Major Age-associated Diseases Research Articles

Steroid Hormones as Modulators of Emotional Regulation in Male Urogenital Cancers

BackgroundTumors develop within an organism operating in a specific social and physical environment. Cortisol and dehydroepiandrosterone (DHEA), two of the most abundant steroid hormones in humans, are involved in both emotional regulation and the tumor progression. Several studies reported preclinical findings that DHEA can have preventive and therapeutic efficacy in treating major age-associated diseases, including cancer, although the mechanisms of action are not yet defined. The main aim of current study was to investigate the relationship between psychological and physiological emotional regulation and cancer development.MethodThis study assessed the quality of life of urogenital cancer male patients using several validated tools, including the Functional Assessment of Cancer Therapy-General and the Profile of Mood States. Saliva samples were collected to monitor peripheral activity of both cortisol and DHEA. It was hypothesized that patients with a better quality of life would have higher levels of the DHEA/cortisol ratios.ResultsWe found that the quality of life was positively related to DHEA, but not cortisol levels. Negative mood increases were related to lower levels of DHEA. Logistic regression of the predictors of metastases indicated three main independent factors involved: DHEA, age, and cortisol. In other words, the higher the DHEA levels in comparison to cortisol levels, controlling for age, the lower the probability of metastases.ConclusionOur results appear to support the hypothesis that emotional dysregulation mediated by DHEA/cortisol activity is a key factor in the probability of metastasis in urogenital cancers.

Dehydroepiandrosterone, Cancer, and Aging.

The biological significance of dehydroepiandrosterone (DHEA) which, in the form of its sulfated ester is the most abundant steroid hormone in human plasma, is an enigma. Over the past years, numerous investigators have reported preclinical findings that DHEA has preventive and therapeutic efficacy in treating major age-associated diseases, including cancer, atherosclerosis, diabetes, obesity, as well as ameliorating the deleterious effects of excess cortisol exposure. Epidemiological studies have also found that low DHEA(S) levels predict an increased all-cause mortality. However, clinical trials, in which oral doses of DHEA at 50 mg-100 mg have been administered to elderly individuals for up to two years, have produced no clear evidence of benefit in parameters such as body composition, peak volume of oxygen consumption, muscle strength, or insulin sensitivity. I discuss why clinical trials, which use doses of DHEA in the 100 mg range, which are the human equivalent of about 1/20th the doses used in animal studies, are an inadequate test of DHEA’s therapeutic potential. I also discuss three mechanisms of DHEA action that very likely contribute to its biological effects in animal studies. Lastly, I describe the development of a DHEA analog which lacks DHEA’s androgenic and estrogenic action and that demonstrates enhanced potency and is currently in clinical trials. The use of such analogs may provide a better understanding of DHEA’s potential therapeutic utility.

A Mini-Review on the Effectiveness of Peptoids as Therapeutic Interventions against Neurodegenerative Diseases.

Neurodegenerative diseases have emerged as one of the major age-associated diseases in recent years. Hence, the urge to understand the mechanism and to find targeted therapeutics becomes inevitable. Peptide-based compounds have emerged as one of the important tools for their therapy. However, due to a lack of tolerability, specificity, and proteolytic degradation, they have lost their applicability in the broader sense. Thus, the search for suitable alternatives or peptidomimetics becomes an important criterion for neurotherapeutics. One of the versatile peptidomimetics is N-substituted glycines or peptoids, which retain many properties of peptides but successfully evade the drawbacks of peptides. Peptoids are manifested with greater cellular permeability, less immunogenicity, and their ability to be administered intra-nasally. These properties enhance their potential as neurotherapeutics with respect to their peptide counterparts. Recently, peptoids have been explored for neurotherapeutic applications as aggregation inhibitors, cell signaling pathways modulators, and agents for inhibiting inflammation via multiple mechanisms. Peptoids, due to their versatility and low production cost, are becoming popular among peptidomimetics as potential neurotherapeutic agents. In this review, the diverse applications of peptoids with respect to neurodegenerative disease have been explored.

A Review of Prostate Organogenesis and a Role for iPSC-Derived Prostate Organoids to Study Prostate Development and Disease.

The prostate is vulnerable to two major age-associated diseases, cancer and benign enlargement, which account for significant morbidity and mortality for men across the globe. Prostate cancer is the most common cancer reported in men, with over 1.2 million new cases diagnosed and 350,000 deaths recorded annually worldwide. Benign prostatic hyperplasia (BPH), characterised by the continuous enlargement of the adult prostate, symptomatically afflicts around 50% of men worldwide. A better understanding of the biological processes underpinning these diseases is needed to generate new treatment approaches. Developmental studies of the prostate have shed some light on the processes essential for prostate organogenesis, with many of these up- or downregulated genes expressions also observed in prostate cancer and/or BPH progression. These insights into human disease have been inferred through comparative biological studies relying primarily on rodent models. However, directly observing mechanisms of human prostate development has been more challenging due to limitations in accessing human foetal material. Induced pluripotent stem cells (iPSCs) could provide a suitable alternative as they can mimic embryonic cells, and iPSC-derived prostate organoids present a significant opportunity to study early human prostate developmental processes. In this review, we discuss the current understanding of prostate development and its relevance to prostate-associated diseases. Additionally, we detail the potential of iPSC-derived prostate organoids for studying human prostate development and disease.

IGF1 receptor inhibition amplifies the effects of cancer drugs by autophagy and immune-dependent mechanisms−

BackgroundPharmacological autophagy enhancement constitutes a preclinically validated strategy for preventing or treating most major age-associated diseases. Driven by this consideration, we performed a high-content/high-throughput screen on 65 000 distinct compounds...

Neurodegenerative dementias: screening for major threats to healthy longevity with blood biomarkers

Clinical screening tests are readily available for most major age-associated diseases, including cardiovascular disease, type 2 diabetes, and common cancers. However, one of the most common causes of death in older adults—dementia—lacks a readily available early screening test that can be used in primary care. According to WHO, approximately 50 million people currently have dementia, and it is a leading cause of disability, dependency, and death among older people worldwide, making it a major threat to healthy human longevity.

Serum eicosapentaenoic acid to arachidonic acid ratio is associated with cardio-healthy exceptional longevity

1. IntroductionLong-chain ω-3 polyunsaturated fatty acids, (PUFAs)eicosapentaenoic acid (EPA; 20:5(n-3)) and docosahexaenoic acid(DHA; 22:6(n-3)) are associated with coronary heart disease (CHD)[1]. Specifically, high serum levels of EPA and DHA as well as reducedconcentrations of the ω-6 PUFA arachidonic acid (AA; 20:4(n-6)) areassociated with lower CHD risk [2] and a higher EPA/AA ratio portendsadecreasedriskofacutemyocardialinfarction(AMI)andsuddencardi-ac death [3]. The biological effects of ω-3 PUFAs on the cardiovascularsystem involve, among numerous pathways, transformation to bioac-tivemetabolites,alterationofphysicalandchemicalpropertiesofcellu-lar membranes, modulation of membrane channels and proteins,regulation of gene expression, or changes in eicosanoid profiles [1].Owing to the limited ability of humans to synthesize EPA, the DietaryGuidelines for Americans recommend obtaining them from marineoils or supplements [4]. However, some controversy exists with recentevidence not supporting a strong cardiovascular benefitofomega-3PUFA consumption [5]. The potential preventive effect of ω-3 PUFAsalso varies depending on the dosages employed and the characteristicsof selected patients [6].Ingeneral,threemajorpointsduringthecourseofhumanagingcanbe identified: 60 years old (the average age of onset of major age-associated diseases), 80 years old (average life expectancyin the West-ern world), and 100 years old (exceptional longevity [EL]). People whoreach EL may be further divided into three subgroups: 1) ‘survivors’—those who survive to become centenarians in spite of the onset ofmajor age-associated diseases, including CHD, at an age comparable tothe general population, i.e. at the age of 60 years (thus characterizedby a long lifespan but a short healthy lifespan); 2) ‘delayers’—thosewho develop age-related diseases much later than the control popula-tion, i.e. at the age of 80 years instead of 60 years (therefore having along healthy lifespan), and 3) ‘dodgers’ or healthy centenarians —those who fail to develop age-related illnesses naturally throughouttheir lifespan [7]. The question as to whether PUFAs may be associatedwith EL — especially in CHD-free centenarian ‘dodgers’—remainsopen. With the intent of gaining insights into the CHD and longevity-predictivevalueofbloodPUFAs,wecomparedunderacase–controlde-signtheEPA/AAratioamongCHD-freecentenarian‘dodgers’andyoun-ger adults with or without CHD.2. MethodsThe study complied with the tenets of the Declaration of Helsinki andwas approved by the local ethics committee. Written informed consentwasobtainedfromallparticipants.Thefollowingthreegroupsofsubjectswere analyzed: CHD-free centenarian ‘dodgers’, patients who experi-encedAMIatlessthan40yearsofage,andapparentlyhealthyyoungcon-trols(Table1).Theparticipants'ageswerede finedbythedatesofbirthasstatedonidentitycards.AllsubjectswereCaucasianwhitesascertainedtobe of Italian descent (Northern Italy, mainly from Lombardy and Pied-mont). The sample has been previously described [8].Thecentenarian‘dodgers’wereascertainedmainlyviageneralprac-titionersinthecommunity.Thehistoryofpastandcurrentdiseaseswasaccuratelycollected,checkingthecentenarians'medicaldocumentationand their current drug therapy. Accordingly, all of them were ‘dodgers’

Direct in vivo imaging of ferrous iron dyshomeostasis in ageing Caenorhabditis elegans.

Iron is essential for eukaryotic biochemistry. Systematic trafficking and storage is required to maintain supply of iron while preventing it from catalysing unwanted reactions, particularly the generation of oxidising reactive species. Iron dyshomeostasis has been implicated in major age-associated diseases including cancers, neurodegeneration and heart disease. Here, we employ population-level X-ray fluorescence imaging and native-metalloproteomic analysis to determine that altered iron coordination and distribution is a pathological imperative of ageing in the nematode, Caenorhabditis elegans. Our approach provides a method to simultaneously study iron metabolism across different scales of biological organisation, from populations to cells. Here we report how and where iron homeostasis is lost during C. elegans ageing, and its relationship to the age-related elevation of damaging reactive oxygen species. We find that wild types utilise ferritin to sustain longevity, buffering against exogenous iron and showing rapid ageing if ferritin is ablated. After reproduction, escape of iron from safe-storage in ferritin raised cellular Fe2+ load in the ageing C. elegans, and increased generation of reactive species. These findings support the hypothesis that iron-mediated processes drive senescence. We propose that loss of iron homeostasis may be a fundamental and inescapable consequence of ageing that could represent a critical target for therapeutic strategies to improve health outcomes in ageing.

Red Cell Distribution Width and Mortality in Older Adults: A Meta-analysis

Red cell distribution width (RDW) is a quantitative measure of variability in the size of circulating erythrocytes with higher values reflecting greater heterogeneity in cell sizes. Recent studies have shown that higher RDW is associated with increased mortality risk in patients with clinically significant cardiovascular disease (CVD). Whether RDW is prognostic in more representative community-based populations is unclear. Seven relevant community-based studies of older adults with RDW measurement and mortality ascertainment were identified. Cox proportional hazards regression and meta-analysis on individual participant data were performed. Median RDW values varied across studies from 13.2% to 14.6%. During 68,822 person-years of follow-up of 11,827 older adults with RDW measured, there was a graded increased risk of death associated with higher RDW values (p < .001). For every 1% increment in RDW, total mortality risk increased by 14% (adjusted hazard ratio [HR]: 1.14; 95% confidence interval [CI]: 1.11-1.17). In addition, RDW was strongly associated with deaths from CVD (adjusted HR: 1.15; 95% CI: 1.12-1.25), cancer (adjusted HR: 1.13; 95% CI: 1.07-1.20), and other causes (adjusted HR: 1.13; 95% CI: 1.07-1.18). Furthermore, the RDW-mortality association occurred in all major demographic, disease, and nutritional risk factor subgroups examined. Among the subset of 1,603 older adults without major age-associated diseases, RDW remained strongly associated with total mortality (adjusted HR: 1.32; 95% CI: 1.21-1.44). RDW is a routinely reported test that is a powerful predictor of mortality in community-dwelling older adults with and without age-associated diseases. The biologic mechanisms underlying this association merit investigation.

Alzheimer disease therapy: can the amyloid cascade be halted?

In the not too distant future, clinical management of Alzheimer disease (AD) is likely to resemble the present management of atherosclerotic disease. Sometime before an individual reaches age 50, an internist will initiate a screening program to determine that person’s risk for developing AD. This assessment will include a comprehensive genetic screen for AD-risk loci, determination of plasma amyloid β peptide (Aβ) levels, family history of AD, and, perhaps, potential environmental risks. Depending on the risk prediction, a follow-up visit with an Alzheimer specialist may be scheduled. During this visit, an amyloid-binding agent will be injected and used to evaluate the extent of amyloid deposition in the brain. Based on the amount of deposition present and the initial risk assessment, the specialist will then develop a personalized therapeutic regimen. This regimen might consist of an Aβ vaccination, an amyloid-lowering drug, an anti-inflammatory agent, a neuronal growth factor, an antioxidant, or a combination of these approaches. The efficacy of therapy will be monitored by measurement of plasma Aβ levels, imaging of amyloid in the brain, and volumetric scanning of the brain. Primary screening, along with monitoring of the presymptomatic indicators of disease, and appropriate intervention will significantly reduce one’s risk for developing AD. Although proposal of such a scenario might seem highly speculative, recent and expected advances in (a) understanding the pathogenesis of AD, (b) identifying the genetic factors that confer risk for AD, (c) validating potential biomarkers for AD, and (d) developing therapeutic agents that target both Aβ and downstream pathological changes greatly increase the likelihood that AD will be managed successfully in the future. AD is the leading cause of dementia in the elderly Estimates of prevalence vary, but 1‐5% of the population over age 65, and 20‐40% of the population over age 85, may be affected by AD (1). Given the increasing number of elderly individuals in industrialized societies, AD represents a burgeoning epidemic that exacts a tremendous toll on the individuals it affects, along with their families and caregivers. Moreover, AD has a tremendous negative economic impact amounting to over $100 billion a year. Treatment of AD in the US reportedly costs more per patient than management of other major age-associated diseases (2, 3). Beginning with short-term memory loss, and continuing with more widespread cognitive and emotional dysfunction, typical late-onset AD (LOAD) occurs after age 65 and follows an insidious 5- to 15-year course. Although AD usually presents without motor or sensory alterations, rare variants (such as spastic paraparesis) with atypical clinical presentations are occasionally recognized (4, 5). Even today, definitive diagnosis of AD is only possible through postmortem analysis of the brain (1). This histopathological analysis of the brain demonstrates the classic triad of AD pathology: (a) senile plaques containing Aβ, (b) neurofibrillary tangles (NFTs) containing tau, and (c) widespread neuronal loss in the hippocampus and select cortical and subcortical areas.

The biochemistry of aging

Although philosophers and scientists have long been interested in the aging process, general interest in this fascinating and highly important topic was minimal before the 1960s. In recent decades, however, interest in aging has greatly accelerated, not only since the elderly form an ever-increasing percentage of the population, but because they utilize a significant proportion of the national expenditures. In addition, many people have come to the realization that one can now lead a very happy, active, and productive life well beyond the usual retirement age. Scientifically, aging is an extremely complex, multifactorial process, and numerous aging theories have been proposed; the most important of these are probably the genomic and free radical theories. Although it is abundantly clear that our genes influence aging and longevity, exactly how this takes place on a chemical level is only partially understood. For example, what kinds of genes are these, and what proteins do they control? Certainly they include, among others, those that regulate the processes of somatic maintenance and repair, such as the stress-response systems. The accelerated aging syndromes (i.e., Hutchinson-Gilford, Werner's, and Down's syndromes) are genetically controlled, and studies of them have decidedly increased our understanding of aging. In addition, C. elegans and D. melanogaster are important systems for studying aging. This is especially true for the former, in which the age-1 mutant has been shown to greatly increase the life span over the wild-type strain. This genetic mutation results in increased activities of the antioxidative enzymes, Cu-Zn superoxide dismutase and catalase. Thus, the genomic and free radical theories are closely linked. In addition, trisomy 21 (Down's syndrome) is characterized by a significantly shortened life span; it is also plagued by increased oxidative stress which results in various free radical-related disturbances. Exactly how this extra chromosome results in an increased production of reactive oxygen species is, however, only partially understood. There is considerable additional indirect evidence supporting the free radical theory of aging. Not only are several major age-associated diseases clearly affected by increased oxidative stress (atherosclerosis, cancer, etc.), but the fact that there are numerous natural protective mechanisms to prevent oxyradical-induced cellular damage speaks loudly that this theory has a key role in aging [the presence of superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase, among others; various important intrinsic (uric acid, bilirubin, -SH proteins, glutathione, etc.) and extrinsic (vitamins C, E, carotenoids, flavonoids, etc.) antioxidants; and metal chelating proteins to prevent Fenton and Haber-Weiss chemistry]. In addition, a major part of the free radical theory involves the damaging role of reactive oxygen species and various toxins on mitochondria. These lead to numerous mitochondrial DNA mutations which result in a progressive reduction in energy output, significantly below that needed in body tissues. This can result in various signs of aging, such as loss of memory, hearing, vision, and stamina. Oxidative stress also inactivates critical enzymes and other proteins. In addition to these factors, caloric restriction is the only known method that increases the life span of rodents; studies currently underway suggest that this also applies to primates, and presumably to humans. Certainly, oxidative stress plays an important role here, although other, as yet unknown, factors are also presumably involved. Exactly how the other major theories (i.e., immune, neuroendocrine, somatic mutation, error catastrophe) control aging is more difficult to define. The immune and neuroendocrine systems clearly deteriorate with age. (ABSTRACT TRUNCATED)

Fibroblast cultures from healthy centenarians have an active proteasome.

Healthy centenarians represent the best example of successful ageing. Various studies have shown that centenarians have escaped the major age-associated diseases, they have several well-conserved immune parameters and at least one gene allele has been identified and linked with their increased longevity. During ageing there is an accumulation of oxidised proteins, a phenomenon that has been related to an impaired function of the 20S proteasome in aged cells. We have, therefore, analysed the expression and the proteolytic activity of the proteasome in centenarian cells. Four fibroblast cultures derived from healthy centenarians were studied and compared with cultures derived from adult donors of different ages. Analysis of several proteasome subunits RNA expression levels, determination of one peptidase activity and identification of oxidised proteins in these samples revealed that centenarian cultures have a functional proteasome. In addition, it was found that the centenarian cultures exhibit characteristics similar to the younger rather than the older control donors derived cultures in all three assays. These data indicate that centenarian cells may be different from elderly donors cells, thus opening up new dimensions for the identification and characterisation of factors that are linked with longevity.

Genetics of aging: lessons from centenarians.

Aging is a universal phenomenon that affects nearly all animal species. It can be considered as the product of an interaction between genetic, environmental and lifestyle factors, which in turn influence longevity that varies between and within species. Several studies have been focused in healthy centenarians, because these exceptional individuals represent the best example of successful aging. These studies have shown that centenarians have escaped the major age-associated diseases, they have well conserved several immune parameters, and at least one gene allele has been identified and linked with longevity. In parallel, studies at cellular level have identified several genes that influence, positively or negatively, normal replicative in vitro life-span. The ability of these genes to regulate aging in vitro, in conjunction with the telomeres shortening hypothesis have raised the intriguing question of the existence of a molecular clock that counts and thus may modulates human aging and longevity. This review article will discuss these issues, focusing in the nature of the genetic factors that associate with these phenomena.

The immunology of exceptional individuals: the lesson of centenarians

Centenarians are the best example of successful ageing, since they have escaped the major age-associated diseases, and most are in good mental and physical condition. Here, Claudio Franceschi and colleagues discuss how the study of their immune systems reveals that several immune parameters are well conserved, suggesting that a complex remodelling of most immune parameters occurs with age, rather than a unidirectional deterioration.

Nutrition, including diet restriction, in mammals

Although diet influences basic aging processes as well as age-associated disease processes, diet is either not mentioned or inadequately described in reports of gerontologic studies using animal models. Studies carried out in our laboratory with male F344 rats are a good example of the importance of diet in the use of an animal model for aging research. Nephropathy, resulting in kidney failure, is often an overwhelming disease problem in life span studies using ad libitum fed male F344 rats. However, by appropriate choice of dietary components, nephropathy can be reduced to only one of several disease processes contributing to the death of these ad libitum fed rats. Such diets greatly increase the value of the male F344 rat as a model for aging research. Because almost all rodent species and strains suffer from one or more major age-associated diseases, nutritional conditions should be sought in the case of each to minimize the occurrence of such diseases during an aging study. Restriction of energy intake (often called food restriction or dietary restriction) delays or prevents most age-associated disease processes in a spectrum of rat and mouse strains. It is, therefore, suggested that the dietary restricted rodent be used as the standard or base model for aging research. Moreover, dietary restriction is proving to be a powerful tool for the study of aging processes. (Aging Clin. Exp. Res. 5: 269–275, 1993)

Chemical protection against aging.

Aging, an individually unwanted biological phenomenon, is important to evolution. Changes in an organism, such as man, leading ultimately to death, can be looked upon as being due to a basic aging process(es), ‘built-in’ by evolution to insure death — and largely determining the maximum life span, on which disease states are superimposed and intertwined. These degradative changes — both from aging and disease process — may be due in part to free radical reactions. Experiments based on the above hypothesis have been encouraging. Thus, several inhibitors of free radical reactions have been found to increase the mean life span of mice when added to the daily diet; 2-mercaptoethylamine (2-MEA) and butylated hydroxytoluene (BHT) were the most effective. Likewise, decreasing the amount and degree of unsaturation of the dietary fat of female C3H mice resulted in a decrease in mortality rate. Accumulating evidence implicates free radical reactions in the pathogenesis of major age-associated diseases, for example, cancer, atherosclerosis and hypertension.