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Older individuals represent a growing population, in industrialized countries, particularly those with cardiovascular diseases, which remain the leading cause of death in western societies. Aging constitutes one of the largest risks for cardiovascular diseases. On the other hand, oxygen consumption is the foundation of cardiorespiratory fitness, which in turn is linearly related to mortality, quality of life and numerous morbidities. Therefore, hypoxia is a stressor that induces beneficial or harmful adaptations, depending on the dose. While severe hypoxia can exert detrimental effects, such as high-altitude illnesses, moderate and controlled oxygen exposure can potentially be used therapeutically. It can improve numerous pathological conditions, including vascular abnormalities, and potentially slows down the progression of various age-related disorders. Hypoxia can exert beneficial effects on inflammation, oxidative stress, mitochondrial functions, and cell survival, which are all increased with age and have been discussed as main promotors of aging. This narrative review discusses specificities of the aging cardiovascular system in hypoxia. It draws upon an extensive literature search on the effects of hypoxia/altitude interventions (acute, prolonged, or intermittent exposure) on the cardiovascular system in older individuals (over 50 years old). Special attention is directed toward the use of hypoxia exposure to improve cardiovascular health in older individuals. [ABSTRACT FROM AUTHOR]

This paper proposes a new estimation formula of the vessel age (VA), an index of the degree of atherosclerosis, based on parameters derived from acceleration plethysmogram (APG), which is the second-order derivative of the photoplethysmogram (PPG). The current estimation formula utilizes the sequence of five extreme values a, b, c, d, e observed in the APG waveform. The multiple regression analysis revealed that the parameters c/a and d/a play a significant role in estimating VA. To improve the estimation accuracy, the slope Sbd between two extreme values b and d is added to parameters c/a and d/a for the estimation. The parameter includes the information which reflects the APG waveform duration known to be an index to probe the large artery stiffness. The new vessel age estimation formula based on the multiple regression of these three parameters is evaluated by the PPG data collected from 347 healthy subjects aged 20-60 years (40.2 ± 12.4). The method will be effectively utilized for the early detection of the development of atherosclerosis. [ABSTRACT FROM AUTHOR]

Oxidative stress and impaired antioxidant defense are believed to be contributors to the cardiovascular aging process. The transcription factor nuclear factor-E2-related factor 2 (Nrf2) plays a key role in orchestrating cellular antioxidant defenses and maintaining redox homeostasis. Our previous study showed that Exendin-4, a glucagon-like peptide-1 analog, alleviates angiotensin II (ANG II)-induced vascular smooth muscle cell (VSMC) senescence by inhibiting Rac1 activation via cAMP/PKA (Zhao L, Li AQ, Zhou TF, Zhang MQ, Qin XM. Am J Physiol Cell Physiol 307: C1130-C1141, 2014). The objective of this study is to investigate if Nrf2 mediates the antisenescent effect of Exendin-4 in ANG II-induced VSMCs. Here we report that Exendin-4 triggered Nrf2 nuclear translocation, a downstream target of cAMP-responsive element-binding protein (CREB) and expressions of antioxidant genes heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase-1 (NQO-1) in a dose- and time-dependent manner. In addition, knockdown of Nrf2 attenuated the inhibitory effects of Exendin-4 on ANG II-induced superoxidant generation and VSMC senescence. PKA/ CREB pathway participated in the upregulations of HO-1 and NQO-1 induced by Exendin-4. Notably, our study revealed that Exendin-4 dose-dependently increased the acetylation of Nrf2 and the recruitment of transcriptional coactivator CREB binding protein (CBP) to Nrf2. The Exendin-4-induced Nrf2 transactivation was diminished in the presence of CBP small interfering RNA. Microscope imaging of Nrf2, as well as immunoblotting for Nrf2, showed that the Exendin- 4-evoked Nrf2 acetylation favored its nuclear retention. Importantly, CBP silencing attenuated the suppressing effects of Exendin-4 on ANG II-induced VSMC senescence and superoxidant production. In conclusion, these results provide a mechanistic insight into how Nrf2 signaling mediates the antisenescent and antioxidative effects induced by Exendin-4 in VSMCs. [ABSTRACT FROM AUTHOR]

Aging has important deleterious effects on the cardiovascular system. We sought to compare intraventricular kinetic energy (KE) in healthy subjects of varying ages with subjects with ventricular dysfunction to understand if changes in energetic momentum may predispose individuals to heart failure. Four-dimensional flow MRI was acquired in 35 healthy subjects (age: 1-67 yr) and 10 patients with left ventricular (LV) dysfunction (age: 28-79 yr). Healthy subjects were divided into age quartiles (1st quartile: <16 yr, 2nd quartile: 17-32 yr, 3rd quartile: 33-48 yr, and 4th quartile: 49-64 yr). KE was measured in the LV throughout the cardiac cycle and indexed to ventricular volume. In healthy subjects, two large peaks corresponding to systole and early diastole occurred during the cardiac cycle. A third smaller peak was seen during late diastole in eight adults. Systolic KE (P = 0.182) and ejection fraction (P = 0.921) were preserved through all age groups. Older adults showed a lower early peak diastolic KE compared with children (P < 0.0001) and young adults (P = 0.025). Subjects with LV dysfunction had reduced ejection fraction (P < 0.001) and compared with older healthy adults exhibited a similar early peak diastolic KE (P = 0.142) but with the addition of an elevated KE in diastasis (P = 0.029). In healthy individuals, peak diastolic KE progressively decreases with age, whereas systolic peaks remain constant. Peak diastolic KE in the oldest subjects is comparable to those with LV dysfunction. Unique age-related changes in ventricular diastolic energetics might be physiological or herald subclinical pathology. [ABSTRACT FROM AUTHOR]

Introduction: Cardiovascular disease is a leading cause of morbidity and mortality in the United States. Heart age (the predicted age of a person's vascular system based on their cardiovascular risk factor profile) and its comparison with chronological age represent a new way to express risk for developing cardiovascular disease. This study estimates heart age and differences between heart age and chronological age (excess heart age) and examines racial, sociodemographic, and regional disparities in heart age among U.S. adults aged 30-74 years. Methods: Weighted 2011 and 2013 Behavioral Risk Factor Surveillance System data were applied to the sex-specific non-laboratory-based Framingham risk score models, stratifying the results by age and race/ethnic group, educational and income level, and state. These results were then translated into age-standardized heart age values, mean excess heart age was calculated, and the findings were compared across groups. Results: Overall, average predicted heart age for adult men and women was 7.8 and 5.4 years older than their chronological age, respectively. Statistically significant (p<0.05) racial/ethnic, sociodemographic, and regional differences in heart age were observed: heart age among non-Hispanic black men (58.7 years) and women (58.9 years) was greater than other racial/ethnic groups, including non-Hispanic white men (55.3 years) and women (52.5 years). Excess heart age was lowest for men and women in Utah (5.8 and 2.8 years, respectively) and highest in Mississippi (10.1 and 9.1 years, respectively). Conclusions and Implications for Public Health Practice: The predicted heart age among U.S. adults aged 30-74 years was significantly higher than their chronological age. Use of predicted heart age might 1) simplify risk communication and motivate more persons to live heart-healthy lifestyles and better comply with recommended therapeutic interventions, and 2) motivate communities to implement programs and policies that support cardiovascular health. [ABSTRACT FROM AUTHOR]

Aging is associated with declines in the neuromuscular and cardiovascular systems, resulting in an impaired capacity to perform daily activities. Frailty is an age-associated biological syndrome characterized by decreases in the biological functional reserve and resistance to stressors due to changes in several physiological systems, which puts older individuals at special risk of disability. To counteract the neuromuscular and cardiovascular declines associated with aging, as well as to prevent and treat the frailty syndrome, the strength and endurance training seems to be an effective strategy to improve muscle hypertrophy, strength and power output, as well as endurance performance. The first purpose of this review was discuss the neuromuscular adaptations to strength training, as well as the cardiovascular adaptations to endurance training in healthy and frail elderly subjects. In addition, the second purpose of this study was investigate the concurrent training adaptations in the elderly. Based on the results found, the combination of strength and endurance training (i.e., concurrent training) performed at moderate volume and moderate to high intensity in elderly populations is the most effective way to improve both neuromuscular and cardiorespiratory functions. Moreover, exercise interventions that include muscle power training should be prescribed to frail elderly in order to improve the overall physical status of this population and prevent disability. [ABSTRACT FROM AUTHOR]

Advanced age is associated with a disproportionate prevalence of cardiovascular disease (CVD). Intrinsic alterations in the heart and the vasculature occurring over the life course render the cardiovascular system more vulnerable to various stressors in late life, ultimately favoring the development of CVD. Several lines of evidence indicate mitochondrial dysfunction as a major contributor to cardiovascular senescence. Besides being less bioenergetically efficient, damaged mitochondria also produce increased amounts of reactive oxygen species, with detrimental structural and functional consequences for the cardiovascular system. The agerelated accumulation of dysfunctional mitochondrial likely results from the combination of impaired clearance of damaged organelles by autophagy and inadequate replenishment of the cellular mitochondrial pool by mitochondriogenesis. In this review, we summarize the current knowledge about relevant mechanisms and consequences of age-related mitochondrial decay and alterations in mitochondrial quality control in the cardiovascular system. The involvement of mitochondrial dysfunction in the pathogenesis of cardiovascular conditions especially prevalent in late life and the emerging connections with neurodegeneration are also illustrated. Special emphasis is placed on recent discoveries on the role played by alterations in mitochondrial dynamics (fusion and fission), mitophagy, and their interconnections in the context of age-related CVD and endothelial dysfunction. Finally, we discuss pharmacological interventions targeting mitochondrial dysfunction to delay cardiovascular aging and manage CVD. [ABSTRACT FROM AUTHOR]

Over the past decade, numerous studies have shown that increased aortic stiffness is associated with major cardiovascular disease end points, including heart disease, stroke, and kidney disease. Cardiac abnormalities and enhanced atherogenesis in the setting of increased pulsatile load on heart and arteries have been well described. However, recent studies have shown a further association between excessive pressure pulsatility and a number of afflictions of aging that share a predominant microvascular etiology, including many forms of kidney disease and cognitive impairment. In these disorders, microvascular remodeling and impaired regulation of local blood flow, which are related to large artery stiffness and pressure pulsatility, are associated with evidence of diffuse microscopic tissue damage. This brief review will summarize age-related changes in aortic and peripheral vascular function and will discuss potential mechanisms leading from changes in properties of large arteries to excessive pressure pulsatility, abnormal microvascular structure and function, and end-organ dysfunction and damage. [ABSTRACT FROM AUTHOR]

Vascular and associated ventricular stiffness is one of the hallmarks of the aging cardiovascular system. Both an increase in reactive oxygen species production and a decrease in nitric oxide (NO) bioavailability contribute to the endothelial dysfunction that underlies this vascular stiffness, independent of other age-related vascular pathologies such as atherosclerosis. The activation/upregulation of arginase appears to be an important contributor to age-related endothelial dysfunction by a mechanism that involves substrate (L-arginine) limitation for NO synthase (NOS) 3 and therefore NO synthesis. Not only does this lead to impaired NO production but also it contributes to the enhanced production of reactive oxygen species by NOS. Although arginase abundance is increased in vascular aging models, it appears that posttranslational modification by S-nitrosylation of the enzyme enhances its activity as well. The S-nitrosylation is mediated by the induction of NOS2 in the endothelium. Furthermore, arginase activation contributes to aging-related vascular changes by mechanisms that are not directly related to changes in NO signaling, including poly- amine-dependent vascular smooth muscle proliferation and collagen synthesis. Taken together, arginase may represent an as yet elusive target for the modification of age-related vascular and ventricular stiffness contributing to cardiovascular morbidity and mortality. [ABSTRACT FROM AUTHOR]

Background: Although generally assumed to be an adaptive response to increased blood pressure (BP), arterial stiffness is now recognized as an independent predictor of cardiovascular (CV) events [1]. Moreover it precedes hypertension in at least two mouse models [2-3]. Therefore, the present study aims to investigate the temporal development of aortic stiffening and peripheral blood pressure (BP) alterations in spontaneously ageing mice. Methods: A longitudinal cardiovascular characterization of spontaneously ageing C57Bl6 mice (2, 4, 6, 9, 12 and 24- month old) (male, n > 8) was performed. This includes in vivo analysis of peripheral BP (Coda) and aortic pulse wave velocity (aPWV, Vevo2100), combined with ex vivo aortic studies of isometric reactivity (organ baths) and aortic stiffness measurements (Peterson modulus, Ep) in the Rodent Oscillatory Tension set-up for Arterial Compliance (ROTSAC). Results: In vivo and ex vivo characterisation confirms that aortic stiffness precedes peripheral BP alterations in spontaneously ageing C57Bl6 mice, with significantly increased aPWV from 6 month of age (Figure A), whereas peripheral BP measurement only shows elevated pulse pressure in 24 month old mice (30% increase vs. all other ages, Figure B). Ex vivo investigation of the thoracic aorta further reveals that the aortic stiffening is both contraction-independent (Figure C) and dependent (Figure D), since older mice display increased contractions to phenylephrine (PE) (Figure E and F). Conclusion: Spontaneously ageing C57Bl6 mice present with significant aortic stiffness by 6-months of age, which is both contraction-dependent and independent in origin. Aortic stiffness thereby precedes the development of peripheral BP alterations by 18 months. [ABSTRACT FROM AUTHOR]

Endothelial dysfunction and increased arterial stiffness contribute to multiple vascular diseases and are hallmarks of cardiovascular aging. To investigate the effects of aging on shear stress-induced endothelial nitric oxide (NO) signaling and aortic stiffness, we studied young (3-4 mo) and old (22-24 mo) rats in vivo and in vitro. Old rat aorta demonstrated impaired vasorelaxation to acetylcholine and sphingosine 1-phosphate, while responses to sodium nitroprusside were similar to those in young aorta. In a customized flow chamber, aortic sections preincubated with the NO-sensitive dye, 4-amino-5-methyl-amino-2′,7′-difluorofluorescein diacetate, were subjected to steady-state flow with shear stress increase from 0.4 to 6.4 dyn/cm². In young aorta, this shear step amplified 4-amino-5-methylamino-2′,7′-difluorofluorescein fluorescence rate by 70.6 ± 13.9%, while the old aorta response was significantly attenuated (23.6 ± 11.3%, P < 0.05). Endothelial NO synthase (eNOS) inhibition, by ZV°-monomethyl-L-arginine, abolished any fluorescence rate increase. Furthermore, impaired NO production was associated with a significant reduction of the phosphorylated-Akt-to-total-Akt ratio in aged aorta (P < 0.05). Correspondingly, the phosphorylated-to-total-eNOS ratio in aged aortic endothelium was markedly lower than in young endothelium (P < 0.001). Lastly, pulse wave velocity, an in vivo measure of vascular stiffness, in old rats (5.99 ± 0.191 m/s) and in Nω-nitro-L-arginine methyl ester-treated rats (4.96 ± 0.118 m/s) was significantly greater than that in young rats (3.64 ± 0.068 m/s, P < 0.001). Similarly, eNOS-knockout mice demonstrated higher pulse wave velocity than wild-type mice (P < 0.001). Thus impaired Akt-dependent NO synthase activation is a potential mechanism for decreased NO bio-availability and endothelial dysfunction, which likely contributes to age-associated vascular stiffness. [ABSTRACT FROM AUTHOR]

The development of myocardial and large vessel stiffness with aging underlies the development of diastolic heart failure and isolated systolic hypertension. Nonenzymatic reaction between glucose and proteins (Maillard reaction) leading to collagen crosslinking in the myocardium and arterial wall has been implicated in age-related increase in cardiovascular stiffness. In the present issue, Chang et al. show that aminoguanidine, an inhibitor of protein crosslinking, retards age-related decline in the elastic properties of the left ventricle and arteries. The significance of these findings is discussed in this commentary. [ABSTRACT FROM AUTHOR]

In light of previous observations that the range of arterial pressures over which cerebral blood flow is autoregulated differs dramatically in neonates and adults, the present experiments explored the hypothesis that pressure-induced intrinsic arterial tone is regulated differently in neonatal and adult cerebral arteries. In cannulated and pressurized endothelium-intact mouse cerebral arteries < 150 μm in diameter, active intrinsic tone was evident at intraluminal pressures as low as 10 mmHg in neonatal arteries, but only at pressures of 60 mmHg or greater in adult arteries. Administration of 10 μM indomethacin produced no significant effect on tone at any pressure in either neonatal or adult arteries, but subsequent addition of 100 μM nitroarginine methyl ester (NAME) significantly vasoconstricted both neonatal and adult arteries at all pressures. Conversely, administration of 100 μM NAME alone significantly vasoconstricted adult arteries only, and subsequent addition of 10 μM indomethacin produced a significant additional vasoconstriction in adult arteries only, indicating an important interaction between the nitric oxide synthase and cyclooxygenase pathways, at least in adult arteries. In the presence of both indomethacin and NAME, intrinsic tone was significantly greater in neonatal than adult arteries, but when the endothelium was removed, tone was similar in neonatal and adult arteries at all pressures. Together, these results suggest that pressure-induced myogenic tone is regulated similarly in neonatal and adult mouse cerebral arteries but that the contribution of endothelial vasoactive factors to intrinsic tone is highly age dependent. [ABSTRACT FROM AUTHOR]

Presents a study which determined whether angiotensin II could reverse age-related, impaired beta-adrenergic receptor-mediated vasorelaxation. Characteristics of an aged cardiovascular system; Methodology; Results and discussion.

Presents information on a stud which examined the use of color kinesis images in the assessment of left ventricular wall motion over a wide range of ages. Methodology of the study; Results and discussion on the study.

Characterizes the effects of aging on autonomic mediation of heart rate, lung volume and interrelationships between lung volume and heart rate. Demonstration of differences in individual heart rate, lung volume time series content and delay in information transfer between lung volume and heart rate.

In this issue of Cell, Loffredo et al. demonstrate that exposing an old mouse to the circulatory system of a young mouse reverses age-related cardiac hypertrophy. The authors demonstrate that this effect can be recapitulated by treating old mice with growth and differentiation factor 11 (GDF11). These data suggest that GDF11 therapy may be a useful tool in combating age-related cardiac hypertrophy. [ABSTRACT FROM AUTHOR]

Atherosclerosis and heart failure are major causes of morbidity and mortality in Western countries. Recent studies are suggesting involvement of telomere biology in the development and progression of age-associated conditions, including hypertension, atherosclerosis, and heart failure. Whether any of these reported associations are based on causal relationships remains to be elucidated. The construction of telomerase-deficient (telomerase RNA component, TERC−/−) mice might provide a potential instrumental model to study the involvement of telomere biology in cardiovascular disease. Here, we review the current available information from all studies performed in TERC−/− mice providing information on the cardiovascular phenotypic characteristics. Although this mouse model has proven its value in the understanding of the role of telomere biology in cancer, stem cell, and basic telomere research, only few studies were specifically designed to answer cardiovascular-related questions. The TERC−/− mice provide exciting opportunities to expand our knowledge of telomere biology in cardiovascular disease and the potential identification of novel targets of treatment. [ABSTRACT FROM AUTHOR]