Why do centenarians escape or postpone cancer? The role of IGF-1, inflammation and p53

Background  

Centenarians are exceptionally long living individuals who escaped the most common age-related diseases. In particular they appear to be effectively protected from cancers. The mechanisms that underlie this protection are quite complex and still largely unclear.     

Nutrigerontology: a key for achieving successful ageing and longevity

During the last two centuries the average lifespan has increased at a rate of approximately 3 months/year in both sexes, hence oldest old people are becoming the population with the fastest growth in Western World. Although the average life expectancy is increasing dramatically, the healthy lifespan is not going at the same pace. This underscores the importance of studies on the prevention of age-related diseases, in order to satisfactorily decrease the medical, economic and social problems associated to advancing age, related to an increased number of individuals not autonomous and affected by invalidating pathologies. In particular, data from experimental studies in model organisms have consistently shown that nutrient signalling pathways are involved in longevity, affecting the prevalence of age-related loss of function, including age-related diseases. Accordingly, nutrigerontology is defined as the scientific discipline that studies the impact of nutrients, foods, macronutrient ratios, and diets on lifespan, ageing process, and age-related diseases. To discuss the potential relevance of this new science in the attainment of successful ageing and longevity, three original studies performed in Sicily with local foods and two reviews have been assembled in this series. Data clearly demonstrate the positive effects of nutraceuticals, functional foods and Mediterranean Diet on several biological parameters. In fact, they could represent a prevention for many age-related diseases, and, although not a solution for this social plague, at least a remedy to alleviate it. Thus, the possibility to create a dietary pattern, based on the combined strategy of the use of both nutraceuticals and functional foods should permit to create a new therapeutic strategy, based not only on a specific bioactive molecule or on a specific food but on a integrated approach that, starting from the local dietary habits, can be led to a “nutrafunctional diet” applicable worldwide.     

Negligible senescence in the longest living rodent,the naked mole-rat: insights from a successfully aging species

Aging refers to a gradual deterioration in function that, over time, leads to increased mortality risk, and declining fertility. This pervasive process occurs in almost all organisms, although some long-lived trees and cold water inhabitants reportedly show insignificant aging. Negligible senescence is characterized by attenuated age-related change in reproductive and physiological functions, as well as no observable age-related gradual increase in mortality rate. It was questioned whether the longest living rodent, the naked mole-rat, met these three strict criteria. Naked mole-rats live in captivity for more than 28.3 years, ∼9 times longer than similar-sized mice. They maintain body composition from 2 to 24 years, and show only slight age-related changes in all physiological and morphological characteristics studied to date. Surprisingly breeding females show no decline in fertility even when well into their third decade of life. Moreover, these animals have never been observed to develop any spontaneous neoplasm. As such they do not show the typical age-associated acceleration in mortality risk that characterizes every other known mammalian species and may therefore be the first reported mammal showing negligible senescence over the majority of their long lifespan. Clearly physiological and biochemical processes in this species have evolved to dramatically extend healthy lifespan. The challenge that lies ahead is to understand what these mechanisms are.     

Down-regulating sphingolipid synthesis increases yeast lifespan

Knowledge of the mechanisms for regulating lifespan is advancing rapidly, but lifespan is a complex phenotype and new features are likely to be identified. Here we reveal a novel approach for regulating lifespan. Using a genetic or a pharmacological strategy to lower the rate of sphingolipid synthesis, we show that Saccharomyces cerevisiae cells live longer. The longer lifespan is due in part to a reduction in Sch9 protein kinase activity and a consequent reduction in chromosomal mutations and rearrangements and increased stress resistance. Longer lifespan also arises in ways that are independent of Sch9 or caloric restriction, and we speculate on ways that sphingolipids might mediate these aspects of increased lifespan. Sch9 and its mammalian homolog S6 kinase work downstream of the target of rapamycin, TOR1, protein kinase, and play evolutionarily conserved roles in regulating lifespan. Our data establish Sch9 as a focal point for regulating lifespan by integrating nutrient signals from TOR1 with growth and stress signals from sphingolipids. Sphingolipids are found in all eukaryotes and our results suggest that pharmacological down-regulation of one or more sphingolipids may provide a means to reduce age-related diseases and increase lifespan in other eukaryotes.     

Endocrine organs of cardiovascular diseases: Gut microbiota

Gut microbiota (GM) is a collection of bacteria, fungi, archaea, viruses and protozoa, etc. They inhabit human intestines and play an essential role in human health and disease. Close information exchange between the intestinal microbes and the host performs a vital role in digestion, immune defence, nervous system regulation, especially metabolism, maintaining a delicate balance between itself and the human host. Studies have shown that the composition of GM and its metabolites are firmly related to the occurrence of various diseases. More and more researchers have demonstrated that the intestinal microbiota is a virtual ‘organ’ with endocrine function and the bioactive metabolites produced by it can affect the physiological role of the host. With deepening researches in recent years, clinical data indicated that the GM has a significant effect on the occurrence and development of cardiovascular diseases (CVD). This article systematically elaborated the relationship between metabolites of GM and its effects, the relationship between intestinal dysbacteriosis and cardiovascular risk factors, coronary heart disease, myocardial infarction, heart failure and hypertension and the possible pathogenic mechanisms. Regulating the GM is supposed to be a potential new therapeutic target for CVD.     

Innate immunity and inflammation in ageing: a key for understanding age-related diseases

The process of maintaining life for the individual is a constant struggle to preserve his/her integrity. This can come at a price when immunity is involved, namely systemic inflammation. Inflammation is not per se a negative phenomenon: it is the response of the immune system to the invasion of viruses or bacteria and other pathogens. During evolution the human organism was set to live 40 or 50 years; today, however, the immune system must remain active for much a longer time. This very long activity leads to a chronic inflammation that slowly but inexorably damages one or several organs: this is a typical phenomenon linked to ageing and it is considered the major risk factor for age-related chronic diseases. Alzheimer's disease, atherosclerosis, diabetes and even sarcopenia and cancer, just to mention a few – have an important inflammatory component, though disease progression seems also dependent on the genetic background of individuals. Emerging evidence suggests that pro-inflammatory genotypes are related to unsuccessful ageing, and, reciprocally, controlling inflammatory status may allow a better chance of successful ageing. In other words, age-related diseases are "the price we pay" for a life-long active immune system: this system has also the potential to harm us later, as its fine tuning becomes compromised. Our immune system has evolved to control pathogens, so pro-inflammatory responses are likely to be evolutionarily programmed to resist fatal infections with pathogens aggressively. Thus, inflammatory genotypes are an important and necessary part of the normal host responses to pathogens in early life, but the overproduction of inflammatory molecules might also cause immune-related inflammatory diseases and eventually death later. Therefore, low responder genotypes involved in regulation of innate defence mechanisms, might better control inflammatory responses and age-related disease development, resulting in an increased chance of long life survival in a "permissive" environment with reduced pathogen load, medical care and increased quality of life.     

The new biology of ageing

Human life expectancy in developed countries has increased steadily for over 150 years, through improvements in public health and lifestyle. More people are hence living long enough to suffer age-related loss of function and disease, and there is a need to improve the health of older people. Ageing is a complex process of damage accumulation, and has been viewed as experimentally and medically intractable. This view has been reinforced by the realization that ageing is a disadvantageous trait that evolves as a side effect of mutation accumulation or a benefit to the young, because of the decline in the force of natural selection at later ages. However, important recent discoveries are that mutations in single genes can extend lifespan of laboratory model organisms and that the mechanisms involved are conserved across large evolutionary distances, including to mammals. These mutations keep the animals functional and pathology-free to later ages, and they can protect against specific ageing-related diseases, including neurodegenerative disease and cancer. Preliminary indications suggest that these new findings from the laboratory may well also apply to humans. Translating these discoveries into medical treatments poses new challenges, including changing clinical thinking towards broad-spectrum, preventative medicine and finding novel routes to drug development.     

Drug Synergy Drives Conserved Pathways to Increase Fission Yeast Lifespan

Aging occurs over time with gradual and progressive loss of physiological function. Strategies to reduce the rate of functional loss and mitigate the subsequent onset of deadly age-related diseases are being sought. We demonstrated previously that a combination of rapamycin and myriocin reduces age-related functional loss in the Baker’s yeast Saccharomyces cerevisiae and produces a synergistic increase in lifespan. Here we show that the same drug combination also produces a synergistic increase in the lifespan of the fission yeast Schizosaccharomyces pombe and does so by controlling signal transduction pathways conserved across a wide evolutionary time span ranging from yeasts to mammals. Pathways include the target of rapamycin complex 1 (TORC1) protein kinase, the protein kinase A (PKA) and a stress response pathway, which in fission yeasts contains the Sty1 protein kinase, an ortholog of the mammalian p38 MAP kinase, a type of Stress Activated Protein Kinase (SAPK). These results along with previous studies in S. cerevisiae support the premise that the combination of rapamycin and myriocin enhances lifespan by regulating signaling pathways that couple nutrient and environmental conditions to cellular processes that fine-tune growth and stress protection in ways that foster long term survival. The molecular mechanisms for fine-tuning are probably species-specific, but since they are driven by conserved nutrient and stress sensing pathways, the drug combination may enhance survival in other organisms.     

NF-κB pathway activators as potential ageing biomarkers: targets for new therapeutic strategies

Chronic inflammation is a major biological mechanism underpinning biological ageing process and age-related diseases. Inflammation is also the key response of host defense against pathogens and tissue injury. Current opinion sustains that during evolution the host defense and ageing process have become linked together. Thus, the large array of defense factors and mechanisms linked to the NF-κB system seem to be involved in ageing process. This concept leads us in proposing inductors of NF-κB signaling pathway as potential ageing biomarkers. On the other hand, ageing biomarkers, represented by biological indicators and selected through apposite criteria, should help to characterize biological age and, since age is a major risk factor in many degenerative diseases, could be subsequently used to identify individuals at high risk of developing age-associated diseases or disabilities. In this report, some inflammatory biomarkers will be discussed for a better understanding of the concept of biological ageing, providing ideas on eventual working hypothesis about potential targets for the development of new therapeutic strategies and improving, as consequence, the quality of life of elderly population.     

Diabetic gut microbiota dysbiosis as an inflammaging and immunosenescence condition that fosters progression of retinopathy and nephropathy

The increased prevalence of type 2 diabetes mellitus (T2DM) and life expectancy of diabetic patients fosters the worldwide prevalence of retinopathy and nephropathy, two major microvascular complications that have been difficult to treat with contemporary glucose-lowering medications. The gut microbiota (GM) has become a lively field research in the last years; there is a growing recognition that altered intestinal microbiota composition and function can directly impact the phenomenon of ageing and age-related disorders. In fact, human GM, envisaged as a potential source of novel therapeutics, strongly modulates host immunity and metabolism. It is now clear that gut dysbiosis and their products (e.g. p-cresyl sulfate, trimethylamine?N?oxide) dictate a secretory associated senescence phenotype and chronic low-grade inflammation, features shared in the physiological process of ageing (“inflammaging”) as well as in T2DM (“metaflammation”) and in its microvascular complications. This review provides an in-depth look on the crosstalk between GM, host immunity and metabolism. Further, it characterizes human GM signatures of elderly and T2DM patients. Finally, a comprehensive scrutiny of recent molecular findings (e.g. epigenetic changes) underlying causal relationships between GM dysbiosis and diabetic retinopathy/nephropathy complications is pinpointed, with the ultimate goal to unravel potential pathophysiological mechanisms that may be explored, in a near future, as personalized disease-modifying therapeutic approaches.     

Buffering mechanisms in aging: a systems approach toward uncovering the genetic component of aging

An unrealized potential to understand the genetic basis of aging in humans, is to consider the immense survival advantage of the rare individuals who live 100 years or more. The Longevity Gene Study was initiated in 1998 at the Albert Einstein College of Medicine to investigate longevity genes in a selected population: the “oldest old” Ashkenazi Jews, 95 years of age and older, and their children. The study proved the principle that some of these subjects are endowed with longevity-promoting genotypes. Here we reason that some of the favorable genotypes act as mechanisms that buffer the deleterious effect of age-related disease genes. As a result, the frequency of deleterious genotypes may increase among individuals with extreme lifespan because their protective genotype allows disease-related genes to accumulate. Thus, studies of genotypic frequencies among different age groups can elucidate the genetic determinants and pathways responsible for longevity. Borrowing from evolutionary theory, we present arguments regarding the differential survival via buffering mechanisms and their target age-related disease genes in searching for aging and longevity genes. Using more than 1,200 subjects between the sixth and eleventh decades of life (at least 140 subjects in each group), we corroborate our hypotheses experimentally. We study 66 common allelic site polymorphism in 36 candidate genes on the basis of their phenotype. Among them we have identified a candidate-buffering mechanism and its candidate age-related disease gene target. Previously, the beneficial effect of an advantageous cholesteryl ester transfer protein (CETP-VV) genotype on lipoprotein particle size in association with decreased metabolic and cardiovascular diseases, as well as with better cognitive function, have been demonstrated. We report an additional advantageous effect of the CETP-VV (favorable) genotype in neutralizing the deleterious effects of the lipoprotein(a) (LPA) gene. Finally, using literature-based interaction discovery methods, we use the set of longevity genes, buffering genes, and their age-related target disease genes to construct the underlying subnetwork of interacting genes that is expected to be responsible for longevity. Genome wide, high-throughput hypothesis-free analyses are currently being utilized to elucidate unknown genetic pathways in many model organisms, linking observed phenotypes to their underlying genetic mechanisms. The longevity phenotype and its genetic mechanisms, such as our buffering hypothesis, are similar; thus, the experimental corroboration of our hypothesis provides a proof of concept for the utility of high-throughput methods for elucidating such mechanisms. It also provides a framework for developing strategies to prevent some age-related diseases by intervention at the appropriate level.     

Determinants of age-dependent change in a secondary sexual character

Many secondary sexual characters vary in a systematic way with the age of individuals, with young and old individuals displaying at lower levels than individuals of intermediate age. Analyses quantifying the within-individual and among-individual components of phenotypic variation can help partition effects of phenotypic plasticity and selective mortality. We analysed phenotypic variation in the expression of a secondary sexual character, tail length, in male and female barn swallows Hirundo rustica from four European populations studied during 11-26 years, using linear mixed effect models to describe age-related expression. Tail length increased from yearlings to intermediate aged birds with a subsequent decrease at old age. In males, this age-related pattern was because of both within-subject and between-subject effects, with no difference among populations. Males having longer lifespan had shorter tails when young than those having shorter lifespan. Females showed similar patterns of age-related variation as males, with no difference among populations. The major difference between sexes was that the between-subject effects (i.e. disappearance effects or selection) were much more important for males compared to females for which lifetime variation in tail length was mainly because of a within-subject effect (i.e., a plastic response). These findings suggest that whereas males trade greater expression of the secondary sexual character at young age against longevity, that was not the case for females. This is consistent with tail length being more costly in males than in females, with the cost of long tails potentially being offset by elevated mating success, whereas that is not the case in females.     

Tetz’s theory and law of longevity

Here, we present new theory and law of longevity intended to evaluate fundamental factors that control lifespan. This theory is based on the fact that genes affecting host organism longevity are represented by subpopulations: genes of host eukaryotic cells, commensal microbiota, and non-living genetic elements. Based on Tetz’s theory of longevity, we propose that lifespan and aging are defined by the accumulation of alterations over all genes of macroorganism and microbiome and the non-living genetic elements associated with them. Tetz’s law of longevity states that longevity is limited by the accumulation of alterations to the limiting value that is not compatible with life. Based on theory and law, we also propose a novel model to calculate several parameters, including the rate of aging and the remaining lifespan of individuals. We suggest that this theory and model have explanatory and predictive potential to eukaryotic organisms, allowing the influence of diseases, medication, and medical procedures to be re-examined in relation to longevity. Such estimates also provide a framework to evaluate new fundamental aspects that control aging and lifespan.     

Therapeutic potential and challenges of targeting sirtuins in neurodegenerative diseases

Aging is the predominant risk factor for major neurodegenerative diseases. The underlying mechanisms are largely unknown. Members of the sirtuin family of protein deacetylases support and promote longevity in diverse organisms and can extend lifespan when upregulated. Sirtuins are involved in fundamental mechanisms in age-related neurodegenerative diseases, including protein aggregation and homeostasis, survival and stress responses, and inflammatory processes. In this review, we will discuss the neurobiology of sirtuins and their multifaceted roles in the pathogenesis of neurodegenerative diseases. We will also examine the potential and challenges of targeting sirtuin pathways to treat these devastating conditions.     

Mammalian models of extended healthy lifespan

Over the last two centuries, there has been a significant increase in average lifespan expectancy in the developed world. One unambiguous clinical implication of getting older is the risk of experiencing age-related diseases including various cancers, dementia, type-2 diabetes, cataracts and osteoporosis. Historically, the ageing process and its consequences were thought to be intractable. However, over the last two decades or so, a wealth of empirical data has been generated which demonstrates that longevity in model organisms can be extended through the manipulation of individual genes. In particular, many pathological conditions associated with the ageing process in model organisms, and importantly conserved from nematodes to humans, are attenuated in long-lived genetic mutants. For example, several long-lived genetic mouse models show attenuation in age-related cognitive decline, adiposity, cancer and glucose intolerance. Therefore, these long-lived mice enjoy a longer period without suffering the various sequelae of ageing. The greatest challenge in the biology of ageing is to now identify the mechanisms underlying increased healthy lifespan in these model organisms. Given that the elderly are making up an increasingly greater proportion of society, this focused approach in model organisms should help identify tractable interventions that can ultimately be translated to humans.     

Healthspan and longevity can be extended by suppression of growth hormone signaling

Average and maximal lifespan are important biological characteristics of every species, but can be modified by mutations and by a variety of genetic, dietary, environmental, and pharmacological interventions. Mutations or disruption of genes required for biosynthesis or action of growth hormone (GH) produce remarkable extension of longevity in laboratory mice. Importantly, the long-lived GH-related mutants exhibit many symptoms of delayed and/or slower aging, including preservation of physical and cognitive functions and resistance to stress and age-related disease. These characteristics could be collectively described as “healthy aging” or extension of the healthspan. Extension of both the healthspan and lifespan in GH-deficient and GH-resistant mice appears to be due to multiple interrelated mechanisms. Some of these mechanisms have been linked to healthy aging and genetic predisposition to extended longevity in humans. Enhanced insulin sensitivity combined with reduced insulin levels, reduced adipose tissue, central nervous system inflammation, and increased levels of adiponectin represent such mechanisms. Further progress in elucidation of mechanisms that link reduced GH action to delayed and healthy aging should identify targets for lifestyle and pharmacological interventions that could benefit individuals as well as society.     

Evolvability,population benefit,and the evolution of programmed aging in mammals

Programmed aging theories contend that evolved biological mechanisms purposely limit internally determined lifespans in mammals and are ultimately responsible for most instances of highly age-related diseases and conditions. Until recently, the existence of programmed aging mechanisms was considered theoretically impossible because it directly conflicted with Darwin’s survival-of-the-fittest evolutionary mechanics concept as widely taught and generally understood. However, subsequent discoveries, especially in genetics, have exposed issues with some details of Darwin’s theory that affect the mechanics of the evolution process and strongly suggest that programmed aging mechanisms in humans and other mammals can and did evolve, and more generally, that a trait that benefits a population can evolve even if, like senescence, it is adverse to individual members of the population. Evolvability theories contend that organisms can possess evolved design characteristics (traits) that affect their ability to evolve, and further, that a trait that increases a population’s ability to evolve (increases evolvability) can be acquired and retained even if it is adverse in traditional individual fitness terms. Programmed aging theories based on evolvability contend that internally limiting lifespan in a species-specific manner creates an evolvability advantage that results in the evolution and retention of senescence. This issue is critical to medical research because the different theories lead to dramatically different concepts regarding the nature of biological mechanisms behind highly age-related diseases and conditions.     

Externally regulated programmed aging and effects of population stress on mammal lifespan

Programmed (adaptive) aging refers to the idea that mammals, including humans and other complex organisms, have evolved mechanisms that purposely cause or allow senescence or otherwise internally limit their lifespans in order to obtain an evolutionary advantage. Until recently, programmed aging had been thought to be theoretically impossible because of the mechanics of the evolution process. However, there is now substantial theoretical and empirical support for the existence of programmed aging in mammals. Therefore, a comprehensive approach to medical research on aging and age-related diseases must consider programmed aging mechanisms and the detailed nature of such mechanisms is of major importance. Theories of externally regulated programmed aging suggest that in mammals and other complex organisms, genetically specified senescence mechanisms detect local or temporary external conditions that affect the optimal lifespan for a species population and can adjust the lifespans of individual members in response. This article describes why lifespan regulation in response to external conditions adds to the evolutionary advantage produced by programmed aging and why a specific externally regulated programmed aging mechanism provides the best match to empirical evidence on mammal senescence.     

Programmed ageing: decline of stem cell renewal,immunosenescence, and Alzheimer's disease

The characteristic maximum lifespan varies enormously across animal species from a few hours to hundreds of years. This argues that maximum lifespan, and the ageing process that itself dictates lifespan, are to a large extent genetically determined. Although controversial, this is supported by firm evidence that semelparous species display evolutionarily programmed ageing in response to reproductive and environmental cues. Parabiosis experiments reveal that ageing is orchestrated systemically through the circulation, accompanied by programmed changes in hormone levels across a lifetime. This implies that, like the circadian and circannual clocks, there is a master ‘clock of age’ (circavital clock) located in the limbic brain of mammals that modulates systemic changes in growth factor and hormone secretion over the lifespan, as well as systemic alterations in gene expression as revealed by genomic methylation analysis. Studies on accelerated ageing in mice, as well as human longevity genes, converge on evolutionarily conserved fibroblast growth factors (FGFs) and their receptors, including KLOTHO, as well as insulin-like growth factors (IGFs) and steroid hormones, as key players mediating the systemic effects of ageing. Age-related changes in these and multiple other factors are inferred to cause a progressive decline in tissue maintenance through failure of stem cell replenishment. This most severely affects the immune system, which requires constant renewal from bone marrow stem cells. Age-related immune decline increases risk of infection whereas lifespan can be extended in germfree animals. This and other evidence suggests that infection is the major cause of death in higher organisms. Immune decline is also associated with age-related diseases. Taking the example of Alzheimer's disease (AD), we assess the evidence that AD is caused by immunosenescence and infection. The signature protein of AD brain, Aβ, is now known to be an antimicrobial peptide, and Aβ deposits in AD brain may be a response to infection rather than a cause of disease. Because some cognitively normal elderly individuals show extensive neuropathology, we argue that the location of the pathology is crucial – specifically, lesions to limbic brain are likely to accentuate immunosenescence, and could thus underlie a vicious cycle of accelerated immune decline and microbial proliferation that culminates in AD. This general model may extend to other age-related diseases, and we propose a general paradigm of organismal senescence in which declining stem cell proliferation leads to programmed immunosenescence and mortality.     

Pathophysiology of ageing, longevity and age related diseases

On April 18, 2007 an international meeting on Pathophysiology of Ageing, Longevity and Age-Related Diseases was held in Palermo, Italy. Several interesting topics on Cancer, Immunosenescence, Age-related inflammatory diseases and longevity were discussed. In this report we summarize the most important issues. However, ageing must be considered an unavoidable end point of the life history of each individual, nevertheless the increasing knowledge on ageing mechanisms, allows envisaging many different strategies to cope with, and delay it. So, a better understanding of pathophysiology of ageing and age-related disease is essential for giving everybody a reasonable chance for living a long and enjoyable final part of the life.