Significant Age-related Decrease Research Articles

Elevated mtDNA content in RBCs promotes oxidative stress may be responsible for faster senescence in men

BackgroundBoth we and others have found that RBC counts are significantly lower in older compared to younger. However, when gender is factored in, a significant age-related decrease of RBC counts is observed only in men but not in women. MethodsqPCR and confocal microscopy were used to detect the presence of mtDNA in RBCs. Flow cytometry and specific inhibitors were used to determine how RBCs uptake cf-mtDNA. The peripheral blood was collected from 202 young adults and 207 older adults and RBC and plasma were isolated. The levels of TLR9+RBCs and apoptotic RBCs after uptake of cf-mtDNA by RBCs were measured by flow cytometry. The kit detects changes in SOD and MDA levels after cf-mtDNA uptake by RBCs. Young RBCs (YR) and old RBCs (OR) from single individuals were separated by Percoll centrifugation. ResultsWe found a significant decrease in RBC counts and a significant increase in the RDW with aging only in men. We also found that significantly elevated mtDNA content in RBCs was observed only in men during aging and was not found in women. Further studies demonstrated that RBCs could take up cf-mtDNA via TLR9, and the uptake of mtDNA might lead to a decrease in the RBC number and an increase in RDW due to an increase of oxidative stress. ConclusionsThe RBC mtDNA content might be a potential marker of RBC aging and the elevated RBC mtDNA content might be the cause of faster senescence in males than females.

Aging effects on dual-route speech processing networks during speech perception in noise.

Healthy aging leads to complex changes in the functional network of speech processing in a noisy environment. The dual-route neural architecture has been applied to the study of speech processing. Although evidence suggests that senescent increases activity in the brain regions across the dorsal and ventral stream regions to offset reduced periphery, the regulatory mechanism of dual-route functional networks underlying such compensation remains largely unknown. Here, by utilizing functional near-infrared spectroscopy (fNIRS), we investigated the compensatory mechanism of the dual-route functional connectivity, and its relationship with healthy aging by using a speech perception task at varying signal-to-noise ratios (SNR) in healthy individuals (young adults, middle-aged adults, and older adults). Results showed that the speech perception scores showed a significant age-related decrease with the reduction of the SNR. The analysis results of dual-route speech processing networks showed that the functional connection of Wernicke's area and homolog Wernicke's area were age-related increases. Further to clarify the age-related characteristics of the dual-route speech processing networks, graph-theoretical network analysis revealed an age-related increase in the efficiency of the networks, and the age-related differences in nodal characteristics were found both in Wernicke's area and homolog Wernicke's area under noise environment. Thus, Wernicke's area might be a key network hub to maintain efficient information transfer across the speech process network with healthy aging. Moreover, older adults would recruit more resources from the homologous Wernicke's area in a noisy environment. The recruitment of the homolog of Wernicke's area might provide a means of compensation for older adults for decoding speech in an adverse listening environment. Together, our results characterized dual-route speech processing networks at varying noise environments and provided new insight for the compensatory theories of how aging modulates the dual-route speech processing functional networks.

Differentiation of the retinal morphology aging trajectories in schizophrenia and their associations with cognitive dysfunctions.

Previous studies evaluating the morphology of the selected retinal layers in schizophrenia showed abnormalities regarding macular thickness, retinal nerve fiber layer (RNLF), and ganglion cell complex (GCC). Concurrently, accumulating neuroimaging results suggest that structural alterations of the brain in this disease might be an effect of accelerated aging. Referring to these findings, we aimed to determine whether the thinning of the retinal layers assessed with the optic coherence tomography (OCT) in a group of schizophrenia patients (n = 60) presents a significant age-related decrease exceeding potential changes noted in the control group (n = 61). Samples of patients and controls were divided into three age subgroups, namely, younger, middle-aged, and older participants. OCT outcomes, such as macular thickness and volume, macular RNFL, peripapillary RNFL, and GCC, were analyzed concerning a diagnosis status (controls vs. patients) and age subgroups. Additionally, associations between retinal parameters, age, and selected cognitive functions were evaluated. post-hoc tests revealed that macular thickness and volume in patients undergo significant age-dependent thinning, which was not observed in the control group. Regression analyses confirmed the association between macular morphology and age. Selected speed-dependent cognitive functions in patients decreased significantly with age, and these features were also significantly associated with some OCT outcomes also after controlling for antipsychotic treatment. Our results suggest that reduced measures of retinal structure detected in schizophrenia may be an effect of accelerated aging; however, further research is needed using computational solutions derived from brain imaging studies based on large datasets covering representatives of all age groups.

ID: 209374 Temporal Lobe Epilepsy Patients Demonstrate Altered Age-Related Segregation Patterns in Brainstem Arousal Networks

Recurrent consciousness-impairing seizures are associated with widespread brain network changes and disabling neurocognitive deficits in patients with temporal lobe epilepsy (TLE) (Englot et al, 2020). We have shown altered functional connectivity in the brainstem ascending reticular acting system (ARAS) found in TLE patients (Englot et al, 2017) that may correlate with impairments in cognitive testing and may improve after surgical treatment (González et al, 2020). Studies of the ARAS network in control subjects have shown a significant age-related decrease in a within-network connectivity metric called segregation. Furthermore, patients with TLE have been shown to have clinical and radiological accelerated age-related changes. Thus, we sought to investigate any possible age-related ARAS network changes in TLE. Understanding how the ARAS is impacted may offer insight into how neurostimulation may improve its network dynamics.

Psychological Well-Being as Cognitive-Emotional Component of Student Self-Regulated Learning

The manuscript reports the theoretical aspects of studying the concepts of students’ psychological well-being in the process of self-regulated learning. The essence of student psychological well-being through a prism of cognitive and emotional personality factors has been theoretically studied. The role of psychological well-being and its components in the process of self-regulated learning activities of HEI students has been described. Psychological well-being has been viewed as an integral indicator of the level of personality, which affects resistance, and manifests itself in subjectively tangible satisfaction and life satisfaction. Self-regulated learning has been considered as a metacognitive level of initiation, motivation, monitoring, evaluation and control of all kinds and forms of internal and external activities by the subject of learning, which are aimed at reaching the predetermined goals of learning, personal and professional self-development and self-realization. The results of empirical research with the use of K. Ryff’s questionnaire entitled “Scales of Psychological Well-being,” as adapted by S. Karskanova, allowed us to evaluate personal growth, positive relationships with others, goals in life, managing environment, autonomy and self-acceptance which are indicators of individuals’ psychological well-being. Methods of statistical data processing such as descriptive statistics (group median - Me, arithmetic mean - M, standard deviation - σ) and the Kruskal-Wallis test, confirmed the existence of a statistically significant linear age-related decrease in indicators on the “Autonomy” Scale for the senior students. Analysis of the empirical data on the levels of defined psychological well-being has showed a linear correlation between psychological well-being and its levels. It has been concluded that the cognitive-emotional aspects of psychological well-being of modern student youth in learning activities have been dominated by dependent types of self-regulation in learning. The results have indicated that the most appropriate means to improve the psychological well-being of students, as a component of the emotional and behavioral level, is the formation of their active life position, responsibility for their own activities, motivation and autonomy in self-regulated learning activities. Prospective directions for future research have been described.

Natural Pattern of Cognitive Aging.

Considering the world's rapidly increasing life expectancy, with people working and maintaining active lifestyles longer than ever before, addressing the effects of aging on cognition is of utmost importance. A greater understanding of cognitive aging may also be critical in distinguishing natural cognitive aging from pre-clinical stages of Alzheimer's disease and related cognitive disorders. To systematically examine the association between aging and cognitive performance in a cognitively and otherwise healthy probability population-based sample using a computer-based method. This cross-sectional study enrolled 673 cognitively and otherwise healthy participants aged 25-89 years (mean age 52.3±14.2 years, 52.5% of whom were female) from the Kardiovize study cohort. Mild cognitive impairment and dementia cases were excluded, followed by measurement of cognitive performance with the computer-administered Cogstate Brief Battery. We used ANCOVA and Modified Signed-Likelihood Ratio tests to examine patterns of cognition across age groups. We found a gradual decrease in cognitive performance across the lifespan, which required two decades to demonstrate significant changes. In contrast to attention and learning, psychomotor speed and working memory showed the most significant age-related decrease and variability in performance. The established pattern of cognitive aging was not altered by sex or education. These findings corroborate, validate, and extend the current understanding of natural cognitive aging and pinpoint specific cognitive domains with the most extensive age-related interindividual differences. This will contribute to the development of strategies to preserve cognition with aging and may also serve to improve early diagnostics of cognitive disorders using computer-based methods.

Biochemical reference intervals in broiler chickens according to age and strain

Abstract. The objective of the research was to study the physiological pattern of biochemical variables and to obtain reference intervals for young (less than 1 month) and adult (more than 1 month) broiler chickens of 2 strains. From the jugular vein, blood for analysis was collected, separated, and then immediately analyzed. The influence of age was significant for the majority of the investigated variables in the 2 groups. In Isa15 strain, a significant age-related decrease in plasma uric acid, glucose, cholesterol, triglycerides, phosphorus, potassium and iron was established. Also, a significant age-related increase in plasma calcium and ASAT was obtained in the same broiler strain. In Arbor Acres Plus strain, a significant age-related decrease in plasma glucose, cholesterol, triglycerides and phosphorus was observed. A significant age-related increase in plasma total protein, calcium and ASAT has also been reported in this broiler strain. A significant difference between the two strains was reported for plasma uric acid, glucose, cholesterol, phosphorus, magnesium and iron (p<0.05). For most estimated parameters in the 2 strains, calculation of separate reference intervals for young and adult animals was appropriate. Except for potassium in young Isa15 strain, and phosphorus in young Arbor Acres Plus strain, all variables did not follow a normal distribution. Reference intervals are presented for both ages using non-parametric or robust method. 90% confidence intervals for both groups were calculated non-parametrically, or by the bootstraping method. The established reference intervals will be a useful guide for interpreting plasma biochemical variables in different strains of broiler chickens raised in Algeria, and reared in a mild Mediterranean climate.

Optical coherence tomography quantifying photo aging: skin microvasculature depth, epidermal thickness and UV exposure.

Photo aging predominantly occurs in the face, neck and hands due to UVA and UVB irradiation. It is associated with skin cancer and histological studies indicate thinning of the epidermis and elastosis occurs. Dynamic Optical coherence tomography (D-OCT) is a non-invasive imaging tool able to visualize the epidermis and upper dermis and its blood vessels as well as to evaluate epidermal thickness (ET) and blood flow. To investigate ET and blood vessel depth using D-OCT in human subjects correlated to UV exposure. We evaluated data from 249 healthy adults, that had D-OCT-scans conducted at four different regions (forehead, neck, arm and hand) and correlated ET and blood vessel depth with occupational UV exposure (total standard erythema dose, Total SED), season and demographic data. Regional differences in ET and blood vessel depth were found (p values < 0.001). Multiple linear regressions showed a seasonal effect on both ET (- 0.113 to - 0.288µm/day, p values < 0.001) and blood vessel depth (0.168-0.347µm/day, p values < 0.001-0.007) during August-December. Significant age-related decrease of ET was seen in forehead, arm and hand (0.207-0.328µm/year, p values = 0.002-0.18) and blood vessel depth in forehead (0.064-0.553µm/year, p values = 0.01-0.61). Males had thicker epidermis (3.92-10.93µm, p values = 0.002-0.15). Changing seasons are a major predictor of both ET and blood vessel depth, showing strongest effect in non-exposed areas, suggesting a systemic effect, possibly due to seasonal vitamin D fluctuation. Sex, age and occupational UV exposure affect ET. This study demonstrated the feasibility of D-OCT to evaluate epidermal thickness and blood vessel depth.

Фактор передбачення закриття кута передньої камери за даними ультразвукової біометрії

The aim. To develop a predictive factor (PF) of anterior chamber (AC) angle closure based on biometric data and to compare its values with the Lowe coefficient and lens thickness to axial length factor (LAF) in healthy patients of different age, cataract patients and patients with chronic and acute angle-closure glaucoma. Materials and methods. The study was performed in 180 variously-aged (20 to 60 years) patients with different types of refraction, and in 20 patients with acute AC angle closure, in 20 patients with primary chronic angle-closure glaucoma and in 20 patients with cataract. The AC depth, the lens thickness (LT) and the axial length (AL) were measured by A-scan ultrasound biomicroscopy. Results. Based on ultrasound biometrics, a PF of anterior angle closure has been developed: PF = AC / AL / LT x 100. There was significant age-related decrease in the PF coefficient in patients with all types of refraction (p&lt;0.001). In case of hypermetropia, PF was significantly less than in cases with myopia and emmetropia (p&lt;0.001). Compared to the Lowe coefficient, the PF coefficient more sensitively showed the trend towards the closure of the AC angle in the age-refraction context. The AC depth in case of an acute glaucoma (2.3 ± 0.16 mm) was significantly less than that in case of chronic angle-closure glaucoma (2.4±0.21 mm) and differed significantly from that in case of cataract (3.32±0.33 mm), in all groups p &lt; 0.001. At the same time, LT did not differ significantly in patients with acute glaucoma, chronic angle-closure glaucoma and cataracts (p&gt;0.05). There was significant difference in PF coefficient between the groups of patients with an acute angle-closure glaucoma and cataracts, as well as chronic angle-closure glaucoma and cataracts (p&lt;0.001). Its significance was higher than the significance of the Lowe coefficient between the respective groups. PF less than 2.5 was a significant risk factor for the closure of the AC angle.

Aryl Hydrocarbon Receptor-Interacting Protein (AIP) in the Human Dermis with Aging

The goal of the present work was to study the content of aryl hydrocarbon receptor–interacting protein (AIP) in dermal fibroblasts from the age of 20 weeks of fetal development and to the age of 85 years and to determine the significance of AIP for age-related changes in the fibroblast number in the human dermis. AIP and proliferating cell nuclear antigen (PCNA) were revealed in skin sections with an indirect immunochemical method. The results demonstrated that a proportion of dermal fibroblasts with positive staining for AIP gradually increases from 20 weeks of fetal development to the age of 85 years. The total number and proportion of PCNA-positive fibroblasts in the dermis decreased with age. The most significant age-related decrease in the total number and PCNA-positive fibroblasts in the dermis was observed from the antenatal period to the age of 40 years. Correlation analysis demonstrated that an age-related decrease in the total fibroblast number and a decrease in their proliferative activity are significantly associated with an increase in the percentage of fibroblasts with positive staining for AIP. The results suggest that AIP is involved in an age-related decrease in the number and proliferation of fibroblasts in the human dermis.

Neuronal Calcium Imaging, Excitability, and Plasticity Changes in the Aldh2-/- Mouse Model of Sporadic Alzheimer's Disease.

Background:Dysregulated signaling in neurons and astrocytes participates in pathophysiological alterations seen in the Alzheimer’s disease brain, including increases in amyloid-β, hyperphosphorylated tau, inflammation, calcium dysregulation, and oxidative stress. These are often noted prior to the development of behavioral, cognitive, and non-cognitive deficits. However, the extent to which these pathological changes function together or independently is unclear.Objective:Little is known about the temporal relationship between calcium dysregulation and oxidative stress, as some reports suggest that dysregulated calcium promotes increased formation of reactive oxygen species, while others support the opposite. Prior work has quantified several key outcome measures associated with oxidative stress in aldehyde dehydrogenase 2 knockout (Aldh2–/–) mice, a non-transgenic model of sporadic Alzheimer’s disease.Methods:Here, we tested the hypothesis that early oxidative stress can promote calcium dysregulation across aging by measuring calcium-dependent processes using electrophysiological and imaging methods and focusing on the afterhyperpolarization (AHP), synaptic activation, somatic calcium, and long-term potentiation in the Aldh2–/– mouse.Results:Our results show a significant age-related decrease in the AHP along with an increase in the slow AHP amplitude in Aldh2–/– animals. Measures of synaptic excitability were unaltered, although significant reductions in long-term potentiation maintenance were noted in the Aldh2–/– animals compared to wild-type.Conclusion:With so few changes in calcium and calcium-dependent processes in an animal model that shows significant increases in HNE adducts, Aβ, p-tau, and activated caspases across age, the current findings do not support a direct link between neuronal calcium dysregulation and uncontrolled oxidative stress.

Lack of effect of short-term DHEA supplementation on the perimenopausal ovary†.

Dehydroepiandrosterone (DHEA) hormonal supplementation can improve oocyte quality in women with diminished ovarian function. However, it is unclear whether DHEA supplementation can also enhance ovarian function during the perimenopause (i.e., when the number of follicles in the ovary has undergone a marked reduction). To address this question, we examined the impact of 2.5-months of daily 5-mg oral DHEA supplementation on the number of ovarian follicles and the concentration of anti-Müllerian hormone (AMH) in perimenopausal rhesus macaques. Like women, these long-lived nonhuman primates have ~ 28-day menstrual cycles and eventually undergo menopause. They also show similar age-related neuroendocrine changes, including a marked decrease in circulating concentrations of DHEA and DHEA sulfate (DHEAS). Our experimental design involved the following three groups of animals (N=6 per group): Young adult (mean age=11.6years), Old control (mean age=23.1years), and Old DHEA-treated (mean age=23.5years). Histological examination of the ovaries revealed a significant age-related decrease in the mean number of primordial follicles despite DHEA supplementation. Moreover, AMH concentrations within the ovaries and circulation, assessed by Western analysis and ELISA, respectively, showed significant age-related decreases that were not attenuated by DHEA supplementation. Taken together, these results fail to show a clear effect of short-term physiological DHEA supplementation on the perimenopausal ovary. However, they do not exclude the possibility that alternative DHEA supplementation paradigms (e.g., involving an earlier start date, longer duration and using pharmacological doses) may extend reproductive potential during aging.

Model-Predicted Balance Between Neural Excitation and Inhibition Was Maintained Despite of Age-Related Decline in Sensory Evoked Local Field Potential in Rat Barrel Cortex.

The balance between neural excitation and inhibition has been shown to be crucial for normal brain function. However, it is unclear whether this balance is maintained through healthy aging. This study investigated the effect of aging on the temporal dynamics of the somatosensory evoked local field potential (LFP) in rats and tested the hypothesis that excitatory and inhibitory post-synaptic activities remain balanced during the aging process. The LFP signal was obtained from the barrel cortex of three different age groups of anesthetized rats (pre-adolescence: 4–6 weeks, young adult: 2–3 months, middle-aged adult: 10–20 months) under whisker pad stimulation. To confirm our previous finding that the initial segment of the evoked LFP was solely associated with excitatory post-synaptic activity, we micro-injected gabazine into the barrel cortex to block inhibition while LFP was collected continuously under the same stimulus condition. As expected, the initial slope of the evoked LFP in the granular layer was unaffected by gabazine injection. We subsequently estimated the excitatory and inhibitory post-synaptic activities through a balanced model of the LFP with delayed inhibition as an explicit constraint, and calculated the amplitude ratio of inhibition to excitation. We found an age-dependent slowing of the temporal dynamics in the somatosensory-evoked post-synaptic activity, as well as a significant age-related decrease in the amplitude of the excitatory component and a decreasing trend in the amplitude of the inhibitory component. Furthermore, the delay of inhibition with respect to excitation was significantly increased with age, but the amplitude ratio was maintained. Our findings suggest that aging reduces the amplitude of neural responses, but the balance between sensory evoked excitatory and inhibitory post-synaptic activities is maintained to support normal brain function during healthy aging. Further whole cell patch clamp experiments will be needed to confirm or refute these findings by measuring sensory evoked synaptic excitatory and inhibitory activities in vivo during the normal aging process.

Magnetic resonance imaging based muscle strain rate mapping during eccentric contraction to study effects of unloading induced by unilateral limb suspension.

Age- and disuse- related loss of muscle force is disproportionately larger than the loss of muscle mass. Earlier studies reported that comparing concentric and eccentric contractions, there is a significant age-related decrease in force only in concentric contractions. Magnetic Resonance Imaging enables mapping of muscle deformation and has been used to study isometric but not eccentric contractions. We report MRI based strain rate mapping of the medial gastrocnemius in subjects pre- and post-unloading induced by Unilateral Limb Suspension. In contrast to isometric contraction, no difference in strain rate indices were observed post-unloading, in conformance with preserved force during eccentric contractions.

Age-related atrophy of cortical thickness and genetic effect of ANK3 gene in first episode MDD patients

Brain ageing is thought to be related to geriatric depression, but the relationship between ageing and depression among middle aged individuals is unknown. The present study aimed to evaluate whether the age-related reduction of brain cortical thickness (CT) can be found in adult first-episode MDD patients, as well as to identify the possible genetic effect of the ANK3 gene polymorphism age-relates CT reduction. This study recruited 153 first-episode MDD patients with a disease duration < 2 years and 276 healthy controls (HC), and the CT of 68 whole brain regions and two ANK3 SNPs (rs1994336 and rs10994359) were analyzed. The results showed that although the CT of both groups was negative correlated with age, the MDD group had significant greater age-related decrease in CT than the HC group (–9.35 × 10−3 mm/year for MDD vs. –1.23 × 10−3 mm/year for HC in the left lateral orbitofrontal lobe). The multivariate analysis of covariance (MANCOVA) results yielded significant interactions of diagnosis × age, genotype × age and diagnosis × genotype interaction for rs10994359. In HC, the C allele showed a protective effect on age-related CT reduction. The reduction in CT with age was several times as greater in non-C carriers as in C carriers (–3.54 × 10−3 vs.–0.15 × 10−3 mm/year in left supramarginal gyrus) for HC. However, this protective effect disappeared in patients with MDD. We did not find a clear effect of rs1994336 on the age-related CT reduction. The findings indicate that the widespread accelerated brain ageing occurs early in adult-onset depression and this ageing may be a pathological mechanisms of depression rather than an outcome of the disease. The ANK3 rs10994359 polymorphism may partially affect regional cortical ageing in MDD.

Imaging P-Glycoprotein Induction at the Blood-Brain Barrier of a β-Amyloidosis Mouse Model with 11C-Metoclopramide PET.

P-glycoprotein (ABC subfamily B member 1, ABCB1) plays an important role at the blood-brain barrier (BBB) in promoting clearance of neurotoxic β-amyloid (Aβ) peptides from the brain into the blood. ABCB1 expression and activity were found to be decreased in the brains of Alzheimer disease patients. Treatment with drugs that induce cerebral ABCB1 activity may be a promising approach to delay the build-up of Aβ deposits in the brain by enhancing clearance of Aβ peptides from the brain. The aim of this study was to investigate whether PET with the weak ABCB1 substrate radiotracer 11C-metoclopramide can measure ABCB1 induction at the BBB in a β-amyloidosis mouse model (APP/PS1-21 mice) and in wild-type mice. Methods: Groups of wild-type and APP/PS1-21 mice aged 50 or 170 d underwent 11C-metoclopramide baseline PET scans or scans after intraperitoneal treatment with the rodent pregnane X receptor activator 5-pregnen-3β-ol-20-one-16α-carbonitrile (PCN, 25 mg/kg) or its vehicle over 7 d. At the end of the PET scans, brains were harvested for immunohistochemical analysis of ABCB1 and Aβ levels. In separate groups of mice, radiolabeled metabolites of 11C-metoclopramide were determined in plasma and brain at 15 min after radiotracer injection. As an outcome parameter of cerebral ABCB1 activity, the elimination slope of radioactivity washout from the brain (kE,brain) was calculated. Results: PCN treatment resulted in an increased clearance of radioactivity from the brain as reflected by significant increases in kE,brain (from +26% to +54% relative to baseline). Immunohistochemical analysis confirmed ABCB1 induction in the brains of PCN-treated APP/PS1-21 mice with a concomitant decrease in Aβ levels. There was a significant positive correlation between kE,brain and ABCB1 levels in the brain. In wild-type mice, a significant age-related decrease in kE,brain was found. Metabolite analysis showed that most radioactivity in the brain comprised unmetabolized 11C-metoclopramide in all animal groups. Conclusion:11C-metoclopramide can measure ABCB1 induction in the mouse brain without the need to consider an arterial input function and may find potential application in Alzheimer disease patients to noninvasively evaluate strategies to enhance the clearance properties of the BBB.

GABAA Receptors in the Mongolian Gerbil: a PET Study Using [18F]Flumazenil to Determine Receptor Binding in Young and Old Animals.

Plastic changes in the central auditory system involving the GABAergic system accompany age-related hearing loss. Such processes can be investigated with positron emission tomography (PET) imaging using [18F]flumazenil ([18F]FMZ). Here, [18F]FMZ PET-based modeling approaches allow a simple and reliable quantification of GABAA receptor binding capacity revealing regional differences and age-related changes. Sixty-minute list-mode PET acquisitions were performed in 9 young (range 5-6months) and 11 old (range 39-42months) gerbils, starting simultaneously with the injection of [18F]FMZ via femoral vein. Non-displaceable binding potentials (BPnd) with pons as reference region were calculated for auditory cortex (AC), inferior colliculus (IC), medial geniculate body (MGB), somatosensory cortex (SC), and cerebellum (CB) using (i) a two-tissue compartment model (2TCM), (ii) the Logan plot with image-derived blood-input (Logan (BI)), (iii) a simplified reference tissue model (SRTM), and (iv) the Logan reference model (Logan (RT)). Statistical parametric mapping analysis (SPM) comparing young and old gerbils was performed using 3D parametric images for BPnd based on SRTM. Results were verified with in vitro autoradiography from five additional young gerbils. Model assessment included the Akaike information criterion (AIC). Hearing was evaluated using auditory brainstem responses. BPnd differed significantly between models (p < 0.0005), showing the smallest mean difference between 2TCM as reference and SRTM as simplified procedure. SRTM revealed the lowest AIC values. Both volume of distribution (r2 = 0.8793, p = 0.018) and BPnd (r2 = 0.8216, p = 0.034) correlated with in vitro autoradiography data. A significant age-related decrease of receptor binding was observed in auditory (AC, IC, MGB) and other brain regions (SC and CB) (p < 0.0001, unpaired t test) being confirmed by SPM using pons as reference (p < 0.0001, uncorrected). Imaging of GABAA receptor binding capacity in gerbils using [18F]FMZ PET revealed SRTM as a simple and robust quantification method of GABAA receptors. Comparison of BPnd in young and old gerbils demonstrated an age-related decrease of GABAA receptor binding.

SAT-LB042 Effect of Dehydroepiandrosterone on the Perimenopausal Ovary

Dehydroepiandrosterone (DHEA) supplementation can improve oocyte quality in women with diminished ovarian function1-2. However, it is unclear if similar beneficial effects of DHEA supplementation can be obtained during the perimenopause, a period when the number of ovarian follicles shows a marked age-associated decline. To address this question we examined the impact of 2.5-months of daily oral DHEA supplementation (5 mg) on the number of ovarian follicles as well as on the concentration of anti-Müllerian hormone (AMH) – a marker of ovarian function. The study used perimenopausal adult rhesus monkeys; like women, these long-lived nonhuman primates show ~28-day menstrual cycles and eventually undergo menopause. Furthermore, they show similar age-related neuroendocrine changes, including a marked decrease in circulating DHEA concentrations3-4. Our experimental design involved the following three groups (N = 6 per group): Young adult (mean age = 11.6 years), Old control (mean age = 23.1 years), and Old DHEA-treated (mean age = 23.5 years). Histological examination of the ovaries revealed a significant (P<0.05) age-related decrease in the mean number of pre-antral follicles but no obvious beneficial effect of DHEA supplementation. Similarly, AMH concentrations within the ovaries and serum, assessed by Western analysis and ELISA respectively, showed a significant (P<0.05) age-related decrease but no obvious beneficial effect of DHEA supplementation. Taken together, the results indicate that short-term DHEA supplementation alone is insufficient to enhance ovarian function during the perimenopause and they complement findings from our earlier studies, which showed no obvious benefit of DHEA supplementation on cognitive function5. On the other hand, it remains plausible that chronic DHEA supplementation, earlier DHEA intervention, and supra-physiological DHEA doses may have more therapeutic potential. 1Gleicher N et al.Reprod Biomed Online, 21:360-365, 2010. 2Yilmaz N et al. Eur J Obstet Gynecol Reprod Biol, 169:257-260, 2013. 3Downs JL & Urbanski HF. Biol Reprod, 75: 539-546, 2006. 4Sorwell KG et al. Neurobiol Aging, 33:1487.e1-e13, 2012. 5Sorwell KG et al. Genes Brain Behav, 16:361-368, 2017. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Abstract P4-06-16: Analysis of tumor infiltrating lymphocytes in three age categories of luminal B-like breast cancer patients and its correlation with lymph node involvement and systemic immunosenescence/frailty markers

Abstract BACKGROUND Immunosenescence, the age-related decrease in immune competence, which is characterized by decreased adaptive immunity and increased low-grade inflammation. It may lead to altered tumor immunity. However, immunosenescence markers have not been correlated yet with tumor infiltrating leukocytes (TILs) nor with clinical frailty. METHODS This is the first study that investigates how age affects the relation between systemic immunity and tumor microenvironment in early luminal B-like breast cancer (BC) in function of age. Luminal B-like BC was defined as grade II-III, ER+, HER2- on core biopsies at inclusion. Three distinct age categories of BC patients were chosen: 35-45 years (y) (N=15), 55-65y (N=19), ≥70y (N=31). Stromal TILs (sTILs) % were assessed according to published guidelines, on representative tumor sections. Further characterization of the TILs by immunohistochemistry, using the antibodies against CD3, CD4, CD8, CD5, CD20, CD68 and FOXP3, is currently ongoing. Immunosenescence was evaluated by looking at eleven inflammatory plasma cytokines and chemokines, circulating insulin-like growth factor-1 (IGF-1), T-cell p16INK4a expression, PBMC subset profiles and expression levels of twenty immune-related microRNAs. In the old age category, geriatric assessment was performed. RESULTS With increasing age, sTILs % significantly decreased, concomitant with significantly increased plasma levels of several inflammatory cytokines (IL-1α, IL-6) and chemokines (IP-10, IL-8, MCP-1), intermediate monocytes, as well as T-cell p16INK4a expression. Significant age-related decrease was seen for plasma IGF-1, naïve CD8+ T-cells and CD8+ T-cells expressing CD27 and/or CD28. Four immune-related microRNAs showed significantly different expression levels between the age groups: miR-18a decreased with age, miR-155 increased with age, miR-19b and miR-20a peaked in the middle group. As expected, various correlations exist between the different blood immunosenescence markers. The % of sTILs showed weak negative correlations with IL-6, IL-8, IL-1α, MCP-1 and the % of regulatory T-cells. Additionally the % of sTILs and several makers of immunosenescence (MCP-1, miR-20a, miR-155, intermediate monocytes) correlated with components of the geriatric assessment (activities of daily living (ADL), mini nutritional assessment (MNA), mini–mental state examination (MMSE)) and with the Leuven oncogeriatric frailty score (LOFS) in the oldest group. Conversely, lymph node involvement was not associated with the % of sTILs nor with any blood aging biomarker. CONCLUSION sTILs % and several blood immunosenescence markers significantly differ between young and older luminal B-like BC patients. Some of these markers correlated with markers of clinical frailty as well. These findings suggest that interactions between tumor cells and immune/inflammatory cells differ with age and therefore applicable immune biomarkers and approaches for immunotherapy may vary depending on patients' age. Citation Format: Berben L, Hatse S, Kenis C, Dalmasso B, Smeets A, Vos H, Neven P, Floris G, Wildiers H. Analysis of tumor infiltrating lymphocytes in three age categories of luminal B-like breast cancer patients and its correlation with lymph node involvement and systemic immunosenescence/frailty markers [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-06-16.

Thickness of retina and choroid in the elderly population and its association with Complement Factor H polymorphism: KLoSHA Eye study.

PurposeTo analyze the associations of retinal and choroidal thickness on enhanced-depth imaging optical coherence tomography (EDI-OCT) with clinical, ophthalmic and genetic factors in the normal elderly population (aged 65 years or older).MethodsIn this prospective, population-based cohort study, people aged 65 years or older were enrolled in the baseline study of the Korean Longitudinal Study on Health and Aging (KLoSHA) Eye Study. All participants underwent spectral domain-OCT scan using the EDI technique. A topographic map of the retina was obtained and subfoveal choroidal thickness (SFCT) was measured manually. Blood samples from all subjects were genotyped for major age-related macular degeneration (AMD)-associated single nucleotide polymorphisms (SNPs) the major AMD-associated SNPs; CFH Y402H rs1061170, CFH I62V rs800292, ARMS2 A69S rs10490924. A statistical analysis was conducted to compare the retinal thickness, choroidal thickness, and AMD risk genotypes.ResultsAmong the three hundred eighty people enrolled, the mean age was 76.6 years (range 65–99 years). Factors that showed correlation with either tomographic retinal parameters, retinal nerve fiber layer, or SFCT, were age and gender. Significant age-related decrease in thickness was observed in the RNFL, mean central thickness (MCT) and SFCT. Gender differences existed in central foveolar thickness (CFT) and MCT, where it was thicker in men. While chorioretinal parameters were not related with other genotypes, CFH rs1061170 risk genotype was significantly associated with thin SFCT. The group containing the AMD- risk allele (CT) had a 14.7% reduction in the SFCT compared to the non-risk TT group.ConclusionsIn addition to the well-known association with AMD, CFH rs1061170 is a significant genetic risk factor associated with choroidal thinning in normal eyes of the elderly population. Such findings may provide further insight into the pathogenesis of age-related macular degeneration as well as normal aging. In addition, our study provides the first normative data on retinal and choroidal thickness in population-based aged groups with a mean age over seventy-five.