Aged Offspring Research Articles

Long-term impact of maternal obesity on the gliovascular unit and ephrin signaling in the hippocampus of adult offspring.

Children born to obese mothers are at increased risk of developing mood disorders and cognitive impairment. Experimental studies have reported structural changes in the brain such as the gliovascular unit as well as activation of neuroinflammatory cells as a part of neuroinflammation processing in aged offspring of obese mothers. However, the molecular mechanisms linking maternal obesity to poor neurodevelopmental outcomes are not well established. The ephrin system plays a major role in a variety of cellular processes including cell-cell interaction, synaptic plasticity, and long-term potentiation. Therefore, in this study we determined the impact of maternal obesity in pregnancy on cortical, hippocampal development, vasculature and ephrin-A3/EphA4-signaling, in the adult offspring in mice. Maternal obesity was induced in mice by a high fat/high sugar Western type of diet (HF/HS). We collected brain tissue (prefrontal cortex and hippocampus) from 6-month-old offspring of obese and lean (control) dams. Hippocampal volume, cortical thickness, myelination of white matter, density of astrocytes and microglia in relation to their activity were analyzed using 3-D stereological quantification. mRNA expression of ephrin-A3, EphA4 andsynaptic markers were measured by qPCR in the brain tissue. Moreover, expression of gap junction protein connexin-43, lipocalin-2, and vascular CD31/Aquaporin 4 were determined in the hippocampus by immunohistochemistry. Volume of hippocampus and cortical thickness were significantly smaller, and myelination impaired, while mRNA levels of hippocampal EphA4 and post-synaptic density (PSD) 95 were significantly lower in the hippocampus in the offspring of obese dams as compared to offspring of controls. Further analysis of the hippocampal gliovascular unit indicated higher coverage of capillaries by astrocytic end-feet, expression of connexin-43 and lipocalin-2 in endothelial cells in the offspring of obese dams. In addition, offspring of obese dams demonstrated activation of microglia together with higher density of cells, while astrocyte cell density was lower. Maternal obesity affects brain size, impairs myelination, disrupts the hippocampal gliovascular unit and decreases the mRNA expression of EphA4 and PSD-95 in the hippocampus of adult offspring. These results indicate that the vasculature-glia cross-talk may be an important mediator of altered synaptic plasticity, which could be a link between maternal obesity and neurodevelopmental/neuropsychiatric disorders in the offspring.

An enriched environment ameliorates maternal sleep deprivation-induced cognitive impairment in aged mice by improving mitochondrial function via the Sirt1/PGC-1α pathway.

Early life stress can cause cognitive impairment in aged offspring. Environmental enrichment (EE) is considered to be an effective non-pharmacological treatment for improving cognitive decline. The aim of this research was to evaluate the effect of EE, on cognitive impairment in aged offspring induced by maternal sleep deprivation (MSD) and the underlying mechanisms involved to investigate its potential value in clinical practice. CD-1 damns were subjected or not to sleep deprivation during late gestation. Twenty-one days after birth, the offspring were assigned to standard or EE cages. At 18 months-old, the learning and memory function of the offspring mice was evaluated using Morris water maze. The hippocampal and prefrontal cortical levels of protein, gene, proinflammation cytokines, and oxidative stress indicators was examined by Western blot, real-time polymerase chain reaction, enzyme linked immunosorbent assay, and biochemical assays. Offspring in MSD group exhibited declined learning and memory abilities compared with control animals. Moreover, the hippocampal and prefrontal cortical levels of Sirtuin1 (Sirt1), peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α), postsynaptic density protein-95, and synaptophysin were lower and those of proinflammation cytokines higher in the MSD group; meanwhile, the superoxide dismutase content was higher and the malondialdehyde and reactive oxygen species contents were lower. However, these deleterious changes were ameliorated by exposure to EE. EE attenuates MSD-induced cognitive impairment, oxidative stress, and neuroinflammation and reverses the reduction in synaptic protein levels in aged offspring mice via the Sirt1/PGC-1α pathway.

Abstract 15128: Impact of Paternal and Maternal Obesity on Offspring Systolic and Diastolic Function, and Liver Steatosis Early in Life

Introduction: Obesity in women and men of reproductive age may lead to adverse cardiovascular and metabolic developmental programing in their offspring. For example, we observed signs of cardiac diastolic dysfunction in offspring from obese rats as early as 3 weeks of age. However, the contribution from paternal and maternal obesity to increased susceptibility for developing cardiac dysfunction in their offspring early in life is unknown. Hypothesis: We hypothesized that paternal and maternal obesity both play important roles in causing impaired cardiac function and metabolic disorders such as fatty liver in their offspring early in life. Methods: Livers from male newborn Sprague-Dawley rats born from obese fathers (fHFD-offs), obese mothers (mHFD-offs), or from both parents being obese (fmHFD-offs) were weighed and analyzed for fat content by oil red-O and ECHOMRI. Additionally, within 1-3 days after weaning, male offspring were submitted to cardiac catheterization for assessment of cardiac function. Age-matched offspring from lean rats (ND-Offs) were used as controls. Results: fmHFD-Offs and mHFD-offs groups were heavier compared to fHFD-offs and ND-offs groups (61±4 and 64±2 vs 57±2 and 48±2 g, respectively) at 1-3 days after weaning. Newborn rats with at least one obese parent had more liver fat infiltration compared to ND-offs controls. Compared to ND-offs, only offspring from obese mothers (mHFD-offs) exhibited reduced dP/dt max (8998±466 vs. 10560±807, 11869±1171, and 11611±436 mmHg/s for mHFD-offs vs fHFD-offs, fmHFD-offs and ND-offs, respectively); fmHFD-offs and mHFD-offs showed additional signs of impaired diastolic function as indicated by increased Tau values (5.7±0.2 and 5.6±0.3 vs. 4.7±0.2 and 5.0±0.1 ms for fmHDF-offs and mHFD-offs vs ND-offs and fHFD-offs, respectively). Conclusions: These results indicate that while increased liver steatosis develops independent of which parent is obese, the presence of maternal obesity appears to be more critical for male offspring to develop cardiac dysfunction early in life. Additional studies in adult and aged offspring are needed to test if the impact of paternal and maternal obesity on offspring cardiometabolic function gets stronger with aging.

Nutrient restriction during pregnancy and litter size affect the feeding behaviour, feed preference and welfare of the aged ewe’s offspring

The present work evaluates the effect of a nutrient maternal restriction induced by a lower forage allowance of natural grassland (LFA) and the type of birth [single (S) and twins (T)] and its interaction on the feed preference, the feeding behaviour, and welfare indicators of aged offspring ewes. A total of 28 Corriedale, seven years old, multiparous ewes in the anestrus period (spring) were used: 11 singles (S) and 4 twins (T) born to high forage allowance mothers (HFA: 10 – 12 DM/100 kg LW·day), and 9 S and 4 T born to LFA (5 – 8 DM/100 kg LW·day) from 23 days before conception to 122–123 days of gestation. The ewes were subjected to a feeding behaviour trial during 5 days after and adaption period of 14 days to eat alfalfa hay ad libitum and 300 g of rice bran. Eight days before the registration began animals were transferred to a roofed barn and located in individual pens with separated alfalfa and rice bran feeders, and a free-available water source. The feed preference was registered twice a day. Dry matter intake (DMI) was daily determined. Behaviour of each ewe was recorded every 10 min from 0800 to 1200 h, and from 1400 to 1800 h. The percentage of ewes that preferred to rice eat bran first was greater in LFA than HFA ewes (73% vs. 45%; P = 0.04). The alfalfa hay intake was greater in LFA than in HFA ewes (3078 vs. 2949 ± 0.61 g/day; P = 0.04) and in S than in T ewes (3126 vs. 2932 ± 61.0 g/day, P < 0.01). All ewes ate the total offered amount of rice bran (300 g/d each), thus DMI showed the same response that alfalfa intake previously described. The % of time eating alfalfa hay was greater for LFA than HFA (38.0 vs 29.2 ± 3.4; P < 0.01). These variables were not influenced by the interaction. The time spent eating and standing up, and time spent resting were affected by the interaction treatment × TB (P ≤ 0.05 in all cases) as T-LFA ewes spent more time eating (P = 0.02) and thus, standing up (P = 0.02), but less resting (P = 0.02) and with no apparent activity (P = 0.05) than T-HFA with no differences between LFA and HFA groups in the S ewes. In conclusion the maternal nutrient restriction affected the preference for feed, the ingestive behaviour and the welfare of aged female offspring.

Long-term environmental enrichment overcomes depression, learning, and memory impairment in elderly CD-1 mice with maternal sleep deprivation exposure.

Early-life stress disrupts central nervous system development and increases the risk of neuropsychiatric disorder in offspring based on rodent studies. Maternal sleep deprivation (MSD) in rodents has also been associated with depression and cognitive decline in adult offspring. However, it is not known whether these issues persist into old age. Environmental enrichment is a non-pharmacological intervention with proven benefits in improving depression and cognitive impairment; however, it is unclear whether these benefits hold for aging mice following MSD exposure. The aim of this study was to explore the effects of MSD on depression and cognition in elderly offspring CD-1 mice and to determine whether long-term environmental enrichment could alleviate these effects by improving neuroinflammation and synaptic plasticity. The offspring mice subjected to MSD were randomly assigned to either a standard environment or an enriched environment. At 18 months of age, the forced swimming and tail suspension tests were used to evaluated depression-like behaviors, and the Morris water maze test was used to evaluate cognitive function. The expression levels of hippocampal proinflammatory cytokines and synaptic plasticity-associated proteins were also measured. MSD increased depression-like behaviors and impaired cognition function in aging CD-1 offspring mice. These effects were accompanied by upregulated interleukin (IL)-1β, IL-6, and tumor necrosis factor-α expression, and downregulated brain-derived neurotrophic factor, tyrosine kinase receptor B, postsynaptic density-95, and synaptophysin expression in the hippocampus. All of these changes were reversed by long-term exposure to an enriched environment. These findings suggest that MSD exerts long-term effects on the behaviors of offspring in mice, leading to depression and cognitive impairment in older age. Importantly, long-term environmental enrichment could counteract the behavior difficulties induced by MSD through improving hippocampal proinflammatory cytokines and synaptic plasticity-associated proteins.

Maternal polychlorinated biphenyl 126 (PCB 126) exposure modulates offspring gut microbiota irrespective of diet and exercise

The gut microbiota plays an important role throughout the lifespan in maintaining host health, and several factors can modulate microbiota composition including diet, exercise, and environmental exposures. Maternal microbiota is transferred to offspring during early life; thus, environmental exposures before gestation may also modulate offspring microbiota. Here we aimed to investigate the effects of maternal exposure to dioxin-like polychlorinated biphenyls (PCBs) on the microbiota of aged offspring and to determine if lifestyle factors, including maternal exercise or offspring high-fat feeding alter these associations. To test this, dams were exposed to PCB 126 (0.5 μmole/kg body weight) or vehicle oil by oral gavage during preconception, gestation, and during lactation. Half of each group was allowed access to running wheels for ≥ 7 days before and during pregnancy and up through day 14 of lactation. Female offspring born from the 4 maternal groups (PCB exposure or not, with/without exercise) were subsequently placed either on regular diet or switched to a high-fat diet during adulthood. Microbiota composition was quantified in female offspring at 49 weeks of age by 16 S rRNA sequencing. Maternal exposure to PCB 126 resulted in significantly reduced richness and diversity in offspring microbiota regardless of diet or exercise. Overall compositional differences were largely driven by offspring diet, but alterations in specific taxa due to maternal PCB 126 exposure, included the depletion of Verrucomicrobiaceae and Akkermansia muciniphila, and an increase in Anaeroplasma. Perturbation of microbiota due to PCB 126 may predispose offspring to a variety of chronic diseases later in adulthood.

Maternal undernutrition model of two generations of rats: Changes in the aged retina.

The impact of maternal undernutrition on morphological changes of the retina was assessed in two generations of aged offspring. Wistar 18 rats (9 of each generation of 20-month-old female offspring; in total - 27 eyes) were analyzed. The first generation offspring were born to mothers who: (a) were restricted to food only before pregnancy (pre-pregnancy); (b) whose food was restricted before and during pregnancy. The control group and all the offspring were fed normally. After enucleating the eyes, paraffin sections were stained with hematoxylin and eosin. The thickness of retina layers was measured. Cryosections were immunostained using glial fibrillary acidic protein, ionized calcium-binding adaptor molecule1, RNA-binding protein with multiple splicing for evaluation of macroglia, microglia and retinal ganglion cells by digital image analysis tools. Our data have shown atrophy of photoreceptor layer and degeneration of outer nuclear layer in all investigated groups, but less damage was found in the control group. Higher Müller cell activity and greater number of microglial cells was observed in the second generation offspring born from both restricted diet groups. Higher numbers of microglial and retinal ganglion cells were observed in the second generation in comparison to the first generation offspring. Malnutrition of the mother may be one of the possible causes of degeneration of the outer layers of the retina and activation of Müller cells in the second generation offspring. The effect of maternal nutritional restriction on the number of microglial and retinal ganglion cells is unclear.

Even periconceptional alcohol consumption can have long-term consequences on heart health in the offspring.

Even periconceptional alcohol consumption can have long-term consequences on heart health in the offspring.

Thermoregulatory, metabolic and stress responses to spring shearing of aged ewes born to undernourished mothers

Maternal undernutrition during gestation affects the behaviour, metabolism, and sensitivity to stressors of the offspring. Shearing is a stressor that triggers physiological and behavioural changes and augments the thermoregulatory demands in sheep. The aim of this study was to compare the thermoregulatory, metabolic, and behavioural responses to spring shearing of aged ewes born to mothers who grazed different pasture allowances during gestation. Nineteen non-gestating six-year-old Corriedale ewes born to mothers who grazed two pasture allowances from 23 days before conception until 122 days of gestation were used. The pasture allowance offered to the mothers was high [HPA group; n = 11; 10–12 kg of dry matter (DM)/100 kg of body weight (BW)/day] or low [LPA group: n = 8; 5–8 kg of DM/100 kg of BW/day]. The adult offspring of both experimental groups were sheared during spring (Day 0), and remained outdoors, grazing natural grassland, and the behaviour, the surface temperature and the rectal temperature were recorded. Blood concentrations of albumin, total protein, glucose, and insulin were also determined. Data were compared with a mixed model. The LPA ewes had lower ear and nose maximum and minimum surface temperatures before shearing (P < 0.05). On Day 15, the average surface temperature of the vulva was lower in LPA than in HPA ewes (P < 0.05). After shearing, rumination frequency was greater in HPA than in LPA ewes (P = 0.01), and LPA ewes were observed more time standing up than HPA ewes (P < 0.0001). Insulin concentration tended to be greater in LPA than HPA ewes (P = 0.06). Maternal undernutrition during gestation modified the thermoregulatory responses and the acute behavioural changes after shearing in aged female offspring, whilst the metabolism was affected to a lesser degree. The long-term effects noticed in this study highlight the importance of providing proper nutrition to pregnant ewes.

Long-Term Impact of the Great Chinese Famine on the Risks of Specific Arrhythmias and Severe Hypertension in the Offspring at an Early Stage of Aging.

Perinatal malnutrition affects postnatal cardiovascular functions. This study used the Great Chinese Famine (GCF) to determine the long-term impact of perinatal undernutrition on hypertension and arrhythmias in older offspring. Subjects (n = 10,065) were divided into an exposed group whose fetal life was in the GCF and an unexposed group. The exposed group showed higher systolic/diastolic pressure, heart rate, and total cholesterol. Perinatal exposure to the GCF was a significant risk to Grade 2 and Grade 3 hypertension (OR = 1.724, 95%CI: 1.441-2.064, p < 0.001; OR = 1.480, 95%CI: 1.050-2.086, p < 0.05) compared to the control. The GCF also increased risks for myocardial ischemia (OR = 1.301, 95%CI: 1.135-1.490, p < 0.001), bradycardia (OR = 1.383, 95%CI: 1.154-1.657, p < 0.001), atrial fibrillation (OR = 1.931, 95%CI: 1.033-3.610, p < 0.05), and atrioventricular block (OR = 1.333, 95%CI: 1.034-1.719, p < 0.05). Total cholesterol, diabetes, and metabolic syndrome were associated with Grade 2 or Grade 3 hypertension after exposure to the GCF; high cholesterol, high BMI, diabetes, metabolic syndrome, and elevated blood pressure were linked to certain types of arrhythmias in exposed offspring. The results first demonstrated perinatal undernutrition was a significant risk factor for the development of Grade 2-3 hypertension and certain arrhythmias in humans. Perinatal undernutrition still significantly impacted cardiovascular systems of the aged offspring even 50 years after the GCF. The results also provided information to a specific population with a history of prenatal undernutrition for early prevention against cardiovascular diseases before aging.

Appetitive Motivation and Associated Neurobiology Change Differentially across the Life Course of Mouse Offspring Exposed to Peri- and Postnatal High Fat Feeding

Alterations in neural pathways that regulate appetitive motivation may contribute to increased obesity risk in offspring born to mothers fed a high fat (HF) diet. However, current findings on the impact of maternal obesity on motivation in offspring are inconclusive, and there is no information about the long-lasting effects in aged animals. This study examined the longitudinal effect of perinatal and chronic postnatal HF intake on appetitive motivation in young and aged offspring. Female C57Bl/6 were fed either a control (C) or HF diet before mating through to lactation. At weaning, offspring were maintained on the C or HF diet, generating the following four diet groups: C/C, C/HF, HF/C, and HF/HF based on the pre/post weaning diet. At 6 months, motivation was higher in HF/C females, but lower in male and female C/HF and HF/HF mice. By 12 months, this difference was lost, as C-fed animals became less motivated, while motivation increased in HF-fed mice. The mRNA levels of dopamine receptor 1 and 2 increased with age, while cannabinoid receptor 1 and μ-opioid receptor expression remained stable or decreased in mesolimbic and mesocortical dopaminergic pathways. Results from this study suggest that perinatal and chronic postnatal HF feeding produced opposite effects on appetitive motivation in young adult offspring mice, which was also reflected in the shift in motivation over time. These results have significant implications for patterns of hedonic eating across the life course and the relative risk of obesity at different time points.

Sex-specific effects of maternal metformin intervention during glucose-intolerant obese pregnancy on body composition and metabolic health in aged mouse offspring

Aims/hypothesisMetformin is increasingly used to treat gestational diabetes (GDM) and pregnancies complicated by pregestational type 2 diabetes or polycystic ovary syndrome but data regarding long-term offspring outcome are lacking in both human studies and animal models. Using a mouse model, this study investigated the effects of maternal metformin intervention during obese glucose-intolerant pregnancy on adiposity, hepatic steatosis and markers of metabolic health of male and female offspring up to the age of 12 months.MethodsC57BL/6J female mice were weaned onto either a control diet (Con) or, to induce pre-conception obesity, an obesogenic diet (Ob). The respective diets were maintained throughout pregnancy and lactation. These obese dams were then randomised to the untreated group or to receive 300 mg/kg oral metformin hydrochloride treatment (Ob-Met) daily during pregnancy. In male and female offspring, body weights and body composition were measured from 1 month until 12 months of age, when serum and tissues were collected for investigation of adipocyte cellularity (histology), adipose tissue inflammation (histology and quantitative RT-PCR), and hepatic steatosis and fibrosis (histochemistry and modified Folch assay).ResultsAt 12 months of age, male Ob and Ob-Met offspring showed increased adiposity, adipocyte hypertrophy, elevated expression of proinflammatory genes, hyperleptinaemia and hepatic lipid accumulation compared with Con offspring. Male Ob-Met offspring failed to show hyperplasia between 8 weeks and 12 months, indicative of restricted adipose tissue expansion, resulting in increased immune cell infiltration and ectopic lipid deposition. Female Ob offspring were relatively protected from these phenotypes but Ob-Met female offspring showed increased adiposity, adipose tissue inflammation, hepatic lipid accumulation, hyperleptinaemia and hyperinsulinaemia compared with Con female offspring.Conclusions/interpretationMaternal metformin treatment of obese dams increased offspring metabolic risk factors in a sex- and age-dependent manner. These observations highlight the importance of following up offspring of both sexes beyond early adulthood after interventions during pregnancy. Our findings illustrate the complexity of balancing short-term benefits to mother and child vs any potential long-term metabolic effects on the offspring when prescribing therapeutic agents that cross the placenta.Graphical abstract

Perinatal low-fat dietary intervention affects glucose metabolism in female adult and aging offspring.

Diabetes confers a high risk of developing poor health in later life in women. Based on the Developmental Origins of Health and Disease theory, the present study was undertaken to investigate the efficacy of perinatal fat restriction in maternal high-fat-exposed female offspring to maintain glucose homeostasis in later life between adulthood and aging. Low-fat dietary intervention during either gestation or lactation was performed using a high-fat diet-induced maternal obesity mouse model (HFD mice). Physiological metabolic parameters, including body weight and serum levels of total cholesterol and triglycerides, were monitored. Glucose tolerance test and insulin sensitivity test were performed in 12- and 70-week-old offspring. Insulin-positive islet cells were also observed using immunohistochemical staining. HFD significantly induced abnormal weight gain, hyperlipidemia and impairment of both glucose tolerance and insulin sensitivity in offspring. Standard diet intake after weaning improved weight gain, serum total cholesterol level and glucose tolerance, but not insulin sensitivity, in 70-week-old offspring. Only perinatal fat restriction during both gestation and lactation, followed by standard food intake for the rest of their life, provided adequate efficacy to restore insulin sensitivity in aging female progeny. Perinatal low-fat intervention may prevent deterioration of glucose metabolism. To improve the health status over a female's lifespan, appropriate nutritional intervention during the early developmental stage may reset the disease trajectory and prevent the onset and development of diabetes. Geriatr Gerontol Int 2022; 22: 441-448.

Advanced paternal age increased metabolic risks in mice offspring

ObjectivesThe Developmental Origins of Health and Disease Science indicate that chronic diseases in adulthood are associated with prenatal and early-life traits. Our study aimed to explore the metabolic phenotype of offspring from advanced paternal age (APA) and the inherited alterations in sperm. Methods3-month-old (Young father, YF-F0) and 21-month-old male (Old Father, OF-F0) C57BL/6J mice were used to study paternal aging's effect on offspring. Blood glucose testing, lipid analysis, indirect calorimetry and RNA sequencing were performed. ResultsThe characterized metabolic changes in OF-F1 male mice offspring were glucose intolerance, hepatic lipid accumulation, increased adipocytes and impaired energy balance that lasted until they were elderly. Gene expression in both 8-week-old and 52-week-old offspring livers significantly altered in lipid metabolism- and thermogenesis-related pathways. PPAR signaling pathway was activated in both young and elderly offspring livers as indicated by significant upregulation of Cyp7a1, Cyp8b1, Cyp4a10, Cyp4a31, Fabp2, and Scd1. These targeted genes were also confirmed to be increased in offspring adipocytes. Furthermore, when examined the differentially expressed genes in F0 and F1 sperm, upregulated pathways including cholesterol metabolism, type II diabetes mellitus and endocrine resistance were strongly related to the APA offspring phenotype. Importantly, approximately 46.7% of enriched pathways in the sperm of APA offspring were consistent with those of APA fathers. ConclusionsThese findings added evidence of the connection between paternal gametes and alterations in progeny genome and raised the possibility that inherited alterations in sperm contribute to the intergenerational effects of paternal aging offspring's chronic metabolic risks.

Severe Gestational Low-Protein Intake Impacts Hippocampal Cellularity, Tau, and Amyloid-β Levels, and Memory Performance in Male Adult Offspring: An Alzheimer-Simile Disease Model?

Background:Maternal undernutrition has been associated with psychiatric and neurological disorders characterized by learning and memory impairment.Objective:Considering the lack of evidence, we aimed to analyze the effects of gestational protein restriction on learning and memory function associated with hippocampal cell numbers and neurodegenerative protein content later in life.Methods:Experiments were conducted in gestational low- (LP, 6% casein) or regular-protein (NP, 17% casein) diet intake offspring. Behavioral tests, isolated hippocampal isotropic fractionator cell studies, immunoblotting, and survival lifetime were observed.Results:The birthweight of LP males is significantly reduced relative to NP male progeny, and hippocampal mass increased in 88-week-old LP compared to age-matched NP offspring. The results showed an increased proximity measure in 87-week-old LP compared to NP offspring. Also, LP rats exhibited anxiety-like behaviors compared to NP rats at 48 and 86-wk of life. The estimated neuron number was unaltered in LP rats; however, non-neuron cell numbers increased compared to NP progeny. Here, we showed unprecedented hippocampal deposition of brain-derived neurotrophic factor, amyloid-β peptide (Aβ), and tau protein in 88-week-old LP relative to age-matched NP offspring.Conclusion:To date, no predicted studies showed changes in hippocampal morphological structure in maternal protein-restricted elderly offspring. The current data suggest that gestational protein restriction may accelerate hippocampal function loss, impacting learning/memory performance, and supposedly developing diseases similar to Alzheimer’s disease (AD) in elderly offspring. Thus, we propose that maternal protein restriction could be an elegant and novel method for constructing an AD-like model in adult male offspring.

The role of cellular senescence in female reproductive aging and the potential for senotherapeutic interventions.

BACKGROUNDAdvanced maternal age is associated with decreased oocyte quantity and quality as well as uterine and placental dysfunctions. These changes lead to infertility, pregnancy complications and birth defects in the offspring. As the mean age of giving birth is increasing worldwide, prevention of age-associated infertility and pregnancy complications, along with the more frequent use of ART, become extremely important. Currently, significant research is being conducted to unravel the mechanisms underlying female reproductive aging. Among the potential mechanisms involved, recent evidence has suggested a contributing role for cellular senescence, a cellular state of irreversible growth arrest characterized by a hypersecretory and pro-inflammatory phenotype. Elucidating the role of senescence in female reproductive aging holds the potential for developing novel and less invasive therapeutic measures to prevent or even reverse female reproductive aging and increase offspring wellbeing.OBJECTIVE AND RATIONALEThe review will summarize the positive and negative implications of cellular senescence in the pathophysiology of the female reproductive organs during aging and critically explore the use of novel senotherapeutics aiming to reverse and/or eliminate their detrimental effects. The focus will be on major senescence mechanisms of the ovaries, the uterus, and the placenta, as well as the potential and risks of using senotherapies that have been discovered in recent years.SEARCH METHODSData for this review were identified by searches of MEDLINE, PubMed and Google Scholar. References from relevant articles using the search terms ‘Cellular Senescence’, ‘Aging’, ‘Gestational age’, ‘Maternal Age’, ‘Anti-aging’, ‘Uterus’, ‘Pregnancy’, ‘Fertility’, ‘Infertility’, ‘Reproduction’, ‘Implant’, ‘Senolytic’, ‘Senostatic’, ‘Senotherapy’ and ‘Senotherapeutic’ where selected. A total of 182 articles published in English between 2005 and 2020 were included, 27 of which focus on potential senotherapies for reproductive aging. Exclusion criteria were inclusion of the terms ‘male’ and ‘plants’.OUTCOMESAging is a major determinant of reproductive wellbeing. Cellular senescence is a basic aging mechanism, which can be exploited for therapeutic interventions. Within the last decade, several new strategies for the development and repurposing of drugs targeting senescent cells have emerged, such as modulators of the anti-inflammatory response, oxidative stress, DNA damage, and mitochondria and protein dysfunctions. Several studies of female reproductive aging and senotherapies have been discussed that show promising results for future interventions.WIDER IMPLICATIONSIn most countries of the Organization for Economic Co-operation and Development, the average age at which women give birth is above 30 years. Currently, in countries such as the Netherlands, Australia, Spain, Finland, Germany and the UK, birth rates among 30- to 34-year-olds are now higher than in any other age groups. This review will provide new knowledge and scientific advancement on the senescence mechanisms during female reproductive aging, and benefit fundamental and clinical scientists and professionals in the areas of reproduction, cancer, immunobiology and fibrosis.

Anxiety and depression-like behaviours are more frequent in aged male mice conceived by ART compared with natural conception.

The number of children born after assisted reproductive technology (ART) is accumulating rapidly, and the health problems of the children are extensively concerned. This study aims to evaluate whether ART procedures alter behaviours in male offspring. Mouse models were utilized to establish three groups of offspring conceived by natural conception (NC), in vitro fertilization and embryo transfer (IVF-ET), and frozen-thawed embryo transfer (IVF-FET), respectively. A battery of behaviour experiments for evaluating anxiety and depression levels, including the open field test (OFT), elevated plus maze (EPM) test, light/dark transition test (L/DTT), tail suspension test (TST), forced swimming test (FST), and sucrose preference test (SPT) was carried out. Aged (18 months old), but not young (3 months old), male offspring in the IVF-ET and IVF-FET groups, compared with those in the NC group, exhibited increased anxiety and depression-like behaviours. The protein expression levels of three neurotrophins in PFC or hippocampus in aged male offspring from the IVF-ET and IVF-FET groups reduced at different extent, in comparison to NC group. RNA sequencing (RNA-Seq) was performed in the hippocampus of 18 months old offspring to further explore the gene expression profile changes in the three groups. KEGG analyses revealed the coexisted pathways, such as PI3K-Akt signalling pathway, which potentially reflected the similarity and divergence in anxiety and depression between the offspring conceived by IVF-ET and IVF-FET. Our research suggested the adverse effects of advanced age on the psychological health of children born after ART should be highlighted in the future.

Prenatal androgen excess impairs beta-cell function by decreased sirtuin 3 expression.

Prenatal androgen exposure induces metabolic disorders in female offspring. However, the long-term effect of maternal testosterone excess on glucose metabolism, especially on pancreatic beta-cell function, is rarely investigated. Our current study mainly focused on the effects of prenatal testosterone exposure on glucose metabolism and pancreatic beta- cell function in aged female offspring. By using maternal mice and their female offspring as animal models, we found that prenatal androgen treatment induced obesity and glucose intolerance in aged offspring. These influences were accompanied by decreased fasting serum insulin concentration, elevated serum triglyceride, and testosterone concentrations. Glucose stimulated insulin secretion in pancreatic beta cells of aged female offspring was also affected by prenatal testosterone exposure. We further confirmed that increased serum testosterone contributed to downregulation of sirtuin 3 expression, activated oxidative stress, and impaired pancreatic beta-cell function in aged female offspring. Moreover, over-expression of sirtuin 3 in islets isolated from female offspring treated with prenatal testosterone normalized the oxidative stress level, restored cyclic AMP, and ATP generation, which finally improved glucose-stimulated insulin secretion in beta cells. Taken together, these results demonstrated that prenatal testosterone exposure caused a metabolic disturbance in aged female offspring via suppression of sirtuin 3 expression and activation of oxidative stress in pancreatic beta cells.

Abstract P184: Aging Male Offspring Of Polycystic Ovary Syndrome Rat Model Have Normal Blood Pressure And Exaggerated Pressor Response To Angiotensin II

Background: Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenemia and elevated blood pressure (BP). Male offspring of hyperandrogenemic female (HAF) rats, PCOS model, have low birth weight, with normal BP, but exaggerated pressor response to Angiotensin (Ang) II as adults. The present study tested the hypothesis that with aging, male HAF offspring are at increased risk of developing hypertension (HT). Methods: Hyperandrogenemia was induced in female SD rats (5α-dihydrotestosterone pellets 7.5 mg/90 d, s.c. at 4 wks of age and throughout life). HAF and controls (10-12 wks of age) were mated, allowed to deliver and lactate. HAF and control male offspring (F1 HAF and F1 Contr. ) were left untreated until 16-20 mos of age. Body composition (echoMRI) and proteinuria were measured in aging offspring. BP was measured (baseline; 9 d, enalapril (25 mg/kg/d); 7d) by telemetry. Rats were then given Ang II (50 ng/kg/min, s.c. minipumps) or saline (No Ang II) for 13 d. High salt (4%) diet (HSD) was started for both Ang II and No Ang II groups on day 8 of Ang II. Results: Aging male F1 HAF had similar fat mass, but lower lean mass (433.7 ± 6 vs 453.6 ± 7 g, p&lt; 0.05) and body weight (552.3 ± 11 vs 590.4 ± 11 g, n = 8-16, p&lt;0.05) than F1 Contr. . Despite higher proteinuria in F1 HAF (412 ± 42 mg/24h vs 292 ± 47 mg/24h, n = 11-13, p&lt;0.05), baseline mean arterial pressure (MAP) was similar between F1 HAF and F1 Contr. (130 ± 1 mmHg vs 126 ± 4 mmHg, respectively, n = 8, p=NS). Enalapril decreased MAP similarly in both F1 HAF and F1 Contr. (110 ± 2 mmHg vs 107 ± 3 mmHg, respectively). On low salt, Ang II increased MAP to higher levels in F1 HAF than F1 contr., saline-treated&gt;F1 HAF and F1 Contr. (140 ± 11 mmHg vs 119 ± 10 mmHg, 105 ± 3 mmHg and 103 ± 4 mmHg, respectively, n = 4, p&lt;0.05 F 1 HAF vs other grps). With 6 days of HSD, MAP was similar between F1 HAF and F1 Contr. not treated with Ang II (142 ± 6 mmHg and 132 ± 9 mmHg, respectively). MAP was also similar between F1 HAF and F1 Contr. with Ang II (169 ± 1 mmHg and 159 ± 9 mmHg, respectively). However, both Ang II-treated groups had significantly higher MAP compared to their respective No Ang II control groups. Conclusion: Aging male HAF offspring do not develop hypertension, but are at increased risk of renal injury and cardiovascular disease due to enhanced pressor sensitivity to Ang II.

Effect of Fetal and Neonatal Hypothyroidism on Glucose Tolerance in Middle- Aged Female Rats.

The effects of hypothyroidism during pregnancy and lactation on carbohydrate metabolism have been mostly studied in male animals. The aim of this study is, therefore, to investigate the effect of fetal and neonatal hypothyroidism (FH and NH) on glucose tolerance in middle-aged female rat offsprings. Pregnant female rats were divided into three groups: Rats in the control group consumed tap water, while those in the FH and NH groups consumed 250 mg/L of 6-propyl-2-thiouracil (PTU) in their drinking water during gestation or lactation periods, respectively. After weaning, the female offspring were separated and divided into 3 groups (n=8/group): Control, FH, and NH. Bodyweight was recorded monthly and an intravenous glucose tolerance test (IVGTT) was performed at month 12. Compared to controls, female rats in the FH group had significantly higher plasma glucose levels than controls throughout the IVGTT except at min 60. Values at min 5 of the FH and control group were 196.1±1.9 and 155.3±5.9 mg/dL, respectively (P<0.05). In the NH group, plasma glucose levels were significantly higher only at min 5 (185.7±14.1 vs. 155.3±5.9 mg/dL, P<0.05). Hypothyroidism during fetal or neonatal periods caused glucose intolerance in middle- aged female offspring rats.