Intersalt revisited: further analyses of 24 hour sodium excretion and blood pressure within and across populations. Intersalt Cooperative Research Group.

OBJECTIVES--To assess further the relation in Intersalt of 24 hour urinary sodium to blood pressure of individuals and populations, and the difference in blood pressure from young adulthood into middle age. DESIGN--Standardised cross sectional study within and across populations. SETTING--52 population samples in 32 countries. SUBJECTS--10,074 men and women aged 20-59. MAIN OUTCOME MEASURES--Association of sodium and blood pressure from within population and cross population multiple linear regression analyses with multivariate correction for regression dilution bias. Relation of sample median daily urinary sodium excretion to difference in blood pressure with age. RESULTS--In within population analyses (n = 10,074), individual 24 hour urinary sodium excretion higher by 100 mmol (for example, 170 v 70 mmol) was associated with systolic/diastolic blood pressure higher on average by 3/0 to 6/3 mm Hg (with and without body mass in analyses). Associations were larger at ages 40-59. In cross population analyses (n = 52), sample median 24 hour sodium excretion higher by 100 mmol was associated with median systolic/diastolic pressure higher on average by 5-7/2-4 mm Hg, and estimated mean difference in systolic/diastolic pressure at age 55 compared with age 25 greater by 10-11/6 mm Hg. CONCLUSIONS--The strong, positive association of urinary sodium with systolic pressure of individuals concurs with Intersalt cross population findings and results of other studies. Higher urinary sodium is also associated with substantially greater differences in blood pressure in middle age compared with young adulthood. These results support recommendations for reduction of high salt intake in populations for prevention and control of adverse blood pressure levels.     

Relationship of body size and body mass to blood pressure: sex-specific and developmental influences.

The relationship of body mass and body fat distribution to blood pressure has been recognized for many years. This relationship has formed the basis for much additional research, including the impact of growth and developmental factors on blood pressure levels. Blood pressure in children is related to somatic growth and is tied to increases in height, skeletal maturation, and sexual maturation. Sexual and ethnic differences in blood pressure levels are already apparent during childhood and may also be related to the process of growth and sexual maturity. Body size exerts a profound influence on a variety of physiological functions, including blood pressure and the onset of sexual maturity. In general, studies have reported a strong linear relationship between height and blood pressure and between body mass and blood pressure such that tracking correlations from childhood to adulthood for both blood pressure and body mass index are significant for most sex and ethnic groups. Studies evaluating the effects of hormone replacement therapy on post-menopausal women have thus far generated results suggesting that the age-related rise of blood pressure is not due directly to hormonal changes associated with menopause. The interrelated effects of growth, maturation, body weight, and body fat are influenced by both genetic and environmental factors. Environmental influences may modify relationships established much earlier, perhaps as early as prenatally, during infancy, or during early childhood. Directions for future research and implications resulting from the complex relationship between body weight and blood pressure are discussed.     

Estrogens and age-related memory decline in rodents: what have we learned and where do we go from here?

The question of whether ovarian hormone therapy can prevent or reduce age-related memory decline in menopausal women has been the subject of much recent debate. Although numerous studies have demonstrated a beneficial effect of estrogen and/or progestin therapy for certain types of memory in menopausal women, recent clinical trials suggest that such therapy actually increases the risk of cognitive decline and dementia. Because rodent models have been frequently used to examine the effects of age and/or ovarian hormone deficiency on mnemonic function, rodent models of age-related hormone and memory decline may be useful in helping to resolve this issue. This review will focus on evidence suggesting that estradiol modulates memory, particularly hippocampal-dependent memory, in young and aging female rats and mice. Various factors affecting the mnemonic response to estradiol in aging females will be highlighted to illustrate the complications inherent to studies of estrogen therapy in aging females. Avenues for future development of estradiol-based therapies will also be discussed, and it is argued that an approach to drug development based on identifying the molecular mechanisms underlying estrogenic modulation of memory may lead to promising future treatments for reducing age-related mnemonic decline.     

Ontogeny of Toll-like and NOD-like receptor-mediated innate immune responses in Papua New Guinean infants

Studies addressing the ontogeny of the innate immune system in early life have reported mainly on Toll-like receptor (TLR) responses in infants living in high-income countries, with little or even no information on other pattern recognition receptors or on early life innate immune responses in children living under very different environmental conditions in less-developed parts of the world. In this study, we describe whole blood innate immune responses to both Toll-like and nucleotide-binding oligomerization domain (NOD)-like receptor agonists including the widely used vaccine adjuvant 'alum' in a group of Papua New Guinean infants aged 1-3 (n?=?18), 4-6 (n?=?18), 7-12 (n?=?21) and 13-18 (n?=?10) months old. Depending on the ligands and cytokines studied, different age-related patterns were found: alum-induced IL-1β and CXCL8 responses were found to significantly decline with increasing age; inflammatory (IL-6, IL-1β, IFN-γ) responses to TLR2 and TLR3 agonists increased; and IL-10 responses remained constant or increased during infancy, while TNF-α responses either declined or remained the same. We report for the first time that whole blood innate immune responses to the vaccine adjuvant alum decrease with age in infancy; a finding that may imply that the adjuvant effect of alum in pediatric vaccines could be age-related. Our findings further suggest that patterns of innate immune development may vary between geographically diverse populations, which in line with the 'hygiene hypothesis' particularly involves persistence of innate IL-10 responses in populations experiencing higher infectious pressure.     

Echinococcosis: an emerging or re-emerging zoonosis?

The aim of this review is a critical discussion of factors actually or potentially contributing to persistence or emergence of echinococcosis in humans. Alveolar echinococcosis (AE), a life-threatening infection of humans, is caused by a larval stage of Echinococcus multilocularis. The adult parasite inhabits the intestine of foxes and other carnivores and has a wide distribution in the northern hemisphere (North America and northern and central Eurasia). Recent surveys in central Europe have extended the known geographical occurrence of E. multilocularis in foxes from four countries at the end of the 1980s to at least 11 countries in 1999. Cases of human AE previously regularly reported from only four countries are now recorded from seven countries, but the annual incidences are low. Since adequate information from earlier surveys is not available, it is not possible to conclude if the new findings reflect a recent extension of the parasite's range or just the first identification of hitherto unnoticed endemic areas. Evidence of parasite spreading has been reported from North America and Japan. Factors with the potential of enhancing the infection risk for humans in the future include increasing fox populations and parasite prevalences, progressing invasion of cities by foxes, the establishment of urban cycles of the parasite, and the spill-over of the E. multilocularis infection from wild carnivores to domestic dogs and cats. In view of the potential severity and fatality of AE in humans health authorities should initiate internationally coordinated countermeasures. Although control programmes against human cystic echinococcosis (CE), caused by E. granulosus, have been established in some countries and effective control strategies are available, the parasite has still a wide geographical distribution affecting many countries of all continents. Thus, human CE is persisting in many parts of the world with high incidences, and in some areas it is a re-emerging problem. For example, alarming increases of the number of human cases have been reported from Bulgaria and Kazakhstan, and the People's Republic of China. Progress in control can only be expected if health authorities attribute a higher priority to this disease and if all modern diagnostic and control options (for example vaccination of intermediate host animals) can be used.     

Weight Status Continuity and Change From Adolescence to Young Adulthood: Examining Disease and Health Risk Conditions

This study examined weight status during adolescence and young adulthood, and young adult health condition diagnosis. Data are from 10,439 African‐American, Hispanic, and white men and women participating in the National Longitudinal Study of Adolescent Health during Waves 1 (adolescence: ages 12–19) and 3 (young adulthood: ages 19–26). Categories were created differentiating individuals based on their weight status during adolescence and young adulthood: (i) obese during adolescence and young adulthood (i.e., continuously obese), (ii) obese during adolescence only, (iii) obese during young adulthood only, and (iv) never obese. Multilevel random intercept regression models were used to examine the impact of obesity category, sex, and race/ethnicity on young adult asthma, diabetes, high cholesterol, and high blood pressure. Continuous obesity increased the likelihood for young adult disease and health risk conditions compared to individuals who were never obese. Obesity isolated to adolescence (Wave 1) increased the likelihood for high cholesterol and high blood pressure, whereas obesity isolated to young adulthood (Wave 3) also increased the likelihood for diabetes—all increases were relative to nonobese weight status during both periods. Associations varied in direction and degree when sex and race/ethnicity were considered. Findings clarify some of the mixed understandings regarding the associations between age of onset and stability of obesity, and health outcomes with important public health implications. Although results indicate obesity isolated to a single developmental period does have health repercussions, obesity experienced continuously during adolescence and young adulthood greatly intensified risk across all health conditions.     

Sex differences in control of blood pressure: role of oxidative stress in hypertension in females

In general, blood pressure is higher in normotensive men than in age-matched women, and the prevalence of hypertension in men is also higher until after menopause, when the prevalence of hypertension increases for women. It is likely then that the mechanisms by which blood pressure increases in men and women with aging may be different. Although clinical trials to reduce blood pressure with antioxidants have typically not been successful in human cohorts, studies in male rats suggest that oxidative stress plays an important role in mediating hypertension. The exact mechanisms by which oxidative stress increases blood pressure have not been completely elucidated. There may be several reasons for the discrepancies between clinical and animal studies. In this review, the data obtained in selected clinical and animal studies are discussed, and the hypothesis is put forward that oxidative stress may not be as important in mediating hypertension in females as has been shown previously in male rats. Furthermore, it is likely that differences in genetics, age, length of time with hypertension, endothelial dysfunction, and sex are all factored in to modulate the responses to antioxidants in humans. As such, future clinical trials should be designed and powered to evaluate the effects of oxidative stress on blood pressure separately in men and women.     

Current treatment of adult Duchenne muscular dystrophy

Patients with Duchenne muscular dystrophy (DMD) are living longer into adulthood due to a variety of improvements in health care practices. This growing patient population presents new therapeutic challenges. In this article, we review the literature on current treatment of adult DMD as well as our own experience as a multidisciplinary team actively caring for 23 men ages 19-38 years of age. Approximately one quarter of our adult DMD patients have remained on moderate dose corticosteroids. Daily stretching exercises are recommended, particularly of the distal upper extremities. Cardiomyopathy is anticipated, detected, and treated early with afterload reduction. Oxygen saturation monitoring, noninvasive positive pressure ventilation and cough assist devices are routinely used. Other medical issues such as osteoporosis, gastrointestinal and urinary symptoms are addressed. Current and future therapies directed at prolonging the lifespan of those with DMD will result in further increases in this adult population with special needs and concerns. These needs are best addressed in a multidisciplinary clinic.     

Evidence for a major gene influencing 7-year increases in diastolic blood pressure with age.

The contribution of genetic factors to blood pressure levels is well established. The contribution of genes to the longitudinal change in blood pressure has been less well studied, because of the lack of longitudinal family data. The present study investigated a possible major-gene effect on the observed increase with age in diastolic blood pressure (DBP) levels. Subjects included 965 unmedicated adults (age > or = 18 years) in 73 pedigrees collected in Utah as part of a longitudinal cardiovascular family study. Segregation analysis of DBP change over 7.2 years of follow-up identified a recessive major-gene effect with a gene frequency of p = .23. There was also a significant age effect on the genotypic means, which decreased expression of the major gene at older ages. For those inferred to have the genotype responsible for large DBP increases, DBP increased 32.3%, compared with a 1.5% increase in the nonsusceptible group (P < .0001). The relative risk of developing hypertension between the susceptible and nonsusceptible groups after 7.2 years was 2.4 (P = .006). Baseline DBP reactivities to mental arithmetic (P < .0001), and isometric handgrip (P < .0001) stress tests were greatest in those assigned to the susceptible genotype. We conclude that age-related changes in DBP are influenced by a major gene. Characteristics of this major-gene effect for greater age-related blood pressure increases include greater reactivity to mental and physical stressors. The present study thus provides evidence for genetic control of changes in blood pressure, in addition to the previously suggested genetic control of absolute blood pressure level.     

Predicting all‐cause mortality from basic physiology in the Framingham Heart Study

Using longitudinal data from a cohort of 1349 participants in the Framingham Heart Study, we show that as early as 28–38 years of age, almost 10% of variation in future lifespan can be predicted from simple clinical parameters. Specifically, we found diastolic and systolic blood pressure, blood glucose, weight, and body mass index (BMI) to be relevant to lifespan. These and similar parameters have been well‐characterized as risk factors in the relatively narrow context of cardiovascular disease and mortality in middle to old age. In contrast, we demonstrate here that such measures can be used to predict all‐cause mortality from mid‐adulthood onward. Further, we find that different clinical measurements are predictive of lifespan in different age regimes. Specifically, blood pressure and BMI are predictive of all‐cause mortality from ages 35 to 60, while blood glucose is predictive from ages 57 to 73. Moreover, we find that several of these parameters are best considered as measures of a rate of ‘damage accrual’, such that total historical exposure, rather than current measurement values, is the most relevant risk factor (as with pack‐years of cigarette smoking). In short, we show that simple physiological measurements have broader lifespan‐predictive value than indicated by previous work and that incorporating information from multiple time points can significantly increase that predictive capacity. In general, our results apply equally to both men and women, although some differences exist.     

Life course trajectories of systolic blood pressure using longitudinal data from eight UK cohorts

Background

Much of our understanding of the age-related progression of systolic blood pressure (SBP) comes from cross-sectional data, which do not directly capture within-individual change. We estimated life course trajectories of SBP using longitudinal data from seven population-based cohorts and one predominantly white collar occupational cohort, each from the United Kingdom and with data covering different but overlapping age periods.

Methods and Findings

Data are from 30,372 individuals and comprise 102,583 SBP observations spanning from age 7 to 80+y. Multilevel models were fitted to each cohort. Four life course phases were evident in both sexes: a rapid increase in SBP coinciding with peak adolescent growth, a more gentle increase in early adulthood, a midlife acceleration beginning in the fourth decade, and a period of deceleration in late adulthood where increases in SBP slowed and SBP eventually declined. These phases were still present, although at lower levels, after adjusting for increases in body mass index though adulthood. The deceleration and decline in old age was less evident after excluding individuals who had taken antihypertensive medication. Compared to the population-based cohorts, the occupational cohort had a lower mean SBP, a shallower annual increase in midlife, and a later midlife acceleration. The maximum sex difference was found at age 26 (+8.2 mm Hg higher in men, 95% CI: 6.7, 9.8); women then experienced steeper rises and caught up by the seventh decade.

Conclusions

Our investigation shows a general pattern of SBP progression from childhood in the UK, and suggests possible differences in this pattern during adulthood between a general population and an occupational population. Please see later in the article for the Editors'' Summary     

Over the Hill at 24: Persistent Age-Related Cognitive-Motor Decline in Reaction Times in an Ecologically Valid Video Game Task Begins in Early Adulthood

Typically studies of the effects of aging on cognitive-motor performance emphasize changes in elderly populations. Although some research is directly concerned with when age-related decline actually begins, studies are often based on relatively simple reaction time tasks, making it impossible to gauge the impact of experience in compensating for this decline in a real world task. The present study investigates age-related changes in cognitive motor performance through adolescence and adulthood in a complex real world task, the real-time strategy video game StarCraft 2. In this paper we analyze the influence of age on performance using a dataset of 3,305 players, aged 16-44, collected by Thompson, Blair, Chen & Henrey [1]. Using a piecewise regression analysis, we find that age-related slowing of within-game, self-initiated response times begins at 24 years of age. We find no evidence for the common belief expertise should attenuate domain-specific cognitive decline. Domain-specific response time declines appear to persist regardless of skill level. A second analysis of dual-task performance finds no evidence of a corresponding age-related decline. Finally, an exploratory analyses of other age-related differences suggests that older participants may have been compensating for a loss in response speed through the use of game mechanics that reduce cognitive load.     

Regular aerobic exercise and the age-related increase in carotid artery intima-media thickness in healthy men.

Carotid artery intima-media thickness (IMT), an independent risk factor for stroke, increases with age. Habitual exercise is associated with a lower prevalence of stroke, but it is unclear whether this protective effect could be mediated through a favorable influence on carotid IMT. We examined this possibility using both cross-sectional and intervention approaches. First, 137 healthy men (age 18-77 yr) who were either sedentary or endurance trained were studied. In both groups, carotid IMT and IMT-to-lumen ratio were progressively higher with age (P < 0.05). There were no significant differences in measures of carotid IMT between sedentary and endurance-trained men at any age. Carotid systolic blood pressure increased progressively with age and was related to carotid IMT (r = 0.63, P < 0.01). Second, 18 healthy sedentary subjects (54 +/- 2 yr) were studied before and after 3 mo of endurance training. Carotid IMT, IMT/lumen ratio, and carotid systolic blood pressure did not change with exercise intervention. Our results do not support the hypothesis that regular aerobic exercise exerts its protective effect against stroke by attenuating the age-related increase in carotid IMT. This lack of effect on carotid IMT may be due to the apparent inability of habitual exercise to prevent or reduce the age-associated elevation in carotid distending pressure.     

Age-related changes in blood pressure in the senescence-accelerated mouse (SAM): aged SAMP1 mice manifest hypertensive vascular disease

Age-related changes in systolic blood pressure were assessed, using the senescence-accelerated mouse (SAM) model for aging research with strains SAMR1, SAMP1, and SAMP8. Each of the strains manifested a characteristic change in blood pressure with age. The SAMR1 strain, with normal aging, did not have chronologic changes from 2 to 27 months of age. The SAMP1 strain, with accelerated senescence, had a significant increase in blood pressure with age, and some (8 of 39) mice manifested hypertensive vascular disease characterized by high blood pressure, cardiac hypertrophy, and arteriolar fibrinoid necrosis at 11 to 14 months of age. The gradual increase in blood pressure after 8 to 10 months was considered to be preceded by progressive renal changes, from glomerulonephritis to contraction of the kidney, suggesting that the high blood pressure in the SAMP1 strain was of renal origin. Blood pressure in the SAMP8 strain, with age-related deficits in learning and memory, gradually decreased after 5 to 7 months of age, and was suggested to be due to the astrogliotic changes in response to spongiform degeneration in the medulla oblongata at 11 to 14 and 15 to 18 months of age.     

Stem cell review series: role of neurogenesis in age-related memory disorders

Neuroplasticity is characterized by growth and branching of dendrites, remodeling of synaptic contacts, and neurogenesis, thus allowing the brain to adapt to changes over time. It is maintained in adulthood but strongly repressed during aging. An age-related decline in neurogenesis is particularly pronounced in the two adult neurogenic areas, the subventricular zone and the dentate gyrus. This age-related decline seems to be attributable mainly to limited proliferation, associated with an age-dependent increase in quiescence and/or a lengthening of the cell cycle, and is closely dependent on environmental changes. Indeed, when triggered by appropriate signals, neurogenesis can be reactivated in senescent brains, thus confirming the idea that the age-related decrease in new neuron production is not an irreversible, cell-intrinsic process. The coevolution of neurogenesis and age-related memory deficits – especially regarding spatial memory – during senescence supports the idea that new neurons in the adult brain participate in memory processing, and that a reduction in the ability to generate new neurons contributes to the appearance of memory deficits with advanced age. Furthermore, the age-related changes in hippocampal plasticity and function are under environmental influences that can favor successful or pathological aging. A better understanding of the mechanisms that regulate neurogenesis is necessary to develop new therapeutic tools to cure or prevent the development of memory disorders that may appear during the course of aging in some individuals.     

A mathematical model of ageing in yeast

Budding yeast, Saccharomyces cerevisiae, is commonly used as a system to study cellular ageing. Yeast mother cells are capable of only a limited number of divisions before they undergo senescence, whereas newly formed daughters usually have their replicative age "reset" to zero. Accumulation of extrachromosomal ribosomal DNA circles (ERCs) appears to be an important contributor to ageing in yeast, and we describe a mathematical model that we developed to examine this process. We show that an age-related accumulation of ERCs readily explains the observed features of yeast ageing but that in order to match the experimental survival curves quantitatively, it is necessary that the probability of ERC formation increases with the age of the cell. This implies that some other mechanism(s), in addition to ERC accumulation, must underlie yeast ageing. We also demonstrate that the model can be used to gain insight into how an extra copy of the Sir2 gene might extend lifespan and we show how the model makes novel, testable predictions about patterns of age-specific mortality in yeast populations.     

Age-Related Changes in Biomarkers: Longitudinal Data from a Population-Based Sample

Identifying how biological parameters change with age can provide insights into the physiological determinants of disease, and ultimately, death. Most prior studies of age-related change in biomarkers are based on cross-sectional data, small or selective samples, or a limited number of biomarkers. We use data from a nationally-representative longitudinal sample of 639 Taiwanese aged 54 and older in 2000 to assess changes over a six-year period in a wide range of biomarkers. Markers that increased most with age were glycoslyated hemoglobin, interleukin-6, and norepinephrine. Markers that decreased most with age were diastolic blood pressure and creatinine clearance. For example, glycoslyated hemoglobin increased by 8-13%, on average, over this six-year period. Several standard clinical risk factors exhibited little evidence of age-related change. Further research is needed to determine whether the observed variation between individuals in biomarker changes represents differences in underlying physiological function that are predictive of future health and survival.     

Melatonin and the cardiovascular system

Melatonin concentrations in serum, as well as urinary levels of its main metabolite, 6-sulphatoxymelatonin, decrease with age. In the course of aging, the frequency of heart diseases, both acute and chronic, systematically increases. The evidence from the last 10 years suggests that melatonin influences the cardiovascular system. The presence of vascular melatoninergic receptors/binding sites has been demonstrated; these receptors are functionally linked with vasoconstrictor or vasodilatory effects of melatonin. Melatonin can contribute in cardioprotection of the rat heart, following myocardial ischemia. It has been shown that patients with coronary heart disease have a low melatonin production rate, especially those with higher risk of cardiac infarction and/or sudden death. There are clinical data reporting some alterations of melatonin in human stroke and coronary heart disease. The suprachiasmatic nucleus and, possibly, the melatoninergic system may also modulate cardiovascular rhythmicity. Hypercholesterolemia and hypertension are the other age-related symptoms. People with high levels of LDL-cholesterol have low levels of melatonin. It has been shown that melatonin suppresses the formation of cholesterol by 38% and reduces LDL accumulation by 42%. A 10-20% reduction of cholesterol concentration in women using the B-oval pill has been observed. It is a very important because, even a 10-15% reduction in blood cholesterol concentration has bee shown to result in a 20 to 30% decrease in the risk of coronary heart disease. People with hypertension have lower melatonin levels than those with normal blood pressure. The administration of the hormone in question declines blood pressure to normal range. It has been observed that melatonin, even in a dose 1 mg, reduced blood pressure and decreased catecholamine level after 90 min in human subjects. Melatonin may reduce blood pressure via the following mechanisms: 1) by a direct effect on the hypothalamus; 2) as an antioxidant which lowers blood pressure; 3) by decreasing the level of catecholamines, or 4) by relaxing the smooth muscle in the aorta wall.     

Finding from Asia, Australia, Europe, and North Amercia on secular change in mean height of children, youths, and young adults.

Studies conducted during the past century in Australia, Canada, Japan, Norway and the United States indicate that the magnitude of secular increase in mean height rose with advancing age from childhood to mid-adolescence. Comparisons for a period approximating two-thirds of a century yield average increases in mean height of 12.2 cm for female youths age 12 years, and 12.5 cm for male youths age 14 years; for the same calendar span, the amount of secular increase in mean height declines from mid-adolescence to early adulthood. Comparisons of Belgian females, spanning a period approximating 130 years, yield increases in mean height of 18.1 cm at age 12 years, 11.9 cm at age 16 years, and 3.7 cm in early adulthood. For a period of 90 years, increases obtained on United States White males are 14.8 cm at age 14 years, 8.8 cm at age 17 years, and 5.3 cm in early adulthood. These and other displayed findings show clearly that the search for causes of secular change should take particular account of a phenomenon widespread among human populations, i.e., the phenomenon of childhood and early adolescent growth in body height proceeding at a faster pace in recent decades than about a century ago.     

Stem cell function and maintenance – ends that matter: Role of telomeres and telomerase

Stem cell research holds a promise to treat and prevent age-related degenerative changes in humans. Literature is replete with studies showing that stem cell function declines with aging, especially in highly proliferative tissues/organs. Among others, telomerase and telomere damage is one of the intrinsic physical instigators that drive age-related degenerative changes. In this review we provide brief overview of telomerase-deficient aging affects in diverse stem cells populations. Furthermore, potential disease phenotypes associated with telomerase dysregulation in a specific stem cell population is also discussed in this review. Additionally, the role of telomerase in stem cell driven cancer is also briefly touched upon.