Daan R. van der Veen

Controlled studies have demonstrated that light supplementation benefits circadian entrainment, sleep and mood. Translating these findings into effective, real‐world usage of light supplementation is, however, challenging because naturalistic and supplemental light exposure are shaped by personal habits and environmental light conditions. Bridging this translation gap is especially critical for older adults, given the reduced ocular light sensitivity associated with natural ageing, which exacerbates low daytime indoor light exposure in urban housing. We therefore set out to investigate the determinants of self‐directed light supplementation in this population, and what the real‐world feasibility and efficacy of daytime light supplementation is. We recruited 202 participants (63–92 years; 139 females) to our interventional, prospective, randomised study in three major EU cities at different latitudes (Amsterdam, Bologna, Tartu). Participants underwent a 2‐week baseline assessment of light exposure, rest–activity patterns and sleep through wearables and daily diaries. Participants were then randomised to either 12 weeks of self‐implemented indoor light supplementation using a lamp placed in their most frequently used room (> 8000 melanopic EDI, N = 98) or a no‐intervention group. A subsequent 2‐week reassessment showed that greater naturalistic light exposure was associated with increased daytime activity, consolidated wakefulness, better subjective sleep quality, and reduced metabolic disorder incidence. Individuals with lower naturalistic light exposure self‐initiated earlier and longer indoor light supplementation across seasons, in which supplementation onset before 10:00 was associated with greater daytime activity and lower rest–activity fragmentation. These results confirm that this simple, non‐pharmacological, and low‐cost intervention has broad potential to support healthy ageing in urban settings.

Peripheral blood metabolite concentrations vary with food intake and time of day, risking confounding effects in metabolomics studies with non-standardised sampling conditions or incomplete metadata. Such effects are often overlooked during study design, limiting the clinical translation of biomarkers and wasting resources for researchers, funders and clinicians. In our random sample of 100 human metabolomics studies, 56% did not control for food intake, and 59% did not explicitly control for sampling time. To provide a study design resource, we analysed a liquid-chromatography–mass-spectrometry-targeted dataset from controlled laboratory studies of 24 young, healthy participants (12 male, 12 female) sampled every 2 h for 34 h, with fixed-macronutrient meals provided at set times. Acute postprandial responses were quantified by effect size using pre- and post-meal windows, while daily rhythmicity was assessed using a mixed-effects cosinor model. Analyses were sex-stratified, and metabolites were classified as meal-responsive, time-of-day-responsive, both, or neither. Amino acids and their derivatives showed strong postprandial increases, whereas lipid classes showed minimal changes. Rhythmicity varied across metabolites, enabling the identification of features sensitive to meal timing and/or time of day. These results aim to provide a comprehensive dictionary of metabolite effect sizes for study design and metadata collection to support reproducibility and the clinical translation of potential biomarkers.

Shift work is associated with insulin resistance, dyslipidaemia and metabolic syndrome, but how consecutive meals at the same clock times differentially shape postprandial metabolism in day‐ and night‐shifts remains unclear. This study used a unique simulated shift work intervention with four consecutive meals and high‐resolution sampling to examine interactions of endogenous rhythms and behavioural timing on postprandial metabolism. Nine healthy non‐shift‐worker participants (age 21–33 years, 3 females) completed a strictly‐controlled laboratory protocol with a day‐shift followed by two night‐shifts of 10‐h delayed sleep and mealtimes. Participants consumed four identical, isoenergetic, mixed‐composition meals per shift. Three of four mealtimes (08:00, 18:00, 22:00) were fixed across conditions; the first and last meals were 1 h after waking and before bedtime. Plasma glucose, insulin, triglycerides, HDL‐cholesterol and total cholesterol were measured hourly, with continuous interstitial glucose monitoring. Subjective hunger and appetite were assessed throughout. Plasma lipid rhythms shifted with the 10‐h delay in sleep–wake times: acrophases delayed ~10–13 h and amplitudes lowered 46%–54% (all p < 0.01). Night‐shifts elevated postprandial glucose (+165 mmol/L·min, 95% CI 1.05–34.31, p = 0.05) and insulin (+7678.7 mmol/L·min, 95% CI 3671.02–11686.38, p < 0.01). Time‐of‐day effects persisted irrespective of shift, with 18:00 meals producing the highest glycaemic responses (+261 mmol/L·min, 95% CI 124.37–398.01, p < 0.01). Insulin dynamics did not fully compensate for elevated glycaemia in night‐shifts, indicating lower glucose tolerance and insulin sensitivity. Mistimed meals suggest a mechanism by which circadian disruption may increase metabolic disease risk.

Rural communities in resource-limited settings are exposed to seasonal patterns in food insecurity. The pre- and early post-natal period is a key developmental window, sensitive to nutritional availability and quality. While season of birth has been associated with differences in epigenetic, developmental and health outcomes, it is unclear if this imprints on the developing metabolome and contributes to adverse phenotypic outcomes. Here we show that urinary and plasma metabolites in Tanzanian infants follow seasonal waveforms dependent upon their month of birth, persisting up to at least 18 months of life, which were related to food insecurity, breastmilk composition and rainfall. This includes developmentally relevant metabolites, including choline, trimethylamine- N -oxide, and polyunsaturated fatty acids. Cognitive measures at 18 months also followed seasonal waveforms based upon month of birth which correlated with seasonal metabolites. Additionally, variation in metabolic status modulated the effectiveness of a maternal-infant nicotinamide intervention targeting stunting. Our findings show that seasonal environmental pressures shape mother-infant dyad food insecurity with lasting ramifications for the infant metabolome and development. These findings support the need for season-dependent nutritional and lifestyle interventions targeting developmental shortfalls in these communities.

The Asian malaria vector Anopheles stephensi is invading Africa, requiring it to adapt to novel climates and ecosystems. In part, this may be facilitated by An. stephensi ’s poorly understood seasonal behavioural plasticity in flight timing, leading to earlier biting activity in cold Asian winters and later biting times in the warm summer. Changes in behavioural timing could be directly imposed by seasonal variation in ambient light and temperature levels or result from altered entrainment of intrinsically expressed circadian rhythms by these factors. We demonstrate that An. stephensi entrained flight activity timing is phase-locked to dawn and is not affected by constant ambient temperature, which cannot explain earlier biting activity in colder winters with later dawn. Instead, we show that where night temperatures are the colder part of daily temperature cycle; the entrained phase-angle between dawn and flight activity is altered, hereby increasingly colder, winter-like nights progressively advance flight activity onset. We propose that seasonal timing plasticity optimizes behaviour to warmer daytime in winter, and colder nights in summer, providing protection against both heat-desiccation and cold immobility. The adaptive advantage of this plasticity could be relevant to the successful invasion and survival of An. stephensi in African climates, and changing climate worldwide. This article is part of the Theo Murphy meeting issue, ‘Circadian rhythms in infection and immunity’.

Low indoor light in urban housing can disrupt health and wellbeing, especially in older adults who experience reduced light sensitivity and sleep/circadian disruptions with natural aging. While controlled studies suggest that enhancing indoor lighting may alleviate the negative effects of reduced light sensitivity, evidence for this to be effective in the real world is lacking. This study investigates the effects of two light conditions on actigraphic rest-activity rhythms and subjective sleep in healthy older adults (≥ 60 years) living at home. Two photon-matched lights were compared; a control white light (4000 K) and a blue-enriched white light (17000 K) at two different intensities (300–450 lx and 1100–1200 lx respectively). Participants (n = 36, 25 female) completed an 11-week randomized, cross-over study, comprising 1 week of baseline, 3 weeks of self-administered light exposure (2 h in the morning and 2 h in the evening), and 2 weeks of washout for each light condition. Participants completed sleep diaries, wore a wrist actigraph and a light sensor necklace, and collected urine to measure 6-sulphatoxymelatonin. Longer duration of morning blue-enriched light significantly improved rest-activity rhythm stability and decreased sleep fragmentation. More time spent above 2500 lx increased actigraphy amplitude, daytime activity, and advanced bedtime. Evening light exposure, however, increased sleep latency and lowered sleep efficiency. Our findings show morning blue-enriched light is beneficial whereas evening light should be avoided. Optimal timing of self-administered light interventions thus may offer a promising strategy to improve sleep and rest-activity rhythms in older adults in real-world settings.

Rapid, ultradian biological rhythms are only partly comparable to circadian (24-h) rhythms. Often, the ensuing expectations from this comparison are that 1) ultradian rhythms should be driven by discrete oscillators, 2) they are biochemically buffered, and 3) they must be functionally linked to extrinsic events and cycles. These three expectations are not always met, but perhaps there is an adaptive benefit to ultradian rhythms not meeting these expectations, which sets them functionally apart from circadian rhythms. In view of the extensive descriptions of the manifold types of ultradian rhythms across all biological levels (e.g., see papers in this research topic), it seems important to ask whether we should actively create a new set of definitions and expectations. To make a start, we here lay out some important questions we need to ask about ultradian rhythms. We then illustrate how these questions highlight one key area of exploration: the linked expression of ultradian rhythms in metabolism and behaviour and the role this plays in addressing a negative energy balance.

Bile acids are trans-genomic molecules arising from the concerted metabolism of the human host and the intestinal microbiota and are important for digestion, energy homeostasis and metabolic regulation. While diurnal variation has been demonstrated in the enterohepatic circulation and the gut microbiota, existing human data are poorly resolved, and the influence of the host circadian system has not been determined. Using entrained laboratory protocols, we demonstrate robust daily rhythms in the circulating bile acid pool in healthy male participants. We identify temporal relationships between bile acids and plasma lipids and show that these relationships are lost following sleep deprivation. We also highlight that bile acid rhythmicity is predominantly lost when environmental timing cues are held constant. Here we show that the environment is a stronger determinant of these temporal dynamics than the intrinsic circadian system of the host. This has significance for the intimate relationship between circadian timing and metabolism.

Time-of-day variation in the molecular profile of biofluids and tissues is a well-described phenomenon, but – especially for proteomics – is rarely considered in terms of the challenges this presents to reproducible biomarker identification. In this work we demonstrate these confounding issues using a small-scale proteomics analysis of male participants in a constant routine protocol following an 8-day laboratory study, in which sleep-wake, light-dark and meal timings were controlled. We provide a case study analysis of circadian and ultradian rhythmicity in proteins in the complement and coagulation cascades, as well as apolipoproteins, and demonstrate that rhythmicity increases the risk of Type II errors due to the reduction in statistical power from increased variance. For the proteins analysed herein we show that to maintain statistical power if chronobiological variation is not controlled for, n should be increased (by between 9% and 20%); failure to do so would increase β, the chance of Type II error, from a baseline value of 20% to between 22% and 28%. Conversely, controlling for rhythmic time-of-day variation in study design offers the opportunity to improve statistical power and reduce the chances of Type II errors. Indeed, control of time-of-day sampling is a more cost-effective strategy than increasing sample sizes. We recommend that best practice in proteomics study design should account for temporal variation as part of sampling strategy where possible. Where this is impractical, we recommend that additional variance from chronobiological effects be considered in power calculations, that time of sampling be reported as part of study metadata, and that researchers reference any previously identified rhythmicity in biomarkers and pathways of interest. These measures would mitigate against both false and missed discoveries, and improve reproducibility, especially in studies looking at biomarkers, pathways or conditions with a known chronobiological component.

Background and Aims: Chemotherapy-induced peripheral neurotoxicity (CIPN) is one of the most common dose-limiting side effects of paclitaxel (PTX) treatment. Many age-related changes have been hypothesized to underlie susceptibility to damage or impaired regeneration/repair after nerve injury. The results of these studies, however, are inconclusive and other potential biomarkers of nerve impairment need to be investigated.Methods: Twenty-four young (2 months) and 24 adult (9 months) Wistar male rats were randomized to either PTX treatment (10 mg/kg i.v. once/week for 4 weeks) or vehicle administration. Neurophysiological and behavioral tests were performed at baseline, after 4 weeks of treatment and 2-week follow-up. Skin biopsies and nerve specimens collected from sacrificed animals were examined for intraepidermal nerve fiber (IENF) density assessment and nerve morphology/morphometry. Blood and liver samples were collected for targeted metabolomics analysis.Results: At the end of treatment, the neurophysiological studies revealed a reduction in sensory nerve action potential amplitude (p < .05) in the caudal nerve of young PTX-animals, and in both the digital and caudal nerve of adult PTX-animals (p < .05). A significant decrease in the mechanical threshold was observed only in young PTX-animals (p < .001), but not in adult PTX-ones. Nevertheless, both young and adult PTX-rats had reduced IENF density (p < .0001), which persisted at the end of follow-up period. Targeted metabolomics analysis showed significant differences in the plasma metabolite profiles between PTX-animals developing peripheral neuropathy and age-matched controls, with triglycerides, diglycerides, acylcarnitines, carnosine, long chain ceramides, sphingolipids, and bile acids playing a major role in the response to PTX administration.Interpretation: Our study identifies for the first time multiple related metabolic axes involved in PTX-induced peripheral neurotoxicity, and suggests age-related differences in CIPN manifestations and in the metabolic profile.