Increase In Average Lifespan Research Articles

Individual and Societal Wisdom: Explaining the Paradox of Human Aging and High Well-Being.

Objective: Although human aging is characterized by loss of fertility and progressive decline in physical abilities, later life is associated with better psychological health and well-being. Furthermore, there has been an unprecedented increase in average lifespan over the past century without corresponding extensions of fertile and healthy age spans. We propose a possible explanation for these paradoxical phenomena. Method: We reviewed the relevant literature on aging, well-being, and wisdom. Results: An increase in specific components of individual wisdom in later life may make up for the loss of fertility as well as declining physical health. However, current data on the relationship between aging and individual wisdom are not consistent and do not explain increased longevity in the general population during the past century. We propose that greater societal wisdom (including compassion) may account for the notable increase in average lifespan over the last century. Data in older adults with serious mental illnesses are limited, but suggest that many of them too experience improved psychosocial functioning, although their longevity has not yet increased, suggesting persistent stigma against mental illness and inadequate societal compassion. Conclusions: The proposed construct of societal wisdom needs more investigation. Research should also focus on the reasons for discrepant findings related to age-associated changes in different components of individual wisdom. Studies of wisdom and well-being are warranted in older people with serious mental illnesses, along with campaigns to enhance societal compassion for these disenfranchised individuals. Finally, effective interventions to enhance wisdom need to be developed and tested.

Drug Discovery Inspired by Mother Nature for Cancer Therapy

Cancer is a hyper-proliferative disorder that arises due to dysregulation of multiple cell signaling pathways. It is one of the most common causes of death worldwide. Globally, about 14.1 million new cases of cancer have reported in 2012, and 8.2 million deaths occurred due to cancer (14.6% of all human deaths) (WHO 2014). The most common types of cancer in females are breast, colorectal, lung, and cervical cancer and in males lung, prostate, colorectal and stomach cancer. The rate of cancer incidences is increasing in developing as well as developed countries due to change in lifestyle and increase in average life span of the people [1]. The risk factors associated with cancer are environmental factors such as diet and obesity (30–35%), infections (15–20%), tobacco consumption (25–30%), radiation (10%), stress, lack of physical activity, and environmental pollutants [2]. The remaining 5–10% is due to inherited genetics. Since most common cause of cancer is environmental factors, changing lifestyle can prevent it [3]. Other than lifestyle, several therapeutic measures are available to treat the cancer that includes surgery, chemo, radiation, hormone, targeted, and biological therapy but these therapies are very expensive, unsafe , and have numerous side effects. Because of these, people are always in search for effective and less expensive, nontoxic drugs from Mother Nature. Natural products have been used for the treatment of different diseases since centuries. Since last few decades a number of drugs have been discovered either by serendipity or by rationale against various diseases including cancer. From last few decades, 74.8% drugs

Epidemiological and Survival Disparities of Multiple Myeloma in Different Ethnicities in the USA: A SEER Database Based Analysis From 1973 to 2009

AbstractAbstract 4967 Background:Multiple myeloma (MM) is a common hematological malignancy affecting all races and the incidence is increasing. The rise in incidence is partly due to an increase in average life span in the patient population above the age of 65. It is estimated that 21, 700 individuals will be diagnosed with and 10, 710 patients will die of myeloma in 2012. The comparative epidemiological and survival data on different ethnic groups has not been analyzed on a large population scale. The aim of this study is to analyze and compare the epidemiologic and survival parameters of MM in major US ethnic groups which may provide new insights into disease pathophysiology. Methods:The SEER (Surveillance Epidemiology and End Results) database has been reporting cancer incidence since 1973. Using SEER 18 registries database 1973–2009, appropriate frequency and survival analyses (Kaplan-Meier survival method age adjusted) were performed and compared. Results:US whites (USW) accounted for the highest reported cases (77%) while the next highest reported cases were AA population (17%) (Table 1). On the contrary, the incidence of MM was highest in AA (11. 7%) and lowest in the US-Hispanic group (3. 4%). Male to female distribution was similar among groups. The median age at diagnosis was 63yrs in AA and 62yrs in US-Asians compared to ∼70yrs in the other ethnic groups. The cancer at presentation was more advanced in the AA and US-Asian groups. However, as shown in both Tables 1 &2, the mortality rates were significantly lower in the US-Asian population when compared to other ethnic groups (2. 4%).Table 1:Comparison of selected variables of MM among major US ethnic groupsVariablesAllUSWAAHispanicUS-AsianReported cases (%)79,186 (100%)61,083 (77%)13,611 (17%)2,393 (3%)1,872 (3%)Incidence rate5.85.311.7*3.44.1Male7.46.914.36.34.7Female4.74.110.14.73.9M% - F%53%–47%54%–46%49%–51%53%–47%49%–51%Median age of diagnosis697163*7062*Age <50 at diagnosis23%21%28%*19%*31%*Advance stages83%79%89%*81%92%*Mortality rate3.73.46.6*2.82.4*Male4.44.183.32.8Female2.72.55.42.31.9*P<0. 01 compared to all reported cases of MM.Table 2:Comparison of survival among major US ethnic groups with MMSurvivalAllUSWAAHispanicUS-Asian1 – year71%70%72%71%76%*2 – year56%55%57%54%59%*3 – year45%44%46%45%51%*4 – year36%35%37%34%42%*5 – year29%28%30%28%34%**P<0. 01 compared to all reported cases of MM. Conclusions:Our analysis shows that the incidence of MM is highest in AA population, with more males affected than females, and least common in US-Asian population, more specifically US-Asian women. Interestingly, we observed that not only the average age of diagnosis is significantly less in both groups, but those presenting with an advanced stage are also significantly increased in number. However, the improved mortality rates and survival in US-Asians may be attributed to differences in tumor biology, cytogenetics, emigrational factors, higher socioeconomic status, better health care, higher educational background with awareness, lifestyle and environmental factors such as dietary habits and obesity. Large scale epidemiological studies performed by Alexander et al in 2007 demonstrated an association between obesity and an increased risk of MM whereas dietary factors such as increased consumption of green vegetables and fish was linked to a decrease in risk. Molecular and cytogenetic studies are warranted to examine the behavior and biology of MM in these AA and US-Asian ethnicities, directly comparing the treatment and management of this particular disease, which may translate into better understanding of pathogenesis and identification of prognostic factors leading to improvements in treatment. Disclosures:No relevant conflicts of interest to declare.

Using Monkeys to Understand and Cure Parkinson Disease

AbstractResearch with nonhuman primates is essential to medical progress and will still be necessary for the foreseeable future. Almost all research scientists agree that animal research is critical to understanding basic biology, discovering new treatments for human (and animal) diseases, and maximizing the safety of new medicines while minimizing their harm to humans. All but two of the Nobel prizes in medicine awarded over the last one hundred years have depended on animal research, and the list of modern medicines, vaccines, and other treatments, as well as basic science discoveries, is so extensive that it could not be adequately covered in even a huge volume. Increases in average life span in the last century are the result of improved public health measures, and many diseases may be related to lifestyle choices. But animal research has contributed to understanding these factors and to the development of vaccines and lifesaving treatments. The philosophical debate regarding the benefits and moral costs of animal research has also filled many volumes by ethicists and philosophers. The major arguments against the use of animals in medical research have been explicitly refuted by a few brave scientists, as well as implicitly by the vast majority of the working biomedical science community.My contribution to this discussion is to provide a personal perspective on my decision if, when, and how to use monkeys in research experiments on Parkinson disease. As a physician researcher, I have been working for many years to understand and cure Parkinson disease.

PGC‐1α protects neurons and alters disease progression in an amyotrophic lateral sclerosis mouse model

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease. We sought to determine whether peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) would have a beneficial effect on this disease. PGC-1α transgenic mice were crossed with SOD1 mutant G93A DL mice. We observed a moderate but non-significant increase in average lifespan in PGC-1α/G93A DL mice, as compared with G93A DL mice (292 ± 3 days vs. 274 ± 7 days). Although the onset of ALS was not altered, progression of the disease was significantly slower (≈34% increase in duration) in the PGC-1α/G93A DL mice. These mice also exhibited markedly improved performance on the rotarod test, and the improved motor activity was associated with a decreased loss of motor neurons and less degeneration of neuromuscular junctions. A sustained level of excitatory amino acid transporter protein 2 (EAAT2) in astrocytes of the PGC-1α/G93A DL mice may contribute to neuronal protection.

A role for Ras signaling in modulating mammalian aging by the GH/IGF1 axis

The discovery that mutations in single genes can modulate aging was not only fascinating but it provided researchers with animal models with which to study aging in cohorts of different aging rates [1-2]. According to the GenAge database [3], at the time of writing, genetic manipulations in 68 genes have been shown to affect lifespan in mice. Among mouse genes in which mutations extend lifespan, a number are part of the growth hormone/insulin-like growth factor 1 (GH/IGF1) axis. As such, it is widely acknowledged that decreased GH/IGF1signaling in mice can extend lifespan, while increased GH levels may accelerate aging [4-5]. Although the GH/IGF1axis is one of the major pathways regulating aging in mammals, its precise downstream mechanisms remain a subject of debate and scrutiny. In this year's March issue of AGING, Borras et al. show that mice deficient in Rasgrf1, a guanine nucleotide–releasing factor for Ras, exhibit a significant increase (~20%) in average and maximum lifespan. This increase in lifespan was independent of cancer mortality and was accompanied by a retardation in age–related functional and physiological decline [6]. Ras homologues have been associated with lifespan modulation in yeast [7], so it seems that Ras signaling is another example of an evolutionary conserved pathway modulating aging. Rasgrf1 is unique among Ras family members, however, as it is only expressed in a few specific tissues, in particular in pancreatic β–cells and in some regions of the brain. Thus far, Rasgrf1 has been primarily associated with learning and memory [6,8-9]. Because of its expression in the brain, Rasgrf1 has been shown to regulate the synthesis and release of GH, and previous studies showed that Rasgrf1 deficient mice have lower levels of GH [9-10]. In line with these previous studies, and given that GH impacts on IGF1 levels, Rasgrf1 deficient mice showed lower IGF1 levels [6]. Decreased GH/IGF1 signaling results in stunted growth and reduced adult body size, which has been associated with life-extension in numerous models [11]. Borras et al. and other authors also observed that Rasgrf1deficient mice are smaller than controls [6,9-10]. Therefore, it is likely that decreased GH/IGF1 signaling is the mechanism by which Rasgrf1 impacts on aging. Changes in GH/IGH1 have also been hypothesized to be related to the mechanisms of caloric restriction [4-5], which is in line with the observation by Borras et al., that Rasgrf1 deficient mice have metabolic profiles similar to mice under caloric restriction. Because Rasgrf1 mutants have altered GH/IGF1 signaling, I had predicted that they would be long-lived [12]. Moreover, it was reported that bi-maternal mice are long-lived and, because Rasgrf1is an imprinted gene expressed from the paternal allele in neonates, it is possible that bi-maternal mice are long-lived due to Rasgrf1 effects [12-13]. Although conducted in different labs and strains, bi–maternal mice had a similar increase in average lifespan (28%), though a more modest increase in maximum lifespan (~5%). Rasgrf1 deficient mice are therefore another model to study the modulation of aging by the GH/IGF1 axis. Interestingly, mice expressing Rasgrf1from both alleles have increased body size and higher IGF1 levels [9]. Although the lifespan of these animals is unknown, they could be seen as a complementary model to the Rasgrf1 knock-outs. Consequently, since they are available with both increased GH (biallelic Rasgrf1 mice) and decreased GH levels (Rasgrf1 knock outs), the different Rasgrf1 mutant mice may be an excellent new model to study aging and its modulation by the GH/IGF1 axis.

The Pharmacotherapy of Chronic Obstructive Pulmonary Disease in the Elderly: An Update

Chronic obstructive pulmonary disease (COPD) is a disorder of the airways characterized by inflammation and airflow limitation. It is a major cause of morbidity and mortality globally and its prevalence is on the rise. COPD is predominantly a disease of the older age group. As the average life-span increases world-wide, and the burden of COPD increases, correct recognition and optimal management of this disease has become essential in the elderly. In the proceeding article, changes in the respiratory system associated with normal aging, as well as with COPD are reviewed. Important implications of aging in COPD management are also discussed.

Insulin Sensitivity as a Key Mediator of Growth Hormone Actions on Longevity

Reduced insulin sensitivity and glucose intolerance have been long suspected of having important involvement in aging. Here we report that in studies of calorie restriction (CR) effects in mutant (Prop1(df) and growth hormone receptor knockout [GHRKO]) and normal mice, insulin sensitivity was strongly associated with longevity. Of particular interest was enhancement of the already increased insulin sensitivity in CR df/df mice in which longevity was also further extended and the lack of changes in insulin sensitivity in calorically restricted GHRKO mice in which there was no further increase in average life span. We suggest that enhanced insulin sensitivity, in conjunction with reduced insulin levels, may represent an important (although almost certainly not exclusive) mechanism of increased longevity in hypopituitary, growth hormone (GH)-resistant, and calorie-restricted animals. We also report that the effects of GH treatment on insulin sensitivity may be limited to the period of GH administration.

Whole Patient Care: Reaching Beyond Traditional Healthcare

AS THE AVERAGE LIFE SPAN increases and more people develop chronic illnesses, it is becoming apparent that our healthcare system is not providing the necessary combination of coordinated systems to an aging and increasingly complex population. The fact that healthcare costs keep rising without comparable increases in national health outcomes proves this. Thirty years ago, when life expectancy was shorter and demands on the healthcare system were not as profound, the system delivered care from personal family physicians (physicians working with less complex patients, with more time, and with better relationships with patients and their families). Population growth, better research, better medications, and more intensive interventions created a new period in healthcare history, a period of endless information and incredible patient needs. Fortunately forward-thinking healthcare analysts and researchers have identified gaps in care and developed proposals and theories to bridge the gap. Beginning with the Institute of Medicine's Crossing the Quality Chasm, new ideologies emerged which impugned current practices while identifying primary areas of need (Institute of Medicine 2000). INTERSECTING MODELS REVOLUTIONIZE HEALTHCARE In 1992, the American Academy of Pediatrics (AAP) repudiated the current system of care for children with special healthcare needs and published a policy statement defining the medical home (American Academy of Pediatrics 2002). The AAP believes care should be accessible, continuous, comprehensive, family centered, coordinated, compassionate, and culturally effective. In 2002, the AAP disseminated an updated policy that refers to a care-delivery system that provides timely access to medical care, improved communication between patients and their healthcare team, coordination and continuity of care, and focus on quality and safety. The medical home concept aims to improve the entire healthcare delivery system. The medical home idea is a family-centered approach, and it stipulates that patients need coordinated and continuous care. In a system that has grown beyond the primary care provider to care from a complex array of providers, coordinated and continuous care has become an absolute necessity. In 2007, the American Academy of Family Physicians (AAFP), the American Academy of Pediatrics (AAP), the American College of Physicians (ACP), and the American Osteopathic Association (AOA) released Joint Principles of the PatientCentered Medical Home (ICIC 2008.) With the support of these organizations the medical home model went beyond an approach to manage children with special needs to become an ideology for improving care for patients across the life span. In 1998, chronic care innovator Dr. Ed Wagner published the first in a series of precedent-setting articles that evolved into the Chronic Care Model (Wagner 1998). Based on the knowledge that 133 million people live with a chronic condition, a number that is projected to increase by more than 1 percent per year, and that nearly half of those individuals have multiple chronic illnesses, Wagner conceptualized a new, transformative delivery system. This system includes not only an informed patient but an active community, plus health systems that use decision support and clinical information systems such as electronic medical records. Similar to the medical home model, the chronic care model has moved the patient from a place of isolation into a larger family and community support structure, acknowledging that people do not function or live in dissociated states. Further, the chronic care model fosters communication between an involved and educated patient and a proactive, interactive care team. No longer is communication of facts and figures acceptable -communication must involve an exchange of knowledge in a collaborative relationship, what Wagner refers to as productive interactions. This cooperative model abolishes the hierarchical, archaic structure of physician-patient care and introduces the concept of equal partners using information and decision support to establish unified and achievable goals. …

Elders in the justice system: how the system treats elders in trials, during imprisonment, and on death row

As the average lifespan increases, it becomes increasingly likely that elders will be involved in the justice system. Elders may be witnesses, victims, plaintiffs, or defendants in a trial. They are also prisoners and, in some cases, death row inmates. Because there are special needs and costs associated with elders, it is important to consider how they are treated in each of these areas of the justice system. For instance, jurors may have age biases; some prisons are unable to address elders' health problems; and critics have questioned the constitutionality of executing frail elders. In order to determine whether the court system is treating elders fairly, this analysis reviews current policies, research, and anecdotal evidence from recent high-profile cases. Recommendations for future research and policy changes are offered to ensure that elders are treated fairly in the justice system.

In the quest to stymie time, will laboratory data stand up in man?

In the quest to stymie time, will laboratory data stand up in man?

Aging and Longevity

See related article, pages 418–426 IGF-1 belongs to the insulin family of peptides and acts as a growth factor in many tissues and tumors. Locally acting isoform of IGF-1 targeted to skeletal muscle enhances muscle growth and differentiation, prevents age-related muscle atrophy, and potentiates regeneration after injury.1,2 Similarly, cardiac restricted expression of IGF-1 increases the formation of ventricular myocytes, attenuates myocyte death, and delays the development of an aging myopathy.3,4 In the heart, the IGF-1–IGF-1 receptor system induces division of cardiac stem cells (CSCs), upregulates telomerase activity, hinders replicative senescence, and preserves the pool of functionally competent CSCs.4,5 After muscle injury, IGF-1 promotes the activation, mobilization, and differentiation of satellite cells which, together with the recruitment of bone marrow progenitor cells, contribute to skeletal muscle regeneration in old animals.1,2 Spontaneous repair of damaged muscle typically occurs in young animals and is severely impaired with age. Importantly, heart failure leads to a catabolic state characterized by a progressive loss in skeletal muscle mass and the appearance of cardiac cachexia in the late stages of the disease. This information formed the basis of the study by Schulze et al6 published in the current issue of Circulation Research . The dramatic problem of skeletal muscle wasting with chronic heart failure has become a common clinical reality. Cardiac decompensation is a disease of the elderly, which has reached endemic proportion with the progressive increase in average lifespan of the population in the Western world.7 Unfortunately, muscle atrophy cannot easily be reversed, and the pharmacology is palliative at best. Similarly, strategies aiming at the reconstitution of muscle mass with systemic administration of growth factors or potential implementation of cell therapy are in an infancy stage. The work of Schulze et al has addressed this major pathological condition with …

Effects of aging and stress on hippocampal structure and function

Aging is often simply defined as the decline in various body systems and functions (eg, endocrine, cognitive, motor, etc) that occur with the passage of time, although the degree of deterioration can vary greatly across individuals. Increases in average life span have brought a greater focus on brain aging. There is an emphasis on understanding how aging contributes to a decline in brain functions (eg, cognition) because such a decline adversely affects the quality of life. The hippocampus is a key brain structure for cognition and the feedback control of the stress response. Herein we describe how the hippocampus changes with age and we examine the idea that age-related changes in the secretory patterns of the hypothalamic-pituitary adrenal (HPA) axis can contribute to hippocampal aging. We also examine the proposal that cumulative stress, perhaps due to compromised HPA axis function, can contribute to hippocampal aging by subjecting it to exposure to excessive levels of glucocorticoids. The aging hippocampus does not appear to suffer a generalized loss of cells or synapses, although atrophy of the structure may occur in humans. Thus, age-related cognitive impairments are likely related to other neurobiological alterations that could include changes in the signaling, information encoding, and plastic, electrophysiological, or neurochemical properties of neurons or glia. Dysfunction of the HPA axis sometimes occurs with aging, and while excessive glucocorticoids can disrupt cognition as well as hippocampal neuronal integrity, these are not an inevitable consequence of aging. The general preservation of cells and the plastic potential of the hippocampus provide a focus for the development of pharmacological, nutritional, or life-style strategies to combat age-related declines.

279. Antitumor activity of native and glycated fibrinogen-methotrexate conjugates

Introduction and goal of the work Due to increased accumulation in tumors and ability to form stable conjugates with chemotherapy agents, fibrinogen may be used as potential antitumor drug carrier. Various methotrexate conjugates have been tested in our laboratory and they revealed significant antitumor activity but also were highly toxic (Cancer Letters, 2000, 148:189–95). Therefore, we attempted to lower their toxicity and preserve therapeutic efficacy at the same time. New original method of glycated fibrinogen conjugate synthesis has been developed in our laboratory. Conjugates synthesized this way are pure, not cross-linked and have low hydrophobicity. The aim of this work was to investigate their antitumor activity and toxicity in comparison with tree methotrexate. Materials and methods Three-month-old (C57BI/6 × DBA/2) F1 mice were injected with 10^6 leukemia (P388) cells i.p. and 24 hours later each mouse was injected with 40 mg/kg of appropriate agent (D1, i.p.). Three different methotrexate (MTX) conjugates were examined: 1) with native bovine fibrinogen (F-MTX), 2) with fibrinogen glycated at 65°C (F65-MTX) and 3) with fibrinogen glycated at 73°C (F73-MTX). Concentrations of MTX in the studied preparations were: MTX – 1,5 mg/mL, F-MTX – 1,5 mg/mL, F65-MTX – 1,4 mg/mL, F73-MTX – 0,8 mg/mL. Average substitution level of these conjugates approached 11,4. Animals were randomly divided into 5 groups: 1) nontreated control, 2–5) treated respectively with MTX, F-MTX, F65-MTX, and F63-MTX. Results Increase in average life span (ILS) over the control group was: MTX – 34%, F-MTX – 137%, F65-MTX – 151%, F73-MTX – 91%. Conclusions In our preliminary investigations all newly synthesized conjugates (F-MTX, F65-MTX, F73-MTX) revealed higher antitumor activity in vivo in comparison with free methotrexate (P

Crystal structure of the ectodomain of Methuselah, a Drosophila G protein-coupled receptor associated with extended lifespan.

The Drosophila mutant methuselah (mth) was identified from a screen for single gene mutations that extended average lifespan. Mth mutants have a 35% increase in average lifespan and increased resistance to several forms of stress, including heat, starvation, and oxidative damage. The protein affected by this mutation is related to G protein-coupled receptors of the secretin receptor family. Mth, like secretin receptor family members, has a large N-terminal ectodomain, which may constitute the ligand binding site. Here we report the 2.3-A resolution crystal structure of the Mth extracellular region, revealing a folding topology in which three primarily beta-structure-containing domains meet to form a shallow interdomain groove containing a solvent-exposed tryptophan that may represent a ligand binding site. The Mth structure is analyzed in relation to predicted Mth homologs and potential ligand binding features.

EFFECTS OFl-HISTIDINOL ON THE ANTITUMOUR ACTIVITY AND ACUTE CARDIOTOXICITY OF DOXORUBICIN IN MICE

l-Histidinol (LHL), a structural analogue of the essential amino acidl-histidine, can improve the therapeutic index of antimetabolites and alkylating agents. The objective of the study was to determine whether LHL would modulate the antitumour activity and acute cardiotoxicity of the anthracycline antibiotic, doxorubicin (DOX). LHL (1.0 mm) potentiated the cytotoxicity of DOX (0.05–0.8 μg ml−1) in cultured Ehrlich ascites carcinoma (EAC) cells. LHL (250 mg kg−1, i.p.) administered for five consecutive doses at 2-h intervals starting 2 h before DOX (5 mg kg−1, i.p.) single injection, enhanced the antitumour activity of DOX in EAC-bearing mice as manifested by a significant increase in average life span and cure rate of mice. In normal mice, LHL, in the same dose regimen, could not alter the acute cardiotoxicity and lethality of DOX (10 mg kg−1, i.p.). The present data indicate that LHL may improve the therapeutic efficacy of DOX in EAC-bearing mice without compromising its toxicity. Also, our finding supports the LHL/anticancer drug combination approach.

Alternative Mini-Invasive Nelle Ostruzioni Cervico-Uretrali Dell'anziano: La Laserterapia: Mini-Invasive Alternatives in Cervico-Urethral Obstructions in the Elderly: Laser Therapy

An ageing general population, increase in average life span and prevailing benign prostatic hypertrophy bring an increasing number of elderly men to surgery for cervico-urethral obstruction. Given the small but significant morbidity of TURP, recently new mini-invasive techniques have been introduced for BPH, laser therapy being the most popular. The authors report on the different methods for delivering laser energy to the prostate, discussing the benefits and defects. They also present their personal experience with 44 patients aged over 75 years subjected to Nd:YAG laser prostatectomy from 1992 until today. In these patients transurethral laser evaporation, as suggested by Narayan and al., produced significant symptomatic and clinical results with low morbidity and invasiveness. The authors therefore believe that this kind of therapy may improve management of the elderly patient with BPH.

THE USE OF α-ADRENOCEPTOR ANTAGONISTS IN THE PHARMACOLOGICAL MANAGEMENT OF BENIGN PROSTATIC HYPERTROPHY: AN OVERVIEW

Benign prostatic hypertrophy (BPH) produces symptomatic urethral obstruction in a significant percentage of older men. Since the incidence of BPH is age related, the clinical and economic impact of this disease will continue to progress as average lifespan increases. BPH is associated with growth of both glandular and stromal elements of the prostate gland. Glandular hyperplasia can be partially reversed by withdrawal of androgenic tone with androgen receptor antagonists or steroid-5- α-reductase inhibitors. However, the reduction in prostatic size produced by these agents has little effect on the dynamic tone induced by nerve mediated contraction of stromal smooth muscle. This tone is mediated by activation of α-adrenoceptors. Therefore the α-adrenoceptor antagonists represent a useful pharmacological approach to the treatment of BPH. Studies in isolated strips of human prostate show that either exogenous α-adrenoceptor agonists or electrical field stimulation will induce contraction. Studies with selective antagonists such as prazosin show that this response is mediated by the α 1-adrenoceptor, even though radioligand binding studies show the presence of α 1and α 2adrenoceptor subtypes in approximately equal density. Following the cloning of multiple α 1-adrenoceptors, the contractile response in human prostate has been assigned to the α 1Aadrenoceptor. However, recent data would suggest a functional role for another subtype, which has not yet been cloned, and designated as α 1Lbased on a relatively low affinity for prazosin. Clinical trials have shown efficacy of a variety of α-adrenoceptor antagonists in BPH, including non-selective agents such as phenoxybenzamine, as well as a variety of selective α 1-adrenoceptor antagonists, most structurally related to prazosin. The agents most commonly employed at the present time include the prazosin analogs terazosin, doxazosin and alfuzosin, as well as the structurally unrelated indoramin and tamsulosin. The design of new α 1-antagonists for BPH has concentrated on agents producing preferential blockage of urogenital vis-á-vis vascular α 1-adrenoceptors, based either on selectivity for the α 1A-adrenoceptor subtype or on functional uroselectivity in animal models. While these newer agents offer the prospect of reducing the incidence of the cardiovascular side effects associated with current therapy their superiority over nonselective α 1-adrenoceptor antagonists remains to be demonstrated in the clinical setting.

The hazard and vitality measures of ageing

A new measure of the ageing process called the vitality measure is introduced. It measures the ‘vitality' of a time period in terms of the increase in average lifespan which results from surviving that time period. Apart from intrinsic interest, the vitality measure clarifies the relationship between the familiar properties of increasing hazard and decreasing mean residual life. The main theorem asserts that increasing hazard is equivalent to the requirement that mean residual life decreases faster than vitality. It is also shown for general (i.e. not necessarily absolutely continuous) distributions that the properties of increasing hazard, increasing failure rate, and increasing probability of ‘sudden death' are all equivalent.

The hazard and vitality measures of ageing

A new measure of the ageing process called the vitality measure is introduced. It measures the ‘vitality' of a time period in terms of the increase in average lifespan which results from surviving that time period. Apart from intrinsic interest, the vitality measure clarifies the relationship between the familiar properties of increasing hazard and decreasing mean residual life. The main theorem asserts that increasing hazard is equivalent to the requirement that mean residual life decreases faster than vitality. It is also shown for general (i.e. not necessarily absolutely continuous) distributions that the properties of increasing hazard, increasing failure rate, and increasing probability of ‘sudden death' are all equivalent.