased at constant rates across all ages, producing an increasing rate of increase in PP. Therefore, increased aortic stiffness is implicated in the age-associated increase in SBP and PP. These findings indicate that PWV is not a surrogate for BP and that arterial properties other than arterial wall stiffness that vary by age and sex also modulate the BP trajectories during aging and lead to the dissociation of PWV, PP, and SBP trajectories in men.
Objective
Age and excessive energy intake/obesity are risk factors for cerebrovascular disease, but it is not known if and how these factors affect the extent of brain damage and outcome in ischemic ...stroke. We therefore determined the interactions of age and energy intake on the outcome of ischemic brain injury, and elucidated the underlying mechanisms.
Methods
We utilized a novel microchip‐based immunoaffinity capillary electrophoresis technology to measure a panel of neurotrophic factors, cytokines, and cellular stress resistance proteins in brain tissue samples from young, middle‐aged, and old mice that had been maintained on control or energy‐restricted diets prior to middle cerebral artery occlusion and reperfusion.
Results
Mortality from focal ischemic stroke was increased with advancing age and reduced by an intermittent fasting (IF) diet. Brain damage and functional impairment were reduced by IF in young and middle‐aged mice, but not in old mice. The basal and poststroke levels of neurotrophic factors (brain‐derived neurotrophic factor and basic fibroblast growth factor), protein chaperones (heat shock protein 70 and glucose regulated protein 78), and the antioxidant enzyme heme oxygenase‐1 were decreased, whereas levels of inflammatory cytokines were increased in the cerebral cortex and striatum of old mice compared with younger mice. IF coordinately increased levels of protective proteins and decreased inflammatory cytokines in young, but not in old mice.
Interpretation
Reduction in dietary energy intake differentially modulates neurotrophic and inflammatory pathways to protect neurons against ischemic injury, and these beneficial effects of IF are compromised during aging, resulting in increased brain damage and poorer functional outcome. ANN NEUROL 2010;67:41–52
The ability of older persons to function independently is dependent largely on the maintenance of sufficient aerobic capacity and strength to perform daily activities. Although peak aerobic capacity ...is widely recognized to decline with age, its rate of decline has been estimated primarily from cross-sectional studies that may provide misleading, overly optimistic estimates of aging changes.
To determine longitudinal rate of change in aerobic capacity and the influence of age, gender, and physical activity on these changes, we performed serial measurements of peak treadmill oxygen consumption (peak VO2) in 375 women and 435 men ages 21 to 87 years from the Baltimore Longitudinal Study of Aging, a community-dwelling cohort free of clinical heart disease, over a median follow-up period of 7.9 years. A linear mixed-effects regression model was used to calculate the predicted longitudinal 10-year rate of change in peak VO2, expressed in milliliters per minute, for each age decade from the 20s through the 70s after adjustment for self-reported leisure-time physical activity. A longitudinal decline in peak VO2 was observed in each of the 6 age decades in both sexes; however, the rate of decline accelerated from 3% to 6% per 10 years in the 20s and 30s to >20% per 10 years in the 70s and beyond. The rate of decline for each decade was larger in men than in women from the 40s onward. Similar longitudinal rates of decline prevailed when peak VO2 was indexed per kilogram of body weight or per kilogram of fat-free mass and in all quartiles of self-reported leisure-time physical activity. When the components of peak VO2 were examined, the rate of longitudinal decline of the oxygen pulse (ie, the O2 utilization per heart beat) mirrored that of peak VO2, whereas the longitudinal rate of heart rate decline averaged only 4% to 6% per 10 years, and accelerated only minimally with age.
The longitudinal rate of decline in peak VO2 in healthy adults is not constant across the age span in healthy persons, as assumed by cross-sectional studies, but accelerates markedly with each successive age decade, especially in men, regardless of physical activity habits. The accelerated rate of decline of peak aerobic capacity has substantial implications with regard to functional independence and quality of life, not only in healthy older persons, but particularly when disease-related deficits are superimposed.
Aging is associated with distinct phenotypical, physiological, and functional changes, leading to disease and death. The progression of aging-related traits varies widely among individuals, ...influenced by their environment, lifestyle, and genetics. In this study, we conducted physiologic and functional tests cross-sectionally throughout the entire lifespan of male C57BL/6N mice. In parallel, metabolomics analyses in serum, brain, liver, heart, and skeletal muscle were also performed to identify signatures associated with frailty and age-dependent functional decline. Our findings indicate that declines in gait speed as a function of age and frailty are associated with a dramatic increase in the energetic cost of physical activity and decreases in working capacity. Aging and functional decline prompt organs to rewire their metabolism and substrate selection and toward redox-related pathways, mainly in liver and heart. Collectively, the data provide a framework to further understand and characterize processes of aging at the individual organism and organ levels.
Abstract
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.
Reduced BMI is an absolute contraindication for lung transplantation (LTx) at most centers in the United States. The objective of this study was to quantify post-LTx survival of moderate to severely ...underweight patients with cystic fibrosis (CF) (BMI < 17 kg/m
) in the United States relative to normal-weight recipients with CF and other frequently transplanted patient cohorts.
Using United Network for Organ Sharing Registry data (undergoing transplant from June 2005-November 2015), Kaplan-Meier estimates of median posttransplant survival were calculated for all patients with CF, COPD, and idiopathic pulmonary fibrosis (IPF), as well as low and normal weight CF subgroups. Cox regression modeling stratified according to transplant center assessed risk of posttransplant mortality in recipients with CF and a BMI < 17 kg/m
compared with recipients with COPD (reference).
Median posttransplant survival (95% CI) for CF, COPD, and IPF was 7.9 (7.2-8.6), 5.9 (5.6-6.2), and 5.5 (5.2-5.8) years, respectively. Although an absolute decrease was noted in posttransplant survival for recipients with CF and a BMI < 17 kg/m
, compared with those with CF and a BMI ≥ 17 kg/m
(7.0 years 4.5-7.9 vs 8.2 years 7.3-9.0), Cox modeling found no increased mortality risk (adjusted hazard ratio, 1.09; 95% CI, 0.90-1.32; P = .38). There was no difference in posttransplant mortality between patients with CF and a BMI < 17 kg/m
and recipients with COPD and all BMIs (adjusted hazard ratio, 1.04; 95% CI, 0.86-1.25; P = .71).
Transplant recipients with CF and a BMI < 17 kg/m
had posttransplant survival rates comparable to those of other groups frequently undergoing transplantation. BMI < 17 kg/m
as a single risk factor in the CF population should not be treated as an absolute contraindication to LTx.
The hypertensive response in Dahl salt-sensitive (DSS) rats on a high-salt (HS) diet is accompanied by central arterial stiffening (CAS), a risk factor for dementia, and heightened levels of a ...prohypertensive and profibrotic factor, the endogenous Na/K-ATPase inhibitor marinobufagenin (MBG). We studied the effect of the in vivo administration of MBG or HS diet on blood pressure (BP), CAS, and behavioral function in young DSS rats and normotensive Sprague-Dawley rats (SD), the genetic background for DSS rats. Eight-week-old male SD and DSS rats were given an HS diet (8% NaCl,
= 18/group) or a low-salt diet (LS; 0.1% NaCl,
= 14-18/group) for 8 weeks or MBG (50 µg/kg/day,
= 15-18/group) administered via osmotic minipumps for 4 weeks in the presence of the LS diet. The MBG-treated groups received the LS diet. The systolic BP (SBP); the aortic pulse wave velocity (aPWV), a marker of CAS; MBG levels; spatial memory, measured by a water maze task; and tissue collection for the histochemical analysis were assessed at the end of the experiment. DSS-LS rats had higher SBP, higher aPWV, and poorer spatial memory than SD-LS rats. The administration of stressors HS and MBG increased aPWV, SBP, and aortic wall collagen abundance in both strains vs. their LS controls. In SD rats, HS or MBG administration did not affect heart parameters, as assessed by ECHO vs. the SD-LS control. In DSS rats, impaired whole-heart structure and function were observed after HS diet administration in DSS-HS vs. DSS-LS rats. MBG treatment did not affect the ECHO parameters in DSS-MBG vs. DSS-LS rats. The HS diet led to an increase in endogenous plasma and urine MBG levels in both SD and DSS groups. Thus, the prohypertensive and profibrotic effect of HS diet might be partially attributed to an increase in MBG. The prohypertensive and profibrotic functions of MBG were pronounced in both DSS and SD rats, although quantitative PCR revealed that different profiles of profibrotic genes in DSS and SD rats was activated after MBG or HS administration. Spatial memory was not affected by HS diet or MBG treatment in either SD or DSS rats. Impaired cognitive function was associated with higher BP, CAS, and cardiovascular remodeling in young DSS-LS rats, as compared to young SD-LS rats. MBG and HS had similar effects on the cardiovascular system and its function in DSS and SD rats, although the rate of change in SD rats was lower than in DSS rats. The absence of a cumulative effect of increased aPWV and BP on spatial memory can be explained by the cerebrovascular and brain plasticity in young rats, which help the animals to tolerate CAS elevated by HS and MBG and to counterbalance the profibrotic effect of heightened MBG.
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/cm2 for 2 min each weekday for a total dose of 1 Einstein (4.5 p.J/cm2 or fluence 3 J/cm2) 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‐β1 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‐β1 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‐β1 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.
Heart rate (HR) and HR variability (HRV), predictors of over-all organism health, are widely believed to be driven by autonomic input to the sinoatrial node (SAN), with sympathetic input increasing ...HR and reducing HRV. However, variability in spontaneous beating intervals in isolated SAN tissue and single SAN cells, devoid of autonomic neural input, suggests that clocks intrinsic to SAN cells may also contribute to HR and HRV
. We assessed contributions of both intrinsic and autonomic neuronal input mechanisms of SAN cell function on HR and HRV via
, telemetric EKG recordings. This was done in both wild type (WT) mice, and those in which adenylyl cyclase type 8 (ADCY8), a main driver of intrinsic cAMP-PKA-Ca
mediated pacemaker function, was overexpressed exclusively in the heart (TG
). We hypothesized that TG
mice would: (1) manifest a more coherent pattern of HRV
, i.e., a reduced HRV driven by mechanisms intrinsic to SAN cells, and less so to modulation by autonomic input and (2) utilize unique adaptations to limit sympathetic input to a heart with high levels of intrinsic cAMP-Ca
signaling. Increased adenylyl cyclase (AC) activity in TG
SAN tissue was accompanied by a marked increase in HR and a concurrent marked reduction in HRV, both in the absence or presence of dual autonomic blockade. The marked increase in intrinsic HR and coherence of HRV in TG
mice occurred in the context of: (1) reduced HR and HRV responses to β-adrenergic receptor (β-AR) stimulation; (2) increased transcription of genes and expression of proteins β-Arrestin, G Protein-Coupled Receptor Kinase 5 (GRK5) and Clathrin Adaptor Protein (Dab2) that desensitize β-AR signaling within SAN tissue, (3) reduced transcripts or protein levels of enzymes dopamine beta-hydorxylase (DBH) and phenylethanolamine
-methyltransferase (PNMT) required for catecholamine production in intrinsic cardiac adrenergic cells, and (4) substantially reduced plasma catecholamine levels. Thus, mechanisms driven by cAMP-PKA-Ca
signaling intrinsic to SAN cells underlie the marked coherence of TG
mice HRV. Adaptations to limit additional activation of AC signaling, via decreased neuronal sympathetic input, are utilized to ensure the hearts survival and prevent Ca
overload.
Highlights ► The relationship between total and visceral adiposity and arterial stiffness, thickness, and diameter is not linear. ► The association between adiposity and arterial properties is ...steeper in women than in men, in younger than in older subjects. ► Waist correlated with arterial properties better than BMI, and independently of BMI.
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