Commentary on the EMA reflection paper on the pharmaceutical development of medicines for use in the older population.

Older people are often affected by impaired organ and bodily functions resulting in multimorbidity and polypharmacy, turning them into the main user group of many medicines. Very often, medicines have not specifically been developed for older people, causing practical medication problems for them like limited availability of easy to swallow formulations, easy to open packaging and dosing instructions for enteral administration. In 2020, the European Medicines Agency (EMA) published a reflection paper 'Pharmaceutical development of medicines for use in the older population', which discusses how the emerging needs of an ageing European population can be addressed by medicines regulation. The paper intends to help industry to better consider the needs of older people during pharmaceutical/clinical medicines development by summarising data on the most relevant topics, providing early suggestions on how to move forward and prompting expert discussions and studies into knowledge gaps. Topics include patient acceptability, (dis)advantages of an administration route, formulation, dosage form, packaging, dosing device and user instruction. While the paper is directed at older people and the pharmaceutical industry, the reflections are also relevant to younger patients with similar disease-related needs and of value to other stakeholders parties, e.g., healthcare professionals, academics, patients and caregivers, as the paper makes clear what can be expected from industry and where collaborative work is needed. This commentary provides an overview of the different steps in the development of the reflection paper, discusses points considered most controversial and/or subject to (multidisciplinary) expert discussions and indicates their value for real world clinical practice.

Handgrip strength, ageing and mortality in rural Africa.

BACKGROUND: muscle strength measured as handgrip strength declines with increasing age and predicts mortality. While handgrip strength is determined by lifestyle through nutrition and physical activity, it has almost exclusively been studied in western populations with a sedentary lifestyle. This study aims to investigate the relation between handgrip strength, ageing and mortality in a population characterised by a predominance of malnutrition and manual labour. DESIGN: a population-based longitudinal study. SETTING: a traditional African rural population in Ghana. SUBJECTS: nine hundred and twenty-three community-dwelling individuals aged 50 and older. METHODS: demographic characteristics were registered. At baseline, height, body mass index (BMI) and handgrip strength were measured and compared with those in a western reference population. Survival of the participants was documented during a period of up to 2 years. RESULTS: handgrip strength was dependent on age, sex, height and BMI. Compared with the western reference population, handgrip strength was lower due to a lower height and BMI but declined over age similarly. Risk of mortality was lower in participants having higher handgrip strength, with a hazard ratio of 0.94 per kg increase (P = 0.002). After adjustment for age, sex, tribe, socio-economic status, drinking water source, height and BMI, only handgrip strength remained predictive of mortality. CONCLUSION: in a traditional rural African population characterised by malnutrition and manual labour, handgrip strength declines over age and independently predicts mortality similar to western populations. Handgrip strength can be used as a universal marker of ageing.

Scarcity of atrial fibrillation in a traditional African population: a community-based study.

BACKGROUND: In western societies, atrial fibrillation is an increasingly common finding among the elderly. Established risk factors of atrial fibrillation include obesity, diabetes, hypertension, and cardiovascular disease. Atrial fibrillation has almost exclusively been studied in western populations where these risk factors are widely present. Therefore, we studied the epidemiology of atrial fibrillation in a traditional African community. METHODS: In rural Ghana, among 924 individuals aged 50 years and older, we recorded electrocardiograms to detect atrial fibrillation. As established risk factors, we documented waist circumference, body mass index (BMI), capillary glucose level, blood pressure, and electrocardiographic myocardial infarction. In addition, we determined circulating levels of interleukin-6 (IL6), a proinflammatory cytokine, and C-reactive protein (CRP), a marker of systemic inflammation. We compared the risk factors with reference data from the USA. RESULTS: Atrial fibrillation was detected in only three cases, equalling 0.3% (95% CI 0.1-1.0%). Waist circumference, BMI, and capillary glucose levels were very low. Hypertension and myocardial infarction were uncommon. Circulating levels of IL6 were similar, but those of CRP were lower compared with the USA. CONCLUSION: Atrial fibrillation is very scarce in this traditional African community. Its low prevalence compared with western societies can be explained by the rareness of its established risk factors, which are closely related to lifestyle, and by possible unmeasured differences in other risk factors or genetic factors.

Older adults exercising ON TIME: protocol for a randomized controlled cross-over study to assess the effect of physical activity timing on insomnia severity.

BACKGROUND: There are increased indications that physical activity timing, irrespective of intensity, impacts insomnia and circadian clock function. Here, we describe the rationale and design of a randomized cross-over study, called ON TIME, to examine the effects of (changing) physical activity timing on insomnia severity and on multiple exploratory outcomes that are linked to circadian clock function. METHODS: We will conduct a randomized cross-over trial in 40 healthy older adults (aged 65 to 75 years) with subclinical or clinical insomnia (Insomnia Severity Index (ISI) scores of ≥ 10) from the Dutch municipality of Leiden and surroundings. Participants will undergo 3 intervention periods (14 days each) consecutively: one sedentary period and two periods of increased physical activity (one period with morning activity and one period with evening activity). The intervention periods are separated by a wash-out period of 1 week. In both active intervention arms, participants will follow coached or uncoached outdoor physical exercise sessions comprising endurance, strength, and flexibility exercises for 14 days. The primary outcome is change in insomnia severity as measured by the ISI. Additional exploratory outcomes include multiple components of objective sleep quality measured with tri-axial accelerometry and subjective sleep quality assessed by questionnaires as well as dim light melatonin onset and 24-h rhythms in heart rate, heart rate variability, breathing rate, oxygen saturation, mood, and objective emotional arousal and stress. Additionally, we will collect diary data on eating patterns (timing and composition). Finally, fasting blood samples will be collected at baseline and after each intervention period for measurements of biomarkers of metabolic and physiological functioning and expression of genes involved in regulation of the biological clock. DISCUSSION: We anticipate that this study will make a significant contribution to the limited knowledge on the effect of physical activity timing. Optimizing physical activity timing has the potential to augment the health benefits of increased physical exercise in the aging population. TRIAL REGISTRATION: Trial was approved by the Medical Ethics Committee Leiden, The Hague, Delft, The Netherlands (June, 2023). The trial was registered in the CCMO-register https://www.toetsingonline.nl/to/ccmo_search.nsf/Searchform?OpenForm under study ID NL82335.058.22 and named ("Ouderen op tijd in beweging" or in English "Older adults exercising on time"). At time of manuscript submission, the trial was additionally registered at ClinicalTrials.gov under study ID: NL82335.058.22 and is awaiting approval.

Collective Prevention of Non-Communicable Diseases in an Ageing Population with Community Care.

The Dutch population is rapidly ageing, and a growing number of people are suffering from age-related health problems such as obesity, cardiovascular diseases and diabetes. These diseases can be prevented or delayed by adapting healthy behaviours. However, making long-lasting lifestyle changes has proven to be challenging and most individual-based lifestyle interventions have not been effective on the long-term. Prevention programs focused on lifestyle should involve the physical and social context of individuals, because the (social) environment plays a large role in both conscious and unconscious lifestyle choices. Collective prevention programmes are promising strategies to mobilize the potential of the (social) environment. However, little is known about how such collective prevention programs could work in practice. Together with community care organization Buurtzorg, we have started a 5 year evaluation project to study how collective prevention can be practised in communities. In this paper, we discuss the potential of collective prevention and explain the methods and goals of our study.

Setting your clock: associations between timing of objective physical activity and cardiovascular disease risk in the general population.

AIMS: Little is known about the impact of daily physical activity timing (here referred to as 'chronoactivity') on cardiovascular disease (CVD) risk. We aimed to examined the associations between chronoactivity and multiple CVD outcomes in the UK Biobank. METHODS AND RESULTS: physical activity data were collected in the UK-Biobank through triaxial accelerometer over a 7-day measurement period. We used K-means clustering to create clusters of participants with similar chronoactivity irrespective of the mean daily intensity of the physical activity. Multivariable-adjusted Cox-proportional hazard models were used to estimate hazard ratios (HRs) comparing the different clusters adjusted for age and sex (model 1), and baseline cardiovascular risk factors (model 2). Additional stratified analyses were done by sex, mean activity level, and self-reported sleep chronotype. We included 86 657 individuals (58% female, mean age: 61.6 [SD: 7.8] years, mean BMI: 26.6 [4.5] kg/m2). Over a follow-up period of 6 years, 3707 incident CVD events were reported. Overall, participants with a tendency of late morning physical activity had a lower risk of incident coronary artery disease (HR: 0.84, 95%CI: 0.77, 0.92) and stroke (HR: 0.83, 95%CI: 0.70, 0.98) compared to participants with a midday pattern of physical activity. These effects were more pronounced in women (P-value for interaction = 0.001). We did not find evidence favouring effect modification by total activity level and sleep chronotype. CONCLUSION: Irrespective of total physical activity, morning physical activity was associated with lower risks of incident cardiovascular diseases, highlighting the potential importance of chronoactivity in CVD prevention.

Linking a peer coach physical activity intervention for older adults to a primary care referral scheme.

BACKGROUND: Physical inactivity has contributed to the current prevalence of many age-related diseases, including type 2 diabetes and cardiovascular disease. Peer coach physical activity intervention are effective in increasing long term physical activity in community dwelling older adults. Linking peer coach physical activity interventions to formal care could therefore be a promising novel method to improve health in inactive older adults to a successful long-term physical activity intervention. METHODS: We evaluated the effects of linking a peer coach physical activity intervention in Leiden, The Netherlands to primary care through an exercise referral scheme from July 2018 to April 2020. Primary care practices in the neighborhoods of three existing peer coach physical activity groups were invited to refer patients to the exercise groups. Referrals were registered at the primary care practice and participation in the peer coach groups was registered by the peer coaches of the exercise groups. RESULTS: During the study, a total of 106 patients were referred to the peer coach groups. 5.7% of patients participated at the peer coach groups and 66.7% remained participating during the 1 year follow up. The number needed to refer for 1 long term participant was 26.5. The mean frequency of participation of the referred participants was 1.2 times a week. CONCLUSION: Linking a peer coach physical activity intervention for older adults to a primary care referral scheme reached only a small fraction of the estimated target population. However, of the people that came to the peer coach intervention a large portion continued to participate during the entire study period. The number needed to refer to engage one older person in long term physical activity was similar to other referral schemes for lifestyle interventions. The potential benefits could be regarded proportional to the small effort needed to refer.

[From healthy individuals to healthy populations]. / Van gezonde individuen naar gezonde populaties.

In the study by Verstraeten et al. higher rates of mortality were observed in Caribbean islands that have a higher degree of autonomy to their original colonizer. This study highlights how population determinants can affect population health. Geoffrey Rose was one of the first to propose to study population determinants and use a population strategy of prevention to create healthy populations. The study by Verstraeten et al. indicates the importance of population determinants and challenges us to think about our own population determinants. We experience an epidemic of obesity, diabetes type 2 and cardiovascular disease in the Netherlands. The current approach of identifying high risk individuals and individually targeting has not brought this epidemic to an end. A population approach could be a promising alternative to greatly improve public health.

Common CFTR gene variants influence body composition and survival in rural Ghana.

Various studies in mice have found support for the hypothesis that heterozygous carriers of cystic fibrosis transmembrane conductance regulator (CFTR) mutations have an increased resistance to fatal infection compared to both homozygous mutation carriers and non-carriers, while in humans such evidence is scarce. In this study, we assessed the CFTR heterozygotes survival advantage hypothesis in a contemporary rural population that lives under adverse environmental conditions in the Upper-East region of Ghana. We genotyped 30 SNPs throughout the CFTR gene in 4,230 participants and tested their influence on survival and on body composition in the population at large. With a sliding-window haplotype analysis, we identified a set of six common haplotypes that influenced survival probabilities (global p = 6.00 x 10(-05)). Individual haplotype analyses revealed two haplotypes of specific interest. One of these haplotypes was enriched (p = 0.003), whereas the other was depleted (p = 0.041) among people of old age (> or = 65 years) compared to young study participants (< or = 5 years). In addition, children (n = 474) carrying the latter haplotype had lower body weight (p (trend) = 0.020) and height (p (trend) = 0.010) compared to non-carriers. For all these analyses, similar associations for heterozygous and homozygous CFTR haplotype carriers were observed, revealing an additive effect of haplotype alleles. In conclusion, we identified common haplotypes in the CFTR gene that influence survival and body composition in the population at large with no evidence for heterozygote advantage.

Genetic variation in pentraxin (PTX) 3 gene associates with PTX3 production and fertility in women.

Pentraxin 3 (PTX3) plays an important role in innate immune responses and in female fertility, as discovered with studies in mice. However, the role of PTX3 in human fertility is unknown. Here, we report on a population-based study from a rural area of Upper East Ghana (n = 4346). We studied the association between the number of children given birth by women during their lifetime and ex vivo, lipopolysaccharide (LPS)-induced PTX3 production (n = 362). In addition, we studied the association of genetic variation in the PTX3 gene with PTX3 production (n = 617) and with female fertility (n = 1999). We found that ex vivo LPS-induced PTX3 production was associated with fertility (P = 0.040). Furthermore, we identified genetic variants in the PTX3 gene that influence PTX3 production, and also fertility. The strongest associations were observed for the rs6788044 single-nucleotide polymorphism (SNP). We found that carriers of this SNP had higher PTX3 production capacity (P = 0.003) and higher fertility (P = 0.043). The results reported here provide the first evidence, based on protein production and analysis of polymorphisms, that the long pentraxin PTX3 plays a role in female fertility in humans.

When grandmothers matter.

In a recent issue of this journal, Herndon discussed the grandmother hypothesis and its implications for studies on cognitive ageing. According to this hypothesis, the long post-reproductive life span in human females is an adaptive mechanism that evolved to maximize female fitness by investing resources in the care of their grandchildren rather than by continuing to reproduce themselves. From this, Herndon deduces that special cognitive robustness to be maintained until after the age of menopause must have co-evolved because grandmothers can only exert the beneficial effect if their cognitive abilities remain intact. He therefore pleas to compare cognitive ageing in humans with other primates, especially chimpanzees, because they lack a long post-reproductive life span and would therefore not have evolved this cognitive robustness. Here, we question the important role of grandmothers in our evolutionary past, first because of the different family structures during this time and second because of the low number of females that actually lived to experience a post-reproductive lifespan. We also show that in a population that reflects our evolutionary past, grandmothers do not have an important role for child survival. Finally, we react on the implications for the study of cognitive ageing as put forward by Herndon.

Self-organizing peer coach groups to increase daily physical activity in community dwelling older adults.

Many older adults do not reach the recommended level of physical activity, despite many professional-delivered physical activity interventions. Here we study the implementation of a novel physical activity intervention for older adults that is self-sustainable (no financial support) and self-organizing (participants act as organizers) due to peer coaching. We implemented three groups and evaluated process and effect using participatory observations, questionnaires, six-minute walk tests and body composition measures from October 2016 to September 2018. The intervention was implemented by staff without experience in physical activity interventions. Facilitators were a motivated initiator and a non-professional atmosphere for participants to take ownership. Barriers were the absence of motivated participants to take ownership and insufficient participants to ensure the presence of participants at every exercise session. The groups exercised outside five days a week and were self-organizing after 114, 216 and 263 days. The initial investments were 170€ for sport equipment and 81-187 h. The groups reached 118 members and a retention of 86.4% in two years. The groups continue to exist at the time of writing and are self-sustainable. Quality of life increased 0.4 on a ten-point scale (95%CI 0.1-0.7; p = 0.02) and six-minute walk test results improved with 33 m (95%CI 18-48; p < 0.01) annually. Self-organizing peer coach groups for physical activity are feasible, have positive effects on health and require only a small investment at the start. It is a sustainable and potentially scalable intervention that could be a promising method to help many older adults age healthier.

Adverse environmental conditions influence age-related innate immune responsiveness.

BACKGROUND: The innate immune system plays an important role in the recognition and induction of protective responses against infectious pathogens, whilst there is increasing evidence for a role in mediating chronic inflammatory diseases at older age. Despite indications that environmental conditions can influence the senescence process of the adaptive immune system, it is not known whether the same holds true for the innate immune system. Therefore we studied whether age-related innate immune responses are similar or differ between populations living under very diverse environmental conditions. METHODS: We compared cross-sectional age-related changes in ex vivo innate cytokine responses in a population living under affluent conditions in the Netherlands (age 20-68 years old, n = 304) and a population living under adverse environmental conditions in Ghana (age 23-95 years old, n = 562). RESULTS: We found a significant decrease in LPS-induced Interleukin (IL)-10 and Tumor Necrosis Factor (TNF) production with age in the Dutch population. In Ghana a similar age-related decline in IL-10 responses to LPS, as well as to zymosan, or LPS plus zymosan, was observed. TNF production, however, did not show an age-associated decline, but increased significantly with age in response to co-stimulation with LPS and zymosan. CONCLUSION: We conclude that the decline in innate cytokine responses is an intrinsic ageing phenomenon, while pathogen exposure and/or selective survival drive pro-inflammatory responses under adverse living conditions.

End-of-life care in the Dutch medical curricula.

INTRODUCTION: Future doctors must be trained in giving appropriate care to terminal patients. In several countries, medical curricula have been reviewed for the attention devoted to end-of-life care (ELC). In the Netherlands, no formal review had been performed. Therefore, the aim of this study was to provide an overview of the Dutch medical curricula regarding ELC. METHODS: We formed a checklist based on international standards consisting of five domains of ELC education that are considered essential. Firstly, we studied the Dutch national blueprint on medical education. Secondly, using a questionnaire based on the checklist we studied the curricula of the eight medical faculties. A questionnaire was sent to all Dutch medical faculties to study the compulsory courses of the curricula. To assess the elective courses, we consulted the study guides. RESULTS: The national blueprint included four of the five domains of ELC. None of the eight medical faculties taught all domains specifically on ELC; they were taught within other courses. Most attention was given to the domains on psychological, sociological, cultural and spiritual aspects; communication and conversational techniques; and juridical and ethical aspects. One faculty taught an elective course that included all essential aspects of the international standards. DISCUSSION: Our study shows that ELC is currently insufficiently mentioned in the national blueprint and that none of the faculties fully integrated ELC as a part of their compulsory medical curricula. To improve ELC education, we recommend the Dutch Federation of University Medical Centres to add the five ELC domains to the national blueprint and we recommend the medical faculties to review their curricula and offer a separate and compulsory course on ELC to prepare their students for their future medical practice.

Vitality club: a proof-of-principle of peer coaching for daily physical activity by older adults.

Many age-related diseases can be prevented or delayed by daily physical activity. Unfortunately, many older adults do not perform physical activity at the recommended level. Professional interventions do not reach large numbers of older adults for a long period of time. We studied a peer-coach intervention, in which older adults coach each other, that increased daily physical activity of community dwelling older adults for over 6 years. We studied the format and effects of this peer coach intervention for possible future implementation elsewhere. Through interviews and participatory observation we studied the format of the intervention. We also used a questionnaire (n = 55) and collected 6-min walk test data (n = 261) from 2014 to 2016 to determine the motivations of participants and effects of the intervention on health, well-being and physical capacity. Vitality Club is a self-sustainable group of older adults that gather every weekday to exercise coached by an older adult. Members attend on average 2.5 days per week and retention rate is 77.5% after 6 years. The members perceived improvements in several health measures. In line with this, the 6-min walk test results of members of this Vitality Club improved with 21.7 meters per year, compared with the decline of 2-7 meters per year in the general population. This Vitality Club is successful in durably engaging its members in physical activity. The members perceive improvements in health that are in line with improvements in a physical function test. Because of the self-sustainable character of the intervention, peer coaching has the potential to be scaled up at low cost and increase physical activity in the increasing number of older adults.

Regulation of human life histories: the role of the inflammatory host response.

Most species with a long life span have few offspring while species with a short life span have many offspring. This evolutionary trade-off between fertility and body maintenance, based on the theory of r/K-selection, is a central theme in the theory of life history regulation. This trade-off is not only found between various species but also between individuals within one species. There is accumulating evidence for this trade-off in humans. We hypothesize that the innate immune system is a critical factor skewing an individual into the direction of either a high fertility or better maintenance strategy. As over thousands of years human survival has been highly dependent on resistance to infectious diseases, genetic adaptations resulting in inflammatory responses were favored. An inflammatory host response is critical to fight infection necessary to survive up to reproductive age. An inflammatory host response is also negatively associated with fertility and can explain for the trade-off between fertility and body maintenance. After human reproductive age, these inflammatory responses contribute also to development of chronic degenerative diseases. These will especially become apparent in affluent societies where the majority of individuals reach old age. Identifying the inflammatory host response as a critical factor both in the regulation of human life histories and in the occurrence of chronic diseases at old age implies means for intervention allowing individuals to live healthier for longer.

Intellectual maturity and longevity: late-blooming composers and writers live longer than child prodigies.

Life history theory links human physical and sexual development to longevity. However, there have been no studies on the association of intellectual development with longevity. This observational study investigates the relationship between the onset of intellectual maturity and lifespan through the life histories of composers and creative writers, whose intellectual development can be gauged through their compositions and writings. In these groups we model the relationship between the age at first creative work, and age at death using multilevel regression, adjusting for sex, date of birth, and nationality. Historical biographical records on 1110 musical composers and 1182 creative writers, born in the period 1400 AD through 1915 AD, were obtained from the Oxford Companion to Music and the Oxford Companion to English Literature. Composers and creative writers lived, respectively 0.16 (p = 0.02) and 0.18 (p < 0.01) years longer for each later year of age at first work. When completion of the first creative work is interpreted as a proxy for the onset of intellectual maturity in composers and creative writers, our findings indicate that a later onset of intellectual maturity is associated with higher longevity.

Early and extraordinary peaks in physical performance come with a longevity cost.

Life history theory postulates a trade-off between development and maintenance. This trade-off is observed when comparing life histories of different animal species. In humans, however, it is debated if variation in longevity is explained by differences in developmental traits. Observational studies found a trade-off between early and high fecundity and longevity in women. Development encompasses more than fecundity and also concerns growth and physical performance. Here, we show a life history trade-off between early and above average physical performance and longevity in male Olympic athletes. Athletes who peaked at an earlier age showed 17-percent increased mortality rates (95% CI 8-26% per SD, p≤0.001) and athletes who ranked higher showed 11-percent increased mortality rates (95% CI 1-22% per SD, p=0.025). Male athletes who had both an early and extraordinary peak performance suffered a 4.7-year longevity cost. (95% CI 2.1-7.5 years, p=0.001). This is the first time a life history trade-off between physical performance and longevity has been found in humans. This finding deepens our understanding of early developmental influences on the variation of longevity in humans.

An Emerging Epidemic of Noncommunicable Diseases in Developing Populations Due to a Triple Evolutionary Mismatch.

With their transition from adverse to affluent environments, developing populations experience a rapid increase in the number of individuals with noncommunicable diseases. Here, we emphasize that developing populations are more susceptible than western populations to acquire these chronic diseases, because their genetic, cultural, and epigenetic characteristics do not match with the eagerly awaited affluent environments. In regard to this, there is an urgent need for public health organizations to reorganize current environments in developing populations so as to fit their inherited characteristics. Unfortunately, this need is neglected as an essential part of the Sustainable Development Goals that form the core of the United Nations' Post-2015 Development Agenda. Only through global collaborative efforts can the environments in developing populations be reorganized and, thereby, the emerging epidemic of noncommunicable diseases be stalled.

Measuring aging rates of mice subjected to caloric restriction and genetic disruption of growth hormone signaling.

Caloric restriction and genetic disruption of growth hormone signaling have been shown to counteract aging in mice. The effects of these interventions on aging are examined through age-dependent survival or through the increase in age-dependent mortality rates on a logarithmic scale fitted to the Gompertz model. However, these methods have limitations that impede a fully comprehensive disclosure of these effects. Here we examine the effects of these interventions on murine aging through the increase in age-dependent mortality rates on a linear scale without fitting them to a model like the Gompertz model. Whereas these interventions negligibly and non-consistently affected the aging rates when examined through the age-dependent mortality rates on a logarithmic scale, they caused the aging rates to increase at higher ages and to higher levels when examined through the age-dependent mortality rates on a linear scale. These results add to the debate whether these interventions postpone or slow aging and to the understanding of the mechanisms by which they affect aging. Since different methods yield different results, it is worthwhile to compare their results in future research to obtain further insights into the effects of dietary, genetic, and other interventions on the aging of mice and other species.