Longevity Health and Wellness Protocol

Get Younger Tomorrow Reversing 20 Years Of Aging

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Methods for Nutrigenomics and Longevity Studies in Drosophila

Nutrigenomics is the study of gene-nutrient interactions and how they affect the health and metabolism of an organism. Combining nutrigenomics with longevity studies is a natural extension and promises to help identify mechanisms whereby nutrients affect the aging process, life span, and, with the incorporation of age-dependent functional measures, health span. The topics we discuss in this chapter are genetic techniques, dietary manipulations, metabolic studies, and microarray analysis methods to investigate how nutrition affects gene expression, life span, triglyceride levels, total protein levels, and live weight in Drosophila. To better illustrate nutrigenomic techniques, we analyzed Drosophila larvae or adults fed control diets (high sucrose) and compared these with larvae or adults fed diets high in the saturated fat palmitic acid, soy, or 95 lean ground beef. The main results of these studies are, surprisingly, that triglyceride and total protein levels are significantly...

High Fat Diets Decrease Longevity in Drosophila

However, the specific mechanism responsible for the deleterious effects of saturated fats is unknown. One of the first studies that attempted to make a connection between Drosophila dietary components and longevity found that isocaloric diets consisting of high saturated fats (such as palmitic acid) and low carbohydrates will, on average, shorten the life span of Drosophila compared with flies fed control diets high in carbohydrates and low in saturated fats (24-26). These early studies, performed in the late 1970s and early 1980s by Driver and colleagues (24-26), did not determine the specific metabolic processes that were negatively affected by the consumption of fat. Instead, they potentially laid the groundwork for further studies. Unfortunately, however, these early studies by Driver and colleagues (24-26) were not followed up by other investigators. Other than dietary restriction, very few recent studies have been done on the effects of diet on...

Longevity Studies With Mated Males and Females

Seven dietary conditions used in this chapter. In the top four conditions, the larvae were raised in control (high sucrose) food. The adults were placed in control, palmitic acid, beef, or soy food for the duration of their lives for the longevity experiments. For the microarray, live weight (LW), triglyceride (TG), and protein level measurements, flies were sacrificed at 10 d (arrow). In conditions five to seven, the eggs were laid in the indicated foods, and the larvae were raised in the same foods (palmitic acid PA , beef, or soy food). Notice that the time from egg laying to eclosion time is longer than in the control food (see Fig. 2). Fig. 1. Seven dietary conditions used in this chapter. In the top four conditions, the larvae were raised in control (high sucrose) food. The adults were placed in control, palmitic acid, beef, or soy food for the duration of their lives for the longevity experiments. For the microarray, live weight (LW), triglyceride (TG), and protein...

Vitalist Health Care

The medical bible of the end-of-century European Naturphilosophie vitalists was the health book by Goethe's friend Christian Wilhelm Hufeland (1762-1836), called Makrobiotik, oder, Die Kunst, das menschliche Leben zu Verlangern (1794), translated into English as The Art of Prolonging Life in 1797 (thus taking the strange foreign word Makrobiotik out of the title).64 Makrobiotik was a handbook on how to control the 'rapid or slow vital consumption' of the life force, and how to regulate the 'vital operations' and 'vital organization' of the body. It held out the hope not only of personally prolonging life, but of being able to perfect it universally, in the future, through physical culture 'by culture alone, man becomes even physically perfect physical and moral health are as nearly related as body and soul. They flow from the same sources become blended together and when united, the result is, human nature ennobled and raised to perfection.'65 There was a new emphasis, in vitalist...

Trygve O Tollefsbol

The aging process encompasses changes at the molecular, cellular, and organismal levels that can be analyzed by a variety of methods. For several decades, a popular mode of studying biological aging has been the analysis of cells cultured in vitro that display cellular senescence. Current interest is also focused on models of senescence that include organismal aging such as aging of yeast and Drosophila. The number of techniques applied to biological aging has increased exponentially over the past decade. Although approaches to biological aging vary greatly, they can be generally grouped into basic techniques, intervention methods, and protocols for analyzing the many molecular and cellular changes seen in aging cells. Hence, this volume organizes the topics into these three categories.

Diversity in Patterns of Health and Aging

Methodological difficulties encountered in the processes of sampling, designing valid interview protocols, achieving subject cooperation, and controlling interviewer and subject bias have hampered attempts to generalize about the health and other characteristics of black, Hispanic, American Indian, and Asian populations in the United States. However, in key areas such as life expectancy, prevalence of chronic health conditions, residential patterns, and education, significant differences have been documented across groups. In the United States in 2001, average life expectancy from birth was 5.5 years longer for white persons than for black Americans (Federal Interagency Forum on Aging-Related Statistics 2004). At age 65, however, the life expectancy gap narrowed to about 2 years, and by age 85, life expectancy was slightly longer for older black persons compared with white persons. In 2000-2001, among people age 65 and older, hypertension and diabetes were more common among black than...

Vulnerable Populations

Difficulty getting to medical appointments, taking medications regularly, or obtaining laboratory tests and follow-up care. As a result, persons with AIDS and untreated psychiatric disorders may present with AIDS-related illnesses not usually encountered in developed countries since the advent of potent antiretrovirals or highly active antiretroviral therapy (HAART). In addition, among those persons who are adherent to care, there has been an increase in the prevalence of endocrine, pulmonary, cardiac, gastrointestinal, renal, and metabolic disorders, some of which may be comorbid and unrelated to HIV and AIDS while others may be related to HIV and AIDS or to its treatments. The life expectancy of persons with HIV and AIDS who are treated with potent antiretroviral therapy is now similar to that of the general population (Manfredi 2004a, 2004b). Among the 68,669 persons with AIDS who died in New York City from 1999 to 2004, the percentage of deaths from non-HIV-related causes...

Treatment Options for Major Cancers and Future Directions

According to the most recent statistics, one in three people will be diagnosed with cancer during their lifetime. Increased life expectancy (cancer can be considered a disease of advanced years), environmental factors (e.g., exposure to carcinogens), and social habits (e.g., diet and or smoking) have dramatically increased the risk of cancer in Western populations. Breast, lung, colorectal, and prostate are the four major types of cancer in adults, and they account for over half of all cases diagnosed. The treatments of these major cancers depend upon a variety of factors, but the most common ones involved surgery combined with radiation and or chemotherapy. These treatments are briefly discussed in this section. Table 1 shows representative examples of anticancer agents and their mechanism of action.

Need To Monitor Multiple Outcomes

It is commonly accepted that adaptive monitoring (interim analyses) of clinical trials can lower the risk that future patients will receive a therapy already shown to be ineffective toxic in earlier patients. Adaptive monitoring of most LI trials is limited to interim analyses of response rate, with response defined so as to include MR, which typically is observed much more commonly than is CR.28-36 The presence of MR indicates that the LI has activity and thus might be worthy of further investigation. However, as emphasized above,the relationship between MR and survival or QOL generally is unknown. Thus, making response the sole focus of interim analyses overlooks the reality that patients are likely to be concerned with response only to the extent that it is known to lead to longer survival and or a better QOL. This is particularly true in secondary AML MDS given the short life expectancy of patients with this condition. Indeed, because formal stopping rules in trials of LIs are...

Methods for Cell Sorting of Young and Senescent Cells

Cellular senescence, the ultimate and irreversible loss of replicative capacity of cells in primary culture, has been a popular model for studying the aging process. However, the replicative life span of human fibroblasts is heterogeneous even in clonal populations, with the fraction of senescent cells increasing at each population doubling, rather than all cells entering senescence simultaneously. Thus, the study of individual cells in a mass culture is of extreme importance to the understanding of replicative senescence. Cell sorting is a method that allows physical separation of cells with different characteristics when measured by flow cytometry. Here, we describe various methods by which cells that reach senescence early can be physically sorted out of a bulk of growing cells, and discuss how different methods can affect the posterior analysis of the sorted populations.

How to Motivate Smokers to Quit

Smoking is associated with a range of diseases, causing a high level of morbidity and mortality. It represents one of the leading causes of preventable death with more than 3 million smokers worldwide dying each year from smoking-related illnesses. Stopping smoking has major health benefits. Smokers who quit before the age of 35 can expect a life expectancy only slightly less than those who have never smoked. Quitting at any age provides both short- and long-term benefits, with those who do so in middle age gaining improvements in health and reducing their excess risk of death. Despite the well-known health consequences of tobacco and the benefits of quitting, a quarter to a third of the adults in industrialized countries continue to smoke 14 . Although a majority of current smokers wish to quit smoking and effective interventions exist 15 , very few request or receive formal smoking cessation interventions. Physicians are in a unique position to intervene yet studies suggest that...

Chemotherapy as a Cancer Therapy

Drugs may be reported to increase survival, but upon closer examination this sometimes turns out to be an increase in relapse-free survival, or time to recurrence, and not an actual increase in median overall survival. The latter are important figures, to be sure, but the most important and reliable figure is that of overall survival. Otherwise, the patient may experience an increase in the relapse-free period, but no increase in his or her actual life expectancy. Such a patient may only be benefited in a psychological sense. Yet real improvements in overall survival for the solid tumors

Cerebral Changes In Physiologic Aging

Aging is an inescapable natural biologic process affecting all organ systems of the body. This process, regulated by genetic factors (longevity genes) and influenced by environmental factors, begins after age 50 to 60 years or later. Aging of the central nervous system primarily The pathomechanism of cerebral aging is complex. Mitochondria play a central role in the aging process. With advancing age, the amount of mitochondria-derived free oxygen radicals increases, damaging cellular lipids and proteins and the mitochondrial DNA. This oxidative stress is not effectively countered due to a decline in antioxidant defense mechanisms. It is noteworthy that aging increases the risk for neurodegenera-tive diseases, vascular diseases, and malignancies, all leading causes of death in the elderly.

Psychosocial Impact of Placebo and Nocebo in Advanced NSCLC

One must wonder about the psychologically beneficial effect of being given a powerful and promising new treatment vs. the contrary nocebo (negative placebo) effect of being abandoned to one's fate without further attempts at therapy (26). What is the effect on longevity of these two dramatically different pathways There are comparisons of aggressive treatment to best support

Cellular effects of nephrotoxins

Environmental effects on health are more difficult to study than those in potentially hazardous occupations. The effects of exposure in the general population are likely to be less severe and studies of these effects should take account of the movement of different populations. Recent studies have demonstrated that children are more susceptible to low levels of exposure than adults 7 , which may reflect their increased risk due to the fact that their organ systems are still developing and they have a greater life expectancy.

Chromatin Perturbations

Heterochromatin also can suppress inappropriate recombination, and thus contribute to overall genomic stability. The best example of how heterochromatin, suppression of genomic instability, replicative senescence, and aging are interrelated is illustrated by the SIR proteins. SIR proteins mediate heterochromatin formation at silenced mating-type and other loci in the yeast Saccharomyces cere-visiae (75). The replicative life span of this single-celled organism is limited in large measure by the accumulation of extrachromosomal circles of rDNA (76). These circles are an indication of genomic instability, as they are produced by inappropriate recombination within the highly repetitive rDNA locus. Loss of SIR3 4 or SIR2 function shortens the life span of yeast, whereas overexpression of SIR2 extends yeast life span and suppresses the formation of extrachromosomal rDNA circles (77). Thus, heterochromatinization by SIR2 suppresses ge-nomic instability (presumably by limiting the access of...

Apoptosis and Cell Death

Apoptosis (programmed cell death) is characterised morphologically by increased cytoplasmic granularity, cell shrinkage and nuclear condensation. The most prominent feature of apoptosis is the activation of an endogenous endonuclease that degrades nuclear DNA at linker sections to fragments. It has been suggested that a decrease in the rate of apoptosis plays a role in the pathogene-sis and age-related events such as tumorigenesis. Energy restriction increases apoptosis, which may be the mechanism for its effect in suppressing tumours, ameliorating autoimmune diseases, and prolonging life span. Programmed cell death is an endpoint for many cellular events, but it has not been examined in nutrition studies 48 .

Influence of Nutritional Status on Immune Response

A survey of the literature shows that most nutritional deficits lead to suppressed immune responses. This is not surprising, since anabolic and catabolic pathways in the immune system require the same sort of building blocks and energy sources as other physiological activities. Caloric restriction is another area of emerging interest, with important implications for human health. In general, moderate caloric restriction appears to have beneficial effects on longevity and disease resistance. However, these trends and generalisations must be approached with some caution 62 .

The Problem of Secondary Efficacy Parameters

Ever since the 1980s, oncologists have attempted to correlate differences in response rates to improved survival time. Their line of argument was simple chemotherapies can induce regression of malignancies, and without exception studies clearly show that responders live longer than non-responders. These two findings were used as definite proof for the life-prolonging effects of certain therapies. This deduction was certainly also responsible for some types of cancer never being tested in randomized comparative trials with untreated controls. Some therapies such as active specific immunotherapy (ASI) of cancer, for example, cause immune responses in a group of patients that can be detected by means of a skin test. In numerous studies it has been shown that patients who respond to ASI with an immune response live longer than those who do not respond, even though there is no visible benefit in survival in patients receiving ASI compared to an untreated control group (8). This can be...

Caroline Ross And Kate E Jones

Compared to 12 years maximum recorded longevity). Despite this, Figure 4.1 shows that the population growth of the patas is only slightly more rapid than that of the titis, with the latter taking only two years more to reach a female population of 2000 (35 years compared to 33 years).

Presynaptic Da Function

A number of studies have demonstrated DAT binding ligands as effective markers of nigrostriatal dopaminergic degeneration in aging and parkinsonism (30,31). Striatal DAT binding indices decline by 6 per decade in normal controls, reflecting cell loss associated with aging process. DAT imaging reliably differentiates PD subjects from normal volunteers and other PD-like syndromes, and the degree of striatal binding correlates inversely with clinical measures of PD severity (27,28,31). DAT binding in the orbitofrontal cortex also is significantly lower in nondemented patients with early PD and correlates negatively with scores for mentation and depression (29). The reduction in mesocortical or mesolimbic function may contribute to the mental and behavioral impairment observed in PD.

Central Dogma Of Tumor Progression

Actually be the same genes involved in a selective growth advantage for these cells. These cells maybe lurking even in early-stage cancers. That is, some cancers are predestined almost from the beginning to evolve into invasive, metastatic tumors and some are not. This possibility has huge implications for cancer screening, diagnosis, and choice of therapy. Numerous women receive a diagnosis of ductal carcinoma in situ of the breast based on mammography screening, and many men receive a diagnosis of prostate cancer based on a prostate-specific antigen (PSA) test and subsequent biopsy. And yet many of these patients have indolent tumors that would not affect their overall life expectancy, and they still often undergo significant surgical and drug treatments. The problem is that we are only beginning to be able to tell (e.g., by gene expression arrays) which of these so-called early-stage cancers will be lethal and which ones won't.

Paola Fabrizio and Valter D Longo

The chronological life span of yeast, which is measured as the survival time of populations of nondividing cells, has been used successfully for the identification of key pathways responsible for the regulation of aging. These pathways have remarkable similarities with those that regulate the life span in higher eukaryotes, suggesting that longevity depends on the activity of genes and signaling pathways that share a common evolutionary origin. Thus, the unicellular Saccharomyces cerevisiae is a simple model system that can provide significant insights into the human genetics and molecular biology of aging. Here, we describe the standard procedures to measure the chronological life span, including both the normal and calorie restriction paradigms.

Dimension of the Nutritional Problem in the World

One-third of young children residing in the world's lowest-income countries suffer from growth deficits and rickets because of malnutrition. One-half of all deaths among young children are, at least in part, a consequence of malnutrition. In the developing world, 40 of women suffer from iron deficiency anaemia, a major cause of maternal mortality and low birth weight infants. Despite such worrying trends, there have been significant increases in life expectancy in almost all countries of the world. The proportion of malnourished children has generally decreased, although the actual numbers have not changed in sub-Saharan Africa and southern Asia. However, inequalities are increasing between the richest developed countries and the poorest developing countries. Social inequality is an important factor in differential mortality in both developed and developing countries. Pockets of malnutrition and a high morbidity and mortality of children are emerging in...

Training and Gymnastics

In the fifth century bce the gymnast Herodicus had gained a wide reputation. Herodicus was famed for his command of the training regimen, especially his heroic methods (as practised on himself) of prescribing 40-mile walks, long runs, deep massage, and hot baths. He seemingly tried most things, but what he was most notorious for (according to Plato) was his carefully crafted approach to long-term health care. He was accused by Plato of inventing a longevity health regime for the older male called 'valetudinarianism', or the 'lingering death' an idea to which Plato was scornfully opposed. Plato thought that an honourable life should be quick and natural, rather than slow and artificially prolonged. Hard training was considered necessary for the defence of the state, but unsuitable for the normal, moderate, or temperate life. Normally the most punishing training regimes were reserved for the fit athlete.23 Regular training consisted of set routines of running, ball games, jumping,...

Overview of Treatment Approach

The transition from stage I would also depend on the definition of behavioral control that is used. We have recently made efforts to opera-tionalize this concept and propose three general categories of outcome, rooted primarily in the notion of normative functioning. First, the individual should have a reasonable (immediate) life expectancy, defined as the absence of suicide threats or attempts, nonsuicidal self-injury, and severe, ongoing victimization. Also within this category is the control of behaviors that would threaten the life expectancy of others the absence of aggravated

Scientific Foundations

In 1999, the National Institutes of Health (NIH) Clinical Organ Transplant Program was formed to develop and test new ways of preventing rejection. The development of new transplantation techniques and better anti-rejection drugs in recent years has helped people with organ transplants live longer. The number of heart- and lung-transplant patients living three years or more after

Premature Replicative Senescence In Mice Deficient For Ku

Embryonic fibroblasts taken either from Ku70 or Ku80 knockout mice reveal a pleiotropic phenotype, which includes premature cellular senescence. Telomeric maintenance appears to be a critical event that controls the ability of cells to continue proliferating in cell culture (58,87). Therefore, factors that control telomere maintenance are potential candidates for components that block proliferation and lead to cellular senescence. Because of the link between replicative capacity and telomere length, the reduction in the replicative capacity of Ku-deficient MEFs may simply be due to loss of telomere length regulation (14, 88). Furthermore, the accumulation of DNA damage that occurs during aging has been suggested by many as a possible cause of aging and cellular senescence (89). In fact, during aging and cellular senescence, mutations accumulate in genomic DNA. Therefore, loss of DNA repair capacity might increase the accumulation of DNA damage and play an important role in cellular...

Disease State Diagnosis

Disease onset occurs typically in midlife and, upon diagnosis, life expectancy is in the range of 3-5 years. Males appear to have a higher incidence of ALS and, overall, 1-7 people in 100000 develop the disease.86-88 In comparison to AD and PD, the incidence of ALS is low.

Ethics Of Dna Testing For Inherited Disease

The applications of recombinant DNA technology are exciting and far-reaching. However, the ability to examine the base sequence of an individual raises important ethical questions. Would you want to know that you had inherited a gene that will cause you to die prematurely Some of you might feel fine about this and decide to live life to the full. We suspect most people would not want to know their fate. But what if you have no choice and DNA testing becomes obligatory should you wish to take out life insurance In the United Kingdom insurance companies are now able to ask for the results of the test for Huntington's disease. This is a fatal degenerative brain disorder that strikes people in their forties. From the insurance company's point of view DNA testing could mean higher premiums according to life expectancy or at worst refusal of insurance cover. There is much ongoing debate on this issue.

Alcohol Induced Persisting Dementia

Models of cognitive impairment in alcoholics include premature aging, which means that alcohol accelerates the aging process, and or that vulnerability to alcohol-induced brain damage is magnified in people over the age of 50 the right-hemisphere model, which is derived from the evidence that nonverbal skills (reading maps, block design tests, etc.) are more profoundly impaired in alcoholics than left-hemisphere tasks (language functions) and the diffuse brain dysfunction model, which proposes that chronic alcoholism leads to widespread brain damage (Ellis & Oscar-Berman, 1989).

B Current data for incidence and survival are for the period 19972001 as reported by Ries4 Historic data for incidence

Period 1950-2001, for a net increase of 85.9 from approx 253 cases to 470 cases per 100000, but 5-year survival rates improved from 35 to 65 over the same period for all cancers (Table 1). The increased incidence in the USA over time, and in developed nations, can be attributed largely to increased life expectancy in the populations. The impact of antimetabolite oncolytics is reflected in significantly improved survival rates for the indications for which these drugs are used, most notably in leukemias and lymphomas. Antimetabolites have only more recently been approved for use in solid tumors of the lung, pancreas, and colon rectum and although survival rates for these cancers have doubled over 50 years, the rates remain low relative to leukemia and lymphoma.

Other characteristics

Other variables with prognostic value, but of lesser importance, include age (which reflects a poorer tolerance to cytopenia-associated complications and the impact of other comorbid conditions associated with older age rather than a more aggressive clinical course)79 FAB classification7 gender (worse prognosis for male patients, which may be explained to some extent by the greater life expectancy of women in industrialized countries)7 percentage of blasts in peripheral blood7 presence of immature myeloid precursors and nucleated RBCs in peripheral blood7 degree of multilineage dysplasia in RA and RARS (as in the recent World Health Organization WHO proposals of classification of MDS14)15-21 marrow basophilia or eosinophilia,22 serum lactate dehydrogenase (LDH) level (which may provide an indirect measure of ineffective hematopoiesis and leukemic burden)23 and some BM biopsy findings, such as abnormal location of immature myeloid precursors (ALIP), hypercellularity, and fibrosis.5 6...

Measuring the Time Between Egg Laying to Eclosion as Adults

In the adult longevity studies, every 2 d the adults were transferred to fresh food in a new cage and the number of dead males and females were counted. The old food with eggs was cut into pieces containing no more than 50 eggs and placed into empty 25 mL vials to determine the fecundity of the parents and to measure the amount of time it takes for the progeny to progress from egg laying to adult. Also, virgin males and females were collected from the vials at least twice a day and kept in separate vials with control food (no more than 20 male or female flies per vial) to determine the life span of these flies. We found that some dietary conditions during larval life affected the life span of the flies. However, these experiments are beyond the scope of this chapter and will be presented at a later time.

Chromatin Versus Other Determinants Of Aging

An intriguing example in this regard is the maternal-effect phenotype of mutations in the C. elegans CLK-1 gene (16). In Drosophila, an unexpected environmental input during development has been observed for flies selected for late-life fitness (13). In this case, the extended longevity characteristic of such flies is not evident unless the larvae are reared at a high density. Numerous examples of alternative life spans encoded by a single genome are cited by Finch (21), but remain at the phenomenological level. Of these, the most striking involves social insects such as honeybees, where alternative developmental pathways, queen versus worker, are associated with 10- to 100-fold differences in life span (21). Third, despite variation and plasticity, senescence can be described as having public versus private components (13). In this context, mechanisms involved in resistance to oxidative and other stresses may apply across multiple taxonomic groups. By contrast, age-related,...

Section 3 alternative translation initiation

The glucocorticoid receptor gene, its products, and their actions represent a paradigm that the expression of different isoforms of any protein resulting from ATI could have physiological and pathological implications. Glucocorticoids interact with GRs (GRs, glucocorticoid receptors), through which they exert their effects. It was found that expression of about 20 of the expressed human leukocyte genome was positively or negatively affected by glucocorticoids. There is the report (Chrousos & Kino, 2005) that the GRa regulates expression of bL-Selection and CD11 CD18 on human neutrophils. Variant mRNA was translated from at least eight initiation sites into multiple GRa isoforms termed GRa.-A through GRa-D (A, B, C1 to C3, and D1 to D3). Recently, a convincing association was made between the ER22 23EK polymorphism of the human GR gene and increased human longevity secondary to a healthier metabolic profile. These polymorphisms were previously found to be associated with subtle...

Role of Apoptosis in CLL

The progressive expansion of CLL in the face of its poor proliferative capacity has led to the notion that the neoplastic cells in this disease enjoy increased longevity owing to defective apoptosis rather than to alterations in cell cycle regulation. Apoptosis, or programmed cell death, consists of a cascade of biochemical events leading to cell destruction that plays a critical role both in normal tissue development and in malignancy (83). The apoptotic failure of CLL has been studied extensively, and numerous mechanisms have been proposed to explain this deficiency. Of course, most investigations have been centered on the Bcl-2 gene family and their proteins (84-86). The importance of the anti-apoptosis Bcl-2 oncogene in B-cell malignancies was established more than 20 years ago in follicular lymphomas with the t(14 18). However, in contrast to follicular lymphomas, translocations of the Bcl-2 gene are relatively infrequent in CLL (87). Indeed, unlike other B-cell...

Overlapping Differential Expression

Found that all three experimental diets significantly decrease longevity, increase the length of time to develop from egg to adult, and alter global gene expression patterns compared with the control high-sucrose diet. Preliminary microarray analyses suggest that a total of 60 genes have significantly (FDR 0.1) altered gene expression diets by all three experimental diets compared with the control diet. The life-shortening effect of palmatic acid confirms previous studies by Driver's laboratory (26). We interpret that time required from egg laying to eclosion as being inversely proportional to the quality of food, at least as it applies to proper Drosophila larval development. If this interpretation is correct, then it suggests that the control (high sucrose) food also has the highest quality. This is not surprising because fruit flies typically lay eggs in rotting fruit, hence their name. Rotting fruits are high in fructose and fermentation products, which like sucrose, are quickly...

Mark A Lane George S Roth and Donald K Ingram Summary

Caloric restriction remains the only nongenetic intervention that has been consistently and reproducibly shown to extend both average and maximal lifespan in a wide variety of species. If shown to be applicable to human aging, it is unlikely that most people would be able to maintain the 30-40 reduction in food intake apparently required for this intervention. Therefore, an alternative approach is needed. We first proposed the concept of caloric restriction (CR) mimetics in 1998. Since its introduction, this research area has witnessed a significant expansion of interest in academic, government, and private sectors. CR mimetics target alteration of pathways of energy metabolism to potentially mimic the beneficial health-promoting and anti-aging effects of CR without the need to reduce food intake significantly. To date, a number of candidate CR mimetics including glycolytic inhibitors, antioxidants and specific gene-modulators have been investigated and appear to validate the...

Experimental Models of Caloric Restriction and Applicability to Humans

The lifespan-extending and other beneficial effects of CR, such as anti-tumor effects and the maintenance of more youthful physiology, have been reported in many hundreds of experiments over the past 70 yr. Nonetheless, the question of relevance to humans remains and will go unanswered until definitive human data are obtained (2). There are, however, data from a number of sources that suggest that CR may be relevant to human aging. For example, based on his study of Spanish nursing home residents, Vallejo (3) concluded that reduced caloric intake was associated with a significant reduction in morbidity and that mortality also tended to be lower in the group provided the fewest calories. Caloric intake in residents of the Japanese island of Okinawa differs by 20-40 in adults and children, respectively, compared to the national average (4). Interestingly, Okinawa has a greater proportion of centenarians, a lower overall death rate, and fewer deaths due to vascular disease and cancer....

Caloric Restriction Mimetics

We first proposed the idea of CR mimetics in 1998 (10) and further expanded on this potential approach in a subsequent article in Scientific American (11). In our initial study, we reported that disruption of cellular glucose metabolism (e.g., glycolysis) using the glucose analogue 2-deoxy-D-glucose (2DG) fed in the diet to rats lowered body temperature and fasting insulin levels without significantly reducing food intake over a 6-mo period at the selected dose (10). The 6-mo duration of this study was insufficient to assess indices of biological aging or longevity, but did validate that it may be possible to mimic metabolic effects of CR without reducing food intake. A follow-up survival study in rats unfortunately indicated that the window between efficacy and toxicity was too narrow to make this particular compound useful. The concept of CR mimetics has been further validated in other experiments. For example, similarly to CR, 2DG has been shown to be neuroprotective in rodent...

Disease Basis 61231 Glaucoma

Elevation of IOP results from a deposition of extracellular matrix (ECM) in the anterior chamber, and thus blockage of the AH drainage pathway, the TM and Schlemm's canal. The ECM is composed of numerous proteins, modified glycoproteins, and glycosaminoglycans, including hyaluronic acid, chondroitin sulfate, dermatan sulfate, keratin sulfate, and heparin sulfate. The abnormal deposition and or clearance of ECM in glaucomatous patients may also result from TM cell death and loss of phagocytic activity during the aging process. Coupled with these phenomena is perhaps the decreased ability of TM cells to liberate local matrix metalloproteinases (MMPs), that can digest the ECM and remodel and maintain the anterior chamber architecture and function. There is increasing evidence that increased concentration of tissue growth factor- 2 (TGF-P2) observed in ocular hypertensive glaucoma patients contributes to the elevation of ECM in the TM. The loss of MMP activity could also be due to TGF-...

Use in Prevention and Therapy

Chronic diseases and the aging process. Cysteine and glutathione (by protecting DNA from free-radical damage) may help slow down aging changes6. The amount of glutathione in cells tends to decrease with age. Elderly people may benefit from supplements of cysteine or glutathione to maintain optimum glutathione activity.

Other Diseases of the Retina

Vision is totally dependent on the ability of the retina to receive images from outside the eye, convert the information through photochemical and biochemical reactions into electrical signals, and transmit these signals to the visual cortex in the brain via the optic nerve. Consequently, the retina is an extremely complex tissue composed of ten different layers of cells that process the visual information and send it on to the brain. Defects and or malfunctions in the physiology of these cells have a significant effect on vision. The major retinal diseases stem from either genetic defects or diabetes (and other systemic diseases) or are related to the normal or abnormal aging process such as AMD.

Classical Prognostic Factors 21

CLL is the most common leukemia of elderly people in Western countries. The incidence of the disease varies greatly with age. Thus, whereas in individuals younger than 30 yr the incidence x 100,000 yr is less than 1, in those older than 80 yr the incidence x 100,000 yr is about 25. As a result of increasing life expectancy in the overall population and the higher incidence of CLL in the elderly, the median age of patients at diagnosis is now 70 yr, compared with 60-65 yr a few decades ago. However, an increasing number of patients (10-20 ) are being diagnosed when they are younger than 50 because they have undergone numerous analyses for routine or trivial reasons. Studies analyzing the influence of age on the natural history of CLL as well as the prognosis of young patients have been conducted in recent years (5,6). Younger and older patients with CLL show similar overall median survival (around 10 yr), but the causes of death are different (6). Younger patients usually die because...

Muscle Mass Changes Sarcopenia

Similar to body mass index (BMI), a common definition of sarcopenia accounts for body size by dividing the ASMM by the height squared 44, 50, 51 . In the New Mexico Aging Process Study 45 , sex-specific cut-off points for kg m2 in the ASMM index were set as two standard deviations below the mean for a healthy young-adult population, similar to the definition of osteoporosis. These cut-off points were 7.26 kg m2 in men and 5.45 kg m2 in women. According to this definition, the prevalence of sarcopenia increases from 13-24 among people under 70 to more than 50 among those over 80 (Table 1). Other authors classified their patients as sarcopenic if their ASMM index fell into the sex-specific lowest 20 of the distribution of the index this definition resulted in very similar cut-off values (7.23 kg m2 in men and 5.67 kg m2 in women) 52 . The same authors also measured sarcopenia using the ALM, adjusted for FM and height 52 . The prevalence of sarcopenia according to the first method was...

Ataxiatelangiectasia

Most, but not all, AT homozygotes express clinically significant, but nonprogressive, humeral and cellular immune defects. These can include one or more of the following thymic hypoplasia, low numbers of circulating T cells, functional impairment of T-cell-mediated immunity, abnormally high levels of IgM, oligo-clonal expansions, and or selective deficiencies of IgA, IgE, IgG2, and IgG4 (8-10). Opportunistic infections are rare however, otitis media and sinus infections are frequent. The risk of lower respiratory infections (pneumonia and bronchitis) increases with age, and the combination of immunodeficiency and progressive loss of cerebellar function makes aspiration pneumonia the leading cause of death in AT patients, whose median life expectancy was estimated in a recent survey to be 30 years (11).

How Can Health Professionals Help

Back et al. (2003) state that by focusing on hope, preparation for the worst may have its downfall, and they suggest that adopting a more hope for the best, and prepare for the worst attitude may be most appropriate. They believe that focusing solely on hope (for a cure) may leave the patient unaware of their limited life expectancy, and may possibly result in missed opportunities to put affairs in order (considered as an important aspect of a good death), and to improve symptom and pain management, as well as to discuss underlying issues such as psychological and or spiritual issues, for example. Back and colleagues (2003 ), however, refer to hope mainly in the context of hoping for a cure, while we have found that hope means more than this for those with a terminal illness, and that in contrast to Back et al., maintaining hope is connected to positive impacts on those psychological, spiritual and existential issues mentioned above.

Stephen J Ferrando and Constantine G Lyketsos

The landscape changed with the advent and widespread use of HAART in the mid-1990s. The incidence of HAD has declined (Sacktor et al., 2001a), but, since patients live longer, these disorders may have a stable or increasing prevalence. Further, milder forms of impairment persist in a substantial proportion of patients (Ferrando et al., 1998 Starace et al., 2002), with higher levels of immune functioning (Dore et al., 1999), and the course is highly variable, including fluctuation over time, progression, or even regression of the symptoms. Motor manifestations, while continuing to occur in some cases, are less frequent. Finally, comorbid and differential diagnostic considerations for the cause of these disturbances have shifted away from opportunistic infections toward entities such as substance abuse, hepatitis C coinfection, and the neu-ropsychiatric and metabolic side effects of antiretro-viral medications. To account for these shifts, the diagnostic criteria for HIV-associated...

Heart Disease Mortality

CHD has an enormous global economic impact in terms of both the costs to society for treatments and hospitalizations as well as in decreased longevity. WHO estimates that in 2002 the 'healthy years of life lost' due to heart disease approached 10 in low and middle-income countries and rose to approximately 18 in higher-income countries.3 In the US alone, the economic costs due to CHD have been estimated at 400 billion annually.

Denotes serious illness in male and female

One of the most difficult times for patients and families is the change from treatment which is aimed at prolonging life to the terminal stage of the illness. Rolland (1991) identifies this as often ambiguous and urges medical practitioners to make this more explicit so that families can concentrate on the quality of their interactions.

The Major Degenerative Diseases

Good health late in life depends largely on avoiding the major degenerative diseases associated with getting old. These common disorders greatly accelerate the aging process -preventing these conditions would allow many to live a healthy life well past the age of 100. (A detailed discussion of the nutritional prevention and treatment of each of these important disorders can be found in later sections.

Remaining Lifetime Fracture Probability

Remaining lifetime fracture probability (RLFP) is a type of future global fracture risk prediction that was proposed by Ross et al. (18). The concept of RLFP is based on the exponential increase in fracture risk as BMD declines and decreased survival after age 75. Therefore, although a 50-year-old woman and an 80-year-old woman may both have the same low bone density, their RLFP will be quite different. Because the expected life span of the 80-year-old woman is much shorter than that of the 50-year-old, the RLFP for the 80-year-old will be less. RLFP is calculated based on the individual's current age and bone density, life expectancy, and anticipated rate of bone loss. These values are entered into a statistical model that predicts the number of osteoporotic fractures that the individual is expected to experience in her lifetime. For example, if the RLFP is 5, the individual is expected to suffer five osteoporotic fractures in her lifetime if no intervention is undertaken to slow the...

Historical Context

Updike gives a powerful cultural critique of American life in Rabbit at Rest. The specific medical issue it addresses is how his everyman protagonist, Harry Rabbit Angstrom, has abused his body, mind, and spirit for most of his life, culminating in a fatal heart attack. Updike's keen language documents the events contributing to Rabbit's heart disease, leading to his death at the age of 55 when the average life expectancy exceeds 82 (IRS table 1). In fact, geriatric experts once viewed over age 85 as the genetically programmed old of the old, but twenty-first-century records exceed 120, with centenarians being the fastest growing segment of the population. To understand how Rabbit diminished his potential life expectancy, study the amazing human heart. Simplistically put, the four-chambered heart, with a complex of arteries, veins, and valves, is a dynamic double-pump-action organ with an all-important pacemaking sinoatrial node. In 100,000 rhythmic beats each day the right side...

Antireductionism and the Organization of Nature

The history of biology is marked by continuing opposition between reductionists and antireductionists. Reductionism thrives on exploiting the charge that it provides the only alternative to the mushy incomprehensibility of vitalism. Antireductionists reply that their opponents have ignored the organismic complexity of nature. Given the picture painted above, where does this traditional dispute now stand

Genetic Instability And Dna Repair

As defined by Foe and collegues (85) may give rise to local pathologies in heterozygous individuals during their lifetimes. As such, mosaicism may underlie defects in proliferative homeostasis and organ pathology that accompany the aging process. For the patient with FA, genetic instability can be seen as a double-edged sword. On the one hand genetic instability implies increased cancer risk, but on the other hand, genetic instability might lead to self-correction and thereby improved bone marrow function. The fact that self-corrected cells emerge in these mosaic patients is highly encouraging with respect to the prospects of gene therapy, since these experiments of nature demonstrate quite clearly that corrected cells can attain an in vivo growth advantage. One of the leading theories of aging is the free radical theory of aging. Many aspects of the aging process can be explained by a gradual loss of endogenous oxygen homeostasis (116). Interspecies comparisons, particularly among...

Puzzles And Perspectives

From a phenotypic view, many of the adolescent and adult patients with FA offer the impression of accelerated aging. These patients mostly are underweight individuals with short stature, a delicate body build, pale appearance, and a hoarse voice. They appear older than their biological age. Survival to age 50 year occurs only in rare instances, and many of the patients surviving to adulthood without bone marrow transplantation may in fact owe their relative longevity to self-correction of bone marrow cells manifesting as mosaicism. There is, however, the puzzle of rare patients with FA who appear phenotypically and clinically normal until adolescence and or adulthood, and who may only be diagnosed when their Symptomatic therapies include steroids and androgens, granulocyte colony-stimulating factor (G-CSF), transfusions, and antioxidant supplementation (153). Gene therapy trials have been conducted with several FANCC and FANCA patients, but success has been difficult to prove (154)....

Osteoporosis and Fracture Risk

Incidence of fracture increases with age, and associated increased risk of trauma with falls, which is an independent contributor. The most common fractures occur in the spine, and their frequency increases progressively in women and men beginning in the sixth and seventh respective decades of life. The most serious fractures are of the hip. The incidence of these increases steadily, reaching a rate of about 5 per year in the ninth decade of life. Approximately 70-75 of all hip fractures occur in women, likely due to their earlier and more dramatic bone loss, gender-based differences in bone mass, and greater longevity. Men reach the fracture threshold about a decade later than women. With the continued increase in life expectancy due to medical and other advancements it is projected that the incidence of osteoporotic fractures will reach epidemic proportions within the next couple of decades if effective means to combat them are not implemented.

The Comprehensive Geriatric Assessment

Originally, the answers to these questions were provided by a comprehensive geriatric assessment (CGA), including function, comorbidity, cognition, emotional, social and nutritional status, and medication review 2-3 . Prior to its adoption in geriatric oncology, in general geriatrics, the CGA reduced the risk of hospitalisation and of admission to adult living facilities 4 and may have improved the survival of older individuals 5-6 . In geriatric oncology, the CGA has unearthed a number of unsuspected conditions that might have interfered with the treatment of cancer in the majority of patients age 70 and older 7-9 , has provided an estimate of life-expectancy and of treatment tolerance, and has allowed the institution of a common language in the description of older individuals 2, 10 . Ongoing clinical studies try to derive from the various elements of the CGA an individualised index predicting life-expectancy and risk of toxicity. Table 1 describes the basic elements of the...

Immortality of Transformed Cells in Culture

Most normal diploid mammalian cells have a limited life expectancy in culture. For example, normal human fibroblast lines may live for 50 to 60 population doublings (the ''Hayflick index''), but then viability begins to decrease rapidly unless they transform spontaneously or are transformed by oncogenic agents. However, malignant cells, once they become established in culture, will generally live for an indefinite number of population doublings, provided the right nutrients and growth factors are present. It is not clear what limits the life expectancy of normal diploid cells in culture, but it may be related to the continual shortening of chromosomal

The Cardiovascular Health Study and the First Clinical Classification of Older Individuals

Relation to life-expectancy, functional dependence and tolerance of stress Relation to life-expectancy and tolerance of stress Relation to life-expectancy and dependence are predictive of mortality and of chemotherapy-related toxicity 13-14 . In clinical decisions, these parameters should be maintained to identify patients for whom symptom management only is preferred. A subclassification of frailty into subgroups of different life-expectancy and functional reserve is an urgent research project (Fig. 1).

The Estimate of Life Expectancy

Short-term life-expectancy determines the institution of life-prolonging treatment, long-term life-expectancy that of curative treatment. Simple and reliable ways to calculate mortality risk, from which life-expectancy may be derived, were described by Walter et al. 20-21 . One-year mortality risk may be estimated from a number of parameters (Table 3), such as gender, function, comorbidity, renal function, and nutrition. A score is assigned to each parameter, and the risk of mortality is calculated from the sum of the scores. For long-term mortality, life-tables may be used. The risk of mortality for each age cohort is divided into quartiles, and the geriatric assessment allows the assignment of patients to the appropriate quartile.

New Research Areas

Large, long-term clinical trials are needed in males over the age of 50 years to determine the benefits and risks of androgen replacement therapy. These studies could determine if cardiovascular risk, prostate cancer, frailty, fractures, osteoporosis, cognitive function, and life expectancy are influenced by androgen replacement therapy. A critical area of uncertainty is what testosterone concentration is needed to provide adequate androgenic effects. This is an important question because it relates to the concentration of testosterone where benefits might or might not be expected. Should free, bioavailable, or total testosterone concentrations be used

The Diagnosis of Benign Prostatic Hyperplasia

Figure 10 The AUA diagnostic and treatment algorithm for benign prostatic hyperplasia (BPH) *In patients with clinically significant prostatic bleeding wpatients with at least a 10-year life expectancy for whom knowledge of the presence of prostate cancer would change management or patients for whom the PSA measurement may change the management of voiding symptoms DRE, digital rectal examination IPSS, International Prostate Symptom Score PE, physical examination PSA, prostate-specific antigen PVR, postvoid residue UTI, urinary tract infection. (Reproduced with kind permission from AUA Practice Guidelines Committee. J. Urol. 2003, 170, 530-547.) Figure 10 The AUA diagnostic and treatment algorithm for benign prostatic hyperplasia (BPH) *In patients with clinically significant prostatic bleeding wpatients with at least a 10-year life expectancy for whom knowledge of the presence of prostate cancer would change management or patients for whom the PSA measurement may change the management...

Biomaterials Surfaces Relevant To Cell Culture And Scaffolding

Many materials have been used for in vivo and in vitro supports of cell and tissue growth, frequently exhibiting a spectrum of favorable characteristics mechanical properties such as flexibility and strength, nontoxicity, low inflammatory responses, poor scaffolds for bacterial growth, and either acceptable implant longevity or a programmed, controlled, short half-life. Table 1 summarizes many current clinically tested biomaterials, including the cells tissues of relevance and selected literature references. The point is that this compilation of materials represents a substantial body of clinically useful biomaterials empirically developed and applied without much knowledge of molecular or cellular signaling processes to date.

Palliative Nutritional Endpoints and Decision Making

As an example, a practical approach towards providing nutritional interventions in patients with advanced cancer may include the following elements (1) relative importance of a starvational component (bowel obstruction 5,6 , radiotherapy for head and neck cancers, intake, surgery 7, 8 , high-dose chemotherapy 9 ) (2) probability of a reversible inflammation (infection, treatment-responsive cancer disease) (3) expected life expectancy 10 (4) integrity of the upper and lower gastrointestinal tract (5) goals of the nutritional intervention and meaningful outcomes (6) dietary counselling (assessment of nutritional status, dietary and educational needs, provision of educational and nutritional supplements, alleviate anxiety and conflict around patient's inability to consume what would normally be considered as normal diet) 11 (7) discussion of the option of enteral nutrition in patients with a starvational component and functioning bowel (8) consideration of parenteral nutrition for a...

Prognostic Factors

There is significant variation in survival of patients with myeloma though median survival is 3 years,1 some patients can live longer than 7-10 years.19-22 Several prognostic factors that identify groups of patients with significantly different survival probabilities have been identified, and have become indispensable for patient care and counseling (Table 86.2). These factors are also increasingly used for risk stratification in clinical trials to ensure that treatment arms are truly comparable.

Clinical And Laboratory Features

Long-term follow-up studies have provided valuable information about the outcome of these patients. It is not clear if the life expectancy of this population as a group is changed compared to those without MGUS. Blade et al., in his study of 128 persons with MGUS, did not find any significant difference in the survival probability of persons with MGUS compared to a control population, even though progression to malignancy was clearly associated with a shorter survival.22 In the initial Mayo Clinic series of 241 patients, the overall survival was shorter among those with MGUS compared to an age- and sex-adjusted population.23 Among the 1384 patients from southeastern Minnesota, evaluated at Mayo Clinic between 1960 and 1994, the median survival among those with MGUS was clearly shorter (8.1 years) compared to the expected survival (11.8) for an age- and sex-matched population.13 Among the 1324 cases of MGUS identified between 1978 and 1993 in North Jutland County, Denmark, a twofold...

Mary Alice ODowd and Maria Fernanda Gomez

Shakespeare's Macbeth recognized the vital role of sleep in the renewal and nourishment of mind and body, but until recently, medical science has tended to give sleep disorders scant attention. Insomnia, the most common sleep disorder, can be a symptom of many disorders and has been described as a major public health problem that impacts the lives of millions of individuals, their families, and communities (NIH, 2005). However, random studies of adults have found that the majority of those with sleep complaints are unlikely to broach the topic with a health care provider (Martin and Ancoli-Israel, 2003). When a patient does complain of insomnia, the complaint may be either given short shrift by the clinician or a sleep medication maybe prescribed for short-term use without much attention to the etiology of the complaint or to follow-up. Insomnia is not just an annoyance. It has been shown to affect cognitive functioning, quality of life, and even longevity (Martin and Ancoli-Israel,...

The Importance of Patient Centred Outcomes

The real value of any cachexia intervention can only be truly measured by assessing the day-to-day impact on the individual patient, whether that be an impact on QoL or patient independence. Over the past 20 years, the importance of such patient-centred outcomes has become evident. Studies have shown that cancer patients receiving palliative care are interested not only in the quantity of their remaining life, but also the quality. For example, in a recent survey of patients with advanced lung cancer, only 22 of patients chose palliative chemotherapy, in preference to supportive care alone, to benefit from the associated 3-month survival advantage 30 . In contrast, 68 of patients chose chemotherapy if it substantially reduced adverse symptoms without prolonging life.

Cardiopulmonary bypass

The effects of cardiac surgery on life expectancy and the neurobehavioural complications associated with cardiopulmonary bypass (CPB) are well documented. The incidence and severity of these complications have been correlated with postoperative S-100ft levels in both adults and children 3 , and seem to be related to the duration of CPB. Raised levels of S-100ft have also been reported to correlate with the duration of aortic cross-clamping and circulatory arrest, preoperative arteriosclerosis of the ascending aorta, and the number and size of cerebral emboli.

The Affected Individual

An affected individual faces a different set of consequences when late-onset diseases are disclosed socially. The uncertainty that the affected individual faces may extend to family and friends. Indeed, the disclosure of a genetic basis for a disease to his or her social circles limits the freedom of an individual to make decisions that might increase his or her levels of sociability (marriage, children, extended family) these, in turn, are known to affect longevity. I am describing here a spiral effect of social disclosure that can, and often does, affect the health status of the individual, usually negatively.

Immunoglobulin Prophylaxis

There are several problems with the use of IVIG. These preparations do not correct deficiencies in IgM and IgA, which also play a role in protecting against infections. Weeks et al. (75) concluded that 1 quality-adjusted life-year achieved per patient costs 6 million without any increase in life expectancy. Hence, while IVIG replacement reduces the frequency of infec

The Magnitude of the Problem

The public health importance of chronic heart failure is attributable not only to its high prevalence, but also to the markedly reduced quality of life and shortened life expectancy associated with its diagnosis. Because patients with symptomatic chronic heart failure commonly require frequent and prolonged hospitalizations, health care expenditure attributed to this patient group is significant. In addition to being a major cause of morbidity, particularly in the elderly, chronic heart failure is associated with a grave prognosis. In the United States the death of about 200,000 patients is attributed to chronic heart failure annually.

Impact Of Innovative Technologies In Health Care

As a result of new medicine and technology, patients live longer and want to live better-quality lives (12). The overall elderly population is increasing thus, the health issues related to age also rise. Such diseases as diabetes, stroke, neurological disorders, cancer, and heart disease will be an even more Innovative medicine, along with better education and sanitary and nutritional conditions, will help increase the total population of individuals over 85 yr of age who will live longer and better lives.

Memory and Concentration Loss

During the aging process the number of functioning brain cells gradually decreases and smaller amounts of neurotransmitters are produced. These changes may impair memory and concentration. However, like most age-associated changes in function, there is great variability in the rate and degree of decline among people. The brain is very sensitive to proper nutrition, and needs a high blood flow and oxygen supply. Poor intake of micronutrients can interfere with mentation and memory and may accelerate functional losses associated with aging.9

Caenorhabditis Elegans As A Model System For Aging Research

Soon the first single-gene mutation (age-1) leading to longer-than-normal life span was identified (8) and subsequently mapped and shown to behave as a single gene (9). Mutations in age-1 are recessive to the wild type and dramatically lengthen life expectancy by an average of about 40 and maximum life span by about 70 (10). These mutants result in a decreased mortality almost 10-fold lower by 13 days of age (11), but have no effect on fertility or development (9). Soon it was recognized that numerous other genes (notably spe-26 12 , daf-2 13 , clk-1 14 , and old-1 formerly tkr-1, (15) ) could also be found to lengthen the life span and slow the rate of mortality (15a). Currently, more than 50 distinct genes have been identified that are directly associated with the aging process (in that altering these genes results in increased longevity see http ibgwww.col-orado.edu tj-lab for an up-to-date list of such mutants ). A number of mutants with shorter life spans also have...

Polygenic Contributions To Aging

The analysis of RIs also has illuminated the roles played by DNA-repair capacity and oxidative stress in determining the life span in wild-type C. elegans. With respect to the former (56), analyses have demonstrated that there is no significant correlation between the mean life span and sensitivity to a number of DNA-damaging agents in four RIs with mean life spans ranging from 13 to 31 days. In addition, excision repair of two UV radiation-induced DNA photoprod-ucts was experimentally identical in a short-lived and a long-lived strain. These data suggest that, at least in the wild-type strains employed to create these RIs, DNA repair plays a minor role in the aging process. Conversely, there is a demonstrated overlap between the polygenes that influence the life span and those that control resistance to reactive oxygen species (ROS). Hartman and associates (57)

The History Of Biological Psychiatry

Georget (1795-1828) proposed an organic aetiology of mental disorder (and introduced the technology alibi). His views seemed confirmed by A.J. Bayle (1799-1858), who 'showed' that dementia, other forms of mental disorder, and general paralysis might be related. This has been hailed as the fons et origo of biological psychiatry, but it is historically and conceptually wrong (Berrios, 1985). Quetel (1990 p. 161) is correct in claiming 16 Vitalism is a doctrine according to which the phenomenon of life results from a principle different from the physical and chemical principles that sustain matter in general. Bichat reacted against metaphysical vitalism, i.e. the idea that the vital principle was part of nature. For Bichat, such a principle can be understood only if it is incorporated into each tissue as sensitivity and contractibility (see Haigh, 1984 Pickstone, 1976). a textbook, a few papers, and the foundation of the Archiv fur Psychiatrie und...

Drosophila As A Model For Aging Studies

An exponentially increasing rate of mortality with age previously was thought to be a defining characteristic of the aging process in all organisms. However, experiments with Drosophila and medflies and examination of human survival data have demonstrated that when large numbers of organisms are analyzed, mortality rates level off at the most advanced ages (8,9). The mechanism of this mortality rate plateau is currently unknown, and its occurrence has significant implications for models and definitions of aging.

Spontaneous Hypertension

Form of human stroke, known as cerebral autosomal dominant arteriopathy with subcortical infarcts. If placed on a highsalt diet they do not survive longer than 8 weeks, but their life expectancy can be substantially prolonged by different types of drugs, including heparin or CCAs. Rossi eta .18 found a markedly increased endothelin receptor (ETA) density in the walls of cerebral arterioles of SPSHRs. This and other findings suggest involvement of endothelin in the pathogenesis of certain types of stroke.

Civil Cleanliness

Sir John Sinclair, Essay on Health and Longevity (London, 1802), 10-11. 5. Sir John Sinclair, The Code of Health and Longevity or, A Concise View of the Principles Calculated for the Preservation of Health and Attainment of Long Life, 4 vols. (Edinburgh, 1807-8), i. 20-4. 65. C. W. Hufeland, The Art of Prolonging Life, ed. E. Wilson (London, 1852), preface, p. xixv.

Cystic Fibrosis Is A Severe Genetic Disease

Until recently babies with CF did not survive to their first birthday. Today, the life expectancy is 22 years. This remarkable improvement is due to intensive therapy designed to reverse individual symptoms. Digestive enzymes are taken by mouth to replace those proteins the pancreas fails to produce. Physiotherapy helping patients to cough up the mucus in their lungs by slapping their backs reduces the severity of the lung disease. Yet, however remarkable the increase in survival, each life that extends only to early adulthood is still a tragedy.

Oxidative Stress And Aging

The free radical theory of aging has consistently lacked direct, definitive support. This primarily has been due to the failures of many intervention studies. The theory lost considerable standing among researchers during the early 1990s, particularly in the light of the then growing evidence that specific genetic loci can influence the rate of aging in model organisms such as Caenorhabditis elegans. In fact, by the mid-1990s, prominent researchers in the molecular gerontological community voiced the opinion that specific genetic regulatory mechanisms, and not oxidative mechanisms, were the likely place to look for the control of aging, and that antioxidant interventions would never forestall aging. The model that then gained adherents postulated specific regulatory mechanisms rather than entropic processes. More recently still, a synthesis of the two views has emerged, as some of the C. elegans genes implicated in the aging process (sometimes called geronto-genes) have revealed...

Correlations Of Oxidative Stress And Aging

The hypothesis that oxidative stress is a major factor in the aging process has existed for more than 40 years (1). During this period, much correlative data were reported that lent support to the idea that cumulative damage inflicted by endogenous pro-oxidants is deleterious to a cell or to an organism's ability to maintain homeostasis (17). For example, a number of interesting findings have recently been reported in relation to specific protein and carbonyl modifications with age (20,21). In Drosophila, carbonyl modifications have been found to accumulate with aging (22,23). In addition, specific carbonyl modification of mitochondrial aconitase and the adenine nucleotide translocator (ANT) have been reported with age (20,21). In addition to model systems such as Drosophila and the mouse, protein oxidation has been described immunohistochemically in tissue sections of aged human brain in association with lipid peroxidation and proteins indicative of stress (24-27).

Hospice Transition And Hematologic Malignancies

Relieved, hope to have a series of better days, hope to live to an important date, hope to have life closure. Inquiry into prognosis is a teachable moment. It is better that patients and families see what is evolving than physicians foretell the date of death. Patients and families value knowledge concerning the symptoms and signs of the dying process. Quantifying life expectancy as an answer to prognosis does not equip the patient or family to understand the dying process, nor discern its presence. Physicians are also usually overly optimistic regarding the time a patient has left. Prognostication by physicians, if taken by families as the gospel, results in sociologic death as the predicted hour approaches. Foreseeing the dying process rather than foretelling life expectancy is the better way of handling questions about prognosis. On the other hand, a relative timetable may help patients with closure and estate planning, and so a general answer as days to weeks or weeks to months or...

Abnormalities Associated With

The introduction of antiretroviral therapy has increased the life expectancy of people infected with HIV-1 and resulted in an immediate decrease in the incidence of severe dementia. Indeed, in a case study, participants have demonstrated remarkable improvement in cognitive function with almost a complete reversal of associated symptoms of HAD over the course of 7 years (Gendelman et al., 1998). In the last decade, however, there has actually been an increase in the prevalence of HAD, perhaps because of the poor penetration of antiretrovirals into the CNS. As a result, antiretroviral therapy has failed to prevent the development of HAD or to reverse the disease in most cases (Major et al., 2000).

Ethical And Emotional Aspects

Physicians should recall that a diagnosis of CLL can have a devastating effect on the pateint's quality of life, independently of age, clinical stage, and the therapy requirements. A leukemia diagnosis at a relatively young age may cause worries about the future course of the disease, the need for therapy, the potential complications, the ability to face professional and familial engagements, and, most of all, the risk of premature death. This is particularly so in light of the progressive increase in mean life expectancy. Patients with a diagnosis of CLL need to be helped to accept their new reality, which is related to the diagnosis of a chronic but incurable disease. Adequate and detailed information should be given to the patients and their families. Because of the high heterogeneity of this form of leukemia, each patient will have his or her own clinical picture, which depends on the stage and clinical activity of the disease. If therapy is required, the treatment strategy should...

Caloric Restriction And Aging

Caloric restriction (30-40 reduction in total caloric intake without malnutrition) has been recognized for over 60 years (33) as a means to extend the life span in many species, including rodents and probably primates. Similar to the dauer pathway in C. elegans, caloric restriction increases stress resistance and postpones reproduction. Certain mutations in C. elegans affect the ability to eat (eat mutants) and the rate of living, including feeding (clk mutants). Genetic epistasis experiments indicate that mutations in eat and clk affect the same pathway (reviewed in Ref. 34). In contrast, the daf pathway is independent, because daf-2 clk-1 double mutants live longer CR also draws a connection between reproduction and aging. In the absence of reproduction, suppressed either by adverse environmental conditions, or by ablation of germ cells in C. elegans or Drosophila, the life span in prolonged. This occurs presumably in an attempt to delay reproduction until a more favorable time in...

Treatment of Indolent CLL

This low-risk stage A group this group constitutes almost two-thirds of patients with CLL and has a median age at diagnosis of 64 yr and an expected survival of more than 10 yr, which is close to the life expectancy of a normal population matched for sex and age (9,10). In addition, deferring therapy until disease progression demands it has been shown not to compromise survival (10).

Basic Facts About Cancer

There has been a steady rise in cancer death rates in the United States during the past 75 years. However, the major reason why cancer accounts for a higher proportion of deaths now than it did in the past is that today more people live long enough to get cancer, whereas earlier in the twentieth century more people died of infectious disease and other causes. For example, in 1900 life expectancy was 46 years for men and 48 years for women. By 2000, the expectancy had risen to age 74 for men and age 80 for women. Thus, even though the overall death rates due to cancer have almost tripled since 1930 for men and gone up over 50 for women,

Cancer Is a Global Problem

Cancer is clearly a worldwide problem. The incidence and mortality rates for various cancers are similar, though not identical, among developed countries. In the developing world, as countries become more westernized and their populations achieve longer life expectancy, cancer rates are increasing. Although there are differ

Description of Cancer

In the expression of multiple genes, leading to dysregulation of the normal cellular program for cell division and cell differentiation. This results in an imbalance of cell replication and cell death that favors growth of a tumor cell population. The characteristics that delineate a malignant cancer from a benign tumor are the abilities to invade locally, to spread to regional lymph nodes, and to metastasize to distant organs in the body. Clinically, cancer appears to be many different diseases with different phenotypic characteristics. As a cancerous growth progresses, genetic drift in the cell population produces cell heterogeneity in such characteristics as cell anti-genicity, invasiveness, metastatic potential, rate of cell proliferation, differentiation state, and response to chemotherapeutic agents. At the molecular level, all cancers have several things in common, which suggests that the ultimate biochemical lesions leading to malignant transformation and progression can be...

Long Life Is Associated With Increased Resistance To Stress

A number of early studies on the long-lived (referred to as age) mutants focused on stress resistance. Long-lived mutants show increased resistance to oxidative stress, heat, and ultraviolet (UV) light (summarized in refs. 20 and 27). A summary of data showing correlations between mean longevity in a variety of mutant strains and subsequent life spans is shown in Figure 1. This information can be supplemented with studies from the Johnson laboratory that are available online (see http ibgwww.colorado.edu tj-lab ) and will be continually updated. Among the various classes of mutants that have been studied for increased stress Figure 1 Correlation between life expectancy and stress resistance. (A) Correlation between relative thermotolerance and life expectancy. (B) Correlation between relative UV resistance and life expectancy. All data are normalized to control for environmental variation by dividing by the corresponding wild-type (N2) life expectancy. Mean life span on agar (life...

Age Related Macular Degeneration

Perhaps the most significant hurdle for dry AMD clinical trials is that disease onset occurs late in life as a cumulative result of chronic damage to the RPE cells and their dependent photoreceptors. Most dry AMD patients are likely unaware of their disease until visual acuity begins to decline, at which point substantial morphological damage and dysfunction have occurred. It is thus unclear that intervening in a recognized AMD risk-increasing pathway (e.g., by administering an anti-inflammatory drug or by cessation of smoking) will work at this late stage. Since the RPE, photoreceptors, and Bruch's membrane target tissue are in the posterior segment of the eye, delivering an efficacious NCE concentration is usually ineffective using a topical eyedrop and instead requires locally invasive (e.g., intraocular injection) or systemic methods. On the positive side, since the most important disease risk factor is aging, a therapy that slows but does not arrest or reverse progression of dry...

Multiple sclerosis

Epilepsy describes a large class of seizure disorders in which normal patterns of neuronal activity become disturbed, leading to unusual emotions, behaviors, sensations, convulsions, muscle spasms, and loss of consciousness. Epileptic seizures can be divided into either partial (focal) or generalized seizures. Partial seizures (see 6.11 Epilepsy) occur in one part of the brain and can be either simple or complex. Simple partial seizures tend to involve sudden and unexplained sensations or emotions, while complex partial seizures typically involve a loss of, or alteration of, consciousness that may present as repetitive unproductive behaviors. Focal seizures are usually brief, lasting only a few seconds. Generalized seizures are more broadly expressed in the brain, typically involve both hemispheres, and may cause loss of consciousness, spasms, and falls. There are multiple classes of generalized seizure including absence, tonic, clonic, atonic, and tonic-clonic. Epilepsy currently...

An Aging World

For the first time in history, most people in societies such as our own can plan on growing old. Life expectancy from birth has increased dramatically in the United States, from about 47 years in 1900 to 77.3 years in 2002 (Federal Interagency Forum on Aging-Related Statistics 2004). Even those people who are currently old can expect to live for many years. For men at age 65, average life expectancy is more than 16 years, and for women at age 65, it is almost 20 years at age 85, men can expect to live 6 more years and women 7 years (Federal Interagency Forum on Aging-Related Statistics 2004). Worldwide, average life expectancy has increased to about 65 years (Cohen 2003), and by 2050, the number of people age 65 years and older is projected at 2.5 billion worldwide (20 of the total population) (Olshansky et al. 1993). Substantial increases in elderly populations are projected in the next quarter century for North America, Europe, Asia, Latin America, and the Caribbean, with smaller...

Conclusions

HAART has transformed HIV infection into a treatable disease. For the vast majority of infected people living in resource-limited regions, however, this transformation has not been completely realized. Knowledge of HIV-1 status remains essential for targeted prevention and early access to care. Life expectancy of persons with AIDS who do have access to care and adhere to therapeutic regimens now approaches that

Cognitive Appraisals

Individual differences in cognitive appraisals of stressors may moderate the association between stressful life events and health status in HIV-positive persons. Specifically, one research group has demonstrated that positive illusions and unrealistically optimistic appraisals may confer health-protective benefits (Taylor et al., 2000). Results from an investigation of bereaved HIV-positive men indicated that those who engaged in cognitive processing (deliberate, effortful, and long-lasting thinking) about the death of a close friend or partner were more likely to report a major shift in values, priorities, or perspectives (i.e., finding meaning) following the loss (Bower et al., 1998). For those who were classified as finding meaning, positive health effects appeared to follow. Finding meaning predicted slower CD4+ decline and greater longevity over a 2- to 3-year follow-up period (Bower et al., 1998). Decreased cortisol is one plausible mediator of the effects of finding meaning on...

Jacob Oluwoye

Mathematical methods are gaining wide acceptance in the study of infectious diseases and putting this powerful tool in the hands of public health community is an extremely important development. It was not until the Seventeenth Century that one of the first practical uses was made of probability when life expectancy tables were published for use in computing life insurance premiums and benefits.

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