Education mediating the associations between early life factors and frailty: a cross-sectional study of the UK Biobank.

OBJECTIVES: Exposures in utero and during infancy may impact the development of diseases later in life. They may be linked with development of frailty, although the mechanism is unclear. This study aims to determine the associations between early life risk factors and development of frailty among middle-aged and older adults as well as potential pathways via education, for any observed association. DESIGN: A cross-sectional study. SETTINGS: This study used data from UK Biobank, a large population-based cohort. PARTICIPANTS: 502 489 individuals aged 37-73 years were included in the analysis. PRIMARY AND SECONDARY OUTCOME MEASURES: Early life factors in this study included being breast fed as a baby, maternal smoking, birth weight, the presence of perinatal diseases, birth month and birth place (in or outside the UK). We developed a frailty index comprising 49 deficits. We used generalised structural equation modelling to examine the associations between early life factors and development of frailty and whether any observed association was mediated via educational attainment. RESULTS: A history of breast feeding and normal birth weight were associated with a lower frailty index while maternal smoking, the occurrence of perinatal diseases and birth month with a longer day length were associated with a higher frailty index. Educational level mediated the relationship between these early life factors and frailty index. CONCLUSIONS: This study highlights that biological and social risk occurring at different stages of life are related to the variations in frailty index in later life and suggests opportunities for prevention across the life course.

Associations between chronotype and employment status in a longitudinal study of an elderly population.

Individuals with an 'evening' chronotype tend to sleep and wake later than people described to be 'morning' type if given a free choice. Since early awakening times, due to school and occupation, may be more challenging for those with evening chronotype, they are expected to be at greater risk of adverse health, occupational and educational outcomes. Our objectives are to investigate associations between chronotype and occupational, educational and health outcomes in a longitudinal cohort. We use sleep, sociodemographic and health data from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age, 1982 through 2010. The relationship between employment and longitudinal midsleep trajectories were estimated using linear mixed models. Associations between employment status and Cornell Medical Index, Beck Depression Inventory scores, cortisol concentrations at different times of the day stratified by chronotype were estimated using regression. The relationship between chronotype, occupational success, education, and cognition were also examined using regression methods. In older adults, compared to non-employed participants, employed participants get up 0.45 hours earlier. Evening-type employed individuals had earlier midsleep time compared to their non-employed counterparts and had abnormal longitudinal trajectories with an increasing trend as they aged. Employed individuals with evening chronotype had a higher risk of depression than employed morning-types. Moreover, employed individuals with evening chronotype had a higher cortisol concentration at 14:00 h than non-employed individuals. In addition, memory score was lower in individuals with morning chronotype, however processing speed was higher in individuals with morning chronotype compared to evening. Morning-types had a higher age when they finished full time education. Relative to evening-types, those with morning chronotype were 6.5% more likely to be in a job classed as professional or intermediate. Our findings suggest that evening-types are at a disadvantage with regards to occupational, educational and health outcomes in older adults due to their vulnerability to circadian and sleep disruption.

Early life factors and COVID-19 infection in England: A prospective analysis of UK Biobank participants.

This study aims to examine whether maternal smoking, birth weight, birth month and breastfeeding are associated with COVID-19 infection and hospitalisation. Maternal smoking was positively associated with COVID-19 infection. Breastfeeding was negatively associated with COVID-19 infection. The odds of being hospitalised due to COVID-19 were higher among those who had lower birthweight and mothers who were smoking during pregnancy.

Interactions between season of birth, chronological age and genetic polymorphisms in determining later-life chronotype.

Human chronotype, the temporal pattern of daily behaviors, is influenced by postnatal seasonal programming and ageing. The aim of this study was to investigate genetic variants that are associated with season of birth programming and longitudinal chronotype change. Longitudinal sleep timing and genotype data from 1449 participants were collected for up to 27 years. Gene-environment interaction analysis was performed for 445 candidate single nucleotide polymorphisms that have previously been associated with chronotype. Associations were tested using linear mixed model. We identified 67 suggestively significant genomic loci that have genotype-ageing interaction and 25 genomic loci that may have genotype-season of birth interaction in determining chronotype. We attempted to replicate the results using longitudinal data of the UK Biobank from approximately 30,000 participants. Biological functions of these genes suggest that epigenetic regulation of gene expression and neural development may have roles in these processes. The strongest associated gene for sleep trajectories was ALKBH5, which has functions of DNA repair and epigenetic regulation. A potential candidate gene for postnatal seasonal programming was SIRT1, which has previously been implicated in postnatal programming, ageing and longevity. Genetic diversity may explain the heterogeneity in ageing-related change of sleep timing and postnatal environmental programming of later-life chronotype.

Seasonality and season of birth effect in the UK Biobank cohort.

OBJECTIVES: Humans live in environments that reduce the impact of seasonal cues. However, studies suggest that many aspects of human biology, such as birth, metabolism, health, and death are still annually rhythmic. METHODS: Using UK Biobank, a large (N = 502 536) population-based resource, we investigated the influence of seasonality on birth rate, basal metabolic rate, health, reaction speed, and sleep. We also investigated the association between season of birth and regional brain volumes, basal metabolic rate, health, reaction speed, and sleep. RESULTS: Our results showed that annual birth rate peaks in April and May. Individuals had the highest basal metabolic rate in December and January. Poorer subjective general health and slower reaction time were observed in May. Susceptibility to insomnia showed an opposite trend that peaked in autumn and winter. People reported shorter periods of sleep, easier waking, earlier chronotype, more daytime dozing, and napping in summer compared with winter. Our results suggest that season of birth may influence later-life characteristics. We also observed that the effect of season of birth is in the opposite direction of the seasonal rhythm for basal metabolic rate, reaction time, and insomnia. Moreover, our analysis showed that prevalence of allergy is higher among people born in spring compared to autumn. CONCLUSIONS: Overall, our findings indicate a significant effect of seasonality on a range of human traits and that early-life seasons appear to have an effect on health and behaviors in adulthood.

Longitudinal sleep efficiency in the elderly and its association with health.

The relationships between older age and sleep efficiency have traditionally been assessed using cross-sectional studies that ignore changes within individuals as they age. This research examines the determinants of sleep efficiency, the heterogeneity in an individual's sleep efficiency trajectory across a period of up to 27 years in later life and its associations with health. The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age cohort (n = 6,375; age 42-94 years) was used in this study. Depression and health data were collected using self-report validated instruments (Cornell Medical Index, Beck Depression Inventory and Geriatric Depression Scale). Longitudinal sleep and sociodemographic data were collected using a study-specific self-report questionnaire. A mixed-effect model was performed for sleep efficiency with adjustments for time-invariant and time-variant predictors. Latent class analysis was used to demonstrate subgroups of sleep efficiency trajectories and associations between sleep efficiency clusters and health history of the participants were investigated. Older adults have decreased sleep efficiency over time, with 18.6% decline between 40 and 100 years of age. Three sleep efficiency trajectory clusters were identified: high (32%), medium (50%) and low sleep efficiency (18%). Belonging to the high sleep efficiency cluster was associated with having lower prevalence of hypertension, circulatory problems, general arthritis, breathing problems and recurrent episodes of depression compared to the low efficiency cluster. Overall, ageing decreases sleep efficiency. However, there are detectable subgroups of sleep efficiency that are related to prevalence of different diseases.

Longitudinal change of sleep timing: association between chronotype and longevity in older adults.

Evening-oriented sleep timing preferences have been associated with risk of diabetes, cardiovascular diseases, obesity, psychiatric disorders, and increased mortality. This research aims to explore the relationship between diurnal preferences (chronotype), daily habits, metabolic health, and mortality, using longitudinal data from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age (6375 participants at inception, recruited in the North of England) with a long follow-up period (up to 35.5 years). Mixed models were used to investigate the influence of aging, socio-demographic, and seasonal factors on sleep timing. Results show that sleep timing shifted towards earlier time with aging. Test seasons influence chronotype of older adults but working schedules challenge seasonality of sleep timing. Moreover, the season of birth may set chronotype in adulthood. Individual chronotype trajectories were clustered using latent class analysis and analyzed against metabolic health and mortality. We observed a higher risk of hypertension in the evening-type cluster compared to morning-type individuals (Odds ratio = 1.88, 95%CI = 1.02/3.47, p = .04). Evening-type cluster was also associated with traits related to lower health such as reduced sport participation, increased risk of depression and psychoticism personality, late eating, and increased smoking and alcohol usage. Finally, Cox regression of proportional hazards was used to study the effects of chronotype on longevity after adjusting for sleep duration, age, gender, smoking, alcohol usage, general health, and social class. The survival analysis (82.6% censored by death) revealed that evening-type chronotype increased the likelihood of mortality (Hazard ratio = 1.15, 95%CI = 1.04/1.26, p = .005). Taken together, chronotype is influenced by aging and seasonal effects. Evening-type preference may have detrimental outcomes for human well-being and longevity.

Postnatal light alters hypothalamic-pituitary-adrenal axis function and induces a depressive-like phenotype in adult mice.

The postnatal light environment that a mouse experiences during the critical first three postnatal weeks has long-term effects on both its circadian rhythm output and clock gene expression. Furthermore, data from our lab suggest that postnatal light may also impact the hypothalamic-pituitary-adrenal (HPA) axis, which is a key regulator of stress. To test the effect of postnatal light exposure on adult stress responses and circadian rhythmicity, we raised mice under either 24-h light-dark cycles (LD), constant light (LL) or constant dark (DD) during the first three postnatal weeks. After weaning we then exposed all animals to LD cycles (basal conditions), followed by LL (stressed conditions) environments. We examined brain neuropeptide and glucocorticoid receptor (GR) expression, plasma corticosterone concentration rhythm and body temperature rhythm, together with depression- and anxiety-related behaviour. Results showed that LL- and DD-raised mice exhibited decreased GR expression in the hippocampus, increased plasma corticosterone concentration at the onset of the dark phase and a depressive phenotype when exposed to LD cycles later in life. Furthermore, LL-raised mice showed increased corticotrophin-releasing hormone mRNA expression in the paraventricular nucleus of the hypothalamus. When exposed to LL as adults, LL-raised mice showed a significant circadian rhythm of plasma corticosterone concentration, together with a shorter period and stronger circadian rhythm of body temperature compared to DD-raised mice. Taken together, these data suggest that altered postnatal light environments have long-term effects on the HPA axis and the circadian system, which can lead to altered stress responses and a depressive phenotype in adulthood.

Effects of type of light on mouse circadian behaviour and stress levels.

Light is the principal synchronizing environmental factor for the biological clock. Light quantity (intensity), and light quality (type of light source) can have different effects. The aim of this study was to determine the effects of the type of light experienced from the time of birth on mouse growth, circadian behaviour and stress levels. We raised pigmented and albino mice under 24 h light-dark cycles of either fluorescent or white light-emitting diode (LED) light source during the suckling stage, and the animals were then exposed to various light environments after weaning and their growth rate, locomotor activity and plasma corticosterone concentration were measured. We found that the type of light the animals were exposed to did not affect the animals' growth rates or stress levels. However, we observed significant effects on the expression of the locomotor activity rhythm under low contrast light-dark cycles in pigmented mice, and under constant light in both albino and pigmented mice. These results highlight the importance of environmental light quality (light source) on circadian behavioural rhythms, and the need for close monitoring of light environments in animal facilities.

Programming of mice circadian photic responses by postnatal light environment.

Early life programming has important consequences for future health and wellbeing. A key new aspect is the impact of perinatal light on the circadian system. Postnatal light environment will program circadian behavior, together with cell morphology and clock gene function within the suprachiasmatic nucleus (SCN) of the hypothalamus, the principal circadian clock in mammals. Nevertheless, it is still not clear whether the observed changes reflect a processing of an altered photic input from the retina, rather than an imprinting of the intrinsic molecular clock mechanisms. Here, we addressed the issue by systematically probing the mouse circadian system at various levels. Firstly, we used electroretinography, pupillometry and histology protocols to show that gross retinal function and morphology in the adult are largely independent of postnatal light experiences that modulate circadian photosensitivity. Secondly, we used circadian activity protocols to show that only the animal's behavioral responses to chronic light exposure, but not to constant darkness or the acute responses to a light stimulus depend on postnatal light experience. Thirdly, we used real-time PER2::LUC rhythm recording to show long-term changes in clock gene expression in the SCN, but also heart, lung and spleen. The data showed that perinatal light mainly targets the long-term adaptive responses of the circadian clock to environmental light, rather than the retina or intrinsic clock mechanisms. Finally, we found long-term effects on circadian peripheral clocks, suggesting far-reaching consequences for the animal's overall physiology.

Differential hypothalamic tyrosine hydroxylase distribution and activation by light in adult mice reared under different light conditions during the suckling period.

In mammals, early light experience during a critical period within the first 3 weeks of postnatal development has long-lasting effects on circadian locomotor activity behaviour and neuropeptide expression in the suprachiasmatic nucleus (SCN) of the hypothalamus, site of the principal pacemaker. Dopamine is thought to be involved in the modulation of photic input within the SCN and in tadpoles, the expression of tyrosine hydroxylase (TH), a rate-limiting enzyme in the synthesis of dopamine, in the SCN is altered by previous light history. We thus hypothesised that dopaminergic neurons may be important for the development of the adapted responses to light that we have previously observed. To test this, we raised mice in either constant darkness, 12:12 h light-dark cycles or constant light during the first 3 weeks after birth, and later examined the expression of TH and FOS in the hypothalamus of these mice as adults, both in the dark and after exposure to a light pulse. We found that early light experience affects TH and FOS expression, both baseline levels and in response to a light pulse, in brain areas which are directly connected to the SCN, and are associated with the circadian control of neuroendocrine function. Therefore, our results suggest that the long-lasting alterations induced by early light environment on several hypothalamic nuclei may be relayed through the SCN, and that TH-expressing cells may play a role in conveying/establishing these alterations. These data suggest a role of early light experience in the regulation of future hormonal homeostasis and circadian behaviour.

Early programming of astrocyte organization in the mouse suprachiasmatic nuclei by light.

The principal pacemaker in mammals, controlling physiology and behavior, is located in the suprachiasmatic nuclei (SCN) of the hypothalamus. Early photic experience has long-term effects on the animal's rhythmic behavior, as indicated by alterations in the phase shift induced by a light pulse, and in the expression of the circadian rhythm of locomotor activity under light-dark (LD), constant light (LL), and constant darkness (DD) environments. However, the brain substrates targeted by early light have not yet been identified. Possible candidates are astrocytes, as they develop postnatally in parallel to the circadian system, and are involved in SCN function by modulating intercellular communication and mediating photic input. Here, we reared three groups of mice under different light environments (LD, LL, and DD) during the suckling period. Later on, all mice were entrained to LD, and we determined associated astrocytic modifications by examining the expression of glial fibrillary acidic protein (GFAP) in the SCN. We observed that although LL-reared mice showed lowest GFAP expression in the SCN, as determined by quantification of immunostaining levels, the number of GFAP-positive cells was highest in this group, suggesting structural remodelling of SCN astrocytes by early light experience. These results indicate the postnatal light environment has long-term effects on the astrocytic population of the SCN. We argue that these neurochemical and structural alterations may affect clock function, which may in turn modify animal behavior