Preventive psychiatry: a blueprint for improving the mental health of young people

Preventive approaches have latterly gained traction for improving mental health in young people. In this paper, we first appraise the conceptual foundations of preventive psychiatry, encompassing the public health, Gordon''s, US Institute of Medicine, World Health Organization, and good mental health frameworks, and neurodevelopmentally‐sensitive clinical staging models. We then review the evidence supporting primary prevention of psychotic, bipolar and common mental disorders and promotion of good mental health as potential transformative strategies to reduce the incidence of these disorders in young people. Within indicated approaches, the clinical high‐risk for psychosis paradigm has received the most empirical validation, while clinical high‐risk states for bipolar and common mental disorders are increasingly becoming a focus of attention. Selective approaches have mostly targeted familial vulnerability and non‐genetic risk exposures. Selective screening and psychological/psychoeducational interventions in vulnerable subgroups may improve anxiety/depressive symptoms, but their efficacy in reducing the incidence of psychotic/bipolar/common mental disorders is unproven. Selective physical exercise may reduce the incidence of anxiety disorders. Universal psychological/psychoeducational interventions may improve anxiety symptoms but not prevent depressive/anxiety disorders, while universal physical exercise may reduce the incidence of anxiety disorders. Universal public health approaches targeting school climate or social determinants (demographic, economic, neighbourhood, environmental, social/cultural) of mental disorders hold the greatest potential for reducing the risk profile of the population as a whole. The approach to promotion of good mental health is currently fragmented. We leverage the knowledge gained from the review to develop a blueprint for future research and practice of preventive psychiatry in young people: integrating universal and targeted frameworks; advancing multivariable, transdiagnostic, multi‐endpoint epidemiological knowledge; synergically preventing common and infrequent mental disorders; preventing physical and mental health burden together; implementing stratified/personalized prognosis; establishing evidence‐based preventive interventions; developing an ethical framework, improving prevention through education/training; consolidating the cost‐effectiveness of preventive psychiatry; and decreasing inequalities. These goals can only be achieved through an urgent individual, societal, and global level response, which promotes a vigorous collaboration across scientific, health care, societal and governmental sectors for implementing preventive psychiatry, as much is at stake for young people with or at risk for emerging mental disorders.     

The growing field of digital psychiatry: current evidence and the future of apps,social media,chatbots, and virtual reality

As the COVID‐19 pandemic has largely increased the utilization of telehealth, mobile mental health technologies – such as smartphone apps, vir­tual reality, chatbots, and social media – have also gained attention. These digital health technologies offer the potential of accessible and scalable interventions that can augment traditional care. In this paper, we provide a comprehensive update on the overall field of digital psychiatry, covering three areas. First, we outline the relevance of recent technological advances to mental health research and care, by detailing how smartphones, social media, artificial intelligence and virtual reality present new opportunities for “digital phenotyping” and remote intervention. Second, we review the current evidence for the use of these new technological approaches across different mental health contexts, covering their emerging efficacy in self‐management of psychological well‐being and early intervention, along with more nascent research supporting their use in clinical management of long‐term psychiatric conditions – including major depression; anxiety, bipolar and psychotic disorders; and eating and substance use disorders – as well as in child and adolescent mental health care. Third, we discuss the most pressing challenges and opportunities towards real‐world implementation, using the Integrated Promoting Action on Research Implementation in Health Services (i‐PARIHS) framework to explain how the innovations themselves, the recipients of these innovations, and the context surrounding innovations all must be considered to facilitate their adoption and use in mental health care systems. We conclude that the new technological capabilities of smartphones, artificial intelligence, social media and virtual reality are already changing mental health care in unforeseen and exciting ways, each accompanied by an early but promising evidence base. We point out that further efforts towards strengthening implementation are needed, and detail the key issues at the patient, provider and policy levels which must now be addressed for digital health technologies to truly improve mental health research and treatment in the future.     

Psychiatric diagnosis and treatment in the 21st century: paradigm shifts versus incremental integration

Psychiatry has always been characterized by a range of different models of and approaches to mental disorder, which have sometimes brought progress in clinical practice, but have often also been accompanied by critique from within and without the field. Psychiatric nosology has been a particular focus of debate in recent decades; successive editions of the DSM and ICD have strongly influenced both psychiatric practice and research, but have also led to assertions that psychiatry is in crisis, and to advocacy for entirely new paradigms for diagnosis and assessment. When thinking about etiology, many researchers currently refer to a biopsychosocial model, but this approach has received significant critique, being considered by some observers overly eclectic and vague. Despite the development of a range of evidence‐based pharmacotherapies and psychotherapies, current evidence points to both a treatment gap and a research‐practice gap in mental health. In this paper, after considering current clinical practice, we discuss some proposed novel perspectives that have recently achieved particular prominence and may significantly impact psychiatric practice and research in the future: clinical neuroscience and personalized pharmacotherapy; novel statistical approaches to psychiatric nosology, assessment and research; deinstitutionalization and community mental health care; the scale‐up of evidence‐based psychotherapy; digital phenotyping and digital therapies; and global mental health and task‐sharing approaches. We consider the extent to which proposed transitions from current practices to novel approaches reflect hype or hope. Our review indicates that each of the novel perspectives contributes important insights that allow hope for the future, but also that each provides only a partial view, and that any promise of a paradigm shift for the field is not well grounded. We conclude that there have been crucial advances in psychiatric diagnosis and treatment in recent decades; that, despite this important progress, there is considerable need for further improvements in assessment and intervention; and that such improvements will likely not be achieved by any specific paradigm shifts in psychiatric practice and research, but rather by incremental progress and iterative integration.     

“Third‐wave” cognitive and behavioral therapies and the emergence of a process‐based approach to intervention in psychiatry

For decades, cognitive and behavioral therapies (CBTs) have been tested in randomized controlled trials for specific psychiatric syndromes that were assumed to represent expressions of latent diseases. Although these protocols were more effective as compared to psychological control conditions, placebo treatments, and even active pharmacotherapies, further advancement in efficacy and dissemination has been inhibited by a failure to focus on processes of change. This picture appears now to be evolving, due both to a collapse of the idea that mental disorders can be classified into distinct, discrete categories, and to the more central attention given to processes of change in newer, so‐called “third‐wave” CBTs. Here we review the context for this historic progress and evaluate the impact of these newer methods and models, not as protocols for treating syndromes, but as ways of targeting an expanded range of processes of change. Five key features of “third‐wave” therapies are underlined: a focus on context and function; the view that new models and methods should build on other strands of CBT; a focus on broad and flexible repertoires vs. an approach to signs and symptoms; applying processes to the clinician, not just the client; and expanding into more complex issues historically more characteristic of humanistic, existential, analytic, or system‐oriented approaches. We argue that these newer methods can be considered in the context of an idiographic approach to process‐based functional analysis. Psychological processes of change can be organized into six dimensions: cognition, affect, attention, self, motivation and overt behavior. Several important processes of change combine two or more of these dimensions. Tailoring intervention strategies to target the appropriate processes in a given individual would be a major advance in psychiatry and an important step toward precision mental health care.     

Designing and scaling up integrated youth mental health care

Mental ill‐health represents the main threat to the health, survival and future potential of young people around the world. There are indications that this is a rising tide of vulnerability and need for care, a trend that has been augmented by the COVID‐19 pandemic. It represents a global public health crisis, which not only demands a deep and sophisticated understanding of possible targets for prevention, but also urgent reform and investment in the provision of developmentally appropriate clinical care. Despite having the greatest level of need, and potential to benefit, adolescents and emerging adults have the worst access to timely and quality mental health care. How is this global crisis to be addressed? Since the start of the century, a range of co‐designed youth mental health strategies and innovations have emerged. These range from digital platforms, through to new models of primary care to new services for potentially severe mental illness, which must be locally adapted according to the availability of resources, workforce, cultural factors and health financing patterns. The fulcrum of this progress is the advent of broad‐spectrum, integrated primary youth mental health care services. They represent a blueprint and beach‐head for an overdue global system reform. While resources will vary across settings, the mental health needs of young people are largely universal, and underpin a set of fundamental principles and design features. These include establishing an accessible, “soft entry” youth primary care platform with digital support, where young people are valued and essential partners in the design, operation, management and evaluation of the service. Global progress achieved to date in implementing integrated youth mental health care has highlighted that these services are being accessed by young people with genuine and substantial mental health needs, that they are benefiting from them, and that both these young people and their families are highly satisfied with the services they receive. However, we are still at base camp and these primary care platforms need to be scaled up across the globe, complemented by prevention, digital platforms and, crucially, more specialized care for complex and persistent conditions, aligned to this transitional age range (from approximately 12 to 25 years). The rising tide of mental ill‐health in young people globally demands that this focus be elevated to a top priority in global health.     

Geroscience‐guided repurposing of FDA‐approved drugs to target aging: A proposed process and prioritization

Common chronic diseases represent the greatest driver of rising healthcare costs, as well as declining function, independence, and quality of life. Geroscience‐guided approaches seek to delay the onset and progression of multiple chronic conditions by targeting fundamental biological pathways of aging. This approach is more likely to improve overall health and function in old age than treating individual diseases, by addressing aging the largest and mostly ignored risk factor for the leading causes of morbidity in older adults. Nevertheless, challenges in repurposing existing and moving newly discovered interventions from the bench to clinical care have impeded the progress of this potentially transformational paradigm shift. In this article, we propose the creation of a standardized process for evaluating FDA‐approved medications for their geroscience potential. Criteria for systematically evaluating the existing literature that spans from animal models to human studies will permit the prioritization of efforts and financial investments for translating geroscience and allow immediate progress on the design of the next Targeting Aging with MEtformin (TAME)‐like study involving such candidate gerotherapeutics.     

Effectiveness of a WHO self‐help psychological intervention for preventing mental disorders among Syrian refugees in Turkey: a randomized controlled trial

Refugees are at high risk of developing mental disorders. There is no evidence from randomized controlled trials (RCTs) that psychological interventions can prevent the onset of mental disorders in this group. We assessed the effectiveness of a self‐help psychological intervention developed by the World Health Organization, called Self‐Help Plus, in preventing the development of mental disorders among Syrian refugees experiencing psychological distress in Turkey. A two‐arm, assessor‐masked RCT was conducted in two Turkish areas. Eligible participants were adult Syrian refugees experiencing psychological distress (General Health Questionnaire ≥3), but without a diagnosis of mental disorder. They were randomly assigned either to the Self‐Help Plus arm (consisting of Self‐Help Plus combined with Enhanced Care as Usual, ECAU) or to ECAU only in a 1:1 ratio. Self‐Help Plus was delivered in a group format by two facilitators over five sessions. The primary outcome measure was the presence of any mental disorder assessed by the Mini International Neuropsychiatric Interview at six‐month follow‐up. Secondary outcome measures were the presence of mental disorders at post‐intervention, and psychological distress, symptoms of post‐traumatic stress disorder and depression, personally identified psychological outcomes, functional impairment, subjective well‐being, and quality of life at post‐intervention and six‐month follow‐up. Between October 1, 2018 and November 30, 2019, 1,186 refugees were assessed for inclusion. Five hundred forty‐four people were ineligible, and 642 participants were enrolled and randomly assigned to either Self‐Help Plus (N=322) or ECAU (N=320). Self‐Help Plus participants were significantly less likely to have any mental disorders at six‐month follow‐up compared to the ECAU group (21.69% vs. 40.73%; Cramer''s V = 0.205, p<0.001, risk ratio: 0.533, 95% CI: 0.408‐0.696). Analysis of secondary outcomes suggested that Self‐Help Plus was not effective immediately post‐intervention, but was associated with beneficial effects at six‐month follow‐up in terms of symptoms of depression, personally identified psychological outcomes, and quality of life. This is the first prevention RCT ever conducted among refugees experiencing psychological distress but without a mental disorder. Self‐Help Plus was found to be an effective strategy for preventing the onset of mental disorders. Based on these findings, this low‐intensity self‐help psychological intervention could be scaled up as a public health strategy to prevent mental disorders in refugee populations exposed to ongoing adversities.     

DJ‐1 depletion prevents immunoaging in T‐cell compartments

Decline in immune function during aging increases susceptibility to different aging‐related diseases. However, the underlying molecular mechanisms, especially the genetic factors contributing to imbalance of naïve/memory T‐cell subpopulations, still remain largely elusive. Here, we show that loss of DJ‐1 encoded by PARK7/DJ‐1, causing early‐onset familial Parkinson’s disease (PD), unexpectedly diminished signs of immunoaging in T‐cell compartments of both human and mice. Compared with two gender‐matched unaffected siblings of similar ages, the index PD patient with DJ‐1 deficiency showed a decline in many critical immunoaging features, including almost doubled non‐senescent T cells. The observation was further consolidated by the results in 45‐week‐old DJ‐1 knockout mice. Our data demonstrated that DJ‐1 regulates several immunoaging features via hematopoietic‐intrinsic and naïve‐CD8‐intrinsic mechanisms. Mechanistically, DJ‐1 depletion reduced oxidative phosphorylation (OXPHOS) and impaired TCR sensitivity in naïve CD8 T cells at a young age, accumulatively leading to a reduced aging process in T‐cell compartments in older mice. Our finding suggests an unrecognized critical role of DJ‐1 in regulating immunoaging, discovering a potent target to interfere with immunoaging‐ and aging‐associated diseases.     

Reducing ER stress with chaperone therapy reverses sleep fragmentation and cognitive decline in aged mice

As the aging population grows, the need to understand age‐related changes in health is vital. Two prominent behavioral changes that occur with age are disrupted sleep and impaired cognition. Sleep disruptions lead to perturbations in proteostasis and endoplasmic reticulum (ER) stress in mice. Further, consolidated sleep and protein synthesis are necessary for memory formation. With age, the molecular mechanisms that relieve cellular stress and ensure proper protein folding become less efficient. It is unclear if a causal relationship links proteostasis, sleep quality, and cognition in aging. Here, we used a mouse model of aging to determine if supplementing chaperone levels reduces ER stress and improves sleep quality and memory. We administered the chemical chaperone 4‐phenyl butyrate (PBA) to aged and young mice, and monitored sleep and cognitive behavior. We found that chaperone treatment consolidates sleep and wake, and improves learning in aged mice. These data correlate with reduced ER stress in the cortex and hippocampus of aged mice. Chaperone treatment increased p‐CREB, which is involved in memory formation and synaptic plasticity, in hippocampi of chaperone‐treated aged mice. Hippocampal overexpression of the endogenous chaperone, binding immunoglobulin protein (BiP), improved cognition, reduced ER stress, and increased p‐CREB in aged mice, suggesting that supplementing BiP levels are sufficient to restore some cognitive function. Together, these results indicate that restoring proteostasis improves sleep and cognition in a wild‐type mouse model of aging. The implications of these results could have an impact on the development of therapies to improve health span across the aging population.     

Risk and protective factors for mental disorders beyond genetics: an evidence‐based atlas

Decades of research have revealed numerous risk factors for mental disorders beyond genetics, but their consistency and magnitude remain uncer­tain. We conducted a “meta‐umbrella” systematic synthesis of umbrella reviews, which are systematic reviews of meta‐analyses of individual studies, by searching international databases from inception to January 1, 2021. We included umbrella reviews on non‐purely genetic risk or protective factors for any ICD/DSM mental disorders, applying an established classification of the credibility of the evidence: class I (convincing), class II (highly suggestive), class III (suggestive), class IV (weak). Sensitivity analyses were conducted on prospective studies to test for temporality (reverse causation), TRANSD criteria were applied to test transdiagnosticity of factors, and A Measurement Tool to Assess Systematic Reviews (AMSTAR) was employed to address the quality of meta‐analyses. Fourteen eligible umbrella reviews were retrieved, summarizing 390 meta‐analyses and 1,180 associations between putative risk or protective factors and mental disorders. We included 176 class I to III evidence associations, relating to 142 risk/protective factors. The most robust risk factors (class I or II, from prospective designs) were 21. For dementia, they included type 2 diabetes mellitus (risk ratio, RR from 1.54 to 2.28), depression (RR from 1.65 to 1.99) and low frequency of social contacts (RR=1.57). For opioid use disorders, the most robust risk factor was tobacco smoking (odds ratio, OR=3.07). For non‐organic psychotic disorders, the most robust risk factors were clinical high risk state for psychosis (OR=9.32), cannabis use (OR=3.90), and childhood adversities (OR=2.80). For depressive disorders, they were widowhood (RR=5.59), sexual dysfunction (OR=2.71), three (OR=1.99) or four‐five (OR=2.06) metabolic factors, childhood physical (OR=1.98) and sexual (OR=2.42) abuse, job strain (OR=1.77), obesity (OR=1.35), and sleep disturbances (RR=1.92). For autism spectrum disorder, the most robust risk factor was maternal overweight pre/during pregnancy (RR=1.28). For attention‐deficit/hyperactivity disorder (ADHD), they were maternal pre‐pregnancy obesity (OR=1.63), maternal smoking during pregnancy (OR=1.60), and maternal overweight pre/during pregnancy (OR=1.28). Only one robust protective factor was detected: high physical activity (hazard ratio, HR=0.62) for Alzheimer’s disease. In all, 32.9% of the associations were of high quality, 48.9% of medium quality, and 18.2% of low quality. Transdiagnostic class I‐III risk/protective factors were mostly involved in the early neurodevelopmental period. The evidence‐based atlas of key risk and protective factors identified in this study represents a benchmark for advancing clinical characterization and research, and for expanding early intervention and preventive strategies for mental disorders.     

Patterns and correlates of patient‐reported helpfulness of treatment for common mental and substance use disorders in the WHO World Mental Health Surveys

Patient‐reported helpfulness of treatment is an important indicator of quality in patient‐centered care. We examined its pathways and predictors among respondents to household surveys who reported ever receiving treatment for major depression, generalized anxiety disorder, social phobia, specific phobia, post‐traumatic stress disorder, bipolar disorder, or alcohol use disorder. Data came from 30 community epidemiological surveys – 17 in high‐income countries (HICs) and 13 in low‐ and middle‐income countries (LMICs) – carried out as part of the World Health Organization (WHO)’s World Mental Health (WMH) Surveys. Respondents were asked whether treatment of each disorder was ever helpful and, if so, the number of professionals seen before receiving helpful treatment. Across all surveys and diagnostic categories, 26.1% of patients (N=10,035) reported being helped by the very first professional they saw. Persisting to a second professional after a first unhelpful treatment brought the cumulative probability of receiving helpful treatment to 51.2%. If patients persisted with up through eight professionals, the cumulative probability rose to 90.6%. However, only an estimated 22.8% of patients would have persisted in seeing these many professionals after repeatedly receiving treatments they considered not helpful. Although the proportion of individuals with disorders who sought treatment was higher and they were more persistent in HICs than LMICs, proportional helpfulness among treated cases was no different between HICs and LMICs. A wide range of predictors of perceived treatment helpfulness were found, some of them consistent across diagnostic categories and others unique to specific disorders. These results provide novel information about patient evaluations of treatment across diagnoses and countries varying in income level, and suggest that a critical issue in improving the quality of care for mental disorders should be fostering persistence in professional help‐seeking if earlier treatments are not helpful.     

Efficacy and acceptability of pharmacological,psychosocial, and brain stimulation interventions in children and adolescents with mental disorders: an umbrella review

Top‐tier evidence on the safety/tolerability of 80 medications in children/adolescents with mental disorders has recently been reviewed in this jour­nal. To guide clinical practice, such data must be combined with evidence on efficacy and acceptability. Besides medications, psychosocial inter­ventions and brain stimulation techniques are treatment options for children/adolescents with mental disorders. For this umbrella review, we systematically searched network meta‐analyses (NMAs) and meta‐analyses (MAs) of randomized controlled trials (RCTs) evaluating 48 medications, 20 psychosocial interventions, and four brain stimulation techniques in children/adolescents with 52 different mental disorders or groups of mental disorders, reporting on 20 different efficacy/acceptability outcomes. Co‐primary outcomes were disease‐specific symptom reduction and all‐cause discontinuation (“acceptability”). We included 14 NMAs and 90 MAs, reporting on 15 mental disorders or groups of mental disorders. Overall, 21 medications outperformed placebo regarding the co‐primary outcomes, and three psychosocial interventions did so (while seven outperformed waiting list/no treatment). Based on the meta‐analytic evidence, the most convincing efficacy profile emerged for amphetamines, methylphenidate and, to a smaller extent, behavioral therapy in attention‐deficit/hyperactivity disorder; aripiprazole, risperidone and several psychosocial interventions in autism; risperidone and behavioral interventions in disruptive behavior disorders; several antipsychotics in schizophrenia spectrum disorders; fluoxetine, the combination of fluoxetine and cognitive behavioral therapy (CBT), and interpersonal therapy in depression; aripiprazole in mania; fluoxetine and group CBT in anxiety disorders; fluoxetine/selective serotonin reuptake inhibitors, CBT, and behavioral therapy with exposure and response prevention in obsessive‐compulsive disorder; CBT in post‐traumatic stress disorder; imipramine and alarm behavioral intervention in enuresis; behavioral therapy in encopresis; and family therapy in anorexia nervosa. Results from this umbrella review of interventions for mental disorders in children/adolescents provide evidence‐based information for clinical decision making.     

Reducing the treatment gap for mental disorders: a WPA survey

The treatment gap for people with mental disorders exceeds 50% in all countries of the world, approaching astonishingly high rates of 90% in the least resourced countries. We report the findings of the first systematic survey of leaders of psychiatry in nearly 60 countries on the strategies for reducing the treatment gap. We sought to elicit the views of these representatives on the roles of different human resources and health care settings in delivering care and on the importance of a range of strategies to increase the coverage of evidence-based treatments for priority mental disorders for each demographic stage (childhood, adolescence, adulthood and old age). Our findings clearly indicate three strategies for reducing the treatment gap: increasing the numbers of psychiatrists and other mental health professionals; increasing the involvement of a range of appropriately trained non-specialist providers; and the active involvement of people affected by mental disorders. This is true for both high income and low/middle income countries, though relatively of more importance in the latter. We view this survey as a critically important first step in ascertaining the position of psychiatrists, one of the most influential stakeholder communities in global mental health, in addressing the global challenge of scaling up mental health services to reduce the treatment gap.     

Biological mechanisms of aging predict age‐related disease co‐occurrence in patients

Genetic, environmental, and pharmacological interventions into the aging process can confer resistance to multiple age‐related diseases in laboratory animals, including rhesus monkeys. These findings imply that individual mechanisms of aging might contribute to the co‐occurrence of age‐related diseases in humans and could be targeted to prevent these conditions simultaneously. To address this question, we text mined 917,645 literature abstracts followed by manual curation and found strong, non‐random associations between age‐related diseases and aging mechanisms in humans, confirmed by gene set enrichment analysis of GWAS data. Integration of these associations with clinical data from 3.01 million patients showed that age‐related diseases associated with each of five aging mechanisms were more likely than chance to be present together in patients. Genetic evidence revealed that innate and adaptive immunity, the intrinsic apoptotic signaling pathway and activity of the ERK1/2 pathway were associated with multiple aging mechanisms and diverse age‐related diseases. Mechanisms of aging hence contribute both together and individually to age‐related disease co‐occurrence in humans and could potentially be targeted accordingly to prevent multimorbidity.     

Emerging experience with selected new categories in the ICD‐11: complex PTSD,prolonged grief disorder,gaming disorder,and compulsive sexual behaviour disorder

Among the important changes in the ICD‐11 is the addition of 21 new mental disorders. New categories are typically proposed to: a) improve the usefulness of morbidity statistics; b) facilitate recognition of a clinically important but poorly classified mental disorder in order to provide appropriate management; and c) stimulate research into more effective treatments. Given the major implications for the field and for World Health Organization (WHO) member states, it is important to examine the impact of these new categories during the early phase of the ICD‐11 implementation. This paper focuses on four disorders: complex post‐traumatic stress disorder, prolonged grief disorder, gaming disorder, and compulsive sexual behaviour disorder. These categories were selected because they have been the focus of considerable activity and/or controversy and because their inclusion in the ICD‐11 represents a different decision than was made for the DSM‐5. The lead authors invited experts on each of these disorders to provide insight into why it was considered important to add it to the ICD‐11, implications for care of not having that diagnostic category, important controversies about adding the disorder, and a review of the evidence generated and other developments related to the category since the WHO signaled its intention to include it in the ICD‐11. Each of the four diagnostic categories appears to describe a population with clinically important and distinctive features that had previously gone unrecognized as well as specific treatment needs that would otherwise likely go unmet. The introduction of these categories in the ICD‐11 has been followed by a substantial expansion of research in each area, which has generally supported their validity and utility, and by a significant increase in the availability of appropriate services.     

Regulatory KIR+RA+ T cells accumulate with age and are highly activated during viral respiratory disease

Severe respiratory viral infectious diseases such as influenza and COVID‐19 especially affect the older population. This is partly ascribed to diminished CD8⁺ T‐cell responses a result of aging. The phenotypical diversity of the CD8⁺ T‐cell population has made it difficult to identify the impact of aging on CD8⁺ T‐cell subsets associated with diminished CD8⁺ T‐cell responses. Here we identify a novel human CD8⁺ T‐cell subset characterized by expression of Killer‐cell Immunoglobulin‐like Receptors (KIR⁺) and CD45RA (RA⁺). These KIR⁺RA⁺ T cells accumulated with age in the blood of healthy individuals (20–82 years of age, n = 50), expressed high levels of aging‐related markers of T‐cell regulation, and were functionally capable of suppressing proliferation of other CD8⁺ T cells. Moreover, KIR⁺RA⁺ T cells were a major T‐cell subset becoming activated in older adults suffering from an acute respiratory viral infection (n = 36), including coronavirus and influenza virus infection. In addition, older adults with influenza A infection showed that higher activation status of their KIR⁺RA⁺ T cells associated with longer duration of respiratory symptoms. Together, our data indicate that KIR⁺RA⁺ T cells are a unique human T‐cell subset with regulatory properties that may explain susceptibility to viral respiratory disease at old age.     

E-mental health interventies voor mantelzorgers van ouderen: een overzicht

E-mental health interventions for family caregivers of older adults: a review Purpose: To present a systematic overview of the different e-mental health interventions for caregivers of older adults. Methods: Systematic literature research of implemented and evaluated e-mental interventions for caregivers of older adults. Results: Thirteen e-mental health interventions are included: six telephone, one camera and six internet interventions. In general, research on user friendliness and client satisfaction shows positive results. The effectiveness of three e-mental health interventions have been studied. The family-based structural in-home intervention with the computer telephone integrated system shows a decrease in depressive symptoms after six and eighteen month. The telephone linked computer system did not show positive mental health effects for the total group of family caregivers. After online lessons, caregivers were more capable to organize respite care and to manage disruptive and challenging behaviours of the care recipient. Their ability to solve their own problems increased and their subjective burden decreased. A cost analysis of an internet intervention shows a reduction in costs in comparison to regular care. Conclusion: E-mental health interventions for caregivers of older adults are encouraging, although research in this field is still in its infancy. Research on the effectiveness and cost-effectiveness of these type of interventions is needed. In addition, the opportunities of internet interventions could be used more extensively. Tijdschr Gerontol Geriatr 2007; 38: 274-287     

Plasma proteome profiling of healthy individuals across the life span in a Sicilian cohort with long‐lived individuals

The study of healthy human aging is important for shedding light on the molecular mechanisms behind aging to promote well‐being and to possibly predict and/or avoid the development of age‐related disorders such as atherosclerosis and diabetes. Herein, we have employed an untargeted mass spectrometry‐based approach to study age‐related protein changes in a healthy Sicilian plasma cohort including long‐lived individuals. This approach confirmed some of the previously known proteins correlated with age including fibulin‐1, dystroglycan, and gamma‐glutamyl hydrolase. Furthermore, our findings include novel proteins that correlate with age and/or with location and uric acid, which could represent a unique signature for healthy aging.     

α‐ketoglutarate delays age‐related fertility decline in mammals

The fecundity reduction with aging is referred as the reproductive aging which comes earlier than that of chronological aging. Since humans have postponed their childbearing age, to prolong the reproductive age becomes urgent agenda for reproductive biologists. In the current study, we examined the potential associations of α‐ketoglutarate (α‐KG) and reproductive aging in mammals including mice, swine, and humans. There is a clear tendency of reduced α‐KG level with aging in the follicle fluids of human. To explore the mechanisms, mice were selected as the convenient animal model. It is observed that a long term of α‐KG administration preserves the ovarian function, the quality and quantity of oocytes as well as the telomere maintaining system in mice. α‐KG suppresses ATP synthase and alterations of the energy metabolism trigger the nutritional sensors to down‐regulate mTOR pathway. These events not only benefit the general aging process but also maintain ovarian function and delay the reproductive decline. Considering the safety of the α‐KG as a naturally occurring molecule in energy metabolism, its utility in reproduction of large mammals including humans deserves further investigation.     

The antagonistic pleiotropy of insulin‐like growth factor 1

While insulin‐like growth factor‐1 (IGF‐1) is a well‐established modulator of aging and longevity in model organisms, its role in humans has been controversial. In this study, we used the UK Biobank (n = 440,185) to resolve previous ambiguities in the relationship between serum IGF‐1 levels and clinical disease. We examined prospective associations of serum IGF‐1 with mortality, dementia, vascular disease, diabetes, osteoporosis, and cancer, finding two generalized patterns: First, IGF‐1 interacts with age to modify risk in a manner consistent with antagonistic pleiotropy; younger individuals with high IGF‐1 are protected from disease, while older individuals with high IGF‐1 are at increased risk for incident disease or death. Second, the association between IGF‐1 and risk is generally U‐shaped, indicating that both high and low levels of IGF‐1 may be detrimental. With the exception of a more uniformly positive relationship between IGF‐1 and cancer, these effects were remarkably consistent across a wide range of conditions, providing evidence for a unifying pathway that determines risk for most age‐associated diseases. These data suggest that IGF‐1 signaling could be harmful in older adults, who may actually benefit from the attenuation of biological growth pathways.