Parental age effects and Rett syndrome.

Rett syndrome (RTT) is a progressive neurodevelopmental disorder, and pathogenic Methyl-CpG-binding Protein 2 (MECP2) variants are identified in >95% of individuals with typical RTT. Most of RTT-causing variants in MECP2 are de novo and usually on the paternally inherited X chromosome. While paternal age has been reported to be associated with increased risk of genetic disorders, it is unknown whether parental age contributes to the risk of the development of RTT. Clinical data including parental age, RTT diagnostic status, and clinical severity are collected from 1226 participants with RTT and confirmed MECP2 variants. Statistical analyses are performed using Student t-test, single factor analysis of variance (ANOVA), and multi-factor regression. No significant difference is observed in parental ages of RTT probands compared to that of the general population. A small increase in parental ages is observed in participants with missense variants compared to those with nonsense variants. When we evaluate the association between clinical severity and parental ages by multiple regression analysis, there is no clear association between clinical severity and parental ages. Advanced parental ages do not appear to be a risk factor for RTT, and do not contribute to the clinical severity in individuals with RTT.

Limiting access to assisted reproductive technologies for males of advanced age-Pros and cons from a Nordic perspective.

It is not controversial to state that parental age is increasing in several countries. But how to deal with this increase might be. Some Nordic countries have set an upper age limit for females seeking assisted reproduction in their national legislation, but none have done so for males. There are also recommendations in place that restrict access to publicly funded assisted reproduction for both females and males of advanced age in some Nordic countries. As recent data now show somatic and psychiatric health risks related to advanced paternal age, we ask if the time has come for countries to set an upper age limit for males seeking assisted reproduction like there already is for females, and summarize some of the risks and rewards involved in treating couples with advanced age in fertility clinics.

Consequences of heterogeneity in aging: parental age at death predicts midlife all-cause mortality and hospitalization in a Swedish national birth cohort.

BACKGROUND: The processes that underlie aging may advance at different rates in different individuals and an advanced biological age, relative to the chronological age, is associated with increased risk of disease and death. Here we set out to quantify the extent to which heterogeneous aging shapes health outcomes in midlife by following a Swedish birth-cohort and using parental age at death as a proxy for biological age in the offspring. METHODS: We followed a nationwide Swedish birth cohort (N = 89,688) between the ages of 39 and 66 years with respect to hospitalizations and death. Cox regressions were used to quantify the association, in the offspring, between parental age at death and all-cause mortality, as well as hospitalization for conditions belonging to the 10 most common ICD-10 chapters. RESULTS: Longer parental lifespan was consistently associated with reduced risks of hospitalization and all-cause mortality. Differences in risk were mostly evident from before the age of 50 and persisted throughout the follow-up. Each additional decade of parental survival decreased the risk of offspring all-cause mortality by 22% and risks of hospitalizations by 9 to 20% across the 10 diseases categories considered. The number of deaths and hospitalizations attributable to having parents not living until old age were 1500 (22%) and 11,000 (11%) respectively. CONCLUSIONS: Our findings highlight that increased parental lifespan is consistently associated with health benefits in the offspring across multiple outcomes and suggests that heterogeneous aging processes have clinical implications already in midlife.

Associations of parental age at pregnancy with adolescent cognitive development and emotional and behavioural problems: a birth cohort in rural Western China.

BACKGROUND: The relationship between parental age at pregnancy and offspring development in low- and middle-income countries remains unclear. We aimed to examine the associations of parental age at pregnancy with adolescent development in rural China. METHODS: We conducted a prospective birth cohort study of offspring born to pregnant women who participated in an antenatal micronutrient supplementation trial in rural Western China. Adolescent cognitive development and emotional and behavioural problems were assessed by using the Wechsler Intelligence Scale for Children-IV and the Youth Self-Report-2001, respectively. After accounting for the possible nonlinear relationships, we examined the linear associations between parental age (in years) at pregnancy and scores of adolescent cognitive development and emotional and behavioural problems by performing generalized estimating equations. RESULTS: Among 1897 adolescents followed from birth to early adolescence, 59.5% were male with a mean age of 11.8 (standard deviation (SD): 0.8) years. The mean ages of mothers and fathers at pregnancy were 24.6 (SD: 4.4) and 27.9 (SD: 4.1) years old, respectively. All the P values of the nonlinear terms between parental age and adolescent development in all domains were greater than 0.05. Each one-year increase in maternal age at pregnancy was associated with a 0.29-point (95% confidence interval (CI) 0.06, 0.52) increase in the full-scale intelligence quotient in early adolescence. After parental age was categorized into quartiles, the total behavioural problem scores of adolescents with fathers with an age in the fourth quartile (Q4) were 6.71 (95% CI 0.86, 12.57) points higher than those of adolescents with fathers with an age in the first quartile (Q1), with a linear trend P value of 0.01. Similarly, higher scores (worse behavioural problems) were observed for internalizing behavioural problems and other emotional and behavioural symptoms related to anxiety, withdrawal, social problems, thought problems and aggressive behaviour. CONCLUSIONS: At conception, older maternal age was independently linked to better adolescent cognitive development, whereas advanced paternal age was independently associated with a greater risk of adolescent emotional and behavioral problems. These findings suggest that public health policies targeting an optimal parental age at pregnancy should be developed in the context of offspring developmental consequences.

Persistence of parental age effect on somatic mutation rates across generations in Arabidopsis.

In the model plant Arabidopsis thaliana, parental age is known to affect somatic mutation rates in their immediate progeny and here we show that this age dependent effect persists across successive generations. Using a set of detector lines carrying the mutated uidA gene, we examined if a particular parental age maintained across five consecutive generations affected the rates of base substitution (BSR), intrachromosomal recombination (ICR), frameshift mutation (FS), and transposition. The frequency of functional GUS reversions were assessed in seedlings as a function of identical/different parental ages across generations. In the context of a fixed parental age, BSR/ICR rates were unaffected in the first three generations, then dropped significantly in the 4th and increased in most instances in the 5th generation (e.g. BSR (F1 38 = 0.9, F2 38 = 1.14, F3 38 = 1.02, F4 38 = 0.5, F5 38 = 0.76)). On the other hand, with advancing parental ages, BSR/ICR rates remained high in the first two/three generations, with a striking resemblance in the pattern of mutation rates (BSR (F1 38 = 0.9, F1 43 = 0.53, F1 48 = 0.79, F1 53 = 0.83 and F2 38 = 1.14, F2 43 = 0.57, F2 48 = 0.64, F2 53 = 0.94). We adopted a novel approach of identifying and tagging flowers pollinated on a particular day, thereby avoiding biases due to potential emasculation induced stress responses. Our results suggest a time component in counting the number of generations a plant has passed through self-fertilization at a particular age in determining the somatic mutation rates.

Early-life telomeres are influenced by environments acting at multiple temporal and spatial scales.

An individual's telomere length early in life may reflect or contribute to key life-history processes sensitive to environmental variation. Yet, the relative importance of genetic and environmental factors in shaping early-life telomere length is not well understood as it requires samples collected from multiple generations with known developmental histories. We used a confirmed pedigree and conducted an animal model analysis of telomere lengths obtained from nestling house sparrows (Passer domesticus) sampled over a span of 22 years. We found significant additive genetic variation for early-life telomere length, but it comprised a small proportion (9%) of the total biological variation. Three sources of environmental variation were important: among cohorts, among-breeding attempts within years, and among nestmates. The magnitude of variation among breeding attempts and among nestmates also differed by cohort, suggesting that interactive effects of environmental factors across time or spatial scales were important, yet we were unable to identify the specific causes of these interactions. The mean amount of precipitation during the breeding season positively predicted telomere length, but neither weather during a given breeding attempt nor date in the breeding season contributed to an offspring's telomere length. At the level of individual nestlings, offspring sex, size and mass at 10 days of age also did not predict telomere length. Environmental effects appear especially important in shaping early-life telomere length in some species, and more focus on how environmental factors that interact across scales may help to explain some of the variation observed among studies.

The psychosocial outcomes of older parenthood in early to mid-childhood: a mini-review.

Recent decades have seen a global trend towards delaying parenthood, referred to as the 'postponement transition'. Whilst there is plentiful research regarding obstetric and paediatric outcomes related to delayed parenthood, relatively little is known about the psychosocial outcomes associated with advanced parental age during early and middle childhood. This mini-review examines the current literature regarding the psychosocial functioning of families headed by older parents. First, we give an overview of the literature that examines the psychological wellbeing of older first-time parents. We then review the literature regarding the quality of the parent-child relationship in older parent families. Finally, we discuss the psychosocial adjustment and cognitive development of children of older parents. We conclude with suggestions for future research avenues.

Advanced parental age affects cardiometabolic risk in offspring.

Advanced age at conception usually refers to human mothers aged 35 years plus and fathers aged 40 years plus. Advanced parental age may be responsible for genetic and/or epigenetic alterations and may affect the health of offspring. Limited epidemiological and experimental studies have addressed the effect of advanced parental age on cardio-metabolic functions in human and rodent offspring. This mini review aimed to present the knowledge by focusing on adverse and favourable outcomes related to sex-specific risks and intergenerational inheritance. The outcomes identified by this review were mainly negative, but there were also some positive results.

Associations of parental mental disorders and age with childhood mental disorders: a population-based cohort study with four million offspring.

This Taiwan study examined the associations of parental age and mental disorders with the offspring risks of attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), major depressive disorder (MDD), and bipolar disorder (BD). Children born between January 1991 and December 2004 in Taiwan were enrolled as the birth cohort (n = 4,138,151) and followed up until December 2011. A logistic regression analysis was performed to identify the odds ratio (OR). The advanced age effects were significant in ADHD (range of OR: 1.04 to 1.49) and ASD (range of OR: 1.35 to 2.27). Teenage mothers, teenage fathers, and fathers ≥ 50 years had higher offspring risks of MDD (range of OR: 1.24 to 1.46); and teenage mothers and fathers ≥ 50 years had increased offspring risks of BD (range of OR: 1.23 to 1.87). Both paternal and maternal mental disorders were associated with higher risks of within-disorder transmission for ADHD, ASD, MDD, and BD (range of OR: 2.64 to 30.41). Besides, parents with one of these four mental disorders (ADHD, ASD, MDD, and BD) might have higher risk of cross-disorder transmission to at least one of the other three mental disorders in the offspring (range of OR: 1.35 to 7.15). Parental age and mental disorders had complex and nuanced patterns in association with offspring mental disorders.

Delayed parenthood and its influence on offspring health: what have we learned from the mouse model†.

Delayed parenthood is constantly increasing worldwide due to various socio-economic factors. In the last decade, a growing number of epidemiological studies have suggested a link between advanced parental age and an increased risk of diseases in the offspring. Also, poor reproductive outcome has been described in pregnancies conceived by aged parents. Similarly, animal studies showed that aging negatively affects gametes, early embryonic development, pregnancy progression, and the postnatal phenotype of resulting offspring. However, how and to what extent parental age is a risk factor for the health of future generations is still a subject of debate. Notwithstanding the limitation of an animal model, the mouse model represents a useful tool to understand not only the influence of parental age on offspring phenotype but also the biological mechanisms underlying the poor reproductive outcome and the occurrence of diseases in the descendants. The present review aims at i) providing an overview of the current knowledge from mouse model about the risks associated with conception at advanced age (e.g. neurodevelopmental and metabolic disorders), ii) highlighting the candidate biological mechanisms underlying this phenomenon, and iii) discussing on how murine-derived data can be relevant to humans.

Causes and consequences of variation in development time in a field cricket.

Variation in development time can affect life-history traits that contribute to fitness. In Gryllus vocalis, a non-diapausing cricket with variable development time, we used a path analysis approach to determine the causative relationships between parental age, offspring development time and offspring life-history traits. Our best-supported path model included both the effects of parental age and offspring development time on offspring morphological traits. This result suggests that offspring traits are influenced by both variation in acquisition of resources and trade-offs between traits. We found that crickets with longer development times became larger adults with better phenoloxidase-based immunity. This is consistent with the hypothesis that crickets must make a trade-off between developing quickly to avoid predation before reproduction and attaining better immunity and a larger adult body size that provides advantages in male-male competition, mate choice and female fecundity. Slower-developing crickets were also more likely to be short-winged (unable to disperse by flight). Parental age has opposing direct and indirect effects on the body size of daughters, but when both the direct and indirect effects of parental age are taken into account, younger parents had smaller sons and daughters. This pattern may be attributable to a parental trade-off between the number and size of eggs produced with younger parents producing more eggs with fewer resources per egg. The relationships between variables in the life-history traits of sons and daughters were similar, suggesting that parental age and development time had similar causative effects on male and female life-history traits.

An exploration of parental age in relation to parents' psychological health, child adjustment and experiences of being an older parent in families formed through egg donation.

RESEARCH QUESTION: Is parental age associated with parents' psychological health, couple relationship satisfaction and child adjustment in egg donation families, and how do parents think and feel about their age in relation to parenting? DESIGN: Seventy-two families with a child born after IVF egg donation were included. Mothers were aged between 32 and 51 years and fathers between 31 and 61 years when the target child was born. When the child was aged 5 years, parents were interviewed and asked to complete questionnaire assessments of parenting stress, anxiety, depression, marital quality and child adjustment. RESULTS: Older parents experienced more parenting stress and poorer couple relationship quality than younger parents. No differences were found for child adjustment. Qualitative content analysis of the interviews revealed themes related to 'health and mortality', 'giving and receiving support', 'treatment and age', 'positive aspects of older parenting' and 'other'. CONCLUSIONS: This exploratory study found that older parents experienced greater parental stress and poorer relationship quality. Some parents had concerns about their older age, specifically in relation to their health and mortality. It would be important to follow up these families as the child grows older to understand the child's thoughts and feelings about having older parents. Furthermore, findings should be replicated in a larger sample of families formed through egg donation, which includes more younger mothers who have used egg donation.

Conception by assisted reproductive technology in infants with critical congenital heart disease in Japan.

RESEARCH QUESTION: What is the proportion of infants born as a result of assisted reproductive technology ART across different types of neonatal critical congenital heart disease (CCHD) in a Japanese population? DESIGN: A retrospective analysis of 418 consecutive infants with CCHD that required catheter treatment or surgery within the first 28 days of life or ductal-dependent lesions, in two paediatric centres in Japan, between January 2014 and December 2019. The proportion of ART in infants with each type of CCHD was evaluated. The proportion of ART in infants with univentricular heart defect (UVH) compared with those with biventricular heart defect (BVH) was evaluated. RESULTS: The study group included 229 boys and 189 girls, with a gestational age of 38 ± 2 weeks. Overall, 61 infants (14.6%) were conceived by fertility treatment with 46 (11.0%) conceived by ART. Univentricular heart defect and BVH were identified in 111 infants (26.6%) and 307 infants (73.4%), respectively. The proportion of infants conceived by ART was significantly higher in UVH (16.2%) than in BVH (9.1%) (OR 2.28, 95% CI 1.11 to 4.68, P = 0.025), regardless of maternal age and maternal history of miscarriage. CONCLUSIONS: The proportion of ART in infants with CCHD, especially UVH, was high. These findings could form the basis of a rationale for carrying out fetal echocardiography in fetuses conceived by ART.

Marital status, immigration, and reproductive health among adolescent mothers in Canada, 1990-2018: A population-based, observational study.

Immigrants to Canada increasingly come from regions where child marriage (<18 years) is prevalent. We described the prevalence, demographic characteristics, and reproductive health correlates of marriage among births to Canadian-born and foreign-born adolescent mothers. Using Canadian birth registrations from 1990 to 2018, marriage prevalence, parental birth region, and parental age gap were examined by maternal birthplace (Canada and 12 world regions) among births to mothers <18 years. Adjusted odds ratios (AORs) of preterm birth (PTB), small for gestational age (SGA), and repeat birth were estimated for the joint associations of adolescent maternal age group (<18-year, 18-19-year, and 20-24-year), marriage, and nativity status (n = 1,904,200). Depending on maternal birthplace, marital births represented 2.6% to 81.8% of births to mothers <18 years. Marriage among mothers giving birth at <18 years was associated with higher proportions of parents from the same birthplace and larger parental age gaps. AORs of PTB tended to increase with lower maternal age. AORs of SGA were generally higher among births to foreign-born mothers. Marriage was associated with lower AORs of PTB and SGA among births to Canadian-born mothers and PTB among births to foreign-born mothers in the older adolescent age groups, but no association existed in the <18-year group. Marriage was positively associated with repeat birth in all adolescent age groups, with stronger associations in the <18-year group. The reproductive health correlates of marriage are similar between births to Canadian-born and foreign-born mothers <18 years but some differ between births to mothers <18 years and those to older adolescent mothers.

The influence of parental age on timing of puberty: A study in the Danish National Birth Cohort.

Aims: Concerns have been raised about the potential negative biological effect of postponed parenthood upon the health of subsequent generations, including reproductive health. This study aimed to estimate if high parental age at birth was associated with accelerated pubertal timing in offspring. Methods: In this large-scale cohort study, 15,819 children born by mothers in the Danish National Birth Cohort from 2000 to 2003 participated in a nationwide puberty cohort (participation rate 71%). Between 2012 and 2018, the children reported half-yearly information on pubertal status using web-based questionnaires from 11 years throughout puberty or 18 years of age. Information on parental age was drawn from nationwide registers. We estimated adjusted mean differences in months for age at attaining the pubertal milestones and pubertal timing overall between the pre-specified parental age groups: 20-29 (reference), 30-34 and advanced parental age groups (35-44 years for mothers and >35 years for fathers). Results: Overall, parental age at birth of the child was not associated with pubertal timing in daughters or sons. For sons of older fathers (>35 years), we observed indications towards slightly earlier pubertal timing in the range of 0.3-2.4 months for nearly all pubertal milestones, but all confidence intervals were wide, and many included the null. Conclusions: We found no strong association between parental age and timing of puberty, and we find it unlikely that the decreasing age in pubertal timing is a result of parental decision to delay childbearing.

Sociodemographic impact of variables on cognitive, language and motor development in very preterm infants.

BACKGROUND: In the last decades, the birth of premature babies has increased, it is important to know the impact of certain variables, especially in the most vulnerable groups. PURPOSE: To analyse the relationship of gestational age (GA), weight and sex of the children, as well as the educational level and age of the parents with the cognitive, motor and language development of a group of very preterm births, assessed at 36 months. DESIGN AND METHODS: The research followed a descriptive, observational and cross-sectional design. Children's development was measured using the Bayley-III Scale. Descriptive analysis, bivariate and linear regression models were carried out. RESULTS: Although the cognitive, motor and language development is within average levels, worse results are evidenced in the group of extreme premature, as opposed to the very premature. Boys score lower than girls, with these differences being more pronounced in the motor area. It also shows how the education level of both parents is related to the levels of development at 3 years of age of children born very prematurely, especially in language. CONCLUSIONS: Lower GA, male sex and lower parental educational level are associated with higher risk of developmental difficulties. PRACTICE IMPLICATIONS: The findings of this study are relevant to clinical practice because they suggest to develop protocols of evaluation and the follow up of all premature children beyond 36 months, as well as developing specific intervention programmes for the most vulnerable of the premature groups.

Beneficial cumulative effects of old parental age on offspring fitness.

Old parental age is commonly associated with negative effects on offspring life-history traits. Such parental senescence effects are predicted to have a cumulative detrimental effect over successive generations. However, old parents may benefit from producing higher quality offspring when these compete for seasonal resources. Thus, old parents may choose to increase investment in their offspring, thereby producing fewer but larger and more competitive progeny. We show that Caenorhabditis elegans hermaphrodites increase parental investment with advancing age, resulting in fitter offspring who reach their reproductive peak earlier. Remarkably, these effects increased over six successive generations of breeding from old parents and were subsequently reversed following a single generation of breeding from a young parent. Our findings support the hypothesis that offspring of old parents receive more resources and convert them into increasingly faster life histories. These results contradict the theory that old parents transfer a cumulative detrimental 'ageing factor' to their offspring.

The role of sperm and oocyte in fetal programming: Is Lamarck making a comeback?

Compelling evidence has shown that parental experiences and age at conception may potentially shape the future health of the next generation(s). Certain factors may affect both the female and, strikingly, the male gametes potentially causing the transmission of acquired traits, which was strongly defended by Jean-Baptiste Lamarck. Neurodevelopmental psychiatric disorders, trinucleotide repeat-associated diseases, cardiovascular pathologies, diabetes, obesity and cancer in the offspring, among others, have now been associated with events occurring at the preconception level. The potential implications of a (trans)generational inheritance of parental disease and exposure effects should be taken into account in counselling and public policy. Further research into how exactly gametes apparently deliver more than DNA to a new generation is warranted.

Estimation of environmental, genetic and parental age at conception effects on telomere length in a wild mammal.

Understanding individual variation in fitness-related traits requires separating the environmental and genetic determinants. Telomeres are protective caps at the ends of chromosomes that are thought to be a biomarker of senescence as their length predicts mortality risk and reflect the physiological consequences of environmental conditions. The relative contribution of genetic and environmental factors to individual variation in telomere length is, however, unclear, yet important for understanding its evolutionary dynamics. In particular, the evidence for transgenerational effects, in terms of parental age at conception, on telomere length is mixed. Here, we investigate the heritability of telomere length, using the 'animal model', and parental age at conception effects on offspring telomere length in a wild population of European badgers (Meles meles). Although we found no heritability of telomere length and low evolvability (<0.001), our power to detect heritability was low and a repeatability of 2% across individual lifetimes provides a low upper limit to ordinary narrow-sense heritability. However, year (32%) and cohort (3%) explained greater proportions of the phenotypic variance in telomere length, excluding qPCR plate and row variances. There was no support for cross-sectional or within-individual parental age at conception effects on offspring telomere length. Our results indicate a lack of transgenerational effects through parental age at conception and a low potential for evolutionary change in telomere length in this population. Instead, we provide evidence that individual variation in telomere length is largely driven by environmental variation in this wild mammal.

Longitudinal evidence that older parents produce offspring with longer telomeres in a wild social bird.

As telomere length (TL) often predicts survival and lifespan, there is considerable interest in the origins of inter-individual variation in TL. Cross-generational effects of parental age on offspring TL are thought to be a key source of variation, but the rarity of longitudinal studies that examine the telomeres of successive offspring born throughout the lives of parents leaves such effects poorly understood. Here, we exploit TL measures of successive offspring produced throughout the long breeding tenures of parents in wild white-browed sparrow weaver (Plocepasser mahali) societies, to isolate the effects of within-parent changes in age on offspring TLs. Our analyses reveal the first evidence to date of a positive within-parent effect of advancing age on offspring TL: as individual parents age, they produce offspring with longer telomeres (a modest effect that persists into offspring adulthood). We consider the potential for pre- and post-natal mechanisms to explain our findings. As telomere attrition predicts offspring survival to adulthood in this species, this positive parental age effect could impact parent and offspring fitness if it arose via differential telomere attrition during offspring development. Our findings support the view that cross-generational effects of parental age can be a source of inter-individual variation in TL.