Longevity Health and Wellness Protocol

Get Younger Tomorrow Reversing 20 Years Of Aging

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Elderly people with mental retardation Life expectancy

As a result of this increasing longevity, causes of death which are more common in a normal ageing population are becoming more prominent among people with mental retardation. The main cause of death for people with mental retardation is non-tubercular respiratory disease, which occurs far more frequently than in the whole population.(27) The high prevalence of respiratory disease as the main cause of death suggests lack of effective care for people with mental retardation. (25)

The Vitalist Challenge To Mechanism In Biology

Mechanists in biology long confronted a challenge from theorists, often called vitalists, who objected that mechanistic accounts were inadequate to account for the distinctive features of living organisms. Mechanistic approaches to physiology proved so successful that by the early-twentieth century vitalism was remembered only for its misbegotten appeals to vital forces or vital spirits. Although some vitalists did posit special powers or forces that they construed as nonphysi-cal, others downplayed the radical nature of their position. They compared their approach to Newton's just as Newton had deviated from the Cartesian mechanists in appealing to gravitational forces to explain the behavior of ordinary physical objects, the vitalists maintained the need to appeal to vital forces to characterize what happened in living organisms. Just as Newton packaged his account in terms of laws of motion, the vitalists sought the distinctive laws of biology that described the operation of forces...

Longevity

Longevity is of prime importance in a chronic electrode that will be implanted in a young adult human for a lifetime that can extend beyond fifty years. Clearly, the NE is ahead in this respect so far 5 , although recent reports from Donoghue's lab show a few signals enduring for years 10 . In all animal and human subjects, the signals from the NE continued until the preparation was destroyed or the subject died. The NE has endured in two humans for more than four years Kennedy et al., manuscript in preparation .

Principles Of Public Health

Public health is the science and art of disease prevention, prolonging life and promoting health and well-being through organized community effort for the sanitation of the environment, the control of communicable diseases, the organization of medical and nursing services for the early diagnosis and prevention of disease, the education of the individual in personal health and the development of the social machinery to ensure for everyone a standard of living adequate for the maintenance or improvement of health (1). The goal of public health is to fulfil every society's ambition to create conditions in which all people can be healthy. Public health addresses the health of the population as a whole rather than the treatment of individuals. WHO defines health as a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity (2). Healthy people in healthy communities is the ultimate goal of all public health interventions, which are aimed at...

Aging as a Risk Factor

It has been proposed that AD might reflect a continuum of the aging process (Brayne & Calloway, 1988). In other words, given the opportunity, every individual should eventually succumb to AD. This view can be supported by the undeniable fact that aging is the most important of the nongenetic risk factors as shown by the ever growing incidence of AD with aging. On the other hand, the prevalent notion is that the incidence of AD is influenced by a multitude of risks factors (as discussed below) in addition to aging, which might act in a cooperative manner. The extent of the life span could also be regulated by the genetic background interacting with environmental as well as lifestyle aspects (Finch & Tanzi, 1997). The role of genetics in determining the life span is complex and paradoxical. In short, the prevalent view is that for the sporadic form of AD, it is not necessarily all in the genes but rather an interplay with the life experience of that particular individual. The...

Example Two Bottle Experiment

The results of the two-bottle experiment are summarized graphically in Figure 3.1. The different cyclophosphamide doses produced TA of differing magnitude and longevity. It may be important to note that the 12.5 mg kg and the 25 mg kg doses both produced initially strong aversions that were of similar magnitude over the first 10 days

The Future Is So Bright

The implications of these two significantly distinct mortality rates are profound. First, these investigators have discovered with genomic technologies and bioinformatics analyses a new subcategory of large B-cell lymphoma, a new diagnosis with clinical significance. Second, they have generated a tool that provides (pending confirmation in other studies) a new prognosis patients can be given much more precise estimates of their longevity. Third, it provides a new therapeutic opportunity patients with an expression pattern predicting a poor response to standard therapy may be treated with different (e.g., much more aggressive) chemotherapy. Fourth, it

Example Single Bottle Experiment

Dose-dependent differences in initial aversion magnitude as measured by single-bottle post-conditioning consumption of the saccharin CS solution were demonstrated (see Figure 3.2). The most noteworthy feature of the single-bottle results is the rapid extinction that occurred at all dose levels. Even the CTA induced by a 50 mg km dose extinguished completely following two test sessions. This rapid extinction is not necessarily a disadvantage, depending on the objective of the researcher. However, it is apparent that the obtainable strength and longevity of CTAs induced by injection of an emetic class agent would not have been observed if all CTA methodology had featured fluid-deprivation driven single-bottle tests of aversive strength to the exclusion of two-bottle free-choice testing methodology.

Anatomical considerations

With advancing age, elastin fragmentation, fibrosis, and medial necrosis lead to degeneration of the aortic lamellas. These changes are most pronounced in the ascending aorta and become less prominent as the aorta descends into the abdomen. These changes occur as part of the normal aging process but are more prominent in hypertensive patients. Pre-existing dilation of the aorta (as occurs in Marfan's syndrome) may also be relevant. Laplace's law relates wall stress to pressure and diameter as the aorta dilates, so wall stress increases. Medial degeneration may result from structural abnormalities (e.g. Marfan's and Ehlers-Danlos syndromes) in which dissection may occur without pre-existing hypertension or, possibly, from ischemic necrosis due to occlusion of the vasa vasorum.

With Type 1 Diabetes Mellitus

At the turn of the century a patient diagnosed with Type 1 diabetes mellitus had average life expectancy of only two years. The development of insulin as a therapeutic agent revolutionized the treatment of diabetes mellitus by changing it from a rapidly fatal disease into a chronic illness. Unfortunately this increased longevity brought to the fore serious secondary complications including nephropathy, neuropathy, retinopathy and macro- and microvascular complications in survivors 10 to 20 years after disease onset. The annual national direct and indirect costs of Type 1 and 2 diabetes in 2002 - including hospital and physician care, laboratory tests, pharmaceutical products, and patient workdays lost because of disability and premature death - exceeded 130 billion.1

Mechanism Of Vitamin A Action

Despite the expectation of exquisite specificity fostered by the various discrete combinations of RAR and RXR isoforms, these receptors exhibit a great deal of apparent functional redundancy and or ability to compensate for loss of another. In gene knockout experiments, more than one receptor can perform the same function in vivo, although this may represent an artifact of the knockouts and demonstrate what can happen, not necessarily what does occur.11 Nevertheless, receptor ablation has provided enormous insight into receptor function. Deletion of the RARa gene results in postnatal lethality within 24 h RARa-null mice represent only 3 of the population by 1 to 2 months of age. Of these, 60 have webbed digits on both fore and hind limbs. A few mice survive 4 to 5 months, but no males are fertile, and all have severe degeneration of the testis germinal epithelium. RARP-null mice have locomotor defects, reminiscent of Parkinson's disease, but are fertile with normal longevity....

TA Conditioning and Assessment Methodology

The basic CTA paradigm will be illustrated by describing an early comparison of the effects of single trial conditioning as assessed via one-bottle and two-bottle test methodologies. The objective was to develop parametric data concerning the magnitude and longevity of cyclophosphamide (Cytoxan , Mead Johnson Laboratories) induced aversions to a saccharin-flavored CS solution.11 Cyclophosphamide is a nitrogen-mustard derivative that produces strong nausea in humans when used during cancer chemotherapy, and presumably has some comparable effect in rats where it can function as a potent CTA inducer. Saccharin solutions are frequently used as CSs during TA experiments with rats. Saccharin is a nonnutritive and therefore does not introduce a caloric source of variability. Additionally, palatable saccharin solutions can be prepared that are usually accepted by fluid-deprived rats without any disruptive neophobia, which is operationally defined as a rejection of unfamiliar flavors.12 The...

Nigrostriatal Pathway And Pd

The role of free radicals in apoptosis, and the aging process has received considerable attention.3 Factors that decrease free radical damage, including limiting caloric intake and the use of antioxidants, have been associated with slowing of the normal aging process and with increasing longevity.3 45-8 Although PD has been reported in relatively young persons, the likelihood of an individual developing PD increases as one ages. The mean age at death in PD patients increased from about 60 years in 1950 to 77 years in 1992 for both sexes living in Japan from 1950 to 1992.16 In the United States, approximately 1 of the population over the age of 60 years is afflicted with PD.17 The number of affected individuals and the cost associated with caring for affected individuals is likely to increase dramatically over the next several decades as the world's population becomes older and those individuals afflicted with PD live longer with the disease.1618 Projections indicate that therapies...

Nonparametric Tests of Significance

The biologic disciplines that are the basis of the health sciences, clinical research is often more concerned with the practical issues of preventing disease, treating illness, and prolonging life. The object of measurement, in turn, is determining the presence or absence of risk factors, assessing the presence or absence of particular diseases, and estimating survival (the presence or absence of death). These measures are all nominal categories, and the numbers are body counts (eg, the number of people with angina, treated with a P-blocker, who survived 1 year). These kinds of data require different kinds of statistical methods, called nonparametric statistics, for analysis. By far the most common nonparametric test is the chi-square test.

Peter Csermely Csaba Soti and Gregory L Blatch Abstract

The most important interactions between cellular molecules have a high affinity, are unique and specific, and require a network approach for a detailed description. Molecular chaperones usually have many first and second neighbors in protein-protein interaction networks and they play a prominent role in signaling and transcriptional regulatory networks of the cell. Chaperones may uncouple protein, signaling, membranous, organellar and transcriptional networks during stress, which gives an additional protection for the cell at the network-level. Recent advances uncovered that chaperones act as genetic buffers stabilizing the phenotype of various cells and organisms. This chaperone effect on the emergent properties of cellular networks may be generalized to proteins having a specific, central position and low affinity, weak links in protein networks. Cellular networks are preferentially remodeled in various diseases and aging, which may help us to design novel therapeutic and anti-aging...

General Clinical Considerations of Brain Computer Interfaces

In addition to the processing issues that define the requirements of a BCI system, there is a unique set of factors that a clinician must consider about a given platform when considering application to a patient population. The most fundamental issue is that a BCI system is safe. First, surgical placement must have acceptable clinical risk, and then subsequently over time the implant must be reliable and durable in its ability to acquire signals. Understanding the risks of initial surgical application is reasonably straightforward as they will most likely utilize variants of standard neurosurgical practices. There are equivalent types of technical procedures, which include the placement of deep brain stimulators, placement of cortical stimulators for pain, and placement of grid electrodes. What will require closer examination is the construct's likelihood for ongoing function. This can be affected by how the device is designed (i.e., will the construct break down in a couple years )...

Dietary Effects on Mortality

Despite the abundance of dietary guidelines, it is hard to find evidence that dietary composition has major effects on longevity. In the Malmo Diet and Cancer Study, all-cause mortality rates were not significantly related to the fat content of the diet in either men or women 7 . The rate of death attributable to cardiovascular disease, however, was significantly inversely related to dietary fat intake in men, but not in women. The EPIC study evaluated dietary intake as a predictor of mortality among over 70,000 people at least 60 years of age in 10 European countries 8 . Instead of evaluating simple dietary composition (i.e. percent of calories from fat, carbohydrate, protein, and alcohol), they constructed a 'Mediterranean diet score' reflecting the dietary composition previously shown in Greece to be associated with longevity. The score was derived from points for answering dietary questions on consumption of various types of foods. Higher scores, indicating dietary composition...

Paradigm Shift Involving Patients in Healthcare Decisions

Accompanying this shift has been a change in clinicians' attitudes. Many clinicians now recognize that healthcare decisions often involve trade-offs that require value judgments. For example, oncology trials used to measure survival rates while paying little attention to quality of life issues. As the science of quality of life measurement matured, however, such measures have been incorporated into the vast majority of trials, thereby providing important information to guide oncologic decision making. But at the same time, quality of life information has made these decisions more complex. In the past, a study might simply have shown that the median survival for chemotherapy A was 3 months greater than chemotherapy B, making the decision about which chemotherapy to choose relatively straightforward. Now, however, a trial might show that chemotherapy A, although leading to longer survival, also leads to a lower quality of life. Now, the best choice depends on patients' preferences for...

Discerning the CFiber Afferent Pathway

Few substances have enjoyed the longevity or the wide utility of another agent, capsaicin (CAP). Many decades before the cloning and mapping of the vanil-loid receptor TRPV1, CAP defined the link of CAP to pain sensation to activation of a particular class of afferents. Early investigations confirmed what every consumer of piquant peppers understands CAP activates primary no-ciceptive afferents that convey the painful, burning sensation of CAP application. These CAP-responsive sensory neurons have slowly conducting axons (C-type and thinly myelinated A6-type) and cell bodies in the dorsal root ganglia (DRG).5 Similar strategies identified CAP-sensitive afferents within the viscera and an association with cardiovascular regulation.2 Many of these visceral afferents are cardiovascular mechanoreceptors,6 and their reflexes utilize vagal afferent pathways.3 Such visceral afferents constitute a unique cranial

Conclusions And Perspectives

Innovative approach to therapeutic intervention in diseases causing tissue damage, such as neurodegeneration, and suggests potential novel therapeutic strategies relying upon the simultaneous activation of cytoprotective genes of the cell life program and down-regulation of pro-inflammatory and pro-oxidative genes involved in programmed cell death. A strong evidence that a crosstalk between stress responsive genes is critical for cell stress tolerance is presented here, highlighting compelling reason for a renewed effort to understand the central role of this most extraordinary defense system in biology and medicine. All of the above evidence support also the notion that stimulation of various maintenance and repair pathways through exogenous intervention, such as mild stress or compounds targeting the heat shock signal pathway, such as acetylcarnitine may have biological significance as a novel approach to delay the onset of various age-associated alterations in cells, tissues and...

Local Field Potentials

Local field potentials have been studied by Andersen et al, 1 , Kennedy et al, 7, 8 , and Leuthardt 9 and found to be useful. Andersen's group found that LFPs indicate the cognitive state of the monkey and has also indicated directionality. The Kennedy group also found directionality within the LFPs 5 and, in addition, used them to control a cursor and a cyber hand on the computer monitor. The subject was able to flex the cyber digits under control of the LFPs with reasonable speed 5 . Again, there is no overwhelming reason why other electrode configurations should be deficient in recording LFPs. In fact, it may minimize the impact of unit instability inherent in other electrodes and thus improve their functional longevity.

Aggregation of Monomeric SOD1

Given that ALS appears to be related to the aging process, it is possible that conditions within neuronal tissue change over time, and that these changes shift the equilibrium toward the SOD1 monomer species and initiating aggregation and or 20 S proteasome overload (see below). Age-related factors that could be involved are an increase in oxidative damage 53 , a change in cellular reduction potential 138,139 , a decrease in proteasomal activity 140 , and an increase in translational errors 141 . These factors may affect the status of SOD1 (and likely, other proteins) and enhance their propensity for aggregation. An important recent study strongly suggests that mildly oxidized pathogenic SOD1 proteins aggregate through a monomeric intermediate 142 . In this context, Lansbury and colleagues have identified a series of FDA-approved compounds that appear to bind at the SOD1 dimer interface, stabilizing the pathogenic, metal-deficient proteins against dissociation and aggregation 143 ....

Apoptosis and Cancer Induction

The role of the apoptotic pathway in the induction and progression of cancer. The normal function of wild type p53 tumor suppressor gene after cell exposure to apoptotic stimuli or DNA damage is the induction of apoptotic cell death. One of the mechanisms involved in p53-mediated apoptosis is increased expression of the pro-apoptotic protein, Bax. Mutations in p53, or increased expression of negative regulators of apoptosis (i.e., Bcl-2, Bcl-xL or Bfl-1) leads to prolonged cell survival. This prolonged longevity increases cell exposure to mutagens with increased risk for further oncogenic lesions. The culmination of these events leads to cancer cell transformation and malignant progression. Reproduced with permission Pan H et al. Apoptosis and cancer mechanisms. In Kastan MB (ed). Cancer Surveys. Checkpoint Controls and Cancer 1997 29 314. Cold Spring Harbor Laboratory Press Plainview, NY. Fig. 4.5. The role of the apoptotic pathway in the induction and progression of...

Lifespan Regulation In C Elegans Aging of C elegans

The wild-type C. elegans lives for 3 weeks. As an animal ages, various senescence symptoms become apparent (35). From studies of ultrastructural observation and the visualization of specific cell types with green fluorescent protein (GFP), the nervous system is shown to be intact even in advanced old age, however, a gradual and progressive deterioration of muscles becomes apparent with increasing age resembling human sarcopenia (36). The stochastic features in the aging processes were clearly shown. Murakami and Johnson (38) showed that the expression of old-1 gene increase with advancing age. The old-1 gene product, OLD-1, is a transmembrane tyrosine kinase protein that is upregulated in daf-2 and age-1 lifespan-extension mutants in a daf-16-dependent manner. Various stresses, such as heat, UV, and starvation induce old-1 expression. The overexpression of old-1 induces stress resistance and lifespan extension. In contrast, the genomic knockout (KO) of old-1 in wild-type animals...

Stress Hormesis and Lifespan in C elegans

Heat treatment at sublethal temperatures induces increased resistance to subsequent lethal heat stress and modestly extends the lifespan of C. elegans (5). Heat shock induces a small heat shock protein (SHSP), HSP-16, in wildtype animals (41). Hsu et al. (42) also showed the increased expression of shsp genes, hsp-16.1, hsp-16.49, hsp-12.6, and sip-1 by heat shock. Yokoyana et al. (43) showed the induction of hsp70F and lifespan extension by heat shock. The overexpression of hsp70F, predominantly in the muscles, induces lifespan extension, and overexpression of the hsp16 gene induces thermal resistance and extended lifespan (44). These HSPs may play an important role as the molecular chaperon for preventing improper protein associations accumulated in the aging process.

InsulinIGFI Signaling and Lifespan Regulation

Longevity Longevity C. elegans worms grow through four larval stages (L1-L4) before reaching maturity. However, when the food supply is limited and the population density is high at the L1 stage, animals become dauer larvae after the L2 stage. The dauer larva is a developmentally arrested dispersal stage and lives up to several months, greatly exceeding the normal adult lifespan of about 3 weeks under stressful environmental conditions (53). It seems that the dauer stage is nonaging, because the post-dauer life span is not affected by a prolonged dauer stage of up to 2 months (54). The dauer larva is more resistant to a variety of environmental stresses, including hypoxia, heat, desiccation, and oxidative stress and has increased levels of SOD and catalase (21,55). The expression of the MnSOD gene (sod-3) is higher in the dauer larvae than in the adults (23). As dauer larvae live much longer than adults, some genes expressing altered levels in dauer state may be the key to longevity....

HSF and Male Reproduction

Hsf1 -null males exhibit normal fertility unless they are challenged by a stress such as heat shock (Izu et al. 2004). Discordant data were obtained regarding the fertility of HSF2-deficient males spermatogenesis in Hsf2tm1Mlv Hsf2tm1Mmr males seemed to be severely affected, with 80 and 58 reductions in sperm count, respectively (Kallio et al. 2002 Wang et al. 2003). In contrast, studying Hsf2tm1IJBmale fertility, we could not detect such dramatic alterations but only a potential faster aging process with the appearance of degenerated tubules in males older than 3 months (McMillan et al. 2002). As mentioned above, discordant results among knockout mouse lines are not uncommon.

Prophylactic Vaccines

Prevention of cervical cancer is not a reasonable efficacy end point for these preventive vaccine studies. Rather, as the precursor of cervical cancer, protection against incident HPV-related CIN is an appropriate measure of vaccine efficacy. Importantly, new HPV16-related CIN only occurred among the placebo recipients, although the numbers were small in this study (11). This study suggests that VLP vaccination can protect throughout the menstrual cycle against HPV infection. It should be noted that a contribution of L1-specific cellular immunity to protection has not been ruled out. The longevity of protection is currently under investigation and is likely to be influenced by the adjuvants used with the VLPs. More clinical trials of VLP vaccines are currently under way (summarized in Table 4), including a large, randomized, double-blind, placebo-controlled trial of HPV16 and HPV18 L1 VLPs in 21,000 Costa Rican women (68) to investigate the long-term protective efficacy of the VLP...

Mitochondrial Electron Transport and Lifespan

Interestingly, these RNAi treatments in early development are critical for lifespan-extension, in contrast with insulin IGF-1 signaling, which functions exclusively in adulthood to influence lifespan, suggesting that a regulatory system monitoring mitochondrial activity during development specifies the aging rate. As animals with reduced ATP levels by these RNAi treatments only in adulthood do not live longer than untreated animals, the mechanism of lifespan-extension by CR in adulthood is not likely to reduce the respiratory rate. Together, these findings indicate that mitochondrial electron transport is generally a regulator of lifespan as well as behavioral rates. This regulator seems to mainly function independently on insulin IGF-I signaling pathway but there seems to be possible cross-talk between them (Fig. 4.2). Rea and Johonson (106) proposed a general model in which the utilization of fermentative malate dismutation as alternative energy generation can induce longevity in a...

Acknowledgments for the Second Edition

The author expresses his loving tribute to his two sons John Ebadi, Ph.D. (Oriental medicine and Eastern healing art) and Mark Ebadi, M.D. (Western medicine and Western healing art) for their input on how to bridge past and present medical wisdom, and how to respect not only the immense contributions of many ancient cultures but also the amazing advances made by physicians today in their quests for preventing diseases, prolonging life, and reducing morbidity.

Advanced Glycosylation End Products AGEs

Glucose binds to amino groups on proteins or to lipids, leading to the generation of weak bonds or Schiff bases by Maillard's reaction. These early nonenzymatic glycosyla-tion products are reversible and are known as Amadori products. Through several oxidative and nonoxidative reactions, including glycoxidation and auto-oxidative glycosylation, they are converted to irreversibly modified cross-linked condensation products of glucose and lysine or arginine residues, so-called advanced glycosylation end products (AGEs). AGEs formation normally occurs at a low rate during the normal aging process, whereas it is accelerated by hyperglycemia thus plasma levels of AGEs are increased in patients with T1DM and may precede the occurrence of microangiopathy. AGEs carry out their harmful effects by accumulating in tissue and generating ROS. AGEs bind to their respective cellular receptors (RAGEs), activate endothelial cells, monocytes, and mesangial cells, and increase oxidative stress. AGEs...

Functions of Glutathione

Because of its many functions, all cells need adequate glutathione. Interestingly, its levels decrease with age, and the aging process itself may be due partly to low levels of glutathione.9-12 In animal studies, low levels are associated with reduced immune response, increased cancer risk, impaired detoxification of noxious substances, and many other detrimental events.13-17

Melatonin Duringaging

The pineal gland, through its hormone melatonin is involved in animal and human reproduction. It has been suggested that melatonin may be involved in the aging process (8). Melatonin is produced and secreted into the blood in a circadian rhythm with maximal production always during the dark phase of the day. The 24h rhythm of melatonin production is very robust in young animals, but this circa-dian rhythm deteriorates with age. Thus, in old animals the amounts of melatonin secreted are lower than that of young individuals and the supplemental administration of melatonin may be beneficial in delaying age-related degenerative conditions (7). Long-term melatonin treatment in rats can postpone the age related decrease in survival rates, circulating sex steroids and 125I-melatonin binding sites in the brain (5).

Late Complications of Transplantation

With improvements in surgical technique and the advent of more potent and selective immunosuppressive agents, early complications of whole organ transplantation have been reduced. This improvement in early outcome has led to a greater emphasis on the management of late complications of the transplant patient. The fact that improvements in long-term graft (and patient) survival have not kept pace with the improvement in short-term survival points out the necessity of concentrating on these late problems. Broadly, late complications can be classified into several areas Those affecting the kidney, e.g., chronic rejection and recurrent renal disease, cardiovascular diseases, metabolic disease, bone disease, and infectious complications. Further, these complications can either be secondary to the medications used to control the acute rejection process, comorbid disease states, the aging process, or some combination of the three. This chapter will attempt to cover these late complications...

Gmp Gmp Gmp Gmp Gmp Gmp Gmp Gmp

Another interesting avenue of research of authenticity is related to whiskey. In the market it is possible to find two whisky presentations. The first is straight whiskey, which is a product aged in a freshly charred oak barrel for a minimum of 2 years and not colored with added caramel. On the other hand, the addition of caramel is permitted in blended whiskey, which is prepared by mixing straight whiskey with neutral spirits. The addition of caramel color to blended whiskey is to compensate for the loss of color due to addition of the colorless neutral spirits. The most common caramels used in this industry are from classes II and IV. As can be expected, it is necessary to evaluate the authenticity of whiskey and a simple color measurement is not enough consequently, to reach this evaluation, HPLC analyses are used to evaluate the 5-HMF that proceeds from caramel. Moreover, oak material contains aldopentoses and hexoses, which in the aging process produce furfural (FF) and 5-HMF....

Loss Of Function Models Of Parkinsons Disease Functional Analysis of a Drosophila Parkin Ortholog

To explore the biological role of PARKIN, we and others generated a series of mutations in the Drosophila ortholog of PARKIN, including deletion, nonsense, and missense mutations. Flies lacking the PARKIN gene are semiviable and display reduced longevity, motor deficits, and male sterility (60,61). The motor deficit of PARKIN mutants is associated with a dramatic and widespread apoptotic degeneration of muscle tissue, and the male-sterility derives from a late defect in spermatid formation in the germline. Ultrastructural studies indicate that mitochondrial dysfunction is the earliest manifestation of muscle degeneration in PARKIN mutants, suggesting a role for PARKIN in mitochondrial integrity (60). This conclusion is further underscored by the finding that late spermatids in PARKIN mutants manifest dramatic structural alterations in the mitochondrial derivatives known as Nebenkern that are responsible for the energy production required for sperm motility (62). While humans and mice...

First Steps The Internal Environment And Negative Feedback Mechanisms

The indeterminacy to which Bichat and other vitalists pointed is the easier of the objections for mechanists to answer, as demonstrated by Claude Bernard (1865) half a century after Bichat. Fundamental to Bernard's conception of science was explanation in terms of deterministic causal relations accordingly, it was critical for his attempt to develop a science of experimental medicine to counter the apparent indeterminism in the activities of living organisms that Bichat had highlighted. The key element in Bernard's response was a focus on the internal organization of living systems. He proposed that each internal part of a living organism resides in an internal environment that is distinct from the external environment in which the organism as a whole dwells. With this move he could contend that whereas the response of a part of an organism to changes in the external environment might not be regular, strict determinism could be observed in the response by a component to conditions of...

Service models and ways forward

In the absence of a coherent strategy in the statutory sector, the voluntary sector has become the champion of good practice, seen by their users as an antidote to inadequate mainstream care. In London alone there are over 100 voluntary organizations for minority ethnic groups dealing with a range of problems from stress and anxiety to psychosis. There are also refugee support groups offering counselling and therapy, and groups for elderly people and carers. These small organizations are generally based on consultation with users, carers, and local mental health professionals and are more in tune with the expressed needs of the community. The best have good working relations with mainstream services, and are generally seen as making an important contribution to wider community care. Given the need to develop ways of working which promote inclusion of black users, carers, and the community in general, it is impossible to overstate the importance of effective liaison between the...

Organ and systembased theories

The underlying rationale of these theories was the belief that the onset and progression of senescence was determined by a reduction in the operational efficiency of a single organ, perhaps resulting from the gradual depletion of an essential cellular component or metabolite. The cardiovascular, immune, and neuroendocrine systems are three major examples that have been variously implicated in the ageing process. Immunity in humans attains maximum potential during adolescence and thereafter the thymus-dependent component gradually declines following early postadolescent involution and atrophy of that organ. Also with advancing age, there are increased rates of chronic autoimmune diseases which, for example, can result in reduced thyroid capacity. Thus, functional decline in the major histocompatibility complex ( MHC) has been identified as a central component of the ageing process, with the MHC, in effect, acting as a 'supergene' system.

The development and focus of the sociology of ageing

The study of ageing is still peripheral to mainstream sociology, which even in the area of the family has tended to concentrate on those who are economically active and their dependent children. The sociology of ageing emerged gradually over the last 40 years in the context of increasing longevity and the perception of social burden of the care of larger numbers of older people. Social gerontology has to a large extent developed as a multidisciplinary field, including sociology, only within the last 20 years.

Demography of the older population

Increasing longevity is occurring in both developed and developing nations. However, in the most developed nations it is unlikely that longevity will continue to increase much beyond the achieved level, while in the developing nations it is happening at an accelerated rate. Longer life expectancy comes about initially as a result of public health measures such as the provision of clean drinking water, more sophisticated sewage systems, improved housing, and the adoption of basic hygiene behaviour, and is reflected in the reduction of infant mortality and other premature deaths. Improvements in access to and new developments in health care make a subsequent impact on survival rates. As a result, in the developed countries most people can expect to live into old age. It is unlikely that average life expectancy will exceed 85 to 90 years. Continued growth in life expectancy is not inevitable. Poor people have lower life expectancies than better-off people in all countries. Life...

Management Of Heart Block With Pacing

Experience with permanent ventricular pacing in Chagas disease is extensive in South American tertiary care centers. In general, the symptomatic status and probably the longevity of patients with Chagas disease are improved by permanent ventricular pacing.181 Single-chamber ventricular pacing is generally used, and dual-chamber or rate-responsive pacing offers little additional benefit for most patients.182 Mortality in patients with permanent pacemakers depends mainly on the severity of the underlying myocardial disease and averages 5 per year.

Tobacco nicotine dependence

Older, 13 per cent of men and 11 per cent of women reported regular daily cigarette smoking. (25) Tobacco use is the leading preventable cause of death in adults. Smoking doubles the risk of death from combined causes in people aged 35 to 70,(6) and longevity is inversely associated with cigarette consumption. Smoking in older people is also associated with loss of mobility and poorer physical function, and may alter the metabolism of many prescribed drugs. Older smokers who quit have a reduced risk of death compared with current smokers that becomes evident within 1 to 2 years after quitting, and their overall risk of death approaches that of never-smokers after 15 to 20 years of abstinence 26' Among smoking cessation methods, some, like rapid smoking aversion therapy or medicinal nicotine substitutes (e.g. polacrilex gum, transdermal patches), may be contraindicated in older patients with coronary artery disease, cardiac arrhythmias, hypertension, or diabetes mellitus. Brief...

Analysis Of Pathogenic Mechanisms In Spontaneous Mouse Models

At the subcellular level, once the gene has been identified, a direct strategy working forward from the gene is productive. Molecular genetic studies can define the precise effects of the mutation on the sequence of the transcribed protein, and cell biology methods can describe its het-eromeric interactions and longevity. At the cellular level, molecular anatomic techniques are required to determine where and when the mutant gene and related members of the gene family are expressed and the cell types and sub-cellular compartments in which the various isoforms are localized. Many mutations impair protein trafficking, and the levels and distribution of the mutant protein must be carefully examined, along with its physiologic or biochemical behavior, to understand how overall function has been impaired. If the hereditary transmission pattern suggests a dominant trait, evaluation must include the possible negative effects of the mutant protein on the function of its wildtype allele, which...

Oxidative enzymes and their applications 1221 Laccases for pulp and paper modification

The reaction and decay of the free radicals generated in a complex substrate such as lignin are difficult to foresee, and the products of the reaction are complex. The complexity of the products of the laccase reaction depends in part on the resonance structures of the free radical, the solubility of the product, other compounds available to react with the radical, and the longevity of the radical 41, 44 . Despite this complexity, carefully designed reactions can predict the reactions taking place and obtain product in reasonable yield 45 .

Synaptic Pathology In Dementia

Alzheimer's disease (AD) is a progressive cognitive disorder characterized by the accumulation of structural and biochemical changes that occur in association areas of the neocortex and the hippocampus. Recent work has demonstrated that synaptic loss provides an excellent correlation with cognitive ability and may provide the best correlate of dementia. The loss of synaptic connectivity in the brain of individuals with AD appears to occur early in the disease process and may represent a loss of brain plasticity. Decline in synaptic plasticity does not appear to be an inevitable consequence of the aging process but may be disease related. This chapter reviews and summarizes some of the morphological evidence for Alzheimer-related synaptic loss in the neocortex and hippocampus.

Normal Aging And Synapse Loss

It has been suggested in the literature that AD-associated cognitive decline may be an inevitable consequence of the aging process. Age-associated changes in neuron number are often cited as the primary reason for age-related cognitive change, yet careful cell counting studies have failed to support this idea9. Recent studies of the entorhinal cortex, an area believed to be an early site of AD-related pathology, shows no significant change in total neuron number as a function of aging10,11. Most notably there does appear to be a significant age-related loss of white matter, suggesting a loss of brain connectivity indicative of a loss of synapses12-15. The loss of such brain connectivity is important since recent work has demonstrated that synaptic loss is strongly associated with cognitive ability and provides a strong correlation with dementia16-23.

Natural Immunity And Aging

Human aging can be considered as a dynamic process that leads to a continuous adaptation of the body to the deteriorative changes occurring lifelong. This picture is conceptualised in the remodelling theory of aging 29,30 , based on experimental evidence obtained from studies on human immunosenescence and on healthy very old people (centenarians) as a model of successful aging. Specifically, these results show that the aging process affects immune responses differently some of them decline while others remain unchanged or increase 31-33 , Accordingly, a variety of immune responses and parameters are well conserved in centenarians 34 10 ,

Fruits and Vegetables

The deeper the color of fruits and vegetables, the higher the antioxidant activity. Oxygen renegades are the target of antioxidants. When an oxygen molecule loses an electron, it becomes what is called a free radical and begins searching for a replacement. In trying to steal an electron from other healthy cells, free radicals cause damage to healthy cells and create scores of new free radicals. Free radicals cause mutations in DNA, the genetic material in the cells, and not only destroy healthy cells but turn the fats in many cells rancid, which disrupts cell metabolism. After years of these silent assaults in the body, individuals can develop a chronic disease or illnesses ranging from atherosclerosis to cancer, and experience an acceleration in the aging process.

Active Vision And Active Memory

The examples I have cited from research on visual processing and memory provide further support for the perspective on mechanisms I have advanced in this chapter, according to which mechanisms are not responsive systems waiting to be activated by a stimulus, but active systems. I motivated this perspective by turning to biology, and in particular to an objection vitalists advanced to mechanistic accounts of life according to which living organisms operate to oppose physical phenomena that would otherwise destroy them and hence are themselves not physical. Rather than showing the error in the mechanist perspective, such phenomena point to the need to focus on the modes of organization found in biological systems. The organization must be such as to enable the system to recruit matter and energy from the environment and utilize it to make and

Key Points Of Inquiry

Sometimes, when marketers get it right, just one added ingredient can start a market boom. For example, there has been significant growth in industries such as skin care products because, for example, interest in anti-aging and sun protection have driven the development of new products that incorporate alphahydroxy acids (AHAs) and sunscreens. In recent years, over a thousand new products are launched annually, more than twice as many as a decade ago. AHAs have been responsible for much of this impressive growth. Marketers need to learn more and manage data better to get to these sweet spots.

Stimulating Additions

The inra researchers tested the second hypothesis by seeding warm (pasteurized) milk with lactic bacteria and then adding rennet (which curdles the milk and transforms it into cheese). In this way they obtained a curd that they then molded and pressed and finally immersed in a brine enriched with ketoglutarate. They followed the transformation of the amino acids during the aging process, and a panel of tasters analyzed the development of the cheese's odor.

Mental health needs

Psychiatric and behavioural disorders increase with age. Among people with Down syndrome the neuropathological changes of Alzheimer's dementia are universal after the age of 35 years, although clinical dementia is not inevitable. Dementia occurs more frequently among elderly people with mental retardation than among the general population, and with the increasing longevity of people with mental retardation the number with dementia is rising. (37) The distress that can result from dementia, both for the elderly people and for their carers, requires understanding and effective management.

Deep brain stimulation for the treatment of Parkinsons disease C Hamani J Neimat and A M Lozano

Abosch A, Hutchison WD, Saint-Cyr JA, Dostrovsky JO, Lozano AM (2002) Movement-related neurons of the subthalamic nucleus in patients with Parkinson disease. J Neurosurg 97 1167-1172 Barichella M, Marczewska AM, Mariani C, Landi A, Vairo A, Pezzoli G (2003) Body weight gain rate in patients with Parkinson's disease and deep brain stimulation. Mov Disord 18 1337-1340 Benabid AL, Pollak P, Gao D, Hoffmann D, Limousin P, Gay E, et al. (1996) Chronic electrical stimulation of the ventralis intermedius nucleus of the thalamus as a treatment of movement disorders. J Neurosurg 84 203-214 Berney A, Vingerhoets F, Perrin A, Guex P, Villemure JG, Burkhard PR, et al. (2002) Effect on mood of sub-thalamic DBS for Parkinson's disease a consecutive series of 24 patients. Neurology 59 1427-1429 Bin-Mahfoodh M, Hamani C, Sime E, Lozano AM (2003) Longevity of batteries in internal pulse generators used for deep brain stimulation. Stereo-tact Funct Neurosurg 80 56-60 Brown RG, Dowsey PL, Brown P,...

Ageing parents and ageing children

The physical work of looking after a still dependent and sometimes very heavy adult takes its toll on parents. With a severely physically handicapped adult 'child', some help can be provided with people coming in to help with bathing, but few houses can be adapted to minimize lifting which may be needed many times during the day and night. Sooner or later the work gets too much, particularly for a sole parent. Parental frailty makes aggressive behaviour much more frightening and potentially dangerous. Where there are few opportunities for outside contact, the adult with mental retardation complicated by severe behaviour disorder can become possessive and may show jealousy, sometimes making visits even from grandchildren impossible. Despite the evident difficulties, a study in Wisconsin, (8> found that many parents, reaching the end of their lives after many years of looking after a retarded child, were fitter than others of the same age and had a much greater sense of having...

Working Psychotherapeutically With Older People

Question may be answered with a resounding yes. In this section, the second key question is explored and answered. It is important to understand that older adults are the least homogeneous of all age groups. Older adults often have many more dissimilarities than similarities (Steuer & Hammen, 1983). As Zeiss and Steffen (1996) point out, there are at least two generations contained within this age grouping. With the increase in longevity, there can be four decades separating the youngest old from the oldest old. In working psychologically with older people, it can often be useful to bear in mind the importance of cohort beliefs (Knight, 1999), which refer to the set of cultural norms, historical events, and personal events that obtained or occurred during a specific generation. Cohort beliefs may influence how easily older adults, particularly older men, will find discussing their feelings, and they may also influence stigmatising beliefs about mental illness. Cohort beliefs can...

Gene Knockdown Therapy

The concept of disabling the function of a mRNA by hybridization of antisense reagents is a simple one, but, like other gene-based therapies, the technology has encountered difficulties in the past. The technical problems experienced in the early pioneering stages of antisense technology are only now being elucidated and are the focus of active study. From these analyses, several features are apparent in the design of effective antisense molecules determining the length of sequence with the greatest activity and specificity cellular uptake specific targeting of the ODN antisense stability and toxicity. Other factors that have influenced the effectiveness of antisense molecules are frequency of protein turnover, the intracellular environment of the cell, and the extent of longevity of ODNs after administration.

Inadequate Personality Disorder

Because there is reasonable evidence that this general cluster of inadequate and insufficient behaviors might have a strongly heritable basis, traditional psychotherapies might have a weak impact on the patient's ultimate prognosis. A lifetime of failure is difficult to overcome in later life. Cognitive, reasoning, and intellectual declines that accompany the normal aging process might well be much more pronounced in the inadequate personality disordered patient. Should this diagnosis be suspected in an older patient, it will be important for the clinician to provide greater structure than is typical with most older patients. Behavioral treatment approaches may be more beneficial to the patient than traditional insight-oriented therapies, with an emphasis on support, encouragement, and arrangements for resources.

The Cost Benefit Analysis of Polymorphisms within Lipoprotein Metabolism

Mthfr C677t Gene Polymorphism

Post-reproductive years, it may, however, in certain cultures feeding modes, offer a distinct survival advantage. The common APO-E3 allele is found in all human populations, but it is particularly prevalent in long-established agricultural economies, such as persist around the Mediterranean Sea. This contrasts with the prevalence of the APO-E4 allele, which is highest in cultures that still have an economy based on foraging, or where food supply is unpredictable and scarce. Such populations include Pygmies, African Khoi San, Malaysian and Australian Aborigines, Papuans, Lapps, and Native Americans (59). Based on this distribution, it has been suggested that the ancestral APO-E4 allele may be a thrifty allele with functional properties that influence lipoprotein metabolism, including cholesterol levels in a beneficial manner in the appropriate ancestral environment. However, out of their ancestral context (i.e., within a contemporary environment where Western diets and longevity...

Future Of Organ Preservation

Improving organ preservation by developing a new cold storage solution is a goal of many investigators. Currently, a common approach is to make minor changes in the UW solution and make a claim for an improved and different preservation. It may be difficult to dramatically improve organ preservation by simple cold storage and we may have reached the limits of safe storage (about 24 to 48 hours). The reason for this conclusion is based upon the organ's need for a source of energy to prevent tissue destruction. Energy must be constantly brought into the thermodynamically unstable tissues and cells otherwise, membranes, cytoskeletal networks, cell-cell interactions, and various complex molecular structures break down. In cold ischemic storage there is no currently known method to maintain a satisfactory energetic state without continuous perfusion with perfu-sate or oxygen. The use of machine perfusion may be the method that could improve organ preservation. Improving the quality and...

Depressive Personality Disorder Dsmivtr Appendix B

Theorized Pattern in Later Life and Possible Impact of Aging The aging process is challenging enough, so one can imagine the outcome of a characteristically dour and self-flagellating person. Little is definitively known about the depressive personality type in general, and even less knowledge is available about the effects of aging. Nonetheless, we see two possibilities for the depressive type. The counterintuitive hypothesis might be that people with Depressive Personality Disorder are likely to do as well as anyone else as they age because any of the negative effects of aging might be seen as confirming their lifelong held suspicions that life is a gloomy and cheerless place and continues to be so You work hard and then you die. The negative events that have been created by older depressive patients as a consequence of their self- and other-critical behaviors appear to them as a constant, which in contrast to psychologically healthier older adults does not necessarily suddenly...

Passive Aggressive Personality Disorder Dsmivtr Appendix B

As noted throughout this book, many of the stressors that often accompany aging such as physical illness or disability, reduced independence, sensory and cognitive declines, changes in physical appearance, social losses, and financial pressures, frequently serve to exacerbate underlying personality disorder features and traits. The Passive-Aggressive Personality Disorder is probably among the most likely of the personality disorders to become more apparent during the aging process, as the loss of autonomy that often accompanies aging heightens the ambivalence that fuels passive-aggressive traits. Given a far-from-perfect health care system, it seems probable that those who have a history of trouble dealing with external authority figures will have additional problems as they age and become increasing more reliant on those systems.

The Host Was a Protoeukaryote Not an Archaebacterium

The evolution of the protoeukaryote, significantly after the origin of phagocytosis, which provided the mechanism of its ingestion, but possibly during the later stages of perfection of such cenancestral eukaryotic characters as efficient nucleocytoplasmic transport and ciliary motion. It is now highly probable that the cenancestral eukaryote had a centriole and cilium and that there are no primitively non-ciliate eukaryotes (Cavalier-Smith et al. 2004 Kudryavtsev et al. 2005 Richards and Cavalier-Smith 2005). Given also the arguments for a simultaneous origin of nuclei and cilia to generate a unicili-ate eukaryote cenancestor (similar to Phalansterium or Mastigamoeba without mitochondria or mitosomes Cavalier-Smith 1987b), it is likely that the protoeukaryote also was uniciliate, not a simple amoeba - contrary to early ideas (Whatley et al. 1979). Because the root of the eukaryote tree is between bikonts and unikonts (Richards and Cavalier-Smith 2005 Stechmann and Cavalier Smith...

Models of vector competence

Tree Eukaryote Cavalier Smith

Garrett-Jones emphasized the entomological components of McDonald's equation, setting them apart as the vectorial capacity, C (Garrett-Jones & Shidrawi, 1969 Garrett-Jones & Grab, 1964), or the daily rate at which new infections arise from an infective case C ma2bpn - lnp. Vectorial capacity can be interpreted as the product of the fraction of vectors capable of transmission (b), the human-biting rate (ma), the human-biting tendency (a) and the longevity factor (pn - lnp). The equation emphasizes that the transmission rate is quite sensitive to the two factors treated exponentially the biting rate (a) because generally a vector has to bite twice to transmit and the daily survival rate (p) because the extrinsic incubation period of the pathogen (n) is usually long compared to the life expectancy of the vector. This latter point played a significant practical contribution to vector control in malaria eradication efforts (Bradley, 1982 Dye, 1992). The relative importance of the...

Transplant Artery Stenosis

String Pearls Fmd Images

End-to-side or internal iliac end-to-end (109). Stenosis of the transplant artery is well recognized. Improved surgical techniques and immunosuppressive therapy have led to increased graft longevity. As a result, transplant artery stenosis is more of a clinical problem with an incidence of 1 to 15 (110,111), mostly within the first three years. Stenosis can occur in the recipient iliac artery, at the anastamosis, or distal to the anastamosis. Causes and predisposing factors include native vessel atherosclerosis, clamp injury, rejection, turbulence distal to the anastamosis, and surgical technique (109). Clinical pointers to stenosis include hypertension and worsening function in the absence of rejection or ureteric obstruction.

Species Scaling Adjusting for Maximum Life Span Potential

Compounds which are substrates for mixed function oxidase enzymes, including P450s, tend to show lower than expected clearance in man based upon the simple allometric scaling incorporating body weight alone. This may be correlated with the enhanced longevity of man compared to most animals, since the faster the pace of life, the shorter it is. Hence slowing the metabolic rate, including that of the mixed function oxidases, allows the MLP to be extended. This reflects a major evolutionary advantage of man over other animal species. Therefore incorporation of MLP into the allometric extrapolation provides a more accurate assessment of physiological time than body weight alone. One additional potential advantage of reduced activity of the mixed function oxidases is decreased activation of pro-carcinogens and decreased free radical formation, hence prolonging life span.

The Real Fountain of Youth

Few people would object to a treatment that prevents heart attacks or Alzheimer's disease, but critics such as conservative ethicist Leon Kass have questioned whether greatly extending overall human lifespan is a good idea. Earth is already overpopulated, these opponents of life extension point out. They claim that adding large numbers of older people, many of whom might need expensive medical care, could produce financial and ecological disaster. At very least, a high proportion of life-extended people might produce an excessively conservative society, eminent Harvard zoologist Edward O. Wilson wrote in Esquire in May 1999. Such people would have the physical capabilities of teenagers but . . . would be culturally, educationally, and emotionally aged. . . . Those who have survived and enjoyed longevity extension . . . won't be revolutionaries. They won't be bold entrepreneurs or explorers who risk their lives.

Therapeutic Studies With Gcp Ii Inhibitors In Rodent Models

Mutant SOD1, as well as in vivo in G93A FALS transgenic mice carrying the SOD1 mutation53. Chronic treatment with 2-MPPA 2-(3-mercaptopropyl)pentanedioc acid , an orally-adminstered analog of 2-PMPA, increased longevity and delayed the onset of 4 out of 5 rated neurological motor symptoms in the G93A FALS transgenic mice. In cultured rat motoneurons transduced to express mutant SOD1, treatment with 2-PMPA was neuroprotective. Interestingly, however, the protective effects of 2-PMPA were not diminished by co-administration of either the group II mGluR antagonist EGLU (2S)-alpha-ethylglutamic acid or an antibody against TGF-beta. The authors concluded that in that sytem, the neuroprotective effects of 2-PMPA were mediated neither via TGF-beta nor through the effects of NAAG on mGluR3 receptors.

Bovine growth hormone

In an interesting survey study on the effect of human size on longevity, researchers Samaras and Heigh found a consistent relationship. They discovered that longevity was associated with smaller stature or size, when not due to malnutrition, childhood disease, or prenatal disease.7 Their study reviewed many other longevity studies, involving many thousands of subjects. While such an effect is unlikely attributable to only one factor, the larger people typically are being exposed to larger amounts of bovine growth hormone, both from natural sources and from the many injections of synthetic hormones currently administered to milk-producing cows.

Oligodendrocytes as the Iron Storage Cell in Development

During development, brain ferritin binding coincides with the onset and progression of myelination 33,57,67,69-71 and increasing brain iron levels are a necessary 64,72,73 and integral part of myelin development and differentiation in childhood and early adulthood 8,21,57,74,75 . With age, myelin breakdown becomes an increasing problem, even in healthy individuals 25,29,36,76,77 and continued repairs and remyelination result in increased numbers of oligo-dendrocytes in old age 37 . This 'normal' aging process is essentially what we postulate for the process observed in HD (see Section 2.2) except that abnormal huntingtin causes the process to occur prematurely and thus preferentially impacts early-myelinating regions.

Mechanisms Of The Effects Of Oxidants And Antioxidants On Inflammation And Immune Function

The molecular mechanisms that underlie the increased inflammatory and oxidant stress that accompanies aging has been examined in aged mice. The role of changes in PPAR-a activity in the process has been examined by Poynter and Daynes (42). Their findings suggest a role for PPAR-a in the maintenance of redox balance during the aging process.

The Critical Role of B Cells in Autoimmunity

Studies of longevity factors (APRIL and BAFF) that influence B cell maturation and survival at several levels also point to a link of MZ B cells with autoimmunity. Mice overexpressing BAFF spontaneously develop an SLE-like syndrome associated with a dramatic increase in MZ B cells (Mackay et al., 1999 Batten et al., 2000). More recently, it was found that the salivary glands of BAFF transgenic mice contain a subpopulation of B cells with an MZ-like phenotype (B22O+HAS+ CD21highCD1high) that could derive from the expanded MZ population present in the spleen of BAFF transgenic mice (Groom et al., 2002). Importantly, MZ-like B cells also have been detected in the thyroid gland of patients with Graves's disease. It is possible that these cells have aberrantly acquired trafficking receptors, enabling them to circulate and home to other lymphoid locations, as occurs in aged (NZB x NZW) F1 mice whose B-1 cells abnormally migrate to ectopic target organs (Ito et al., 2004).

Functional benefits of trans fatty acids

Mildly hydrogenated oils are preferred in frying applications because their semi-liquid nature permits convenient handling while their chemical composition, in particular the absence of linolenic acid (18 3), ensures longevity of the frying medium. The extremely steep melting behavior related to high levels of TFA qualifies partially hydrogenated fats as good cocoa butter substitutes and coating fats. Compared with alternative fats with a similar melting range, TFA-containing fats show a solidification behavior that is clearly superior in manufacturing processes under quiescent conditions (the term 'quiescent' indicates the absence of shear during crystallization). A number of other applications require long-term storage at ambient temperatures. Examples are bouillon cubes, cookies and the like. In these applications aspects such as chemical stability, crystallization behavior for manufacturing and melting profile are of key importance. While the first two aspects are self-evident,...

Broads Distinction between Emergent and Mechanically Explainable Properties

At the start of the twentieth century the question of whether life could be explained in purely mechanical terms was as hotly debated as the mind-body problem is today. Two factions opposed each other. Biological mechanists claimed that the properties characteristic of living organisms (metabolism, perception, goal-directed behavior, procreation, morphogenesis) could be explained mechanistically, in the way the behavior of a clock can be explained by the properties and the arrangement of its cogs, springs, and weights. Substantial vitalists, on the other hand, maintained that the explanation envisaged by the mechanists was impossible and that one had to postulate a special nonphysical substance in order to explain life an entelechy or lan vital. When C. D. Broad developed his theory of emergence in the early 1920s, his aim was to create room for a third position mediating between these two extremes a position he called emergent vitalism. Broad's first step was to point out that the...

Table 52 Some Key Definitions for Hazard Identification

Apparent conflicts between statistics and toxicology can arise when toxicologically insignificant effects are statistically significant or vice versa. For example, the observation in a chronic study of a 5 decrease in net body weight in an experimental group compared to the control group may be statistically significant but may not be considered toxicologically important if both groups are fed ad libitum because such a decrease is often associated with increased longevity. Instead of a real conflict, however, the statistical significance suggests that the effect is real, but the biological reasoning indicates that the effect is not adverse. A special case in this situation is where the toxicological relevance of the statistically significant effect is uncertain. In this case, it is incumbent upon the professionals to judge whether the effect is toxicologically significant.

MtDNA mutagenesis in the brain

Histological examination, the cells were microdissected under microscopical control and mtDNA was analyzed in a single-cell PCR. For each of the ten individuals, at least 30 cells per cell type were collected in this way and subjected to PCR individually. Screening for the presence of the 4977 common deletion yielded no significant differences in relative distribution, neither between astrocytes and neurons, nor between healthy young and old individuals (171). These findings imply that cellular susceptibility to copy errors during mtDNA replication does not change as a function of age and that the mere passage of time is crucial for intracellular fixation and expansion of the 4977-bp deletion. Thereby the cellular origin of the aging process of mtDNA in the brain and the cellular specificity of hypoxic changes of the level of mtDNA is still unclear. However, a more quantitative approach could definitely lead to more reliable and reproducible insights into the occurrence of...

Melatonin Aging And The Circadian System

Aging is associated with a number of changes in the morphology, physiology and biochemistry of the pineal gland resulting in a significant reduction of the nocturnal melatonin levels in rodents and humans alike (12,20,27). It has been hypothesized that the age-related disruption of this robust signal affects the integrity of circadian time structures and is a precursor of disease states (2,21). Recent studies indicate that decreased binding of melatonin to the SCN of old rats is correlated with disruption in overt circadian rhythmicity (43), whereas treatment with the melatonin agonist, S-20242, can partially reverse the age-related decrease in the amplitude of the circa-dian temperature rhythm (13). We have recently found that in some hamsters treatment with melatonin in the food increases the amplitude and cohesiveness of the rhythm of locomotor activity which often becomes fragmented and disorganized in old animals (Van Reeth, unpublished results). Further support for some linkage...

The Case of Toby Dependent Personality Disorder

And profound inadequacy, puts them into great conflict. They cannot risk confrontation and alienation from those on whom they depend and induce in themselves great suffering when even contemplating this. Their help-seeking and reassurance-seeking behavior can be annoying, but to their protector, this behavior, at least originally, often is gratifying. It is frequently the case, as with Mel and Toby, that what began as a match made in heaven only shifted to living hell when there was a significant change in the system. In this instance, the change was inherent in the aging process. Mel developed a few age-related health problems that were minor, but nonetheless were terrifying intimations of mortality to Toby. Toby also was aging, and was not able to tolerate the usual age-related aches and pains. In addition to an Axis II diagnosis of DPD, she also meets the criteria for an Axis I diagnosis of Undifferentiated Somatoform Disorder. She presents with complaints of fatigue,...

Box 311 Stages and symptoms of dementia Alzheimers disease

Relatives and friends (and sometimes professionals as well) see it as old age, just a normal part of the ageing process. Because the onset of the disease is gradual, it is difficult to be sure exactly when it begins. The person may Studies in developed countries have consistently reported AD to be more prevalent than VaD. Early surveys from South-East Asia provided an exception, though more recent work suggests this situation has now reversed. This may be due to increasing longevity and better physical health AD, whose onset is in general later than that of VaD, increases as the number of very old people increases, while better physical health reduces the number of stroke sufferers and thus the number with VaD. This change also affects the sex distribution among dementia sufferers, increasing the number of females and reducing the number of males.

Sacrospinous Ligament Fixation

The sacrospinous fixation is likely the most popular vaginal approach to vaginal vault suspension in the United States (US). Initially described in Germany and popularized in the US during the 1980s, this procedure has a high degree of effectiveness and longevity in restoring vaginal vault support. The vaginal apex is attached to the sacrospinous ligaments with permanent or delayed absorbable sutures. The procedure can be performed via a posterior vaginal dissection or anterior paravaginal dissection, and unilaterally or bilaterally. The main drawback of this procedure is the well-recognized recurrence of anterior vaginal wall defects. Because of the downward deviation of the vaginal axis, the anterior vaginal wall is more subject to transmission of intraabdominal pressure and creation of a significant cystocele. In our experience, the resultant cys-tocele typically does not extend beyond the vaginal introi-tus and is typically not symptomatic. In addition, when a bladder neck...

Figure

However, the 12.5 mg kg dose produced aversions that extinguished to a greater degree than those of the 25 mg kg dose over the remaining 40 days of preference testing. These data indicate that resistance to extinction can be a useful indicator of aversion strength. The figure also reveals the remarkable longevity of TAs that were produced by the 25 mg kg cyclophosphamide dose when aversion strength was measured by two-bottle tests, which afforded the subjects access to plain water and did not force them to endure fluid deprivation or to drink the saccharin solution.

Geriatrics

Despite stabilization of the acute illness, the elderly have less recuperative powers after discharge 46 and have more frequent hospital readmissions, placing them at increased risk of death within 1 to 4 years after discharge 26, 47, 48 . In a comparison study with younger men with equal health status, elderly men were found to have poorer eating habits and took longer to recover. After 1 year, they had greater weight loss and more health problems 49 , suggesting the aging process might play a role in recovery.

MtDNA maintenance

Oxidative stress may play a role in the aging process The idea that oxidative stress can be important for the aging process (37) is strongly supported by the findings that amelioration of oxidative stress by the overexpression of Cu, Zn superoxide dismutase, and catalase significantly lowers the level of oxidative The 4977-bp deletion might be a marker molecule for the aging process

Neurochemistry

Schizophrenia 2) However, despite its longevity there is still no consensus as to precisely what the dopamine hypothesis explains, nor the nature of the supposed abnormality. There are two main difficulties. First, antipsychotics have marked effects on the dopamine system, seriously confounding most studies. Second, molecular biology has revealed an unexpected complexity of the dopamine receptor family, increasing the potential sites of dysfunction and mechanisms by which it might occur.

Method

The following description is for preparing cultures based on the method of New (6) but with some modifications as described in Stern and Ireland (14). The procedure has been adapted from (15,16). You may also follow the method described in Chapter 15 (7). The main difference between these methods and that originally described by New (6) is the use of rings cut from glass tubing, rather than bent from a glass rod with circular cross-section. The advantage of these rings, with rectangular profile, is that they grip the vitelline membrane tightly and therefore allow transfer of the assembly to a flat plastic dish. Above, I have recommended rings of 27 mm outer diameter, because it is easier to wrap the membrane around these for a novice. However, if larger (ca. 30 mm diameter) rings are used, the embryos will develop up to 6-9 h longer. The longevity of the cultured embryo appears to depend both on the amount of thin albumen under the ring and on the length of time for which it can be...

Discussion

Nonhuman primate models of drug self-administration provide a rigorous, systematic approach to characterize the reinforcing effects of psychoactive drugs. The longevity of nonhuman primates is an important consideration, allowing for long-term studies to be conducted and repeated-measures designs to be employed. A single venous catheter can be maintained readily for over a year, and multiple implants permit the conduct of self-administration experiments for several years in individual subjects. Long-term studies with repeated measures are well suited for comprehensive drug-interaction experiments. While rodent models of drug self-administration have contributed substantially toward an understanding of neuropharmacology, the nonhuman primate represents an animal model with unique relevance to understanding the neu-rochemical basis of substance abuse in humans. For example, the complexity of the topographical organization of the striatum and its connections with surrounding areas in...

Conclusions

Although many issues remain to be resolved regarding both normal aging and age-related disease states, the ability to track myelin breakdown and iron accumulation with MRI provides the opportunity to assess these processes directly in humans. MRI biomarkers can also provide a means to assess the efficacy of treatments aimed at mitigating myelin degeneration and iron toxicity in clinically healthy as well as symptomatic populations. Such treatments may have a wide spectrum of efficacy and potentially could delay or prevent brain aging and some of the uniquely human disorders associated with the aging process of the human brain.

Plasticity

Plasticity is an important feature of single units and one that is probably not available from LFPs. It ought to be easier to train one unit than an unruly classroom of poorly correlated units. The expectation is that perhaps any unit recorded from anywhere in the brain can be trained to control a specific output. If this plasticity expectation is to be fulfilled, however, there must be a priori stability of the unit. Without stability and longevity, repeated sessions of retraining would be required. Thus far, the NE is unique in achieving the goals of plasticity, stability, and longevity 4, 5, manuscript in preparation .

Anatomy

The sacrum is a block of bone at the base of the vertebral column. The sacrum is the largest vertebral element, consisting of five fused vertebrae and is the place where the spine meets the pelvis vis-a-vis the SI joint. It supports the spine and transmits load to the lower extremities. It has a triangular shape, which is broader cephalad and tapers caudally. There are foramina anteriorly and posteriorly. It provides two roles with respect to dispersing forces longitudinally and transversely. The lateral margins of the sacrum have two regions. One area is an auricle-shaped (ear-like) surface, which is smooth and provides the articulation for the SI joint. The other area is ligamentous, which is rough and provides the interosseous portion of the SI joint. The SI joint itself has a small range of motion. There is no muscle that executes active movements across the SI joint. All of the movements are passive and thus it is considered a stress relieving type of articulation. Nevertheless,...

Thirst

If you ignore thirst often enough in your daily lifestyle, you will eventually lose the ability to be properly sensitive to varying levels of dehydration throughout your body. You may survive, but you will make just about every cellular task that your body must perform more difficult. Eventually, these cellular tasks will not be performed completely, resulting in the appearance of new diseases or the worsening of old diseases. Either through this ignoring of thirst or through the natural aging process, or both, the thirst mechanism is consistently seen to lessen and even fail as we become older. In fact, increasing age is directly associated with a steadily decreasing water content in the cells of the body. Such a steady decline in the cellular water content may well be a significant independent reason for the acceleration of the aging process.

Vesiculation

We have demonstrated that spleen-mediated vesiculation is an integral part of the physiological aging process, and we postulate that vesicle-mediated removal of damaged hemoglobin occurs mostly in the liver during the second half of the eryth-rocyte lifespan 27, 28 . We have recently obtained data suggesting that vesicles may also serve to remove damaged membrane components, and that alterations in band 3 structure are involved in the vesiculation process (Bosman et al., unpublished observations). The mechanism by which vesicles are formed is largely unknown, but it is known that an artificial increase in the intracellular calcium concentration results in the formation of various types of vesicles 22 . In a series of pilot experiments we observed that upon incubation with a calcium ionophore in the presence of low concentrations of Ca2+, erythrocytes from various NA patients produced both microvesicles and nanovesicles that were qualitatively and quantitatively different from the...

Cytokines

Although cytokines traditionally have been viewed as products of monocyte-macrophages or lymphocytes, it has become clear that mast cells ( 56) generate many, including tumor necrosis factor-a (TNF-a), IL-1, IL-1ra, IL-3, IL-4, IL-5, IL-6, IL-9, IL-13, IL-16, and GM-CSF ( 57,58 and 59) in an NF-kB-dependent process (22). These molecules may be central to local regulation of mast cell growth and differentiation and may also provide new functions for mast cells in health and disease. Basophils are also a prominent source of IL-4 and IL-13 (56). The preponderance of these mast cell and basophil cytokines can be categorized as proinflammatory (IL-1, IL-6, TNF-a) possess properties important in IgE synthesis (IL-4, IL-13) stimulate eosinophil growth, longevity, localization, and activation (IL-3, IL-5, and GM-CSF) and participate in airway remodeling (IL-9).

Conclusion

In the last decades, gene-manipulation studies have revealed that gene networks exist for the determination of lifespan in diverse species. There appear to be common and different features among species. ROS appear at various points in the aging processes, and play a variety of roles, including the manifestation of oxidative stress and the mediation of signal transduction. The precise role of ROS in the aging process is not yet clear. DNA microarray technology allows us to show global gene expression profiles governing the lifespan and aging rate, although these studies are just beginning. Using the data from DNA micro-array analysis, painstaking studies are needed to clarify the aging mechanism to analyze how various gene products work in concert to regulate the aging rate.

Vector Genetics

The suggestion that vector-borne diseases might be controlled better by reducing the vectors' ability to transmit pathogens than by reducing vector populations (Curtis, 1968) has been embraced by many scientists and there has certainly been great progress towards being able to test the feasibility of this approach. To this end, we now possess the ability to manipulate several different species of mosquito vectors genetically and with relative ease (Allen et al., 2001 Catteruccia et al., 2000 Coates et al., 1998 Grossman et al., 2001 Handler & James, 2000 Jasinskiene et al., 1998), we have identified some mechanisms by which virus replication in the mosquito can be altered (Higgs et al., 1998 Olson et al., 1996, 2002 Powers et al., 1996), and can manipulate the expression of endogenous genes that might influence pertinent aspects of mosquito biology (Attardo et al., 2003 Shiao et al., 2001). However, the challenge of spreading and establishing mosquitoes with reduced vector...

Elderly people

This is an area of relatively new therapeutic exploration which is bound to become more important as clinical problems amongst elderly people increase with longevity. A range of groups has been found useful in helping the aged to face their problems, improve their functioning, and feel happier about themselves. Just as elderly people are a varied population with many different needs, catered for in a wide range of different settings, so the groups vary widely. They include groups offering support, activity, psychoeducation, problem-solving, and insight, and they take place in all the settings in which elderly people are to be found. Common themes include the ubiquity of loss, the acceptance of death, and the value of humour in lightening mood. Finally, the healing power of human communities is clearly seen throughout the lifespan, and it generates hope while life lasts. (iS144,,145)

Scott C Baraban

Pediatric epilepsy models are confined primarily to rodents. Although using a rodent model of a human neurologic disorder has distinct advantages, there is no rationale to support our almost exclusive reliance on this species. Indeed research questions related to genetic modifiers of pediatric epilepsy syndromes, high-throughput anticonvul-sant drug screening, and rapid genetic manipulations aimed at analysis of basic cellular mechanisms of epilepto-genesis could be better suited to a simple vertebrate system. Exciting new discoveries in the general field of neurobiol-ogy exploit the experimental advantages of simpler organisms such as Caenorhabditis elegans (worms), Drosophila melanogaster (fruit flies), and Danio rerio (zebrafish). Analysis of Parkinson (parkin) gene function in flies (Pesah et al., 2004) and discovery of daf genes regulating the aging process in worms (Hsin and Kenyon, 1999 Lin et al., 1997) are just two examples. Similar discoveries are possible in the epilepsy...

Ageing and lifespan

The genetic contribution to longevity has been assessed in studies of twins, which have produced quite low heritability estimates of 0.26 for males and 0.23 for females,(1) and among centenarians whose siblings have significantly increased life expectancies. (2) A notable example of this latter phenomenon is the family of Jeanne Calment, who died in France in 1997 aged 122 years. Of her 55 immediate relatives whose life histories were studied, 24 per cent lived to over 80 years of age compared with just 2 per cent in a matched control group.(3) However, the enhanced lifespans of families that exhibit above-average longevity may be primarily associated with the absence of major life-threatening pathologies. For example, it has been shown that the prevalence of the e4 allele of apolipoprotein E ( ApoE), which promotes premature atherosclerosis and is a significant risk factor in the development of late-onset familial Alzheimer's disease, is less frequent in centenarians.(4) Conversely,...

Stochastic damage

The rate-of-living theory is based on the demonstration of an inverse relationship between basal metabolic rate and longevity. An associated hypothesis is that species which become sexually mature at a very young age are short-lived and vice versa, with humans placed in the latter category. More recently, the theory has been extended to incorporate resistance to external stress as the primary inherited trait determining longevity, since the efforts needed to combat the adverse effects of external stress are held to impose a significant energy burden on the organism. As free radicals are produced in the inner mitochondrial membrane during the course of normal respiration, it has been suggested that they could exert major disorganizing effects both directly at their site of production in the mitochondrial membrane and on mitochondrial DNA ( mtDNA). An inverse correlation has been demonstrated between the longevity of mammalian species and rates of peroxidation, at least partially...

Genomebased theories

The remarkable level of consistency in life expectancy displayed by individual members of mammalian species served as a major underlying impetus to the development of programmed theories of ageing. A further important factor was the demonstration of the 'Hayflick limit'. This phenomenon is observed in normal human cells after a specific number of laboratory subcultivations that are characteristic of the cell strain. ( 4> The cells undergo irreversible cessation of mitosis and enter a non-dividing state known as replicative senescence. Replicative senescence is independent of culture conditions, and cells derived from tumour tissue, or cultures which have been transformed in vitro, do not display a finite growth pattern of this nature. Intriguingly, cell strains cultured from individuals with inherited progeroid syndromes (Werner and Hutchinson-Gilford syndromes), characterized by the early appearance of ageing-like physical symptoms and a greatly truncated lifespan, also show many...

Research

In the past, research in geriatrics was focused mainly on the basic sciences, and as a result much more is understood about the ageing process. Attention now needs to be paid to health services research, to evaluate the efficacy and economic viability of existing services, and to help plan future services. There must be continuous assessment of programmes in operation, incorporating measures of patient and family satisfaction. Studies of local prevalence and need should be undertaken as

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How To Add Ten Years To Your Life

How To Add Ten Years To Your Life

When over eighty years of age, the poet Bryant said that he had added more than ten years to his life by taking a simple exercise while dressing in the morning. Those who knew Bryant and the facts of his life never doubted the truth of this statement.

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