“Positive biology”: the centenarian lesson

The extraordinary increase of the elderly in developed countries underscore the importance of studies on ageing and longevity and the need for the prompt spread of knowledge about ageing in order to satisfactorily decrease the medical, economic and social problems associated to advancing years, because of the increased number of individuals not autonomous and affected by invalidating pathologies. Centenarians are equipped to reach the extreme limits of human life span and, most importantly, to show relatively good health, being able to perform their routine daily life and to escape fatal age-related diseases. Thus, they are the best example of extreme longevity, representing selected people in which the appearance of major age-related diseases, such as cancer, and cardiovascular diseases among others, has been consistently delayed or escaped. To discuss the relevance of genetics and life style in the attainment of longevity, five papers mostly focused on Italian centenarians have been assembled in this series. The aim is to realize, through a?? positive biology?? approach (rather than making diseases the central focus of research, ??positive biology?? seeks to understand the causes of positive phenotypes, trying to explain the biological mechanisms of health and well-being) how to prevent and/or reduce elderly frailty and disability.     

Genetics of longevity. data from the studies on Sicilian centenarians

ABSTRACT: The demographic and social changes of the past decades have determined improvements in public health and longevity. So, the number of centenarians is increasing as a worldwide phenomenon. Scientists have focused their attention on centenarians as optimal model to address the biological mechanisms of "successful and unsuccessful ageing". They are equipped to reach the extreme limits of human life span and, most importantly, to show relatively good health, being able to perform their routine daily life and to escape fatal age-related diseases, such as cardiovascular diseases and cancer. Thus, particular attention has been centered on their genetic background and immune system. In this review, we report our data gathered for over 10 years in Sicilian centenarians. Based on results obtained, we suggest longevity as the result of an optimal performance of immune system and an over-expression of anti-inflammatory sequence variants of immune/inflammatory genes. However, as well known, genetic, epigenetic, stochastic and environmental factors seem to have a crucial role in ageing and longevity. Epigenetics is associated with ageing, as demonstrated in many studies. In particular, ageing is associated with a global loss of methylation state. Thus, the aim of future studies will be to analyze the weight of epigenetic changes in ageing and longevity.     

Glycomics and glycoproteomics focused on aging and age-related diseases — Glycans as a potential biomarker for physiological alterations

BackgroundSince glycosylation depends on glycosyltransferases, glycosidases, and sugar nucleotide donors, it is susceptible to the changes associated with physiological and pathological conditions. Therefore, alterations in glycan structures may be good targets and biomarkers for monitoring health conditions. Since human aging and longevity are affected by genetic and environmental factors such as diseases, lifestyle, and social factors, a scale that reflects various environmental factors is required in the study of human aging and longevity.Scope of reviewWe herein focus on glycosylation changes elucidated by glycomic and glycoproteomic studies on aging, longevity, and age-related diseases including cognitive impairment, diabetes mellitus, and frailty. We also consider the potential of glycan structures as biomarkers and/or targets for monitoring physiological and pathophysiological changes.Major conclusionsGlycan structures are altered in age-related diseases. These glycans and glycoproteins may be involved in the pathophysiology of these diseases and, thus, be useful diagnostic markers. Age-dependent changes in N-glycans have been reported previously in cohort studies, and characteristic N-glycans in extreme longevity have been proposed. These findings may lead to a deeper understanding of the mechanisms underlying aging as well as the factors influencing longevity.General significanceAlterations in glycosylation may be good targets and biomarkers for monitoring health conditions, and be applicable to studies on age-related diseases and healthy aging. This article is part of a Special Issue entitled "Glycans in personalised medicine" Guest Editor: Professor Gordan Lauc.     

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.     

Healthy aging: the Swiss experience

The quantitative importance of ageing both in developed or in developing countries raised the subtle question of the quality of life of the ageing person. Precise definitions of life expectancy, healthy life expectancy and quality of life are presented. Then, presentation of the results of two cross-sectional studies performed with the same methodology at a 15-year time interval in French-speaking Switzerland illustrates compression of morbidity theory, with increased longevity, increased good perception of health and increased quality of life. Moreover, quantitative data concerning the longevity impact of hospital geriatric care are presented from Geneva. The 4-year survival rate of over 85 year old women, discharged from the hospital for acute care, reached 48%. Explanations of these outstanding medical progresses on longevity and socio-economical challenges of extreme ageing are discussed in the world context.     

'Positive biology' as a new paradigm for the medical sciences. Focusing on people who live long, happy, healthy lives might hold the key to improving human well-being

The nearly exclusive focus on understanding and treating chronic disease might not be the most efficient way to improve public health, especially as an effective alternative strategy exists.On 27 April 2009, during a speech at the National Academy of Sciences, US President Barack Obama pledged to invest more than 3% of US GDP in scientific research and development—the amount represented the largest ever investment in research and innovation. However, even a financial investment of such magnitude does not ensure that science is ''well-ordered'' [1], in the sense that the scientific research that is prioritized aspires to address the most significant challenges and problems for humanity.Among the many issues facing society that research must address, improving human health and tackling disease rank high, if not first, on the agenda. Accordingly, a huge fraction of research funding is spent on basic and applied research to further our understanding of the causes of disease and to find new cures and therapies. But is this focus on pathology the most efficient way to conduct research with the aim to improve human health and well-being?…a huge fraction of research funding is spent on basic and applied research to further our understanding of the causes of disease and to find new cures and therapiesMost of today''s medical research could be called ''negative biology''. It is conducted in an intellectual framework that presumes that the most important question to answer is: what causes pathology? Disease is its central focus and this explains why medical research and research funding is mainly concerned with trying to understand, prevent and treat specific diseases. The design of the US National Institutes of Health, which is largely composed of individual institutes dedicated to specific diseases such as cancer, mental illness or infectious diseases, reflects this prevalence of pathology-oriented negative biology.Positive biology, by contrast, focuses on a different set of questions and priorities. Rather than making pathology and disease the central focus of intellectual efforts and financial investments, positive biology seeks to understand positive phenotypes: why do some individuals live more than a century without ever suffering from the chronic diseases that afflict most humans much earlier in their lives? Why are some individuals more happy, optimistic, talented, or have a better memory than most people? The paradigm of positive biology is based on the insight that the process of evolution by natural selection does not create a perfect organism in terms of life expectancy, resistance to disease or other abilities. Observations of exceptional longevity or superior cognition therefore present fascinating puzzles for positive biology: which biological mechanisms would explain these exemplars of health and well-being? The goal of understanding positive phenotypes is that such knowledge might lead to new interventions that generally improve human well-being. This might be achieved by modulating the rate of ageing or by increasing opportunities for play and joy at all stages of the human lifespan, or by developing pharmaceuticals that safely enhance cognition or positive emotions, and so on.The goal of understanding positive phenotypes is that such knowledge might lead to new interventions that generally improve human well-beingThis is distinct from negative biology, which focuses on the proximate causes of specific diseases, rather than on the evolutionary causes of positive phenotypes. It presumes that health, survival and happiness are the default states and aims to explain the deviations: why do we develop cancer? Why do we suffer from depression? Why do we develop hypertension? Negative biology therefore faces the laudable but insurmountable task of trying to prevent or cure all disease. This is a costly and ultimately futile endeavour. Eliminating all types of cancer would increase life expectancy in the USA by approximately only three years [2]. Even eliminating cancer as a cause of death would not prevent any of the other chronic diseases of ageing—cardiovascular disease, Alzheimer and Parkinson disease, diabetes and so on—from afflicting the elderly. Moreover, the more than 40 years of ''war against cancer'' has not defeated a single type of cancer: we still have a long way to go before we can realistically expect to reap the three-year increase in life expectancy that eliminating all cancers could yield.In fact, negative biology has not yet developed a single cure for any one of the hundreds of chronic diseases that afflict millions of people living today. Of course, it has made significant advances to help prevent and treat chronic disease, but the fixation on pathology has meant that other potential avenues for research have been neglected.Indeed, a better understanding of exemplars of health and happiness—the goal of positive biology—could create more benefits for humans more quickly and more easily. A drug that would safely mimic the effects of caloric restriction, for instance, might delay, simultaneously, most diseases and afflictions of ageing. It would generate a much greater health dividend for ageing populations than defeating any one specific disease of ageing because slowing down the rate of ageing by seven years would reduce the age-specific risk of death, frailty and disability by about half at every age [3].Scientists are already making good progress on the project of positive biology, even if the intellectual framework is not yet clearly defined and their topics are rather piecemeal. Richard Miller, for example, a professor of pathology at Michigan University, USA, studies the genetics of ageing in mice and participates in the National Institute of Aging''s multi-institutional programme that evaluates the effects of drugs and nutriceuticals on the ageing process in mice. David Sinclair from Harvard University, USA, and others found that the plant compound resveratrol, which is found in the skin of grapes, can modulate the ageing process. Nir Barzilai and colleagues at the Albert Einstein School of Medicine in New York, USA, have conducted genetic research on more than 500 healthy elderly people between the ages of 95 and 112 years. Michael Rose from the University of California, Irvine, USA, has quadrupled the lifespan of fruit flies by delaying the age of reproduction. Finally, the biologist Cynthia Kenyon demonstrated that in Caenorhabditis elegans, a single gene can control the ageing process. Any of these research projects could eventually lead to the development of a new drug that retards the ageing process and diminishes the onslaught of chronic diseases that typically afflict humans after their sixth decade of life.Similarly, a lot of pioneering work is being undertaken in the burgeoning field of ''positive psychology''. Rather than studying why people suffer from mental illnesses such as depression, schizophrenia or ADHD (attention deficit hyperactivity disorder), positive psychology is primarily interested in how to improve the happiness of the ''average'' person. Martin Seligman, a psychologist at the University of Pennsylvania, USA, and a pioneer in the field of positive psychology, distinguishes different kinds and levels of happiness [4]. Hedonists who pursue immediate rewards such as the pleasure of buying something or receiving a compliment seek momentary happiness or what Seligman calls ''the pleasant life''. But these pleasures fade quickly and do not leave a lasting impact on subjective well-being. Enduring happiness, by contrast, is realized when we lead a meaningful life. After years spent studying what makes people happy, Seligman contends that it is rooted in attachment to something larger, and the larger the entity to which you attach yourself, the more meaning your life has [4].Eliminating all types of cancer would increase life expectancy in the USA by approximately only three yearsThis is clearly illustrated by the role of wealth. People often assume that being richer will mean being happier, yet surveys in many countries indicate that global levels of life satisfaction or happiness have not changed much during the past four decades despite large increases in real income per capita [5]. Most disposable income is spent on consumer goods that do little to actually enhance our well-being.In a recent study of the daily behaviour of happy people, researchers used an electronically activated recorder to record, and then later classify, participants'' daily conversations with others as either ''small talk'', that is banal conversations, and ''substantive talk'', where meaningful information was exchanged. They found that higher well-being was associated with less small talk and more substantive conversations [6]. While such a study does not establish the truth of Socrates'' famous claim that “the unexamined life is not worth living”, it does suggest that our need to feel attached to something larger is important to our happiness and well-being. This hypothesis is supported by recent studies on how people spend their money. Researchers from the University of British Columbia and Harvard Business School found that when individuals spend more money on prosocial goals, such as charity, they actually experience greater happiness than when they spend money on consumer products for themselves [7]. Similarly, the psychologist Barbara Fredrickson''s research on positive emotions—joy, serenity and gratitude—suggests that these expand cognition and behavioural tendencies [8].Finally, research on exemplars of resilience, that is, the ability of some people to cope and manage with tragic and traumatic events, could lead to the development of drugs that would increase people''s resilience. Avshalom Caspi and colleagues found that individuals with one or two copies of the short allele of the promoter of the 5-HTT serotonin receptor experience more depressive symptoms, diagnosable depression and suicidal thoughts in response to stressful events compared with individuals who are homozygous for the long allele [9].Cognitive functioning is another central topic of positive biology. What are the genetic and environmental determinants of high IQ, exceptional memory or social intelligence? Barbara Sahakian and colleagues found that the analeptic drug modafinil significantly enhanced performance tests of digit span, visual pattern recognition memory, spatial planning and stop-signal reaction time in healthy volunteers [10]. These findings of positive biology will eventually give us a better understanding of our human nature than the very limited focus on disease and pathology of negative biology and might then lead to new interventions, environments and attitudes that improve human well-being and happiness.Negative biology dominates medical research, from the questions research scientists tackle to the education of physicians and government regulation of health interventions. The dominance of this approach to the medical sciences presumes that the most important questions concern the causes of pathology rather than the causes of exemplar health and happiness. Positive biology takes a different approach: it does not limit the moral duty to apply knowledge and technology to improve human welfare to only treating specific diseases or impairments. Rather, it works under the assumption that if knowledge and research can improve people''s lives, there is a moral duty to advance that knowledge and promote well-being. Nor is positive biology predicated on a sharp distinction between therapy and enhancement. Instead, as the bioethicist John Harris has argued, “the overwhelming moral imperative for both therapy and enhancement is to prevent harm and confer benefit. Bathed in that moral light, it is unimportant whether the protection or benefit conferred is classified as enhancement or improvement, protection or therapy” [11].Generally, the medical system as a whole could be much more efficient if it concentrated its efforts on making people healthier and happier in the first place instead of its current focus on understanding and treating disease. Advancing the paradigm of positive biology should therefore help the medical sciences transcend the limited perspectives and aspirations of negative biology. Such a paradigm could help the world''s population to reap the benefits that new knowledge and technologies can offer in terms of making people healthier and happier. Societies and individuals already seek to achieve these goals: we educate our children to eat healthily and exercise and to develop their social goals to find fulfilment in life. The paradigm of positive biology simply encourages us to make use of the full range of options to realize these goals.…the medical system as a whole could be much more efficient if it concentrated its efforts on making people healthier and happier in the first place…In conclusion, positive biology is not contrary to the goals and aspirations of negative biology. Indeed the two paradigms are often complementary. For example, understanding why some high-risk individuals, such as sex workers, seem to have an intrinsic resistance to HIV-1 might spur the development of an HIV vaccine [12]. Similarly, understanding human brains with exceptional cognitive functioning might lead to new avenues for developing drugs and therapies against severe cognitive impairment. Understanding exemplars of health could create real benefits for those who are more vulnerable to disease and disability.     

Inflammation and genetics: an insight in the centenarian model

The number of centenarians is growing worldwide. This specific cohort has aroused the attention of scientists worldwide and is considered one of the most valuable models to study the mechanisms involved in the aging process. In fact, they have reached the extreme limits of human life span and, most important of all, they show relatively good health being able to perform their routine daily life. Because they have escaped the common lethal diseases, the role of their genetic background has been brought into focus. In fact, sequence variations, in a variety of pro- or anti-inflammatory cytokine genes, have been found to influence successful ageing and longevity. The key role played by cytokines has been also confirmed in centenarians as we know that inflammation has been related to several pathological burdens (e.g., obesity, atherosclerosis, and diabetes). Successful ageing seems to be related to an optimal functioning of the immune system, pointing out that polymorphisms for the immune system genes, which are involved in the regulation of immune-inflammatory responses, may play a key role in the genetics of ageing. This review provides an update in the field of ageing related to inflammation and genetics.     

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.     

Zinc–gene interaction related to inflammatory/immune response in ageing

The pivotal role played by zinc-gene interaction in affecting some relevant cytokines (IL-6 and TNF-alpha) and heat shock proteins (HSP70-2) in ageing, successful ageing (nonagenarians) and the most common age-related diseases, such as atherosclerosis and infections, is now recognized. The polymorphisms of genes codifying proteins related to the inflammation are predictive on one hand in longevity, on the other hand they are associated with atherosclerosis or severe infections. Since the health life-span has a strong genetic component, which in turn also affected by nutritional factors like zinc, the association of these polymorphisms with innate immune response, zinc ion bioavailability and Metallothioneins (MT) homeostasis is an useful tool to unravel the role played by zinc-gene interactions in longevity, especially due to the inability of MT in zinc release in ageing and chronic inflammation. In ageing, this last fact leads to depressed innate immune response for host defence. In contrast, in very old age the inflammation is lower with subsequent more zinc ion bioavailability, less MT gene expression and satisfactory innate immunity. Therefore, the zinc-gene (IL-6, TNF-alpha, Hsp70-2) interactions, via MT homeostasis, are crucial to achieve successful ageing.     

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.     

Disease Prevention: Saving Lives or Reducing Health Care Costs?

Background

Disease prevention has been claimed to reduce health care costs. However, preventing lethal diseases increases life expectancy and, thereby, indirectly increases the demand for health care. Previous studies have argued that on balance preventing diseases that reduce longevity increases health care costs while preventing non-fatal diseases could lead to health care savings. The objective of this research is to investigate if disease prevention could result in both increased longevity and lower lifetime health care costs.

Methods

Mortality rates for Netherlands in 2009 were used to construct cause-deleted life tables. Data originating from the Dutch Costs of Illness study was incorporated in order to estimate lifetime health care costs in the absence of selected disease categories. We took into account that for most diseases health care expenditures are concentrated in the last year of life.

Results

Elimination of diseases that reduce life expectancy considerably increase lifetime health care costs. Exemplary are neoplasms that, when eliminated would increase both life expectancy and lifetime health care spending with roughly 5% for men and women. Costs savings are incurred when prevention has only a small effect on longevity such as in the case of mental and behavioural disorders. Diseases of the circulatory system stand out as their elimination would increase life expectancy while reducing health care spending.

Conclusion

The stronger the negative impact of a disease on longevity, the higher health care costs would be after elimination. Successful treatment of fatal diseases leaves less room for longevity gains due to effective prevention but more room for health care savings.     

Geriatric dentistry--meet the need

Geriatric dentistry or gerodontics is the delivery of dental care to older adults involving the diagnosis, prevention, and treatment of problems associated with normal ageing and age-related diseases as part of an inter-disciplinary team with other health care professionals. Geriatric health is an ignored and under-explored area worldwide. Oral health reflects overall well being for the elderly population. Conversely, elderly patients are more predisposed to oral conditions due to age-related systemic diseases and functional changes. The major barriers to practising geriatric dentistry are the lack of trained faculty members, a crowded curriculum and monetary concerns. For successful treatment, the practitioner must adopt a humanitarian approach and develop a better understanding of the feelings and attitudes of the elderly. Prevention and early intervention strategies must be formulated to reduce the risk of oral diseases in this population. In future, dental professionals must have a proper understanding of the magnitude of the services to be provided to the elderly. This could only be realised through an education programme in geriatric dentistry, which should be started without further delay. This article hence sets out the objectives, needs, present scenario, strategies and types of dental treatment required by the elderly population.     

Endless paces of degeneration—applying comparative genomics to study evolution's moulding of longevity

Why do mice and humans have such different lifespans? Genome sequencing efforts are allowing researchers to pick apart the genetic foundations of longevity, with some promising results beginning to emerge.Why can mice not live more than five years and dogs not more than 30, yet bats can live over 40 years and humans over a century? Differences in longevity between closely related species are one of the greatest mysteries in biology, and identifying the processes responsible could ultimately presage the development of therapies against a multitude of age-related diseases. The variation in mammalian longevity must have a genomic basis, with recent genome sequencing efforts opening up exciting opportunities to decipher it; some promising results are beginning to emerge. Analysis of two bat genomes revealed that a high proportion of genes in the DNA damage checkpoint–DNA repair pathway, including ATM, TP53, RAD50 and KU80, are under selection in bats [1]. This finding is exciting because these genes have been directly associated with ageing in model systems and, therefore, it points towards a potential role for averting DNA damage in longevity assurance mechanisms; a notion dating back several decades that remains contentious. In addition, the report of a systematic scan for proteins with accelerated evolution in mammalian lineages in which longevity increased over the course of their evolution, hinted that some repair systems, such as the ubiquitin–proteasome pathway and a few proteins related to DNA damage repair, might have been selected for in long-lived lineages [2]. However, much work remains to improve the signal-to-noise ratio of this and similar methods.With decreasing costs of sequencing, the growing number of genomes of species with diverse lifespans is expected to facilitate studies in this area. As such, we can make an increasing number of comparisons such as those described above. Put simply, if we study long-lived species and find that they share genetic adaptations—for example in DNA damage response pathways—then we might assume that those adaptations are important to increase longevity. There are major intrinsic difficulties with this type of analysis, however, that one must keep in mind. Perhaps the best illustration is that despite the dramatic phenotypic divergence between humans and chimpanzees, only a relatively small number of genetic adaptations that are probably responsible for such divergence have thus far been identified [3]. One difficulty is that the genomic elements underlying species differences remain controversial. Possible processes include mutations in coding and non-coding sequences, gene family expansion and contraction, and copy number variation, all of which we think must be explored in the context of longevity adaptations. Whilst changes in regulatory regions might be important, standard methods are lacking for the detection of selection on functional non-coding sequences on a genome-wide scale and this, we think, is a limitation for progress in this area. Another limitation is that experimental validation of promising candidates is often extremely difficult to obtain.Applying comparative genomics to study the evolution of longevity also has unique challenges. For one, the force of natural selection weakens with age, indicating that, although under low-hazard conditions selection favours genes and pathways conferring longevity, selective pressure for longevity is significantly less than for other traits. Furthermore, we think that the integration of additional data—for example gene expression and age-related phenotypic data—is crucial to link genotypes to phenotypes and identify physiological adaptations that are required for extended longevity. Unfortunately, such data and even the necessary samples to generate it are as yet only available for a subset of species. In our opinion, another crucial issue is the extent to which common mechanisms underlie the extension of longevity by evolution in different species. Just as rare variants contribute to missing human heritability, taxa-specific adaptations might contribute to longevity. It can be assumed that the environment—for example, diet—of each species will influence the physiological and biochemical pathways that must be optimized to fend off ageing and age-related diseases. However, the ageing process, despite progressing at different rates, is remarkably similar across most mammals studied [4], hinting that retarding ageing might involve adaptations in similar pathways. The degree of overlap between longevity assurance mechanisms is, in our view, a crucial determinant of how much we can expect to learn about species differences in ageing in the foreseeable future. If common pathways do indeed underlie longevity evolution in multiple species, even if involving different genetic elements in different taxa, then it is reasonable to expect that they can be identified by using comparative genomics as more genomes of short- and long-lived species are sequenced. We hope to live long enough to help unravel this age-old problem.     

Calorie restriction, SIRT1 and metabolism: understanding longevity

Calorie restriction (CR) is the only experimental manipulation that is known to extend the lifespan of a number of organisms including yeast, worms, flies, rodents and perhaps non-human primates. In addition, CR has been shown to reduce the incidence of age-related disorders (for example, diabetes, cancer and cardiovascular disorders) in mammals. The mechanisms through which this occurs have been unclear. CR induces metabolic changes, improves insulin sensitivity and alters neuroendocrine function in animals. In this review, we summarize recent findings that are beginning to clarify the mechanisms by which CR results in longevity and robust health, which might open new avenues of therapy for diseases of ageing.     

DNA damage and ageing: new-age ideas for an age-old problem

Loss of genome maintenance may causally contribute to ageing, as exemplified by the premature appearance of multiple symptoms of ageing in a growing family of human syndromes and in mice with genetic defects in genome maintenance pathways. Recent evidence revealed a similarity between such prematurely ageing mutants and long-lived mice harbouring mutations in growth signalling pathways. At first sight this seems paradoxical as they represent both extremes of ageing yet show a similar 'survival' response that is capable of delaying age-related pathology and extending lifespan. Understanding the mechanistic basis of this response and its connection with genome maintenance would open exciting possibilities for counteracting cancer or age-related diseases, and for promoting longevity.     

A review and appraisal of the DNA damage theory of ageing

Given the central role of DNA in life, and how ageing can be seen as the gradual and irreversible breakdown of living systems, the idea that damage to the DNA is the crucial cause of ageing remains a powerful one. DNA damage and mutations of different types clearly accumulate with age in mammalian tissues. Human progeroid syndromes resulting in what appears to be accelerated ageing have been linked to defects in DNA repair or processing, suggesting that elevated levels of DNA damage can accelerate physiological decline and the development of age-related diseases not limited to cancer. Higher DNA damage may trigger cellular signalling pathways, such as apoptosis, that result in a faster depletion of stem cells, which in turn contributes to accelerated ageing. Genetic manipulations of DNA repair pathways in mice further strengthen this view and also indicate that disruption of specific pathways, such as nucleotide excision repair and non-homologous end joining, is more strongly associated with premature ageing phenotypes. Delaying ageing in mice by decreasing levels of DNA damage, however, has not been achieved yet, perhaps due to the complexity inherent to DNA repair and DNA damage response pathways. Another open question is whether DNA repair optimization is involved in the evolution of species longevity, and we suggest that the way cells from different organisms respond to DNA damage may be crucial in species differences in ageing. Taken together, the data suggest a major role of DNA damage in the modulation of longevity, possibly through effects on cell dysfunction and loss, although understanding how to modify DNA damage repair and response systems to delay ageing remains a crucial challenge.     

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 discovery of how gender influences age immunological mechanisms in health and disease,and the identification of ageing gender-specific biomarkers,could lead to specifically tailored treatment and ultimately improve therapeutic success rates

The control of human health and diseases in the elderly population is becoming a challenge, since mean age and life expectation are progressively increasing as well as chronic degenerative diseases. These disorders are of complex diagnosis and they are difficult to be treated, but it is hoped that the predictive medicine will lead to more specific and effective treatment by using specific markers to identify persons with high risk of developing disease, before the clinical manifestation. Peripheral blood targets and biomarkers are currently the most practical, non-invasive means of disease diagnosing, predicting prognosis and therapeutic response. Human longevity is directly correlated with the optimal functioning of the immune system. Recent findings indicate that the sexual dimorphism of T helper (Th) cytokine pathways and the regulation of Th cell network homeostasis are normally present in the immune response and undergoes to adverse changes with ageing. Furthermore, immune senescence affects both men and women, but it does not affect them equally. Therefore, we hypothesize that the comprehension of the interferences between these gender specific pathways, the ageing immunological mechanism in pathological or healthy state and the current therapies, could lead to specifically tailored treatment and eventually improve the therapeutic success rates. Reaching this aim requires the identification of ageing gender-specific biomarkers that could easily reveal the above mentioned correlations.     

Melatonin,Longevity and Health in the Aged: An Assessment

This brief review considers the potential role of melatonin in the processes of aging, the prolongation of life span and health in the aged. Studies completed to date generally suggest that exogenously administered melatonin may serve to extend life span in invertebrates, but evidence supporting this conclusion in mammals is less compelling. Thus, any conclusion regarding a role for melatonin in extending normal longevity, particularly in mammals, would be premature. With regard to deferring the signs of chemically-induced neurodegenerative conditions in experimental animals, the data are remarkably strong and there is a modicum of evidence that in humans with debilitating diseases melatonin may have some beneficial actions. Indeed, this should be one focus of future research since as the number of elderly increases in the population, the frequency of costly age-related diseases will become increasingly burdensome to both the patient and to society as a whole.     

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.