Early life interventions metformin and trodusquemine metabolically reprogram the developing mouse liver through transcriptomic alterations.

Recent studies have demonstrated the remarkable potential of early life intervention strategies at influencing the course of postnatal development, thereby offering exciting possibilities for enhancing longevity and improving overall health. Metformin (MF), an FDA-approved medication for type II diabetes mellitus, has recently gained attention for its promising anti-aging properties, acting as a calorie restriction mimetic, and delaying precocious puberty. Additionally, trodusquemine (MSI-1436), an investigational drug, has been shown to combat obesity and metabolic disorders by inhibiting the enzyme protein tyrosine phosphatase 1b (Ptp1b), consequently reducing hepatic lipogenesis and counteracting insulin and leptin resistance. In this study, we aimed to further explore the effects of these compounds on young, developing mice to uncover biomolecular signatures that are central to liver metabolic processes. We found that MSI-1436 more potently alters mRNA and miRNA expression in the liver compared with MF, with bioinformatic analysis suggesting that cohorts of differentially expressed miRNAs inhibit the action of phosphoinositide 3-kinase (Pi3k), protein kinase B (Akt), and mammalian target of rapamycin (Mtor) to regulate the downstream processes of de novo lipogenesis, fatty acid oxidation, very-low-density lipoprotein transport, and cholesterol biosynthesis and efflux. In summary, our study demonstrates that administering these compounds during the postnatal window metabolically reprograms the liver through induction of potent epigenetic changes in the transcriptome, potentially forestalling the onset of age-related diseases and enhancing longevity. Future studies are necessary to determine the impacts on lifespan and overall quality of life.

Early-life participation in cognitively stimulating activities and risk of depression and anxiety in late life.

BACKGROUND: Early-life stressful experiences are associated with increased risk of adverse psychological outcomes in later life. However, much less is known about associations between early-life positive experiences, such as participation in cognitively stimulating activities, and late-life mental health. We investigated whether greater engagement in cognitively stimulating activities in early life is associated with lower risk of depression and anxiety in late life. METHODS: We surveyed former participants of the St. Louis Baby Tooth study, between 22 June 2021 and 25 March 2022 to collect information on participants' current depression/anxiety symptoms and their early-life activities (N = 2187 responded). A composite activity score was created to represent the early-life activity level by averaging the frequency of self-reported participation in common cognitively stimulating activities in participants' early life (age 6, 12, 18), each rated on a 1 (least frequent) to 5 (most frequent) point scale. Depression/anxiety symptoms were measured by Patient Health Questionnaire (PHQ-9) and Generalized Anxiety Disorder Screener (GAD-7). We used logistic regressions to estimate odds ratios (OR) and 95% confidence intervals (CI) of outcome risk associated with frequency of early-life activity. RESULTS: Each one-point increase in the early-life composite cognitive activity score was associated with an OR of 0.54 (95% CI 0.38-0.77) for late-life depression and an OR of 0.94 (95% CI 0.61-1.43) for late-life anxiety, adjusting for age, sex, race, parental education, childhood family structure, and socioeconomic status. CONCLUSIONS: More frequent participation in cognitively stimulating activities during early life was associated with reduced risk of late-life depression.

Early Life Interventions Can Shape Aging.

It is well documented that the environment of the developing fetus, including availability of nutrients and presence of toxins, can have major impact on adult phenotype, age-related traits and risk of chronic disease. There is also accumulating evidence that postnatal environment can impact adult characteristics related to evolutionary fitness, health, and aging. To determine whether early life hormonal interventions can alter trajectory of aging, we have examined the effects of early life growth hormone (GH) replacement therapy in Prop1df (Ames dwarf) mice which are GH deficient and remarkably long lived. Twice-daily GH injections between the ages of two and eight weeks completely normalized ("rescued") a number of adult metabolic characteristics believed to contribute to extended longevity of these mutants. Importantly, longevity of Ames dwarf mice was reduced by early life GH treatment. This was associated with histone H3 modifications. We conclude that the trajectory of mammalian aging can be modified by early life interventions. Mechanistic links among interventions during postnatal development, adult metabolic characteristics, aging, and longevity, apparently involve epigenetic phenomena.

Social Nesting, Animal Welfare, and Disease Monitoring.

The assessment of welfare and disease progression in animal models is critical. Most tools rely on evaluating individual subjects, whereas social behaviors, also sensitive to acute illness, chronic diseases, or mental health, are scarcely monitored because they are complex and time-consuming. We propose the evaluation of social nesting, a species-typical behavior naturally occurring in standard housing conditions, for such behavioral monitoring. We provide an example of its use to evaluate social deficits and the long-term effects of neonatal tactile-proprioceptive sensorial stimulation from postnatal day 1 to 21, in male and female adult 3xTg-AD mice for Alzheimer's disease compared to sex- and age-matched non-transgenic (NTg) counterparts with normal aging. Social nesting was sensitive to genotype (worse in 3xTg-AD mice), sex (worse in males), profile, and treatment (distinct time to observe the maximum score and incidence of the perfect nest). Since social nesting can be easily included in housing routines, this neuroethological approach can be useful for animal welfare, monitoring the disease's progress, and evaluating potential risk factors and effects of preventive/therapeutical strategies. Finally, the noninvasive, painless, simple, short time, and low-cost features of this home-cage monitoring are advantages that make social nesting feasible to be successfully implemented in most animal department settings.

Paternal origins of obesity: Emerging evidence for incorporating epigenetic pathways into the social determinants of health framework.

Over the past 40 years a global discourse on population obesity has emerged, with moral outrage surrounding the rise in childhood obesity during this time. Women are portrayed as predominantly to blame for the intergenerational transmission of obesity, due to gender norms emphasising maternal responsibility during early-life events. Through a structured review of recent studies exploring epigenetic and social mechanisms of obesity risk transmission, we argue that the role of the father in influencing the obesity risk of children during early life is underappreciated. Paternal actions, embedded within a structural network of the social determinants of health, operate both pre-conception to induce epigenetic changes to the spermatozoa and during the gestational period to influence developmental programming. Paternal contributions influenced by social structures including poor diet and stress influence the subsequent metabolic functioning of the child. An examination of epigenetic pathways, operating at the nexus of genomics and human behaviour, sheds new light on shared parental responsibility for the intergenerational origins of obesity. These emergent findings call into question the effectiveness of early-life obesity interventions that focus exclusively on the mother. More broadly, an examination of the epigenetics of obesity reveals a two-way dynamic between social processes and genomic health information. On the one hand, epigenetic pathways could be an explanatory link between the social determinants of health and physiological outcomes such as obesity. Conversely, a critical appraisal of how this emerging epigenetics knowledge is debated and employed can highlight the very processes that reinforce existing gender disparities in the social determinants of health framework. Ultimately this critical appraisal could lead to a reconfiguration of research and health services agendas, towards more equitable responsibilities across genders for preventing obesity.

The returns to early-life interventions for very low birth weight children.

We use comprehensive administrative data from Rhode Island to measure the impact of early-life interventions for low birth weight newborns. Our analysis relies on a regression discontinuity design based on the 1,500 g threshold for Very Low Birth Weight (VLBW) status. We find that threshold crossing causes more intense in-hospital care, in line with prior studies. In terms of later-life outcomes, we show that threshold crossing causes a 0.34 standard deviation increase in test scores in elementary and middle school, a 17.1 percentage point increase in the probability of college enrollment, and a $66,997 decrease in social program expenditures by age 14.

Early-Life Obesity Prevention: Critique of Intervention Trials During the First One Thousand Days.

PURPOSE OF REVIEW: To critique the evidence from recent and ongoing obesity prevention interventions in the first 1000 days in order to identify evidence gaps and weaknesses, and to make suggestions for more informative future intervention trials. RECENT FINDINGS: Completed and ongoing intervention trials have had fairly modest effects, have been limited largely to high-income countries, and have used relatively short-term interventions and outcomes. Comparison of the evidence from completed prevention trials with the evidence from systematic reviews of behavioral risk factors shows that some life-course stages have been neglected (pre-conception and toddlerhood), and that interventions have neglected to target some important behavioral risk factors (maternal smoking during pregnancy, infant and child sleep). Finally, while obesity prevention interventions aim to modify body composition, few intervention trials have used body composition measures as outcomes, and this has limited their sensitivity to detect intervention effects. The new WHO Healthy Lifestyles Trajectory (HeLTI) initiative should address some of these weaknesses. Future early obesity prevention trials should be much more ambitious. They should, ideally: extend their interventions over the first 1000 days; have longer-term (childhood) outcomes, and improved outcome measures (body composition measures in addition to proxies for body composition such as the BMI for age); have greater emphasis on maternal smoking and child sleep; be global.

Early postnatal handling and environmental enrichment improve the behavioral responses of 17-month-old 3xTg-AD and non-transgenic mice in the Forced Swim Test in a gender-dependent manner.

Forced Swimming Test (FST) models behavioural despair in animals by loss of motivation to respond or the refusal to escape. The present study was aimed at characterizing genetic (genotype and gender) and environmental factors (age/stage of disease and rearing conditions: C, standard; H, early postnatal handling; EE, environmental enrichment consisting in physical exercise as well as social and object enrichment) that may modulate the poor behavioural and cognitive flexibility response we have recently described in 12-month-old male 3xTg-AD mice in the FST. The comprehensive analysis of the ethogram shown in the FST considered the intervals of the test (0-2 and 2-6min), all the elicited behavioural responses (immobility, swimming and climbing) and their features (total duration and frequency of episodes). The long persistence of behaviours found in 17-month-old (late-stages of disease) 3xTg-AD mice was comparable to that recently described in males at 12 months of age (beginning of advanced stages) but also suggested increased age-dependent frailty in both genotypes. The poor behavioral flexibility of 3xTg-AD mice to elicit the behavioural despair shown by the NTg mice, was also found in the female gender. Finally, the present work demonstrates that early-life interventions were able to improve the time and frequency of episodes of immobility, being more evident in the female gender of both old NTg and 3xTg-AD mice. Ontogenic modulation by early-postnatal handling resulted in a more effective long-term improvement of the elicited behaviours in the FST than that achieved by environmental enrichment. The results talk in favor of the beneficence of early-life interventions on ageing in both healthy and disease conditions.