Study Of Human Aging Research Articles

N-Glycan profiling in the study of human aging

Most secreted proteins produced by the human body are modified by glycosylation. It is well known that the oligosaccharides (glycans) of glycoproteins are important for initiation of various cellular recognition signals that are essential for the maintenance of the ordered social life of each cell within a multi-cellular organism. The sugar chains can be altered by the physiological or pathophysiological condition of the cell. We describe a detailed protocol for the analysis of N-linked glycans in blood via DNA sequencing equipment-Fluorophore Assisted Carbohydrate Electrophoresis (DSA-FACE). The key features of this technique are its robustness, high throughput, high sensitivity and reliable quantification. Based on DSA-FACE technology, we previously reported that N-glycan profiling of the human serum shows substantial changes with increasing age in three major N-glycan structures. We proposed that measurement of the N-glycan level changes could provide a surrogate marker for general health or for age-related disease progression, and for monitoring the improvement of health after therapy.

The neonatal progeroid syndrome (Wiedemann–Rautenstrauch): A model for the study of human aging?

The Wiedemann–Rautenstrauch syndrome (WRS) characterises a premature aging syndrome in which several features of human aging are apparent at birth therefore allowing their grouping as a neonatal progeroid condition. This differentiates WRS from other progeroid entities such as Hutchinson–Gilford progeria syndrome (HGPS) in which characteristics of premature aging become apparent some time after birth. The etiology of WRS remains unknown. Some studies have observed an autosomal recessive mode of inheritance. Several studies analysing telomere length and lamin A gene have not revealed any alterations. However, mutations in LMNA have been reported in several other atypical progeroid syndromes. Based on these observations, several hypothesis could be withdrawn concerning the etiology of WRS. The study of genes associated with lamin A metabolism, such as Zmpste24, and the metabolic pathways associated with insulin, such as protein kinase B or AKT, are of particular interest. We believe that WRS characteristics indicate that discovery of the gene and the metabolic pathway associated with this syndrome will most likely lead to new knowledge about the physiopathology of human aging.

Werner syndrome protein: Functions in the response to DNA damage and replication stress in S-phase

Werner syndrome (WS) is an excellent model system for the study of human aging. WRN, a nuclear protein mutated in WS, plays multiple roles in DNA metabolism. Our understanding about the metabolic regulation and function of this RecQ helicase has advanced greatly during the past decade, largely due to the availability of purified WRN protein, WRN knockdown cells, and WRN knockout mice. Recent biochemical and genetic studies indicate that WRN plays significant roles in DNA replication, DNA repair, and telomere maintenance. Interestingly, many WRN functions require handling of DNA ends during S-phase, and evidence suggests that WRN plays both upstream and downstream roles in the response to DNA damage. Future research should focus on the mechanism(s) of WRN in the regulation of the various DNA metabolism pathways and development of therapeutic approaches to treat premature aging syndromes such as WS.

The accuracy of statistical estimates in genetic studies of aging can be significantly improved

The sample size of the data used in genetic studies is often a factor limiting the accuracy of statistical estimates. In this paper we suggest a new approach to evaluation of genetic influence on risk of development of aging-related health disorders. The approach results in substantial improvement of the accuracy of statistical estimates without an increase in the size of the genetic sample. The approach is based on the joint analysis of data from the genetic samples and easily accessible non-genetic data, such as data collected in epidemiological, demographic, and longitudinal studies of human aging and aging-related pathologies.

Search for correlations between serotonin 5-HT1A receptor expression and cognitive functions—a strategy in translational psychopharmacology

Animal studies and studies of human aging have suggested that the serotonin 5-HT1A receptor may serve as a biomarker for cognitive functioning and a target for pharmacological treatment of cognitive deficits. The purpose of this positron emission tomography (PET) study was to search for relationships between interindividual variability in serotonin 5-HT1A receptor binding potential (BP) and cognitive functioning. Twenty-four male control subjects, age 20-55 years, were examined with [11C]WAY100635 PET and a battery of cognitive tests. 5-HT1A receptor binding potential were calculated for the raphe nuclei, the hippocampus and the neocortex. Correlation coefficients between BP and cognitive performance were obtained for each region. There was a severalfold of variability in 5-HT1A BP between individuals. We found no significant correlation between regional [11C]WAY100635 binding and cognitive performance. The results do not provide support for involvement of the 5-HT1A receptor in cognitive functioning in man and question the predictive validity of some currently used animal models in translational neuroscience.

Application of an automated voxel-based morphometry technique to assess regional gray and white matter brain atrophy in a canine model of aging

In recent years, voxel-based morphometry (VBM) has emerged as a technique to examine regional brain changes associated with normal and pathological aging. Despite its popularity in studies of human aging, application of VBM to animal models of brain aging is rare. In the present study, VBM techniques were developed to validate earlier region of interest (ROI) measures of brain aging in the dog and to provide a more comprehensive analysis of local changes in a canine model of brain aging. Consistent with previous findings, frontal lobe atrophy increased with age, most notably in aged male dogs. Age-related gray matter reductions were also observed in parietal and temporal lobes, thalamus, cerebellum, and brainstem. Temporal lobe atrophy was particularly prominent in old females. A number of age-related changes in white matter not previously explored in the dog were also identified with VBM. Specifically, aged males exhibited greater decreases in the internal capsula and cranial nerve bundles compared to decreased volumes in the alveus of the hippocampus in old female dogs. Together, the present results indicate that application of VBM techniques in a canine model of aging yields more comprehensive information regarding topographical patterns of brain aging in male and female dogs than previously reported using traditional manual ROI methods.

Geriatric medicine training in UK undergraduate medical schools

It is generally accepted that the study of human aging and the health-care needs of older people should form part of the undergraduate medical curriculum. This view was supported by policy documents from the World Health Organization, the Royal College of Physicians of London and the General Medical Council. Surveys in the 1980s showed that geriatric medicine was being taught in almost all medical schools, most commonly by a compulsory attachment to a hospital-based department of geriatric medicine.

Multidisciplinary Approaches in Genetic Studies of Human Aging and Longevity

The amount of research on human aging and longevity has been growing rapidly in recent years. Multidisciplinary approaches, which integrate classic population genetics methods with the principles of epidemiological and demographic investigation, are emerging as powerful tools for disentangling the complex gene network which modulates human lifespan. We try to summarize the different approaches and discuss the various aspects concerning their applications in studies of human aging and longevity. We also discuss the significance of the newly emerging DNA chip technology and its implications by highlighting new research topics. In fact, with the entering of the post-genomic era, hints given by observational studies, and thus founded on statistical evidence, can be exploited to cast light upon biological pathways crucial in aging and longevity. Keywords: statistical genetics, longevity

The Victoria Longitudinal Study: From Characterizing Cognitive Aging to Illustrating Changes in Memory Compensation

The article is divided into two sections. First, we describe the key characteristics of the Victoria Longitudinal Study (VLS), including the rationale, design, measures, and research objectives. In general, the VLS may be described as a large-scale, multi-cohort, longitudinal sequential study of human aging. Accordingly, the VLS provides data suitable for multiple descriptive, explanatory, and epidemiological research projects. Second, we present the background, methods and results of three new programmatic studies on intraindividual change and variability in memory compensation. Study 1 reports 6-year change and variability information on five mechanisms of memory compensation. Study 2 describes both personality and health influences on 6-year changes in memory compensation. Study 3 focuses on the influence of initial memory skill on 6-year change and variability in memory compensation.

Sam Greenhouse's scholarly contributions to human aging studies.

Sam Greenhouse's scholarly contributions to human aging studies.

Behavior analysis and the study of human aging

As the population of older adults continues to rise, psychologists along with other behavioral and social scientists have shown increasing interest in this age group. Although behavior analysts have contributed to research on aging, the focus has been on applications that remedy age-related deficits, rather than a concern with aging as a developmental process. In particular, there has been little interest in the central theoretical questions that have guided gerontologists. How does behavior change with advancing years, and what are the sources of those changes? We consider the possibility that this neglect reflects the long-standing commitment of behavior analysts to variables that can be experimentally manipulated, a requirement that excludes the key variable-age itself. We review the options available to researchers and present strategies that minimize deviations from the traditional features of behavior-analytic designs. Our comments are predicated on the view that aging issues within contemporary society are far too important for behavior analysts to ignore.

Monkey in the Middle

Beware, food-loving humans: Proof of calorie restriction's life-extending effects is approaching your species. A new study suggests that dieting rhesus monkeys live twice as long as normal and identifies three physiological changes shared between the primates and enduring humans. Calorie restriction is the only treatment that consistently prolongs the lives of numerous species, from yeast to mice. Whether the regime works in humans remains unclear, in part because a study that measures any intervention's effect on human life-span would be prohibitively expensive and time-consuming (see Walford et al. abstract and comments ). To circumvent that problem, scientists seek physiological parameters--or biomarkers--that provide surrogate measures of aging (see Miller Perspective ). Such biomarkers would likely maintain youthful concentrations in long-lived creatures. In the new work, gerontologist George Roth of the National Institute on Aging (NIA) in Baltimore, Maryland, and colleagues tested whether biomarkers of calorie-restricted monkeys also characterize long-lived humans. For 5 years, Roth's team has fed 30 rhesus monkeys 30% fewer calories than controls. Preliminary data add to previous evidence that calorie restriction works in primates: To date, 13% of the treated animals and 24% of the controls have perished. Although not statistically significant, the results suggest that calorie-restricted monkeys die at half the rate of normal animals. Roth's team previously showed that body temperatures and insulin concentrations of the calorie-restricted monkeys hover well below normal, consistent with observations of dieting mice and rats. For their age, the monkeys also harbor large amounts of dehydroepiandrosterone sulfate (DHEAS), a steroid hormone with an uncertain role in aging whose amounts decline with age. To investigate whether these biomarkers also correlate with longevity in people, the scientists analyzed data gathered as part of the Baltimore Longitudinal Study of Aging (BLSA), the world's longest running study of human aging. Among deceased human males, those who lived longer tended to have lower body temperatures and insulin concentrations and higher DHEAS concentrations. No one knows how calorie restriction works, but recent evidence suggests that it causes organisms to shift metabolic strategies (see "High-Octane Endurance--Yeast in the Metabolic Fast Lane Live Longer" ). The monkeys' low body temperatures mean that their metabolism is producing less heat than normal, so "a lower body temperature is a symptom of metabolic change," says Roth. In addition, reduced insulin concentrations could curb signaling pathways that normally trigger growth at the expense of longevity, he proposes. "This paper is a clever marriage of two NIA data sets [BLSA and rhesus] that advances the knowledge of aging in primates," says gerontologist Richard Weindruch of the University of Wisconsin, Madison. Next, says zoologist Steven Austad of the University of Idaho in Moscow, researchers will need to "determine whether these are general biomarkers or just a quirk of the data set." Numbers already available from studies similar to BLSA, but with fewer subjects, could answer the question quickly, he adds. If the results hold up, they could help scientists identify physiological changes that extend life. Gourmets shouldn't immediately renounce their Port Salut and profiteroles, but they might want to brace their bellies for the possibility. --Bijal P. Trivedi G. S. Roth, M. A. Lane, D. K. Ingram, J. A. Mattison, D. Elahi, J. D. Tobin, D. Muller, E. J. Metter, Biomarkers of caloric restriction may predict longevity in humans. Science 297 , 811 (2002). [Full Text]

The gifts reserved for age.

Many disciplines from the biological and social sciences are relevant to the study of human ageing. The unique contribution of epidemiology lies in defining the phenomenon of ageing and identifying the influences that determine its manifestations. With sadness we recognise, wherever we look in the world, that these influences include privilege, prejudice, and politics. Ageing, in the sense of senescence, is characterized by progressive loss of adaptability of individual organisms as time passes. Such loss of adaptability is revealed by a rise of agespecific mortality rates. In the human being, mortality rates fall from infancy to a nadir at the age of ten or eleven. Thereafter with minor perturbations in early adult life due to deaths from accident and violence, senescence is manifest as a steady and approximately exponential rise in mortality rates for the rest of the lifespan. Perhaps more importantly, loss of adaptability is also declared in the prevalence of disability, which rises exponentially throughout adult life. 1 Most ageing individuals fear disability, and the loss of independence and autonomy it may bring, more than death. Age-associated loss of adaptability comes about through interactions of extrinsic factors in lifestyle and environment with intrinsic, genetically determined susceptibilities. Some interactions are specific; in genetically susceptible organisms a high dietary sodium intake will raise blood pressure. Genetically determined metabolic pathways may turn cigarette smoke into carcinogens. Some of the age-associated syndromes produced by such interactions are dignified with the name of diseases, usually because they have a characteristic pathology or because they can be benefited by treatment. Both in a public health and a biological context, however, attempts to draw some fundamental distinction between disease and ‘normal ageing’ are likely to hinder rather than help. Extrinsic factors also modify the trajectory of human ageing through cohort and secular effects. The work of Barker and colleagues 2 suggests that a powerful form of cohort effect may be generated during life in utero where the metabolism of the fetus adjusts to cues indicative of the sort of environment it is likely to be born into. This form of plasticity can be seen as one example of metabolic switches that may be available to organisms, of some species at least, in other contexts. 3 Examples include the well known life prolongation effects of caloric restriction in rodents 4 which may also prove to exist in primates 5 and in the amenorrhoea precipitated by anorexia nervosa or starvation in women. The evolutionary significance of such switches presumably lies in the efficiency of reproduction, particularly in adjusting reproductive activity to the availability of food supplies. 6 If such switches exist in the human, we

Assessing serial irregularity and its implications for health.

Approximate entropy (ApEn) is a recently formulated family of parameters and statistics quantifying regularity (orderliness) in serial data, with developments within theoretical mathematics as well as numerous applications to multiple biological contexts. We discuss the motivation for ApEn development, from the study of inappropriate application of dynamical systems (complexity) algorithms to general time-series settings. ApEn is scale invariant and model independent, evaluates both dominant and subordinant patterns in data, and discriminates series for which clear feature recognition is difficult. ApEn is applicable to systems with at least 50 data points and to broad classes of models: it can be applied to discriminate both general classes of correlated stochastic processes, as well as noisy deterministic systems. Moreover, ApEn is complementary to spectral and autocorrelation analyses, providing effective discriminatory capability in instances in which the aforementioned measures exhibit minimal distinctions. Representative ApEn applications to human aging studies, based on both heart rate and endocrinologic (hormonal secretory) time series, are featured. Heart rate (HR) studies include gender- and age-related changes in HR dynamics in older subjects, and analyses of "near-SIDS" infants. Endocrinologic applications establish clear quantitative changes in joint LH-testosterone secretory dynamics in older versus younger men (a "partial male menopause"), via cross-ApEn, a related two-variable asynchrony formulation; a disruption in LH-FSH-NPT (penile tumescence) synchrony in older subjects; and changes in LH-FSH secretory dynamics across menopause. The capability of ApEn to assess relatively subtle disruptions, typically found earlier in the history of a subject than mean and variance changes, holds the potential for enhanced preventative and earlier interventionist strategies.

Using yeast to discover the fountain of youth.

The budding yeast Saccharomyces cerevisiae has long served as a model organism for the study of basic cellular processes. Its short generation time, well-established molecular genetics, and fully sequenced genome have made this organism a favorite of researchers in diverse fields. Much of the information obtained has been shown to apply to higher eukaryotes, including humans. Recently, researchers have begun using yeast to tackle one of the outstanding questions in science: How and why do organisms age? The identification of individual genes in yeast that can affect the aging process itself has elevated this single-celled fungus to full contender status in the aging field. In this Perspective, we present two fundamentally different measures of aging in yeast: replicative life-span and stationary phase survival (chronological life-span). We describe the benefits and limitations of each and present models that attempt to explain these "aging" phenomena. Finally, we present compelling evidence that the use of yeast as a model system will ultimately prove beneficial to the study of human aging.

The Werner Syndrome: A Model for the Study of Human Aging

Human aging is a complex process that leads to the gradual deterioration of body functions with time. Various models to approach the study of aging have been launched over the years such as the genetic analysis of life span in the yeast S. cerevisiae, the worm C. elegans, the fruitfly, and mouse, among others. In human models, there have been extensive efforts using replicative senescence, the study of centenerians, comparisons of young versus old at the organismal, cellular, and molecular levels, and the study of premature aging syndromes to understand the mechanisms leading to aging. One good model for studying human aging is a rare autosomal recessive disorder known as the Werner syndrome (WS), which is characterized by accelerated aging in vivo and in vitro. A genetic defect implicated in WS was mapped to the WRN locus. Mutations in this gene are believed to be associated, early in adulthood, with clinical symptoms normally found in old individuals. WRN functions as a DNA helicase, and recent evidence, summarized in this review, suggests specific biochemical roles for this multifaceted protein. The interaction of WRN protein with RPA (replication protein A) and p53 will undoubtedly direct efforts to further dissect the genetic pathway(s) in which WRN protein functions in DNA metabolism and will help to unravel its contribution to the human aging process.

Aging Change of Lumbar Vertebral Bodies in Japanese Macaques (Macaca fuscata fuscata)

This study aimed to examine the occurrence of osteophytic upping (irregular bone formation around the vertebral bodies) and flexion of the vertebral column (wedge-shaped vertebral bodies) using measurements of Japanese macaque (Macaca fuscata fuscata, 22 males and 24 females) lumbar vertebral bodies. It was assumed a priori that osteophytic lipping is reflected in the sagittal and transverse diameters of the vertebral body. In order to evaluate the flexion of the vertebral column, the angle between the cranial and caudal plateaus was measured from the lateral view.Aged female subjects exhibited remarkable lipping. Outstanding disordered values were found particularly in sagittal diameters. The cumulation of the angles revealed the occurrence of wedge shaped vertebral bodies in the caudal lumbar region among aged male subjects. These vertebral bodies might cause hunched curvature of the vertebral column.Those two aspects of vertebral deformation are also found in aged human skeletons. The result shows the affinity between the degenerative deformations of aged human vertebral bodies and those of aged Japanese macaques'. This affinity indicates their importance as an animal model for human aging studies.

Pioglitazone-reduced insulin resistance in patient with Werner syndrome

Werner syndrome is a rare disorder that has provided a useful model for the study of human ageing. Patients with Werner syndrome usually display an aged appearance with various features including loss of hair, cataracts, atrophy of skin and peripheral fat, and diabetes. Mutations in the DNA helicase gene have been shown to be responsible for this disorder. One common feature of Werner syndrome is insulin resistance. However, as is the case in most patients with non-insulin-dependent diabetes mellitus (NIDDM), the precise mechanism underlying the disease is not known. As a step toward understanding the molecular mechanism of insulin resistance in Werner syndrome, we used pioglitazone, a new antidiabetic drug classified as a thiazolidinedione derivative, in a patient with Werner syndrome. Thiazolidinediones improve hyperglycaemia by enhancing insulin sensitivity without stimulating insulin secretion. These drugs have been shown to bind peroxisome proliferator-activated receptor (PPAR ), a dominant activator of fat-cell differentiation. This receptor is likely to mediate the antidiabetic effects of thiazolidinediones, since their affinity to PPAR correlates well with the strength of their effect as insulin sensitisers. A 53-year-old man with Werner syndrome was admitted for glycaemic control. The diagnosis was based on his clinical features and the reduced life-span of cultured fibroblasts. Although he was thin (body-mass index 14·2 kg/m) and had only a small amount of subcutaneous fat (%fat 4·9%), he had a moderate degree of insulin resistance as judged by the exogenous glucose infusion rate (GIR) during euglycaemic hyperinsulinaemic clamp (3·7 mg/kg per min, normal value 10·5 [SD 2·2]). His glycaemia was poorly controlled with a sulfonylurea agent, gliclazide. Written informed consent was obtained and the study was approved by the Institutional Ethical Committee. After 1 week of treatment by dietary restriction alone, pioglitazone 30 mg daily was initiated. After 12 weeks, the GIR had improved to 5·2 mg/kg per min (figure). This effect on the insulin sensitivity was similar to those observed in obese NIDDM patients; according to our data, the average GIR values for NIDDM patients (body-mass index 23 [SD 1·8]%, HbA1c 8·4 [1·4]%) before and after pioglitazone treatment was 8·2 [2·2] and 9·2 [2·0] mg/kg per min, respectively [p=0·003]; Kawamori R, Yamasaki Y, unpublished data). After 12 weeks of pioglitazone treatment, the patient’s fasting plasma glucose had decreased from 187 mg/dL (10·4 mmol/L) to 105 mg/dL (5·8 mmol/L) and glycated haemoglobin from 8·3% to 7·8%. All these glycaemic values deteriorated immediately after discontinuation of pioglitazone (figure). The fasting plasma insulin remained unchanged. These results suggest that pioglitazone was effective in ameliorating impaired insulin sensitivity and thus improved the glycaemic control in our patient. Recently, it was suggested that thiazolidinedione derivatives have direct effects on some tissues other than the adipose tissue, which has been considered to be the target organ of thiazolidinedione derivatives. Among the two isoforms of PPAR , PPAR 1, and PPAR 2, which can be activated to the same extent by a thiazolidinedione derivative, PPAR 1 (and maybe PPAR 2 also) seems to be weakly expressed in skeletal muscle. Also, a weak expression of PPAR 1 can be observed in liver, which seems to increase glucose uptake in response to pioglitazone. Thus, especially for this patient with Werner syndrome whose %fat was as low as 4·9%, the effects of pioglitazone on those non-adipose tissues may have had a role in improving the insulin sensitivity.

The Natural History of Benign Prostatic Hyperplasia: Implications for Patient Care and Clinical Trial Design

Benign prostatic hyperplasia (BPH) is a nearly universal concomitant of male aging, yet its natural history is largely undocumented. Most information on the clinical course of untreated prostatism has come from a limited number of studies. This lack of information makes it difficult for urologists to know when, how, and in whom to intervene. This is reflected by the controversy surrounding surgical indications and by the considerable variability in rates of prostatectomy. Over the last 2 years, information on the natural history of BPH has been obtained from analyses of limited data from long-term, general-purpose, government-sponsored prospective studies of human aging. This paper briefly reviews these studies and discusses implications for patient care decisions and clinical trial design.

Relevance of the rodent model to human aging studies

Rodents have proven to be a useful general model for aging research. Although they are not necessarily appropriate for the study of such specific human age-associated diseases as atherosclerosis, rodents have provided the basis for important age-related findings in many diverse areas, including nutrition, behavior, immunology, physiology, oncology, biochemistry, and neurobiology. Contributions in these areas are briefly reviewed.