Depression might be associated with accelerated cellular aging. However, does this result in an irreversible state or is the body able to slow down or recover from such a process? Telomeres are DNA‐protein complexes that protect the ends of chromosomes and generally shorten with age; and therefore index cellular aging. The majority of studies indicate that persons with depression have shorter leukocyte telomeres than similarly aged non‐depressed persons, which may contribute to the observed unfavorable somatic health (...) outcomes in the depressed population. Some small‐scale preliminary studies raise the possibility that behavioral or pharmacological interventions may either slow down or else reverse this accelerated telomere shortening, possibly through increasing the activity of the telomere‐lengthening enzyme telomerase. This paper covers the current state of evidence in the relationship between depression and the telomere‐telomerase system and debates whether depression‐related cellular aging should be considered a reversible process or permanent damage. (shrink)

Critical cellular functions, including stem cell maintenance, fate determination, and cellular behavior, are governed by canonical Wnt signaling, an evolutionarily conserved pathway whose intracellular signal is transduced by β‐catentin. Emerging evidence suggests that canonical Wnt signaling influences cellular aging, indicating that increases in Wnt signaling delay age‐related deficits.1 However, recent Science papers suggest that Wnt signaling accelerates the onset of aging.2,3 In an attempt to resolve this paradox and clarify how Wnt signaling affects aging, (...) we provide a selective review of research relevant to Wnt signaling and aging. BioEssays 30:102–106, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

The capacity of cells and organisms to respond to external stimuli and to maintain stability in order to survive decreases progressively during ageing. The mitogenic and stimulatory effects of growth factors, hormones and other agents are reduced significantly during cellular ageing. The sensitivity of ageing cells to toxic agents including antibiotics, phorbol esters, radiations and heat shock increases. This failure of homeostasis during cellular ageing does not appear to be due to any quantitative and qualitative defects in the (...) receptor systems. Instead, metabolic defects in the pathways of macromolecular synthesis may be the basis of altered cellular responsiveness during ageing. (shrink)

Age‐related and cancer‐related epigenomic modifications have been associated with enhanced cell‐to‐cell gene expression variability that characterizes increased cellular stochasticity. Since gene expression variability appears to be highly reduced by—and epigenetic and phenotypic stability acquired through—direct or long‐range cellular interactions during cell differentiation, we propose a common origin for aging and cancer in the failure to control cellular stochasticity by cell–cell interactions. Tissue‐disruption‐induced cellular stochasticity associated with epigenetic drift would be at the origin of organ dysfunction (...) because of an increase in phenotypic variation among cells, ultimately leading to cell death and organ failure through a loss of coordination in cellular functions, and eventually to cancerization. We propose mechanistic research perspectives to corroborate this hypothesis and explore its evolutionary consequences, highlighting a positive correlation between the median age of mass loss onset (a proxy for the onset of organ aging) and the median age at cancer diagnosis. (shrink)

The study of cellular senescence and proliferative lifespan is becoming increasingly important because of the promises of autologous cell therapy, the need for model systems for tissue disease and the implication of senescent cell phenotypes in organismal disease states such as sarcopenia, diabetes and various cancers, among others. Here, we explain the concepts of proliferative cellular lifespan and cellular senescence, and we present factors that have been shown to mediate cellular lifespan positively or negatively. We review (...) much recent literature and present potential molecular mechanisms by which lifespan mediation occurs, drawing from the fields of telomere biology, metabolism, NAD+ and sirtuin biology, growth factor signaling and oxygen and antioxidants. We conclude that cellular lifespan and senescence are complex concepts that are governed by multiple independent and interdependent pathways, and that greater understanding of these pathways, their interactions and their convergence upon specific cellular phenotypes may lead to viable therapies for tissue regeneration and treatment of age‐related pathologies, which are caused by or exacerbated by senescent cells in vivo. (shrink)

Alzheimer's disease results from the degeneration of neurons. Degenerating nerve cells express atypical proteins, and amyloid is deposited. We suggest that some of these events are strongly influenced by genetic factors and age. Animal models should be useful in investigating the pathogenic mechanisms that lead to the brain abnormalities seen in this disease.

Asymmetric cell division generates cell diversity and contributes to cellular aging and rejuvenation. Here, we review the molecular mechanisms enabling budding yeast to recognize spindle pole bodies (SPB, centrosome equivalent) based on their age, and guide their non‐random mitotic segregation: SPB inheritance requires the distinction of old from new SPBs and is regulated by the SPB‐inheritance network (SPIN) and the mitotic exit network (MEN). The SPIN marks the pre‐existing SPB as old and the MEN recognizes these marks translating (...) them into spindle orientation. We next revisit other molecules and structures that partition depending on their age rather than their abundance at mitosis as, for example, DNA, centrosomes, mitochondria, and histones in yeast and other systems. The recurrence of this differential behavior suggests a functional significance for numerous cell types, which we then discuss. We conclude that non‐random segregation may facilitate asymmetric cell fate determination and thereby indirectly aging and rejuvenation. (shrink)

Inflamm‐aging is a relatively new terminology used to describe the age‐related increase in the systemic pro‐inflammatory status of humans. Here, we represent inflamm‐aging as a breakdown in the multi‐shell cytokine network, in which stem cells and stromal fibroblasts (referred to as the stem cell niche) become pro‐inflammatory cytokine over‐expressing cells due to the accumulation of DNA damage. Inflamm‐aging self‐propagates owing to the capability of pro‐inflammatory cytokines to ignite the DNA‐damage response in other cells surrounding DNA‐damaged cells. Macrophages, (...) the major cellular player in inflamm‐aging, amplify the phenomenon, by broadcasting pro‐inflammatory signals at both local and systemic levels. On the basis of this, we propose that inflamm‐aging is a major contributor to the increase in cancer incidence and progression in aged people. Breast cancer will be presented as a paradigmatic example for this relationship. (shrink)

Mitochondrial dysfunction has long been considered a key mechanism in the ageing process but surprisingly little attention has been paid to the impact of mitochondrial number or density within cells. Recent reports suggest a positive association between mitochondrial density, energy homeostasis and longevity. However, mitochondrial number also determines the number of sites generating reactive oxygen species (ROS) and we suggest that the links between mitochondrial density and ageing are more complex, potentially acting in both directions. The idea that increased density, (...) especially when combined with mitochondrial dysfunction, might accelerate ageing is supported by a negative correlation between mitochondrial density and maximum longevity in an interspecies comparison in mammals, and by evidence for an intimate interconnection between cellular ROS levels, mitochondrial density and cellular ageing. Recent data suggest that retrograde response, which activates mitochondrial biogenesis, accompanies cellular ageing processes. We hypothesise that increased mitochondrial biogenesis, and possibly also impaired degradation and segregation of mitochondria, if occurring as adaptation to pre‐existing mitochondrial dysfunction, might aggravate ROS production and thus actively contribute to ageing. BioEssays 29:908–917, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Emerging data connects the aging process in dermal fibroblasts with metabolic reprogramming, provided by enhanced fatty acid oxidation and reduced glycolysis. This switch may be caused by a significant expansion of the dermal white adipose tissue (dWAT) layer in aged, hair‐covered skin. Dermal adipocytes cycle through de‐differentiation and re‐differentiation. As a result, there is a strongly enhanced release of free fatty acids into the extracellular space during the de‐differentiation of dermal adipocytes in the catagen phase of the hair follicle (...) cycle. Both caveolin‐1 and adiponectin are critical factors influencing these processes. Controlling the expression levels of these two factors also offers the ability to manipulate the metabolic preferences of the different cell types within the microenvironment of the skin, including dermal fibroblasts. Differential expression of adiponectin and caveolin‐1 in the various cell types may also be responsible for the cellular metabolic heterogeneity within the cells of the skin. (shrink)

John Davis (_New Methuselahs_: _The Ethics of Life_ _Extension_, The MIT Press, Cambridge, 2018) advances a novel ethical analysis of longevity science that employs a three-fold methodology of examining the impact of life extension technologies on three distinct groups: the “Haves”, the “Have-nots” and the “Will-nots”. In this essay, I critically examine the egalitarian analysis Davis deploys with respect to its ability to help us theorize about the moral significance of an applied gerontological intervention. Rather than focusing on futuristic scenarios (...) of radical life extension, I offer a rival egalitarian analysis that takes seriously (1) the health vulnerabilities of today’s aging populations, (2) the health inequalities of the “aging status quo” and, (3) the prospects for the fair diffusion of an aging intervention over the not-so-distant future. Despite my reservations about Davis’s focus on “life-extension” vs. increasing the human “healthspan”, I agree with his central conclusion that an aging intervention would be, on balance, a good thing and that we should fund such research aggressively. But, I make an even stronger case and conjecture that an intervention that slows down the rate of molecular and cellular decline from the inborn aging process will likely be one of the most important public health advancements of the twenty-first century. This is so because aging is the most prevalent risk factor for chronic disease, frailty and disability, and it is estimated that there will be over 2 billion persons age > 60 by the year 2050. (shrink)

Epigenetic control of gene expression by chromatin remodeling is critical for adult stem cell function. A decline in stem cell function is observed during aging, which is accompanied by changes in the chromatin structure that are currently unexplained. Here, we hypothesize that these epigenetic changes originate from the limited cellular capability to inherit epigenetic information. We suggest that spontaneous loss of histone modification, due to fluctuations over short time scales, gives rise to long‐term changes in DNA methylation and, (...) accordingly, in gene expression. These changes are assumed to impair stem cell function and, thus, to contribute to aging. We discuss cell replication as a major source of fluctuations in histone modification patterns. Gene silencing by our proposed mechanism can be interpreted as a manifestation of the conflict between the stem cell plasticity required for tissue regeneration and the permanent silencing of potentially deleterious genomic sequences. (shrink)

A recent report by Tyner et al.1 suggests that p53 is bad for longevity. Heterozygotic mice carrying a p53 mutation that apparently enhances the stability of the wild‐type protein showed shorter lifespans and faster ageing while also developing fewer tumours. This fits with the idea that cellular ageing is the price paid for better protection against unlimited proliferation of cancer cells. But other work shows that there is a strong positive association between DNA repair‐mediated protection against cancer and ageing. (...) So what are we to make of the new data with regard to overall understanding of the mechanisms of ageing? BioEssays 24:577–579, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

What the causes of aging are and which factors define lifespan are key questions in the understanding of aging. Here, it is argued that cellular life involves (i) inevitable accumulation of damage resulting from imperfectness and heterogeneity of every cellular process, and (ii) dilution of damage when cells divide. While severe damage is cleared by protective systems, milder damage can only be diluted. This is due to the high cost of accuracy, the greater number of damage (...) forms compared to protective systems, and the constraints on cellular life inherited from the prokaryotic world. This strategy also applies to cancer cells, which are particularly dependent on damage dilution. Imposing restriction on cell division necessarily leads to aging. Interventions that extend lifespan act through metabolic reprogramming, thereby changing both damage composition and the rate of damage accumulation. Thus, heterogeneity leading to myriad mild damage forms represents the cause of aging, whereas the processes that affect the damage landscape and damage accumulation are lifespan regulators. (shrink)

The model organism Saccharomyces cerevisiae is providing new insights into the molecular and cellular changes that are related to aging. The yeast protein Sir2p (Silent Information Regulator 2) is a histone deacetylase involved in transcriptional silencing and the control of genomic stability. Recent results have led to the identification of Sir2p as a crucial determinant of yeast life span. Dosage, intracellular localization, and activity of Sir2p all have important effects on yeast longevity. For instance, calorie restriction apparently increases (...) yeast life span by increasing Sir2p activity. Since Sir2p‐related proteins have been identified in many prokaryotic and eukaryotic organisms, the fundamental principles derived from the studies in yeast may prove valuable in directing our future research toward an understanding of the mechanisms of aging in higher eukaryotes. BioEssays 23:327–332, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

This article looks at the history of the stem cell as an experimental life-form and situates it within the context of biological theories of cellular ageing which emerged in the 1960s, under the banner of ‘biogerontology’. The field of biogerontology, I argue, is crucially concerned not only with the internal limits to a cell's lifespan, but also with the possibility of overcoming limits. Hence, the sense of ‘revolution’ that has surrounded the isolation of human embryonic stem cells. The article (...) goes on to situate the problematic of cellular ageing within the larger historical transition from Fordist to post-Fordist modes of production – a transition whose effects on the life sciences have been insufficiently theorized – and points to resonances between the concerns of biogerontology and an emerging political rhetoric on the crisis of ageing and limits to growth. Having surfaced in parallel with the neo-liberal euphoria of the 1990s, the field of regenerative medicine presents itself as a biomedical solution to the problem of limits to growth. What is at stake in the contemporary biosciences, I suggest, is not so much the mass commodification of life itself as its transformation into a source of speculative surplus value. (shrink)

Fused, elongated mitochondria are more efficient in generating ATP than fragmented mitochondria. In diverse C. elegans longevity pathways, increased levels of fused mitochondria are associated with lifespan extension. Blocking mitochondrial fusion in these animals abolishes their extended longevity. The long‐lived C. elegans vhl‐1 mutant is an exception that does not have increased fused mitochondria, and is not dependent on fusion for longevity. Loss of mammalian VHL upregulates alternate energy generating pathways. This suggests that mitochondrial fusion facilitates longevity in C. elegans (...) by increasing energy metabolism. In diverse animals, ATP levels broadly decreases with age. Substantial evidence supports the theory that increasing or maintaining energy metabolism promotes the survival of older animals. Increased ATP levels in older animals allow energy‐intensive repair and homeostatic mechanisms such as proteostasis that act to prevent cellular aging. These observations support the emerging paradigm that maintaining energy metabolism promotes the survival of older animals. (shrink)

Despite recent progress in the identification of genes that regulate longevity, aging remains a mysterious process. One influential hypothesis is the idea that the potential for cell division and replacement are important factors in aging. In this work, we review and discuss this perspective in the context of interventions in mammals that appear to accelerate or retard aging. Rather than focus on molecular mechanisms, we interpret results from an integrative biology perspective of how gene products affect (...) class='Hi'>cellular functions, which in turn impact on tissues and organisms. We review evidence suggesting that mutations that give rise to features resembling premature aging tend to be associated with cellular phenotypes such as increased apoptosis or premature replicative senescence. In contrast, many interventions in mice that extend lifespan and might delay aging, including caloric restriction, tend to either hinder apoptosis or result in smaller animals and thus may be the product of fewer cell divisions. Therefore, it appears plausible that changes in the number of times that cells, and particularly stem cells, divide during an organism's lifespan influence longevity and aging. We discuss possible mechanisms related to this hypothesis and propose experimental paradigms. BioEssays 30:567–578, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Geroscience and philosophy of aging have tended to focus their analyses on the biological and chronological dimensions of aging. Namely, one ages with the passage of time and by experiencing the cellular-molecular deterioration that accompanies this process. However, our concept of aging depends decisively on the social valuations held about it. In this article, we will argue that, if we study social aging in the contemporary world, a novel phenomenon can be identified: the paradox of (...) aging in the digital era. If the social understanding of aging today is linked to unproductivity and obsolescence; then there is a possibility that, given the pace of change of digital technologies, we become obsolete at an early chronological and biological age, and therefore, feel old at a younger age. First, we will present the social dimension of aging based on Rowe and Kahn's model of successful aging. We will also show that their notion of social aging hardly considers structural aspects and weakens their approach. Second, departing from social aging in its structural sense, we will develop the paradox of aging in the digital era. On the one hand, we will explain how the institutionalization of aging has occurred in modern societies and how it is anchored in the concepts of obsolescence and productivity. On the other hand, we will state the kind of obsolescence that digitalization produces and argue that it can make cohorts of biologically and chronologically young individuals obsolete, and thus they would be personally and socially perceived as old. (shrink)

Cancer is a singular cellular state, the emergence of which destabilises the homeostasis reached through the evolution to multicellularity. We present the idea that the onset of the cellular disobedience to the metazoan functional and structural architecture, known as the cancer phenotype, is triggered by changes in the cell's external environment that occur with ageing: what ensues is a breach of the social contract of multicellular life characteristic of metazoans. By integrating old ideas with new evidence, we propose (...) that with ageing the environmental information that maintains a multicellular organisation is eroded, rewiring internal processes of the cell, and resulting in an internal shift towards an ancestral condition resulting in the pseudo‐multicellular cancer phenotype. Once that phenotype emerges, a new local social contract is built, different from the homeostatic one, leading to tumour formation and the foundation of a novel local ecosystem. (shrink)

The 2013 Rostock Symposium on Systems Biology and Bioinformatics in Aging Research was again dedicated to dissecting the aging process using in silico means. A particular focus was on ontologies, as these are a key technology to systematically integrate heterogeneous information about the aging process. Related topics were databases and data integration. Other talks tackled modeling issues and applications, the latter including talks focussed on marker development and cellular stress as well as on diseases, in particular (...) on diseases of kidney and skin. (shrink)

In this article, I consider ‘skin portraiture’: a mode of representation that privileges quasi-anonymous, fragmented, magnified and anatomized images of skin. I argue that this mode of representation permits a heightened awareness of embodied experiences such as reflexivity, empathy and relationality. Expanding understandings of difference through its engagement with haptic imagery and visuality, skin portraiture reorients the boundaries between ‘I’/‘not I’ and subject/object – often through touch – and challenges the cultural commitment to traditional notions of bodily autonomy. By doing (...) so, skin portraiture functions as an antagonistic form of portraiture; that is, as a kind of anti-portraiture that pushes the genre into an expanded visual field and, at times, beyond representation. Exploring the skin-as-technology metaphor, I show that bio art skin portraiture creates chimeric skins through tissue culturing practices, permitting bodies to become radically relational. Bio art skin portraits celebrate the genetic and cellular differences between bodies through a visible collapse of epidermal boundaries, which engenders a hyper-haptic mode of seeing beyond the subject and her or his skin. Analysing the bio art of Jalia Essaïdi, ORLAN and Julia Reodica, and drawing on the work of Laura Marks and Erin Manning, this article explores the skin-as-technology metaphor in order to offer the arts and humanities an innovative understanding of contemporary embodiment. (shrink)

Bone‐marrow mesenchymal stem cell (BM‐MSC) proliferation and lineage commitment are under the coordinated control of metabolism and epigenetics; the MSC niche contains low oxygen, which is an important determinant of the cellular metabolic state. In turn, metabolism drives stem cell fate decisions via alterations of the chromatin landscape. Due to the fundamental role of BM‐MSCs in the development of adipose tissue, bones and cartilage, age‐associated changes in metabolism and the epigenome perturb the balance between stem cell proliferation and differentiation (...) leading to stem cell depletion, fat accumulation and bone‐quality related diseases. Therefore, understanding the dynamics of the metabolism‐chromatin interplay is crucial for maintaining the stem cell pool and delaying the development and progression of ageing. This review summarizes the current knowledge on the role of metabolism in stem cell identity and highlights the impact of the metabolic inputs on the epigenome, with regards to stemness and pluripotency. (shrink)

Werner syndrome (WS) is an inherited disorder that produces somatic stunting, premature ageing and early onset of degenerative and neoplastic diseases. Cultured fibroblasts derived from subjects with WS are found to undergo premature replicative senescence and thus provide a cellular model system to study the disorder. Recently, several overexpressed gene sequences isolated from a WS fibroblast cDNA library have been shown to possess the capacity to inhibit DNA synthesis and disrupt many normal biochemical processes. Because a similar constellation of (...) genes is overexpressed in WS and senescent normal fibroblasts, these data suggest the existence of a common molecular genetic pathway for replicative senescence in both types of cell. We propose that the primary defect in WS is a mutation in a gene for a trans‐acting repressor protein that reduces its binding affinity for shared regulatory regions of several genes, including those that encode inhibitors of DNA synthesis (IDS). The mutant WS repressor triggers a sequence of premature expression of IDS and other genes, with resulting inhibition of DNA synthesis and early cellular senescence, events which occur much later in normal cells. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Alzheimer's Disease, Mild Cognitive Impairment, and the Biology of Intrinsic AgingThomas B. L. Kirkwood (bio)Keywordsaging, Alzheimer’s disease, genetic mutation, mild cognitive impairment, telomereThe article by Gaines and Whitehouse (2006) raises key questions about the uncertain relationship between (i) the intrinsic, "normal" aging process, and (ii) the clinicopathologic states represented by the labels of Alzheimer's disease (AD) and mild cognitive impairment (MCI). This short commentary offers a perspective on (...) this debate that is drawn from a consideration of underlying biological mechanisms.Because age is unquestionably the greatest single risk factor associated with AD and MCI, I begin by asking what we know about the intrinsic processes of aging. The central feature of current understanding of intrinsic aging is that it consists of the gradual, lifelong accumulation of a wide variety of molecular and cellular faults that begins very early in life and eventually leads to overt functional impairments resulting in age-related frailty, disability, and disease (Kirkwood 2005). This is an essentially bottom-up process. A strong consensus has emerged in recent years that there is no active program for aging and that there are no genetic factors that have evolved specifically to cause aging or age-related diseases. Unquestionably, there are genes that influence susceptibility to disease and even length of life, but these genes are genes for maintenance and repair functions, not for aging. It is the limitation in the past evolutionary pressure to invest in greater longevity than was required, within an environment where life was usually truncated by hazards such as starvation, injury, or infection, that means that our maintenance systems—good as they are—are insufficient to keep us going indefinitely. Added to this is the idea that there are probably also genes that program processes that are good for the young organism, but which may in later life have harmful effects. Processes like inflammation and apoptosis, which are seen to occur extensively in aged tissues, including brain, surely evolved to help cope with infection and cellular damage arising earlier in life. That they are called into play in aged tissues is a direct, but secondary, consequence of accumulated damage.With this general framework to understand the intrinsic biology of aging, let us now ask what we might expect a priori for the aging of an organ such [End Page 79] as the brain. Although we cannot pretend complete ignorance of how the brain actually does age, our enquiry can be based entirely on data from other organ systems, so we can develop our predictions about brain aging without prejudice.Aging begins very early during human development, faults accumulating from the first stages of embryonic development. Each time a cell divides, each of the daughter cells is likely to acquire a few new mutations. We know this from the estimates for the error rate in DNA replication and the size of the human genome. It is confirmed by direct evidence that at individual gene loci where mutations have been measured, mutation frequency increases with age (Morley 1998; Vijg 2000). In addition to replication errors, DNA is damaged on a daily basis to a very considerable degree by agents such as reactive oxygen species (free radicals), which are formed as byproducts of normal cellular metabolism. Although most of this damage is corrected by repair, the repair mechanisms themselves are not error free and additional mutations accumulate through this route. If a mutation is lethal to the cell, the cell dies and thus the mutation is eliminated. However, the majority of mutations are nonlethal, either because the mutation is recessive and the cell carries an intact gene copy on the other chromosome, because the gene is not currently required, or because the mutation produces only a delayed deleterious effect. Examples of genes that produce delayed deleterious effects include the genes responsible for familial AD. It is interesting to reflect that on statistical grounds alone, it is almost certain that each of us carries a randomly determined fraction of cells in our brains that bear amyloid precursor protein or presenilin mutations associated with AD. We also carry a heterogeneous array of random mutations that compromise essential cell maintenance functions. How many such... (shrink)

Macromolecular interactions play a central role in many biological processes. Protein‐protein interactions have mostly been studied by co‐immunoprecipitation, which cannot provide quantitative information on all possible molecular connections present in the complex. We will review a new approach that allows cellular proteins and biomolecular complexes to be studied in real‐time at the single‐molecule level. This technique is called single‐molecule pull‐down (SiMPull), because it integrates principles of conventional immunoprecipitation with the powerful single‐molecule fluorescence microscopy. SiMPull is used to count how (...) many of each protein is present in the physiological complexes found in cytosol and membranes. Concurrently, it serves as a single‐molecule biochemical tool to perform functional studies on the pulled‐down proteins. In this review, we will focus on the detailed methodology of SiMPull, its salient features and a wide range of biological applications in comparison with other biosensing tools. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Medicine-Based Values?Åge Wifstad (bio)KeywordsEthics committees, judgment, common moralityToulmin's DiagnosisIn his classical article with the unforgettable title "How medicine saved the life of ethics" (Toulmin 1982), Stephen Toulmin claims that medicine saved ethics by giving the philosophers a positive reality check through medical challenges: (1) Ethics in medicine is a serious topic, not just something to discuss at seminars. If, for example, both A and B need treatment and there (...) are only enough resources for one, the fundamental interests of these two people compete against each other. (2) In clinical medicine, the individual case might demand a different approach than that suggested by theory. Similarly, an ethicist who is confronted by a diversity of medical cases becomes aware of the fact that solutions drawn from ethical theory can be irrelevant in practice. (3) The moral philosopher has often focused on the individual and his or her universal commitments. The fact that ethical dilemmas can have deep roots in practical challenges and must be understood within a certain context has been "forgotten." (4) In clinically relevant ethics, it is important to find solutions that all involved parties find reasonable. This revitalizes central Aristotelian schools of thought on, for example, ethical judgment and situational understanding.Today, there is a common understanding that in both the education of doctors and in the implementation of medical knowledge and technology there needs to be ethical guidelines and control. Toulmin wants us to see that the background for this agreement is multifaceted. It was not just the ethicists who saved the doctors. The doctors helped the ethicists to escape their academic isolation.Ethics CommitteesThe establishment of ethics committees is perhaps the most interesting example of this. Here it is especially clear how ethical judgment establishes a basis for decision making: Each case presented to an ethics committee is special because one cannot reference decisions made in similar cases. At the same time, we are expected to handle similar cases equally. Consideration of the concrete, individual case must be balanced with the principle of similar treatment. Second, as a committee member, one must interpret and respect ethical principles that cannot be easily defined. Every principle must be interpreted and implemented within a specific and concrete context. Third, one must consider the law, but seen isolated, the implications of relevant rules can be difficult to determine. Fourth, the status of principles and rules are open for interpretation. The most important example of this is the Declaration of Helsinki, which was established through cooperation between the worlds' doctors unions. The strength and end result of such a document can be discussed. Fifth, multiple but partly conflicting juridical and ethical considerations can be [End Page 179] relevant at the same time. An example: Decisions about confidentiality can prevent data gathering that is crucial in ensuring that a research project is scientifically acceptable. Two important ethical considerations are then put up against one another. As a sixth and final point, it can be mentioned that the ethics committee is expected to make a qualitative, scientific judgment. But what kind of quality judgment and how detailed it should be is up for discussion.Two Definitions of Ethical JudgmentThe fact that the committee must base their holistic decision on ethical judgment means that the committee, in an important sense of the word, stands freely: It can be difficult to refer to specific ethical rules or laws when making an external review of the committee's decision. Unless the committee has clearly not followed known principles and rules, then the committee is able to confront criticism by replying that the decision is based on holistic considerations, where many views have been taken into account. In this way, the usage of ethical judgment makes sure that the committee has freedom to act. The catch here is that the committee's responsibility becomes even more obvious. One cannot simply say that the decision is made based on rules and principles formulated by others, such as the state. The committee must, as a unit, be able to defend their decision.The complexity of the work of the committee can, however, make it more tempting to think about ethics in... (shrink)

Combining information from two or possibly several blocks of data is gaining increased attention and importance in several areas of science and industry. Typical examples can be found in chemistry, spectroscopy, metabolomics, genomics, systems biology and sensory science. Many methods and procedures have been proposed and used in practice. The area goes under different names: data integration, data fusion, multiblock analyses, multiset analyses and a few more. This book is an attempt to give an up-to-date treatment of the most used (...) and important methods within an important branch of the area; namely methods based on so-called components or latent variables. These methods have already obtained an enormous attention in for instance chemometrics, bioinformatics, machine learning and sensometrics and have proved to be important both for prediction and interpretation. The book is primarily a description of methodologies, but most of the methods will be illustrated by examples from the above-mentioned areas. The book is written such that both users of the methods as well as method developers will hopefully find sections of interest. In the end of the book there is a description of a software package developed particularly for the book. This package is freely available in R and covers many of the methods discussed. To distinguish the different type of methods from each other, the book is divided into five parts. Part I is introduction and preliminary concepts. Part II is the core of the book containing the main unsupervised and supervised methods. Part III deals with more complex structures and, finally, Part IV discusses alternative unsupervised and supervised methods. The book ends with Part V discussing the available software. Our recommendation for reading the book are as follows. A minimum read of the book would involve chapters 1, 2, 3, 5 and 7. Chapters 4, 6 and 8 are more specialized and chapters 9 and 10 contain methods we think are more advanced or less obvious to use. We feel privileged to have so many friendly colleagues who were willing to spend their time on helping us to improve the book by reading separate chapters. We would like to express our thanks to: Rasmus Bro, Margriet Hendriks, Ulf Indahl, Henk Kiers, Ingrid MaÌ⁽ge, Federico Marini, AÌ⁽smund Rinnan, Rosaria Romano, Lars Erik Solberg, Marieke Timmerman, Oliver Tomic, Johan Westerhuis and Barry Wise. Of course, the correctness of the final text is fully our responsibility! (shrink)

A certain kind of externalism—"the view from nowhere"—lies at the heart of evidence-based medicine (EBM). As a consequence, the individual case glides out of focus. However, to judge to what extent external knowledge is applicable to an individual case, the clinician has to rely on some sort of knowledge of the case at hand. The article focuses on the tension between the externalism of EBM and the "internal evidence" one has to presuppose when making clinical judgments.