This paper indicates how continental philosophy may contribute to a diagnostics of contemporary life sciences research, as part of a “diagnostics of the present” . First, I describe (as a “practicing” philosopher) various options for an oblique (or symptomatic) reading of emerging scientific discourse, bent on uncovering the basic “philosophemes” of science . Subsequently, I outline a number of radical transformations occurring both at the object-pole and at the subject-pole of the current knowledge relationship, namely the technification of the object and the anonymisation or collectivisation of the subject, under the sway of automation, ICT and big machines. Finally, I further elaborate the specificity of the oblique perspective with the help of Lacan’s theorem of the four discourses. Philosophical reflections on contemporary life sciences concur neither with a Master’s discourse , nor with university discourse , nor with what Lacan refers to as hysterical discourse , but rather with the discourse of the analyst, listening with evenly-poised attention to the scientific files in order to bring to the fore the cupido sciendi  which both inspires and disrupts contemporary life sciences discourse. It is not sufficiently clear how the main objectives of the research can be reached” For continental philosophers working in interdisciplinary environments and committed to assessing the philosophical and societal dimensions of contemporary technoscience, the methodology section of grant proposals may pose a challenge. How to explain  what continental philosophers studying technoscience actually do? Although standard phrases  are available for such occasions, compared to the methodologies of the social sciences, or even bioethics, the tools and methods for this type of work seem much less clearly defined. To what extent and in what way may continental philosophical inquiry be considered “applicable” or even “replicable”, for instance?Gerede, as Heidegger , the focus is rather on the subject-pole: the researcher or research team, the interaction between experimenters and their targets, “observing the observer”, as Bachelard , philosophy reflects on how this object is allowed to emerge  is oriented towards the object under study, the “reflected” direction  is typical for philosophy. The distinction goes back to medieval scholasticism. Thomas Aquinas already stated that, whereas human understanding is initially directed towards external reality, critical reflection on human understanding requires a change of perspective, an intentio obliqua . Such terms are closely connected with machinery, with big computers and high-throughput sequencing contrivances. They are the textual by-products of high-tech equipment, while their research targets are represented by a second series of signifiers , ending with the suffix ‘–ome’ . New labels containing an –ome or –omics component continue to show up, as new signifiers  make their appearance. This grammar of –omes and –omics plays a performative role, rearranging rather than merely describing the evolving fields in question. Intriguing recent examples of –omics neologisms include the “unknome”  been able to identify); the “environome” or “exposome” ; and last but not least the “complexome” (i.e. the complex interactions between some of the –omes listed above).Let me elucidate this with the help of some examples, taken from my own experience as a “practicing” philosopher. Since the 1990s, scientific discourse has produced a whole series of ‘-omics target is studied by an unfolding research field called “complexomics”, a term which I encountered for the first time during a lecture on protons in mitochondrial research, so that my evenly-poised attention gave way to a Socratic stance. What does “complexomics” mean? Why was it coined? On the one hand, this signifier seems to underscore the bewildering complexity of life, allegedly beyond the grasp even of large-scale research consortia, notwithstanding the high-tech equipment (such as next-generation sequencing machines) and substantial funding arrangements available to them. But at the same time the label conveys the opposite idea, namely that (in the terabyte age) even the most complex interactions can be opened-up through digital analysis. In other words: the term complexomics conveys an attitude of modesty compensated by hubris. It is a “symptom”, a symptomatic phrase reflecting a basic ambivalence by both emphasising and obfuscating the complexities of living systems.The latter –gnotobiology became a key signifier in contemporary microbiome research.gnoto- comes from the Greek word γνῶσις (=knowledge). Gnotobiotic animals can only exist under gnotobiotic conditions: they spend their lives in germ-free bubbles inside laboratories, unable to survive in the open. In other words they are laboratory artefacts or bio-objects, units for experimental study and products of the “obsession” to eliminate microorganisms from human existence (Gilbert & Neufeld homunculus) produced in the laboratory of Goethe’s Faust  likewise spent his life in a bubble, a gnotobiotic crystal vial  must be validated by further analysis, but the tension between complexity and reductionism, or between purification and control, may claim an epistemological urgency which, I would argue, transcends these (more or less impromptu) examples. Thus, philosophers may overcome the concern already brought forward by Michel Serres , namely Complexomics and gnotobiology are symptoms of a more basic discursive ambivalence, as we have argued. Although scientific research is allegedly awed by the complexities of living systems, it is also spurred on by the idea that the know-how and devices of technoscience have evolved sufficiently for life to become fully controllable and technologically reproducible. Terms such as complexomics and gnotobiology seem worthwhile to explore in detail because they provide a window into basic desires and tensions fuelling current life sciences discourse. Notably, they may tell us something about how basic concepts such as ‘life’, ‘nature’, ‘truth’ and ‘technology’ are envisioned and enframed in evolving research practices. As discursive events, neologisms such as complexomics may put us on the track of the guiding convictions at work in contemporary scientific discourse. Building on Hegel, but also on Bachelard, I will refer to these basic signifiers  as the philosophemes of scientific discourse , the prefix complex- rather refers to the complex interactions and emerging properties of living systems. In other words, complexomics terminologically combines a reductionist view of life  with a holistic view (life as an evolving synthesis of intimately entangled molecular processes). In other words, the term sublates  two  tendencies, namely reductionism  and holism (synthesis). It merges a focus on rewriting the barcodes of life with a focus on managing complexity, so that contemporary life sciences not only provide a high resolution understanding of life, but also allow the scientific gaze to leap towards a higher level complexity: beyond genetic determinism.The signifier complexomics provides access into latent answers to some of the basic questions addressed in life sciences laboratories of today, such as: What is nature? What is life? What is technology? It reflects (in a highly condensed and symptomatic manner) basic conceptual categories. The term complexomics is symptomatic for how life sciences research is currently conducted. Hegel refers to these basic categories (these basic answers to questions such as What is nature? What is life? What is technology? etc.) as philosophemes. Moreover, all revolutions, in science no less than in world history, he argues, come about when the spirit (Geist) changes its basic categories.complexomics may be regarded as a symptom of a basic zeitgeist shift on the level of the philosophemes, a sublation away from genetic determinism (which focusses excessively on the explanatory power of biomolecular particles) towards complexity . According to Hegel, philosophy’s vocation is to bring these basic categories to the fore, to discern and critically assess them. In other words, a philosophical reading entails a focus on symptomatic discursive events, reflecting basic shifts, tensions or inconsistencies on the level of the philosophemes: a symptomatic reading of the discourses produced by science.In other words, the signifier philosophemes, the basic signifiers of scientific inquiry. During periods of transformation and disruption, such as we are witnessing today, exemplified by the emergence of big science and the advent of the terabyte age, the basic signifiers are under siege and in a state of flux, amenable to change. Genetic determinism  entails the conviction that the protein-coding genes on our genome are the program (in Hegelian terms: the “idea”) which realises itself in the life of the organism. This philosopheme , seeing genomes as programs and genes as the ultimate causal determinants of organismal phenomena, is now challenged and complemented by post-determinist approaches which emphasise complexity. This transition entails a shift of focus from linear causal relationships to emergent properties of complex systems, concurrent with similar shifts in other research areas and realms of culture. Philosophical intellectual labour consists in bringing to the fore , for instance, he claims that contemporary science evidently developed an unprecedented sway over reality, acquiring a tremendous impact on how reality presents itself to us  keeps escaping us and is bound to remain something other, something Real: nature as that which continues to withdraw itself, which refuses to become completely identifiable and compatible with the techno-scientific way of making reality visible; nature as that which flashes up, in a recalcitrant manner, in the folds and margins of the scientific representation of the world. Furthermore, are we humans really in control? According to Heidegger, another force seems to determine the whole process: technology as such, expanding and proliferating, dragging research along. Something other than human inquisitiveness seems to hold sway over this endeavour. According to Heidegger, this hidden power will remain concealed from us if we fail to really question the fundamental terms at work in contemporary, technology-driven science, − first and foremost: the term nature.termino-logical ambiance, which blinds us to other possible answers concerning the question What is nature? The conception of nature is the “philosopheme of philosophemes”, the basic metaphysical conviction guiding scientific research, affecting experimental and discursive practices as an epistemological pandemic, pre-structuring the way in which derivative terms and concepts are defined.The view of nature as an immense outdoors in vivo laboratory discloses nature in an outspokenly technical way. As long as we merely adopt this latent view, rather than questioning it, it will pervade scientific discourse up to the point of becoming self-evident and seemingly unquestionable, so that not only science but also philosophy of science will fall victim to its sway. Researchers will be put to work in research laboratories to confirm its truth. It is only by questioning the grounding dominating terms, the philosophemes, via an oblique perspective, that we can distance ourselves from this obfuscating complexome), discursive phenomena associated with the subject-pole may likewise arouse attention, such as the current endemic focus on (or even obsession with) “misconduct” and “integrity” in research. A possible explanation for the current prevalence of such labels could be to regard them as symptomatic compensations in response to the decentralisation, anonymisation and collectivisation of the scientific “subject”, of the researchers themselves. The focus on misconduct could reflect growing tensions between traditional research ethics  and the emerging trend towards large-scale research consortia, which includes automation and multiple authorship, resulting in a marginalisation of the scientific individual  and critically assess the basic philosophemes  of contemporary scientific discourse. Although they often remain inarticulate, they provide pervasive guidance. Building on Lacan  and its guiding premises (S1) can be represented as: S2/S1, so that normal scientific discourse  builds on, but is at the same time literally barred from explicitly addressing its basic metaphysical premises (S1).The key objective of the ex cathedra fashion. In that case, S1 is posited at the top-side of the bar, resulting in what Jacques Lacan (Aristoteles dixit). The Master is regarded as infallible, his claims and premises provide guidance to readers (students spelling his oeuvre) and the Master’s name serves as index of truth. Any uncertainties or doubts on the part of the Master, which must have troubled him during his life-time as a practicing philosopher , are disavowed and suppressed, that is: placed beneath the bar: S1/$. The discourse of the Master addresses a scholastic readership. In contemporary philosophy, this role is conducted by author studies experts, the custodian of the Master’s oeuvre (S2). Such experts are put to work, as discursive servants and servile subjects, to explain and defend the integrity and authority of the Master’s corpus (body of writing), resulting in a particular kind of expertise or expert discourse: S2 (which refers both to the discourse as such and to the subjects who generate it). Such university experts focus their attention on the cardinal signifiers of the Master’s oeuvre, which (due to their opacity and intricacy) often prove a source of frustration, but of intellectual jouissance as well. Scholars may be drawn towards one particular ungraspable, unfathomable, “impossible” concept, functioning as the intractable, inexorable “object a” of the Master’s discourse, as Lacan phrases it. Aristotle’s concept of the Divine Intellect which thinks itself, for instance, may stand as an example: God conceived as “thinking thinking thinking” , while a more mundane example would be the causa finalis . Such “impossible” key concepts result in a plethora of books and papers and offer windows into the oeuvre as a whole. This combination of frustration and jouissance, circling around the object a, and resulting in a particular type of  discourse, is regarded as the by-product of the Master’s discourse.In principle these basic philosophemes and imperatives may be presented in a top-down, apodictic, authoritative, 1, S2, $ and a), Lacan distinguishes four basic types of discourse. The four basic symbols may be inserted as “variables”  in four positions in a rotating, revolving, quadruped scheme:With the help of four key symbols  may have fallen victim in real life, are decidedly left out of the picture, suppressed beneath the bar (S1/$). Masters address disciples  and produce a particular type of discourse, immersed in contemplation, metaphysics and basic geometry. Plato and Aristotle may count as paradigmatic examples of Master-thinkers or gentlemen-philosophers. They contemplate nature as a harmonious spherical whole: a κόσμος, and hardly concern themselves with concrete interactions with real nature (Zwart The Master (in the upper-left position of the agent) is an acknowledged, allegedly infallible, authoritative voice, as we have seen. Uncertainties, disappointments and doubts to which the Master as a real, craving individual (re Zwart . They de1) contrasts with the discourse of the servant, whose knowledge is basically know-how  will by subverted by the practical know-how of the servant (S2), so that in the end S2 will come to occupy (usurp) the upper-left position as agent. The power of the Master is subverted (S2/S1), the Master’s voice suppressed and the scheme takes a quarter turn to the left.But in the end, the practical knowledge of the servants will prove much more powerful and effective compared to the lofty contemplations of the Masters who, instead of really interacting with and transforming nature, rather develop a worldview, i.e. an imaginary vision of nature . Eventually, the supremacy of the Master , while the meta-physical pontifications of the Master becomes a superfluous burden, so that the power relationship becomes subverted, and a new type of discourse emerges, to which Lacan refers as the university discourse:But the emancipation of the servants does not stop there. Rather, instead of relying on the signifiers coined by the Master to understand nature, the servants will explore and interact with nature more directly. Increasingly, the Master’s apodictic views are suppressed (pushed beneath the bar), as servants rely on hands-on, practical interactions with nature, developing powerful tools to manipulate and manage natural objects more effectively: the birth of the experimental method. Exegesis increasingly gives way to experimental work (manipulating and quantifying nature). Via skills and know-how, the servants assume mastery over the situation. They become scientists, scientific agents (Sa). Rather than studying living nature as a whole, a κόσμος, nature becomes condensed and compressed into a particularly intriguing but highly demanding entity (a). Although initially the scientists (S2) seem in control of the situation, eventually the unfathomable object may prove a demanding, addictive, toxic lure. Instead of the expert being in control (manipulating the object) it is the other way around: the object becomes the active force, drawing the researcher towards it.Now the Master no longer addresses the Servant explicitly. The Master’s imperatives are disavowed, repressed and pushed beneath the bar. The former servants have emancipated themselves: they have become scientific experts, addressing nature on their own accord. They focus their attention on a particular object, however, a particular problem or process, a particular molecule or model organism: a particular object of choice ($). Rather than experiencing gratification and success, scientific subjects will often find themselves hopelessly chained to and drained by their inexorable object a.Take for example John Sulston’s research on the (hermaphrodite) nematode worm C-Elegans. In his auto-biography he explains how he “first met the worm” (Sulston & Ferry 1 as agent). The former servants acquired agency via experimental, hands-on, technology-based research , actively interacting with their research objects. Scientists develop increasingly effective lab tools to generate robust knowledge and refurbish nature. The contemplating gentleman is dethroned, and metaphysics no longer provides apodictic guidance. Metaphysics is marginalised, becomes a research field in statu moriendi, and yet it is still there, occupying the position of the  truth of scientific discourse (S1 below the bar).This dialectical schema may also help to understand the changing relationships between philosophy and science. Philosophy no longer occupies the position of the Master, as it did during previous epochs, when metaphysics was still in vogue . By taking up this challenge, a new dawn (‘Morgenröte’) may set in. Philosophers may question and critically assess the latent but guiding philosophemes (S1) of science. Rather than being delisted from the agenda, the metaphysical question “What is nature?” proves inescapable. We are both drawn to and repelled by this question: difficult to answer, but impossible not to ask (Hegel 2) it not a purely technical or empirical endeavor, but entails a profound, yet tacit understanding of nature (S1), an inspiring truth, which can and should be brought to the fore and critically examined by philosophy. Science is adrift, moreover. We are in the middle of a scientific revolution, so that the philosophemes of science are becoming fundamentally questionable, are being drastically redefined (S1 → S1).In the Introduction to his Philosophy of Nature, Hegel /1970 depsk Hegel /1970. We2) as agents (upper-left position) focus their attention on various kinds of objects as targets of their cupido sciendi, their will to know. Laboratory objects  function as the intractable entity (object a in the upper-right position) which drains their intellectual energy, time and resources, but continues to escape them, for instance because initial results cannot be replicated. In normal science, the laboratory expert (S2) as agent seems firmly in control, but in real laboratory life, scientists may fall victim to the situation, become trapped by the inexorable object a, on which a whole life-time may be wasted. Due to frustrations awaiting them, scientists become tormented subjects ($ in the lower-right position), with discontent and doubt as by-products of experimental research.Experimental researchers , the oblique perspective involves hard labour, with philosophers working their way through the archives, the multiple and interminable discourses of science. Philosophy becomes research, but in its own (oblique) way. The focus is neither on the oeuvre of the Master (as in author studies), nor on developing a specific type of expertise , but rather on the ways in which life science research is enacted and life sciences discourse is framed.2) relinquish the ideal of becoming genuine philosophers themselves , but rather settle for the more moderate joys of the disciple, guarding the Master’s treasures against vulgarisation.Some instances of philosophical inquiry may reflect what Lacan refers to as university discourse, namely when philosophers aspire to develop specialized expert knowledge, as ethical experts for instance, applying basic sets of principles or argumentative skills to cases. Such experts serve as ethical engineers. Mainstream applied bioethics reflects the university mode of discourse when ethical expertise basically consists in a particular kind of literacy and fluency concerning a particular ethical grammar, developed for analysing and addressing moral dilemmas in preformatted ways. Other philosophers may become the custodians of an oeuvre, of the intellectual legacy of a deceased author, which threatens to become a dead letter (discursive “litter” as it were) and therefore has to be reinterpreted, reanimated. In this discursive mode, the experts  emphatically takes the floor as agent, raising a voice of societal protest. This type of discourse figures prominently in societal debates on science and technology, where philosophers may become activists, challenging the voice of authority, the authoritative Other as the recipient of the message (S1 in the upper-right position):Philosophers may also opt for what Lacan refers to as the Critique of Cynical Reason, Peter Sloterdijk , what kind of uneasiness or desire is at work beneath the bar, pointing beyond the issue at hand perhaps, towards a more basic discontent in science, or in civilisation even? What do these activists really want? By asking such questions, philosophers have already entered a different type of discourse, namely the discourse of the analyst.An oblique perspective, however, confronted with the (often boisterous and passionate) interactions between 1 as agent), as experts (in author studies or applied ethics: S2 as agent), or as activist ($ as agent), a fourth type of discourse is more recommendable and concurrent with the oblique perspective, namely the discourse of the analyst, a paradoxical term, since  the analyst is the one who does not speak, but rather listens, with evenly-poised attention. For this type of discourse to work, the philosopher’s expertise and knowledge (S2) must be suspended, placed beneath the bar (lower-right position), at least temporarily: a position known as learned ignorance (docta ignorantia). But precisely because of this intellectual self-constraint, this willingness to bracket established philosophical views concerning life, science, nature and technology (ἐποχή), the floor is open to other voices, to experiences of practicing researchers, driven by a scientific will to know (their cupido sciendi). Thus, the ultimate target of desire, referred to by Lacan as the inexorable object a, comes into view, occupying the position of agent: triggering, commanding and frustrating the scientists’ interminable work. This object challenges the scientists’ prowess and arouses their desire, but continues to escape them, so that they emerge as tormented subjects ($ in the upper-right position).Although philosophers may play various roles and may function as Master  into philosophical laboratories, where the philosophemes of contemporary discourse can be articulated and examined:a? Why do they waste the most fruitful years of their life on this alluring entity, why do they consider it the panacea or missing link? Oblique philosophy basically entails embedded dialogue, however and philosophical interpretations and assessments are only valid and effective insofar as they provoke further deliberations and reflections on the part of the scientific subjects themselves .Psychoanalysis is not a science, but a discursive practice prompting self-reflection. What is it that researchers find so fascinating about their object 1 in the lower-right position), as happened with authors such as Freud and Lacan, so that their followers fall into the trap of posing as servile, apologetic “experts” of an oeuvre, rather than as active philosophers themselves, oriented towards assessing and questioning the emerging discourses of technoscience from an oblique perspective. But in the current era, where philosophical reflection has become a collective and distributed endeavour, such a scenario has become less likely.A risk involved in this type of discourse is that, in the end, the analyst is mistaken for a Master, the author of an opaque, authoritative and apodictic discourse, giving rise to discursive servitude  have already spoken. The philosopher’s intellectual labour consists in reading and listening with evenly-poised attention to how others have already responded to the situation. Rather than opting for expertise, activism or pontification, oblique philosophers point to discursive symptoms, ambiguities, blind spots and contradictions that reflect the philosophemes adrift. The starting point is that we no longer know what nature, life, truth, technology, etc. really is. Such issues emerge in the context of a critical dialogue, a living oblique laboratory, a mutual learning exercise.This does not imply that philosophers should engage in the discourse of the analyst continuously. In the unfolding process they may switch to other types of discourse, opt for other discursive modes, temporarily acting as author studies expert, for instance or ethics expert, or social activist, but the discourse of the analyst, concurring with the oblique perspective, allows us to discern the strengths and weaknesses, opportunities and traps of these discursive options. As Hegel phrased it, rather than being the first to speak (as agent), philosophers spread their wings at dusk, as owls of Minerva, when other types of discourse have already thrived, when other agents (S2) to the philosophemes that actually guide and structure it (S1), but also to the tormented subjects ($) who aspire to adhere to normalised discourse and its imperatives, but experience challenging obstacles and inhibitions in their interactions with their object of desire (a). Such researchers may even be tempted to commit “misconduct” in order to maintain a semblance of normality and performativity. In order to detect and disclose the philosophemes (S1), specific signifiers are singled out as especially relevant. Building on the etymology of λόγος (Heidegger lectio) tends to be selective, so that lectio becomes selectio and attention becomes fixed on specific, revelatory terms, reflecting in a symptomatic manner the shifting philosophemes. But it is via the discourse of the  scientific subjects that these philosophemes are disclosed (S2 → $ → S1).Thus, an oblique (symptomatic) reading of contemporary life sciences (as an interminable flow of university discourse) will focus on the symptoms that allow philosophical intentionality to shift from scientific discourse as such  and the speech acts of challenged, tormented scientists ($), the oblique perspective exposes the philosophemes of science (S1), i.e. the imperatives that guide researchers towards the object of their cupido sciendi (a). In Lacanian algebra normal scientific discourse can be represented as (S2 ◊ a), where S2 refers to the discourse of university experts (as agents) while a represents the target of their will to know, and the lozenge or poinçon (◊) stands for laboratory contrivances, for instance optic devices such microscopes, enabling experimenters to zoom out (<) or in (>), bringing the object into view while keeping their distance. This suggests that the scientific agent is firmly in control, but in reality researchers may fall victim to the situation and revert to the position of the tormented, desiring subject (S2 → $) while the allegedly normalised object may prove an ungraspable, inexorable, disturbing factor, putting the subject out of balance, so that the standard formula (S2 ◊ a) actually is a cover-up, a façade for what really should be represented as ($ ◊ a), − a Lacanian equation known as the matheme of desire.Via established scientific discourse , a tendency which is reinforced by automation and high-tech research contrivances (represented by the lozenge), but also by the use of technical terms, standardised formats and formulaic phrases in academic writing (S2). Research has become large-scale teamwork conducted by consortia employing big machines and resulting in multiple author output, where hundreds of researchers may be listed as author, in alphabetic order. Thus, the technification and standardisation of the object is paralleled by technical forms of authorship  or quality assessment (of research groups) or as shorthand for theorems, syndromes or instruments (eponymy). Authorship attribution is increasingly becoming a device for facilitating the production, storage, circulation and retrieval of texts (preferably in electronic formats) or for detecting and penalising misconduct.The basic tendency in scientific research is towards Foucault /1994, whDawn of Day . To single out one particular author , in the context of Nobel Prize award procedures for instance, seems increasingly unfeasible and unfair  but rather, via him, to reason as such.ir Zwart .Thus, the subject-pole of the knowledge dynamics is exposed to similar processes of purification and standardisation as the object-pole. The subject is effectively decentred, depersonalised and emptied of its ideological, subjective content, through training and socialisation, but also via automation and laboratory equipment. The subject is cleansed of its sociocultural heritage of ideas and associations concerning ‘nature’, ‘life’, ‘embodiment’ etc. (Bachelard 1). They are tormented by desire, mistrusted as potential frauds and hyper-actively obsessed with their research object of choice ($ ◊ a), filtering out anything else as noise. They become introverts, stubbornly refusing to displace their intentionality to something else, or to be replaced themselves (as this would imply separation from their laboratory object). This may raise intriguing questions, such as: why has this particular object  become such an object of desire, such a fetish: the sole and life-long target of the scientist’s cupido sciendi? By addressing such questions, however, we have already opted for an oblique style of reading, a change of perspective and the focus of attention reverts from ‘context of justification’ to ‘context of discovery’, analysing concrete subjects who, in concrete research settings, face demanding objects (a). Thus, the oblique perspective develops an interest in science biographies or autobiographies, “case histories” which report in detail how researchers not only manipulate and purify their object, but also are addressed and edified (as well as tormented and frustrated) by these demanding entities.Yet, this can never be fully achieved, due to the recalcitrance of the research targets involved. Individuals will eventually prove unable to completely live up to the methodological imperatives proclaimed by the demanding superego of Big Science (SLife Story (Jackson 2) is actually a desiring subject ($), confronted with a demanding object ($ ◊ a). The oblique perspective concurs with the discourse of the analyst, focussing on the object a (in the upper-left position of agent) as something which actively addresses and enforces itself upon the subject (in the upper-left position as recipient).An intriguing example is DNA-researcher Maurice Wilkins /2005 who Jackson , based o Jackson . In othe$) and their objects of desire (a). And instead of opting for a top-down, metaphysical approach, philosophers read and reread the scientific files, the avalanche of papers produced by laboratories worldwide, with evenly-poised attention, from a tilted, oblique perspective, using revelatory signifiers  as discursive symptoms, probing them with the help of a diagnostic reflex hammer, a plessor, a stethoscope, a magnifying-glass.While continental philosophers often act as custodians of a Master’s discourse (as experts of an oeuvre), the oblique perspective entails a different role, analysing the dialectical interaction between tormented researchers (a” comes into view ($ ◊ a). In normal science, researchers prefer to work with normalised, standardised objects of research . Although they once were challenging targets, they are now domesticated and transformed into a research tool, a fully controllable laboratory device. Research targets such as gnotobiotic model organisms become reproducible units within techno-scientific arrangements. Model organisms (from C. elegans down to bacteriophages) are products of laboratory settings. And “-omics” entities  are likewise intimately connected with technology. They are hyper-technical “objects” and can only exist in a highly specialised technological ambiance. Yet, in the folds and margins of normalised and established research practices, unexpected findings may point to the presence of disruptive factors: the intrusion of a treacherous object a, a factor X, inciting suspicion and evoking desire. The oblique perspective implies that the object-pole comes into view via the discourse of the scientific expert. It is not our decision to study genomes, amino acids or synthetic cells. Rather, the intentionality of the oblique perspective is determined by the scientific research practices under study. Their objects  become our objects as well, approaching them from an obliquely perspective.It is via discourse that the scientific object comes into focus. In post-phenomenology Verbeek /2005 and


Traumatic life events (TLEs) have been associated with multiple psychiatric diagnoses, including anxiety disorders, major depression, PTSD, and psychosis. To advance our understanding of the complex interactions between forms of adversity as they manifest across the lifespan, psychosis, and symptom content, we undertook a mixed-methods investigation of TLEs and psychosis. Our research explored the association between cumulative exposures, type of TLE, and proximity to the traumatic event and psychosis; the association between TLEs and clinical symptomology including specific types of delusions and/or hallucinations; and how qualitative data further inform understanding of complex relationships and patterns of past trauma and symptoms as they unfold over time. There were a total of 97 participants in the quantitative study sample, 51 participants with present state psychosis and 46 non-clinical. There were a total of 34 qualitative study participants, all of whom were experiencing psychosis. The quantitative analysis showed that when comparing persons with psychosis to the non-clinical group, there were no group differences in the overall total score of TLEs. However, there was a significant difference in cumulative TLEs that “Happened,” demonstrating that as the number of TLEs increased, the likelihood of clinical psychosis also increased. We also found a correlation between lifetime cumulative TLEs that “Happened” and PANSS five-factor analysis: positive, excitement, depression, thought disorder, activation, and paranoia scores. The qualitative analysis further built on these finding by providing rich narratives regarding the timing of trauma-related onset, relationships between trauma and both trauma-related and religious–spiritual content, and trauma and hallucinatory modality. Analysis of participant narratives suggests the central role of localized cultural and sociopolitical influences on onset, phenomenology, and coping and contributes to a growing literature calling for strengths-based, client-driven approaches to working with distressing voices and beliefs that centers the exploration of the personal and social meaning of such experiences including links to life narratives. Findings also underscore the clinical importance of trauma assessment and trauma-informed care. Traumatic life events (TLEs) have been associated with multiple psychiatric diagnoses, including anxiety disorders, major depression, PTSD, and psychosis –3. In a In addition to research linking trauma to psychosis, multiple studies have examined the associations between traumatic experiences and specific symptom domains, including auditory hallucinations (voices), paranoia and delusions , 7, as wIn spite of a large body of research linking TLEs to psychosis and specific symptom domains, mechanisms of action and the interrelationships between multiple social and environmental risk factors are still not well understood , 21–23. While a number of studies have investigated the role of migration, far fewer have addressed the relationship between race, non-migration-related racism, trauma, and psychosis  and foun(1)Is there an association between cumulative exposure, type of TLE, proximity to the traumatic event, and psychosis?(2)Is there an association between TLEs and clinical symptomology including specific types of delusions and/or hallucinations and in what ways are trauma and past adversity reflected in the form and content of participant’s symptoms?(3)How does qualitative data further inform our understanding of the complex relationships and patterns of past trauma and adversity and symptoms as they unfold over time?To advance our understanding of the complex interactions between forms of adversity as they manifest across the lifespan, psychosis, and symptom content, we undertook a mixed-methods investigation of TLEs and psychosis. Coding and analysis of a separate qualitative sample followed initial analyses of a quantitative sample. A majority of participants were African-Americans, and the qualitative analyses explicitly focused on the experiences of African-Americans participants. Our research questions were as follows:n = 97) focuses on quantitative data from a sample of individuals with and without psychotic disorders recruited from a large urban university medical center, private referrals, and community treatment facilities from January 2013 through January 2015 in Chicago, IL, USA. Participants were recruited using flyers and direct communication with clinical staff regarding study information from a convenience sample. Participants in the quantitative arm of the study were administered standardized measures that are described in detail in Section “This study reports the analyses from a novel mixed-methods investigation into the intercept of TLEs and psychosis. The first set of analyses (n = 34) focuses on a set of individual interviews (n = 10) and group interviews  conducted with individuals reporting experiences of psychosis. The majority of these participants were recruited from a public mental health agency, which serves individuals with serious mental illness and significant, established disability also located in Chicago, Illinois during the same time period. Researchers queried participants about the circumstances surrounding the onset of psychosis; their understanding of the causes and origins of their experiences; and the content, development, and phenomenology of positive symptoms, including the characterological qualities of any voices.The second set of analyses  persons diagnosed with schizophrenia and 16 (17%) diagnosed with bipolar disorder with psychotic features, per consensus diagnosis. Consensus diagnosis was determined by reviewing all research data and collateral information by the study personnel that included an Attending Physician, Psychologists, and a Mental Health Nurse Practitioner. Inclusion criteria for the study included participants between the ages of 21 and 60. The clinical sample must have met criteria for schizophrenia or bipolar disorder/psychosis. A group of 46 (47%) non-clinical controls, with no history of DSM-IV-TR Axis 1 diagnosis per the SCID, were also recruited. Exclusion criteria for both groups included current substance dependence, seizure disorders, and neurological conditions. All participants, clinical and non-clinical, were reimbursed equally for their time and transportation. Demographic characteristics for the sample , subthreshold (“2”), and threshold or present (“3”). The SCID includes an assessment of forms of delusions  and hallucinations  .The Life Events Checklist consists of 17 items that measure exposure to various TLEs . The itevia data reduction strategies guided by prior empirical studies of symptom domains assessed by the PANSS  to seven (extreme symptom severity). Analysis was conducted he PANSS . Scores he PANSS , 39. Coepost hoc tests were used to identify significant pairwise group differences. We conducted a binary logistic regression to examine the probability that cumulative TLEs increased the likelihood of psychosis. An independent sample t-test was conducted to compare the association of TLEs and aspects of psychosis. Bivariate spearman correlations were conducted to determine separate associations between TLEs and clinical symptomology with particular attention to forms of delusions and hallucinations between persons with psychosis and the non-clinical group. All quantitative data were analyzed using SPSS software version 24.Demographic data were analyzed using chi-square tests and analyses of variance (ANOVA). For ANOVAs that yielded significant results , Newman–Keuls a priori codes were generated following the associations identified as significant and/or unexplained in the quantitative analyses. For example, we explicitly sought to identify and unpack cumulative associations between diverse traumatic events and broader adversity, a topic that the trauma measure utilized in the quantitative study could not address. We also coded the content of participant’s symptoms, looking for associations between past adversity, trauma, and the themes of voices and/or unusual beliefs. Transcripts were independently coded at different time points to establish reliability.For the qualitative component of the project, 2 = 15.38, df = 6, p < 0.02). In total, just over three quarters (77%) of clinical participants were African-American. We also found a significant difference in age across diagnostic groups, showing that participants with bipolar/psychosis were older than participants with schizophrenia and non-clinical controls . There was no significant sex difference between diagnostic groups or the non-clinical group.Demographic characteristics of the quantitative sample are presented in Table n = 51) to the non-clinical group (n = 46), there were no group differences in the overall total score of TLEs exposure . However, we did find a significant group difference in the exposure of TLEs that “Happened” to the individual (as opposed to those who “Witnessed” or “Learned” about the event), showing that as lifetime cumulative TLEs exposures that “Happened” to the individual increased, the more likely the individual was to exhibit symptoms of psychosis . We also examined differences in exposure of TLEs that “Happened” and race and found a significant increase in TLEs that “Happened” in the African-Americans sample  . In addition, we found a significant effect of cumulative TLEs on psychosis . Thus, as the number of TLEs increased by one unit, the likelihood of the presence of psychosis also increased.When comparing persons with psychosis , excitement , depression , thought disorder , activation , and paranoia . However, there was no correlation between the number of TLEs and negative, cognitive, anergia, or prosocial symptom domains.Spearman’s correlations between the number of exposures of TLEs that “Happened” to the individual and clinical symptomology as measured by the PANSS are presented in Table r = 0.196, n = 97, p = 0.05), commenting hallucinations , conversing hallucinations , visual hallucinations ,; tactile hallucinations , and olfactory hallucinations .We also examined the correlations between the number of exposures of TLEs that “Happened” to the individual and hallucinations Table . With thr = 0.196, n = 97, p = 0.05) and delusions of control  were statistically significant, with an additional trend in persecutory delusions . There was no correlation between the number of TLEs that “Happened” and delusions of reference, grandiosity, somatic, guilt, jealous, erotomanic, thought insertion, thought withdrawal, and thought broadcasting.Correlations between the number of TLEs that “Happened” to the individual and forms of delusions are reported in Table t-test to explore associations between specific TLEs involving physical and/or sexual assault, unwanted or uncomfortable sexual experiences, and religious delusions and tactile hallucination. Interestingly, we found a positive relationship between tactile hallucinations and physical assault , sexual assault , and unwanted or uncomfortable sexual experiences . We also found a positive association between religious delusions and unwanted or uncomfortable sexual experiences .Given the highly correlated findings between TLEs in both religious delusions and tactile hallucinations, we conducted an independent sample Interviews and focus groups were transcribed verbatim, and a modified grounded theory approach was used to identify themes related to the intersections of race, trauma, and psychosis. Transcripts were comprehensively coded and recoded after a 3-month interval to establish reliability (kappa > 0.90). Findings revolve around four major thematic umbrellas: (1) developmental relationships between multiple, intersecting adverse experiences; (2) variations in the timing of onset related to trauma; (3) trauma, spirituality, and religious symptom content; and (4) trauma and hallucinatory modalities.Virtually all participants, and all African-American participants, described some form of trauma and, in the majority of cases, multiple forms of adversity, including structural discrimination and racism that interacted synergistically over the course of childhood, adolescence, and early adulthood. Many participants also reported family members with serious mental illness, poverty, unstable home environments, neglect, verbal and/or physical abuse, and disruption of attachment relationships.“The voices that I heard was bad ones for the most part. I came from an abusive background, meaning that my family was abusive physically, emotionally and sexually. I was raped and I just heard all these voices. That’s why the doctors thought initially I had schizophrenia.”“I would get very mad at my mother for being gone. For having passed away. My mother put me in the hospital kind of like my dad. He was in the same hospital, too. He had a mental illness. My father was also in jail. He was put into a hospital in the past too. He was a patient there. He had voices. He often talked to himself and I would wonder why is he talking to himself? Who is he talking to? My dad heard voices. I caught him in that, too, many times talking to himself. Sometimes I would go to church and people were talking like they heard voices. Sometimes I would see my father talking about [voices] and ready to beat me up and he got very angry. He would say, ‘Just get out of here. Go on back home.’ He would just get really agitated….”“Since I was like 12, 13 years old, I used to talk to myself, caught my voices. I didn’t know what it was then. I assumed it was me, cuz I heard it very early. I came introverted somewhat cuz there’s a lotta violence in the streets. I was more of a homebody. I think, for me being a homebody, that’s when the voices got brought up. I just had to entertain myself with the voices and talking.”Narratives of gangs, substance use, and drug trafficking were often woven throughout. One participant described learning (as an older teen) that his mother had been drinking heavily while pregnant with him, while others described parents with severe addictions throughout their childhoods, as well as parents incarcerated for drug-related offenses. Still others indicated pressure from siblings or peers to start using drugs, as well as more complicated entanglements of money, gangs, and drug use.“The kids I hanging with. They got me on drugs. I think it was a negative factor, negative influence on my life, the kids I was with. Other than that, I probably wouldn’t be doing drugs. Yeah, definitely drugs is a factor in [my diagnosis].”“I was just getting angry, depressed, sad. My parents, I heard my mother say—she was drinking. She was drinking when she […] was pregnant with me. I heard my father was on my marijuana. Other than them, my mental illness is from both sides of my family, my father and mother’s side. They both have mental illness. I’m just sure that I get—I see it in my auntie, too, on my mother’s side. I see some mental illness with her and everything. It runs in the family.”“My mother, she was a heroin addict. I had a problem with her ‘cause people wanna take advantage of her. That’s where most my problems start. They pissed me off ‘bout my mother. I started stickin’ up, stealin’ to start supplyin’ my mother’s heroin so she wouldn’t have to go out there in the streets. That caused conflict between me and my brother. Me and him got in a fight one time. The second time I shot him in the foot. All that’s to say is that I never had no chance at life—childhood or life.”Among African-American men, a strong subtheme was bullying and/or verbal abuse  related to perceptions of effeminate behavior. For example, several participants reported having been bullied due to perceived homosexuality. Several participants reported responding to such accusations by engaging in stereotypically masculine behaviors such as joining a gang or drinking, while others, publicly or in private, embraced gender minority identities, with one engaging in same-sex sex work as a teen.“I was bullied, too, in high school and grammar school. I was bullied. People messing with me and everything, beating me up. I got jumped on by some gang bangers. Used to pick on me a lot like I don’t know how to defend myself or something. Pick on me and everything. I know how to protect myself, though. I ain’t gonna let too many people try to mess me up. My father said that I was gay. He said, ‘People think you gonna be gay cuz you don’t have many women around. [But] I wasn’t gay…. I’m not gay.’”The above experiences virtually all unfolded in racially segregated neighborhoods and housing projects with high rates of poverty, gang violence, and limited access to quality job and/or secondary education. About half the participants remained in such neighborhoods and explicitly foregrounded the risks of violence in their communities as a major factor in their experiences of ongoing treatment and recovery. Just 2 weeks before, a focus group held at a Chicago South Side drop-in center, for example, participants noted that, only a few blocks away at a public park, over a dozen community members (including children) had been killed or seriously injured in a day-time drive-by shooting.single traumatic event.In discussing the relationship between traumatic events and the onset of psychosis, most participant accounts fell into one of two categories: childhood onset of voices in the midst of acute traumatic experiences  and older adolescent or adult onset following a series of adversities  but that was nevertheless temporally disconnected from any The content and characteristics of voices arising during acute traumatic events in childhood were generally much more likely to mirror real-life abusive figure(s). For instance, voices that began during episodes of severe sexual or physical abuse were typically verbally abusive, telling participants that they “deserved what [they] got,” were “whores” or “sluts,” would never amount to anything and/or never succeed.“There’s a lot of voices that I hear. All grown men saying the same thing over and over. I’m no good, I’m worthless. Kill yourself. Just repeatedly over and over and over and over by men.”“…they keep telling me to kill myself. I’m no good. I’m worthless. To kill myself repeatedly.”“A lot of negative remarks, they ain’t gonna amount to being nothing, they gonna grow up to be nothing, you’re a failure, and all that stuff.”One participant with trauma-onset voices described her voices as “glued to your experience through childhood experience.” In spite of hearing voices from an early age—typically beginning in early to mid-childhood within this subgroup—most participants reported not receiving a diagnosis of (or treatment for) a psychotic disorder until a much later time point. It was generally ambiguous whether these later diagnoses were exclusively tied to voices, or in fact stemmed from the addition of later onset symptoms and/or functional disability.For those with later onset and multiple forms of adversity and associated risk taking , connections between psychotic symptoms and particular experiences were less clear—e.g., it was far less common for participants to report voice or symptom contact that amplified or re-played a particular event and associated interpersonal exchanges (such as the messages of an abusive figure). Themes consistent with participants’ lives and broad experiences of individual and community adversity and discrimination were nevertheless common, for example, delusions involving gangs or pimps or demonic voices tempting participants to use drugs or engage in illegal activities.The majority of participants described multiple entanglements between religious faith, spiritual beliefs, and their experiences of psychosis and adversity. Examples ranged from distinct voices that reflected demonic forces, or a G-d or Jesus-like messianic figure, ostensible delusions of reference involving messages from G-d or the devil, automatic thoughts related to participants’ addictions, and perceived temptations as attributable to the devil while automatic protective thoughts were attributed to G-d; and the involvement of pastors or other religious figures who helped participants make sense of their experiences and distinguish between those that were divine versus demonic in origin.“Well, there are voices from above. I label it as G-d. It’s a noise, but it’s a feeling of ‘I must something.’ It is like a voice of something talking. Sometimes it’s sort of like an amen kind of a noise. Like a church music kind of noise. That kind of noise. There are voices within that.”“I think they’re demons. I think that G-d talks to you and I think that demons talk to you. When I was drinking and using drugs, they was always telling me to kill myself. That I wasn’t worthy, that I didn’t amount to nothing. When I gave my life to G-d and turned my life over, the devil still tried to come at me. I would hear his voice, but I also read the bible and I believe in the word of G-d. I had to choose G-d’s word over what the devil was tellin’ me. The bible tells me that the devil is a liar. Whatever he’s tellin’ me that’s negative, he’s tellin’ me to kill myself, that’s not something that G-d would want me to do.”Interviewer: Your pastor at church does?] Yeah, tells me not to listen to the voices telling me to hurt yourself.”“When I go to church and all, they teaches me to tell me why the voices are talking like that.  how to do good things, too, but he be telling why the bad things be happening, like getting jumped on or getting beat up a lot. They tell you what spirit that is telling you to hurt yourself.”Trauma was often tied to these experiences in both direct and indirect ways. For example, demonic “temptations” (whether communicated through voices or non-auditory messages) often involved risk behaviors deeply interwoven with neighborhood poverty and a lack of supports and access to child and family services such as drug use, drug trafficking, gang involvement, and survival sex. Positive voices, even when not explicitly religious or spiritual in nature, were not infrequently described as forces or entities, which would protect the participant against adversity or violence or to reassure them of their core morality or humanity in spite of “immoral” activities and events they had been exposed to (or previously participated in).“One time I go outside at 2:00 a.m. Somethin’ tells me that somethin’ ain’t right. Like you talkin’ to me like it’s a warning sign. Like you talkin’ to me, that’s the way—that’s how I hear it. Like you talkin’ to me. I changed my mind. I’m not gonna catch the bus. I turned around and went upstairs. Where I live there’s a park across the street. One of the bus stops is right there. About 2-min long up the steps I heard some shootin’. As I look out the window, I saw a body layin’ down and a couple guys runnin’. The very same bus stop I was gonna catch the bus at. That’s why I say it’s a good voice and a bad voice. The voice that I heard, I feel it was comin’ from G-d. If it was an evil voice, I feel that I wouldn’t got that notice.”Several participants whose narratives involved accusations and/or internalized concerns about sinful behavior and/or stigmatized gender or sexual identit(ies) described various uses of religious faith or spiritual practice to address their concerns or reassure themselves that they were (in fact) good, ethical people.“Jesus [described as a voice earlier in the interview] reassures me…that He loves everyone. Regardless of sexual orientation.”[Pause] “You can get through this day without thinking about going back and using drugs.”[Reporting what her voices say]: “I get, ‘That’s not the right thing to do, Carol [pseudonym].’” While participants most frequently described, and spent the most time discussing, ostensible delusions (particularly paranoia) and auditory hallucinations (“voices”), altered perceptual or somatic experiences in other modalities were common. Participants’ descriptions generally revolved less around literal “hallucinatory” experiences than they did around more existential alterations of experience and/or “felt presences,” which tended to be subtler and harder to describe. In many cases, participants reported that such presences represented ghosts or spirits, generally of deceased loved ones.Q: In some way that’s different from the air that’s already there?] “Right, it’s not the same. It’s different.”“A smell like, let’s see—maybe it tastes like you wanna drink some water cuz I’m dizzy. Almost like a shocking feeling, but the smell it’s like maybe more like a taste. Maybe it smells like air, like air.” [“I can see my [deceased] aunt and my uncle and you see, I see them. Yeah, I see a lot of people up there when I look up [toward the voices].”“I feel like, like it’s a lifting, sort of like a lifting feeling, like of something being lifted.”“For me it’s more like a feeling, too. Like something that makes me turn my head. Like something that’s there that I—almost like a buzz or a tone or something.”“It’s bothersome and there’s noise, but then it’s like this singing like this noise, and I feel like G-d, you know, G-d makes these noises [‘voices’].”A number of participants connected non-auditory–verbal experiences directly to G-d or spirituality. For example:In contrast to the previous themes, direct links between these non-verbal experiences and trauma were unclear, and no participant in this sample explicitly described non-auditory experiences as sexual or violent in nature.The urban experience for African-Americans living in segregated neighborhoods and/or housing projects often involves exposure to high rates of poverty, gang violence, and limited access to quality secondary education and job opportunities , 41. IncThe mixed-methods data reported here replicate existing findings in identifying strong and significant links between cumulative trauma exposure and psychosis that cut across traditional diagnostic boundaries , 51, 52.Beyond demonstrating a general link of greater TLEs and psychosis, we found specific types of psychosis symptoms associated with TLEs, including multiple types of hallucinations, religious delusions, and delusions of control. We further found that tactile hallucinations and religious delusions were significantly correlated with history of unwanted sexual experiences and, for tactile hallucinations, with past physical and sexual assault. We discuss these findings and their implications in the sections that follow.Our qualitative analyses were designed to further unpack, potentially confirm, and deepen the findings from the quantitative study. The qualitative findings underscore the complex and synergistic relationships between multiple forms of individual trauma  as they unfold against a backdrop of racial segregation, poverty, drug trafficking, gang violence, and neighborhood disadvantage. In addition, we report multiple ways in which both individual-level and neighborhood-level themes and dynamics are reflected in the form and content of both voices and unusual beliefs. For example, we found that an array of themes related to participants’ childhood experiences and associated attempts to cope with these experiences were reflected in both the content of voices and subject’s interpretations of their meaning and significance.n = 5,782) and the British Psychiatric Morbidity Survey  found that after adjusting for demographic confounds, substance use, and depression, experiencing two TLEs increased psychosis risk by 3.37 times (NCS) and 4.31 times (BPMS), respectively, compared to 30.16 times (NCS) and 192.97 times (BPMS) for individuals reporting five TLEs . The University of Illinois at Chicago Institutional Review Board approved the study, and signed consent was obtained from all participants in accordance with the Declaration of Helsinki before initiation of study procedures. The qualitative analysis by DePaul University’s Institutional Review Board where two of the researchers were employed at the time the study was approved and data were collected.CR, NJ, and RS designed the study. CR and NJ collected the data. CR, NJ, KC, and RS developed the methodology and performed the analysis. CR, NJ, EL, KC, MS, JM, SK, and RS wrote, edited, and approved the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Like all somatic tissues, the human immune system changes with age. This is believed to result in an increased frequency of, and susceptibility to, infectious disease and to contribute to a wide range of non-communicable age-associated diseases in later life, especially cancer, cardiovascular disease, and autoimmunity. The majority of studies addressing immune ageing has been cross-sectional, but limited longitudinal studies are contributing to a better understanding of age-associated changes, as opposed to differences, and their clinical relevance. However, intriguing differences are emerging that implicate highly context-dependent immune ageing processes, mitigating against current generalisations concerning human immunosenescence and indicating the necessity for detailed comparisons of different populations, even those that would appear quite similar at first glance. Here, limiting the discussion to humans and focusing on adaptive immunity, I reconsider the veracity of the above assertion in light of data published over the last 3 years and in the face of a certain degree of confusion in the literature, which may be perplexing and misleading to the uninitiated.As reflected in numberless papers, it is commonly accepted as received wisdom that “declining function of the immune system, termed "immunosenescence", leads to a higher incidence of infection, cancer, and autoimmune disease related mortalities in the elderly population”5. However, this is not what immunologists generally mean by “immunosenescence”, as illustrated by referenceth century and young people born towards the end of that century. These differences are essentially impossible to control for and are likely to include genetic, nutritional, environmental, psychosocial, and educational factors as well as many others. What mostly remains possible in human studies is to perform longitudinal follow-up on people already advanced in years, as in cohorts such as the Leiden 85-Plus, which already initiated some immunological studies nearly 20 years ago6. At least in such selected populations, one can determine immune parameters at baseline, and their changes over time, that can be associated with clinical outcome within a feasible time-frame. These could then be tested for their applicability in younger subjects.First, it is necessary to clearly state what we think we mean by the term “immunosenescence”, which tends to mean different things to different people. It is often assumed, especially by non-immunologists, that this term refers to the cell biological concept of “replicative senescence”, whereby somatic human cells cease dividing at the “Hayflick limit” after a finite number of cell divisions owing to telomere attritionNotwithstanding the above considerations, much useful information can of course be garnered from cross-sectional studies establishing differences in immune biomarkers in older adults and determining which are associated with properties assigned to a person who is “immunosenescent”, i.e. infection, cancer, cardiovascular disease, autoimmunity (and response to vaccination), etc. A comparison of clinically relevant differences and similarities between younger and older populations, in agreement or disagreement with immune biomarkers found to predict certain clinical outcomes in longitudinal studies of the elderly, will help to define the lowest common denominator likely to be globally relevant to these health outcomes. Thus, of all the myriad of age-associated factors reported to be different in younger and older people, and the far fewer parameters also found to be informative in longitudinal studies, it may be possible to select those that are crucial, which could provide information on mechanisms and offer opportunities for rational intervention. Now the critical question becomes do we have any idea what these immune parameters are?+ T cells in their peripheral blood, as first reported many years ago, for example+ T cells were reported to be higher in the elderly in that same study7. However, unlike the findings on naïve CD8+ T cells, higher CD8+ memory cells in the elderly are not universally reported. In the meantime, the reason for this is well established, although still not understood—namely, that accumulations of late-stage memory cells are seen in older people infected with human herpesvirus 5  but not other herpesviruses10, as confirmed in a recent systematic review11. Because CMV seroconversion increases with age12 and is affected by socioeconomic factors13, it confounds the effect of age on immune parameters, as was also seen in the systematic review11. It is important to note that these results have been reproduced not only in Western populations, which are the most commonly studied but not necessarily the most representative human population, but also in people living in less-industrialized countries. There is some evidence that this loss of CD8+ naïve cells occurs at an earlier chronological age in low- and middle-income countries14, possibly due at least partly, if not only, to greater exposure to pathogens driving the naïve CD8+ T cells to differentiate to effector and memory cells in these populations, something that is harder to detect in Western societies. This provides enduring protection against pathogens encountered earlier in life but may reduce the naïve T cell repertoire forde novo challenges in later life and contribute to the greater susceptibility of the elderly to emerging pathogens. It is also important to note that in those rare studies that have considered sex differences, the markedly lower levels of CD8+ naïve T cells have been found in both women and men, as for example in our study of Berliners15. Differences between younger and older adults are seen to a lesser extent for CD4+ naïve T cells, and for B cells, as well as for some elements of innate immunity, especially dendritic cells (DCs) and neutrophils17, but all immune cells are affected to some degree. In all instances, it must be borne in mind that tissue compartments other than peripheral blood may not, or most likely do not, exhibit the same patterns of cell subset distribution18. Thus far, the data on immune cell distribution in tissues other than blood in humans are too sparse for any clinical correlates to be established.Of many disparate findings in the literature, one immune parameter stands out as universally different in younger and older adults, consistently reported in a multitude of studies. This is the finding that older adults possess vanishingly low numbers and percentages of naïve CD8+ T cells that are predominantly acting as cytolytic effectors eliminating virally infected cells, the CD4+ T cells that help B cells to produce neutralising antibodies, and DCs that present antigen to the T cells, one might expect that a paucity of such cells could result in higher susceptibility to viral infections in old age. There are some data on this question in the context of vaccination against infectious agents, where the major public health interest in immunosenescence lies. While most studies have focussed on seasonal influenza, the question of whether lower numbers of naïve T cells really compromise immune responses has been relatively rarely addressed because it is necessary to study responses to pathogens to which the person has definitely not been previously exposed. Vaccinating volunteers with yellow fever (YF) vaccine does provide such an opportunity, and such studies confirm that differences in the CD4+ and CD8+ T cell response, and in DC function, are demonstrable in older adults with poorer responses relative to the young19. Amongst other parameters, this study quantified recent thymic emigrants as a measure of naïve T cells and demonstrated that their paucity indeed correlated with poorer responses to a new pathogen (i.e. the vaccine). This is consistent with the long-held belief that thymic involution early in life contributes decisively to the very small numbers of naïve T cells in the elderly20. Although it is not perfectly clear why thymic involution occurs, it is hypothesized that the requirement for maximising immune defence potential is greatest during childhood to prevent death from infection21. After puberty and reproductive age, exposure to new pathogens is less likely and immune memory for local pathogens is paramount. In many documented cases, we know that immune memory can be very long-lasting, so resources are concentrated on maintaining defence against tangible pathogens rather than investing resources in the potentially hazardous (due to possible errors in negative selection leading to autoimmunity) and certainly energy-intensive production of new naïve T cells that will most likely never be needed. Again, relatively few studies have been performed to test this, but, in the case of YF vaccination as described above, a different group of investigators demonstrated the presence of “stem-cell-like” CD8 memory cells in YF vaccinees up to 25 years later22. Owing to these stem-cell-like self-renewal properties, memory can be maintained perhaps over the lifetime; ageing of these cells is thus not necessarily a problem. Nonetheless, and for largely unknown reasons, adaptive immunological memory to a wide range of different pathogens (as reflected in the duration of protection after successful vaccination) is extremely variable. It may last a lifetime (e.g. measles) but it may last only half a decade (e.g. pertussis) and all times in between . In the case of persistent pathogens such as VZV and TB, waning of immune control with age can result in reactivation and clinically relevant disease manifestations. But despite waning of memory for these pathogens, protection is maintained for decades in the majority of cases, so the main problem remains the paucity of naïve cells in older people who have survived for a much longer period of time than would mostly be expected to be the case “in the wild”. For these people, exposures to neoantigens might be hazardous if they happened not to have any remaining antigen-specific T cells in their shrunken repertoire. This may explain, for example, why older people suffered a very much higher mortality rate than younger people during the SARS epidemic, but this was not demonstrated at the time23.Because it is the CD824. However, protection against infection requires the integrity of T-cell-mediated responses, and here data show that a lower proportion of elderly than younger people may be capable of mounting a T cell response, especially if they are infected with CMV, as many older people are25, and that they may not respond as well as the young26. In this context, we may approach a definition of the harm that immunosenescence can do rather than acting merely as a variety of immune deficiency. Thus, evidence is emerging that CD8+ memory cells in elderly people may behave in a pathogenic manner to a greater degree than in the young. A suggested mechanism for this is based on the recent finding that at least some late-stage differentiated CD8+ T cells, characterised by a lack of expression of the costimulatory receptors CD27 and CD28, with short telomeres and with little clonal expansion capacity, and expressing receptors such as HNK-1, shared with natural killer (NK) cells, otherwise known as CD57 (commonly referred to as “senescent cells” in the literature), may indeed be malfunctional. This has been established for NK cells and is mediated by the inappropriate release of granzyme27, which causes tissue damage and inflammation28. There is preliminary evidence that CD8+ T cells can behave in a similar manner and contribute to “inflammaging”29.The impact of immunosenescence on influenza vaccination is much more complicated to dissect because of the ever-changing balance of seasonal strains and indeterminate degree of T cell memory. Seasonal vaccines seek to stimulate the production of neutralising antibodies or increase the level already present but are not directed at stimulating T cell responses that may be critical for clinical protection. The way in which the antibody “response” is assigned as “responder” or “non-responder” is in itself problematic because the presence of an already-high titre of antibody that is not further increased by vaccination can result in classification as a “non-responder”. This alone may help to account for discrepancies in the literature as to differences in the fraction of older people versus younger people who do respond to the vaccine. Indeed, one recent study taking vaccination history into account concluded that from the point of view of antibody titre, older people did in fact respond as well as younger people30 (hence dubbed “inflammaging”31) is part of the state referred to as “immunosenescence”. However, the tissue of origin of the pro-inflammatory mediators is, to a great extent, unclear, and it is likely that the majority is not derived from immune cells but rather from other, possibly replicatively senescent, cells32. Indeed, in early studies in a very elderly Swedish population, we found that 2-, 4-, and 6-year mortality at follow-up was weakly associated with a cluster of immune parameters including higher levels of late-stage differentiated CD8+CD28– T cells and lower levels of B cells but was more strongly associated with higher levels of IL-6 together with cognitive impairment. These two clusters were independent of each other and were at least additive in their effects on mortality33. Similar findings on these variables as independent mortality risk factors have sometimes been reported from some other studies in different countries, e.g. the Spanish CARRERITAS study34. Therefore, in my opinion, the terms “inflammaging” and “immunosenescence” should also be used independently of one another. It is also noteworthy that the “immune risk profile”, or IRP as we called it35, did not include the numbers or percentages of naïve CD8+ T cells, suggesting that in this very elderly population probably no longer exposed to many novel pathogens, it was not important to survival to maintain an extensive naïve T cell repertoire. In fact, in studies in other populations, a disadvantage was found to accrue in individuals with higher proportions of naïve cells (see below).It is often considered that the state of slightly raised inflammatory mediators commonly seen in elderly people, some of which are associated with frailty and mortalityper se. As discussed above, the main differences between younger and older people reside in the different distribution of naïve and memory elements of the adaptive immune system  and more subtle differences in innate immunity. The first line of defence against pathogens is usually the neutrophil, and in older people neutrophil function may be compromised relative to the young36. Neutrophils have been included in clusters of larger numbers of immune and non-immune parameters, many related to inflammation, that are associated with mortality37. Such clusters of parameters may be informative for ageing trajectories, even at a relatively young age. Thus, an influential study by Belskyet al.38 followed nearly 1,000 young people (26 years of age) in New Zealand for 12 years and measured a panel of biomarkers that they then correlated with relative physical and cognitive performance and appearance. Even at the age of only 38, some individuals were biologically more aged than others, and this correlated with clusters of markers including CRP, white blood cell count, and leucocyte telomere length. Extending such studies in future to include more granular and discriminatory immune biomarkers will allow us to determine whether there really are any biomarkers of immunosenescence in the strict sense of mediating a direct association with detrimental clinical outcomes or whether the differences in immune parameters observed in older people relative to young people mostly or entirely reflect adaptive responses to the immunological history and current situation of the individual. Where limited knowledge of the relevance of immune parameters like the IRP for predicting survival does exist, it appears that there are notable differences even between populations that one mighta priori expect to be quite similar, such as Swedish, Dutch, and Belgian. However, different birth cohorts separated by decades, coupled with nutritional variation, associated differences in the gut microbiota and pathogen exposures (including CMV), socioeconomic circumstances, and any number of other variables could explain why these differences arise. Hence, at this stage, we should resist generalising the outcomes associated even with the same simplest biomarkers of “immunosenescence” in different populations. This is most strikingly illustrated by our findings in the Belgian population as opposed to the Swedish, where a CD4:8 ratio of <1 and CMV-seropositivity indicated a risk profile in the latter, but exactly this combination was associated with better survival in the former39. Even more strikingly, associations with survival in the Belgian study were seen exclusively in women, with absolutely no differences in men39. A deeper analysis at the single-cell level using more advanced techniques such as CyTOF, RNA-Seq, Nanostring, and others should soon begin to provide a more detailed view of the relevant differences. Nonetheless, the above considerations will still apply to ever-richer datasets and will need to be borne in mind when interpreting these studies.According to the definition given at the beginning, senescence has to be defined in terms of known detrimental clinical associations. The fact that one of the main surrogate markers of inflammaging, IL-6 (together with cognitive impairment), correlated better with mortality than did the IRP suggests that many of the unequivocal negative health effects associated with old age and attributed to immunosenescence actually have little to do with immunosenescence40 and the poorly defined detrimental systemic milieu in older animals41. Hence, my answer to the question posed in the title is yes, in my opinion the human immune system does undergo senescence, and this is predominantly as a result of increasing holes in the naïve T cell repertoire and creeping exhaustion and malfunction of some of the cells responsible for immune memory of certain pathogens. The latter phenomenon, together with changes to haematopoiesis and innate immunity, contributes to the enhanced inflammatory status and tissue damage associated with “inflammaging”.Biomarkers of immune ageing as established in cross-sectional studies unequivocally document multiple differences between younger and older populations. Some markers distinct to older people can be associated with important health parameters such as frailty and responses to vaccination, but these and especially factors associated with mortality must be viewed in the context of the particular population in which they were established. Truly universal age-associated changes in immune markers mostly seem limited to the reduction in numbers and proportions of peripheral blood naïve T cells due to thymic involution and possibly to dysfunctional short-lived innate immune cells, reflecting ageing of the haematopoietic stem cell systemCMV, cytomegalovirus; DC, dendritic cell; IRP, immune risk profile; NK, natural killer; YF, yellow fever.