Age-related Impairment Research Articles

Therapeutic approaches for improving cognitive function in the aging brain.

The rapid aging of populations around the world has become an unprecedented challenge. Aging is associated with cognitive impairment, including dementia and mild cognitive impairment. Successful drug development for improving or maintaining cognition in the elderly is critically important. Although 4 drugs for improving cognition in Alzheimer's disease have been approved, a variety of potential drugs targeting age-related cognitive impairment are still in development. In addition, non-pharmacological interventions, including cognition-oriented treatments, non-invasive brain stimulation physical exercise, and lifestyle-related interventions, have also been suggested as cognitive enhancers in the last decade. In this paper, we reviewed the recent evidence of pharmacological and non-pharmacological interventions aimed at improving or maintaining cognition in the elderly.

SIRT1 haplo-insufficiency results in reduced cortical bone thickness, increased porosity and decreased estrogen receptor alpha in bone in adult 129/Sv female mice.

Sirtuin 1 (SIRT1) is a key player in aging and metabolism and regulates bone mass and architecture. Sexual dimorphism in skeletal effects of SIRT1 has been reported, with an unfavorable phenotype primarily in female mice. To investigate the mechanisms of gender differences in SIRT1 skeletal effect, we investigated femoral and vertebral cortical and cancellous bone in global Sirt1 haplo-insufficient 129/Sv mice aged 2,7,12 months lacking Sirt1 exons 5,6,7 (Sirt1+/Δ ) and their wild type (WT) counterparts. In females, femoral bone mineral content, peak cortical thickness, and trabecular bone volume (BV/TV%), number and thickness were significantly lower in Sirt1+/Δ compared to WT mice. Increased femoral cortical porosity was observed in 7-month-old Sirt1+/Δ compared to WT female mice, accompanied by reduced biomechanical strength. No difference in vertebral indices was detected between Sirt1+/Δ and WT female mice. SIRT1 decreased with aging in WT female mice and was lower in vertebrae and femur in 18- and 30- versus 3-month-old 129/Sv and C57BL/6J female mice, respectively. Decreased bone estrogen receptor alpha (ERα) was observed in Sirt1+/Δ compared to WT female mice and was significantly higher in Sirt1 over-expressing C3HT101/2 murine mesenchymal stem cells. In males no difference in femoral indices was detected in Sirt1+/Δ versus WT mice, however vertebral BV/TV%, trabecular number and thickness were higher in Sirt1+/Δ vs. WT mice. No difference in androgen receptor (AR) was detected in bone in Sirt1+/Δ vs. WT male mice. Bone SIRT1 was significantly lower in male compared to female WT mice, suggesting that SIRT1 maybe more significant in female than male skeleton. These findings demonstrate that 50% reduction in SIRT1 is sufficient to induce the hallmarks of skeletal aging namely, decreased cortical thickness and increased porosity in female mice, highlighting the role of SIRT1 as a regulator of cortical bone quantity and quality. The effects of SIRT1 in cortical bone are likely mediated in part by its regulation of ERα. The age-associated decline in bone SIRT1 positions SIRT1 as a potential therapeutic target to ameliorate age-related cortical bone deterioration in females. The crosstalk between ERα, AR and SIRT1 in the bone microenvironment remains to be further investigated.

Instability of non-REM sleep in older women evaluated by sleep-stage transition and envelope analyses.

Traditionally, age-related deterioration of sleep architecture in older individuals has been evaluated by visual scoring of polysomnographic (PSG) recordings with regard to total sleep time and latencies. In the present study, we additionally compared the non-REM sleep (NREM) stage and delta, theta, alpha, and sigma wave stability between young and older subjects to extract features that may explain age-related changes in sleep. Polysomnographic recordings were performed in 11 healthy older (72.6 ± 2.4 years) and 9 healthy young (23.3 ± 1.1 years) females. In addition to total sleep time, the sleep stage, delta power amplitude, and delta, theta, alpha, and sigma wave stability were evaluated by sleep stage transition analysis and a novel computational method based on a coefficient of variation of the envelope (CVE) analysis, respectively. In older subjects, total sleep time and slow-wave sleep (SWS) time were shorter whereas wake after sleep onset was longer. The number of SWS episodes was similar between age groups, however, sleep stage transition analysis revealed that SWS was less stable in older individuals. NREM sleep stages in descending order of delta power were: SWS, N2, and N1, and delta power during NREM sleep in older subjects was lower than in young subjects. The CVE of the delta-band is an index of delta wave stability and showed significant differences between age groups. When separately analyzed for each NREM stage, different CVE clusters in NREM were clearly observed between young and older subjects. A lower delta CVE and amplitude were also observed in older subjects compared with young subjects in N2 and SWS. Additionally, lower CVE values in the theta, alpha and sigma bands were also characteristic of older participants. The present study shows a decrease of SWS stability in older subjects together with a decrease in delta wave amplitude. Interestingly, the decrease in SWS stability coincided with an increase in short-term delta, theta, sigma, and alpha power stability revealed by lower CVE. Loss of electroencephalograms (EEG) variability might be a useful marker of brain age.

Is Periodontitis Associated with Age-Related Cognitive Impairment? The Systematic Review, Confounders Assessment and Meta-Analysis of Clinical Studies.

It has been suggested that molecular pathological mechanisms responsible for periodontitis can be linked with biochemical alterations in neurodegenerative disorders. Hypothetically, chronic systemic inflammation as a response to periodontitis plays a role in the etiology of cognitive impairment. This study aimed to determine whether periodontitis (PDS) is a risk factor for age-related cognitive impairment (ACI) based on evidence of clinical studies. A comprehensive, structured systematic review of existing data adhering to the Preferred Reporting Items for Systematic Review and Meta Analyses (PRISMA) guidelines was carried out. Five electronic databases, PubMed, Embase, Scopus, Web of Science, and Cochrane, were searched for key terms published in peer-reviewed journals until January 2021. The Newcastle-Ottawa scale was used to assess the quality of studies and risk of bias. The primary and residual confounders were explored and evaluated. A meta-analysis synthesizing quantitative data was carried out using a random-effects model. Seventeen clinical studies were identified, including 14 cohort, one cross-sectional, and two case-control studies. Study samples ranged from 85 to 262,349 subjects, with follow-up between 2 and 32 years, and age above 45 years, except for two studies. The findings of studies suggesting the PDS-ACI relationship revealed substantial differences in design and methods. A noticeable variation related to the treatment of confounders was observed. Quality assessment unveiled a moderate quality of evidence and risk of bias. The subgroups meta-analysis and pooled sensitivity analysis of results from seven eligible studies demonstrated overall that the presence of PDS is associated with an increased risk of incidence of cognitive impairment (OR = 1.36, 95% CI 1.03-1.79), particularly dementia (OR = 1.39, 95% CI 1.02-1.88) and Alzheimer's disease (OR = 1.03 95% CI 0.98-1.07)). However, a considerable heterogeneity of synthesized data (I2 = 96%) and potential publication bias might affect obtained results. While there is a moderate statistical association between periodontitis and dementia, as well as Alzheimer's disease, the risk of bias in the evidence prevents conclusions being drawn about the role of periodontitis as a risk factor for age-related cognitive impairment.

Age-Related Decline in Nrf2/ARE Signaling Is Associated with the Mitochondrial DNA Damage and Cognitive Impairments

In this research, we compared the cognitive parameters of 2-, 7-, and 15-month-old mice, changes in mitochondrial DNA (mtDNA) integrity and expression of genes involved in the nuclear erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) signaling pathway. We showed an age-related decrease in the Nfe2l2 expression in the cerebral cortex, not in the hippocampus. At the same time, we find an increase in the mtDNA copy number in the cerebral cortex, despite the lack of an increase in gene expression, which is involved in the mitochondrial biogenesis regulation. We suppose that increase in mtDNA content is associated with mitophagy downregulation. We supposed that mitophagy downregulation may be associated with an age-related increase in the mtDNA damage. In the hippocampus, we found a decrease in the Bdnf expression, which is involved in the pathways, which play an essential role in regulating long-term memory formation. We showed a deficit of working and reference memory in 15-month-old-mice in the water Morris maze, and a decrease in the exploratory behavior in the open field test. Cognitive impairments in 15-month-old mice correlated with a decrease in Bdnf expression in the hippocampus, Nfe2l2 expression, and an increase in the number of mtDNA damage in the cerebral cortex. Thus, these signaling pathways may be perspective targets for pharmacological intervention to maintain mitochondrial quality control, neuronal plasticity, and prevent the development of age-related cognitive impairment.

The Clinical Evidence-Based Paradigm of Topical Anti-Aging Skincare Formulations Enriched with Bio-Active Peptide SA1-III (KP1) as Collagen Modulator: From Bench to Bedside.

A substantial reduction in the amount and quality of collagen leads to age-related deterioration of the elasticity and firmness of the skin. In recent years, multiple compounds have been developed aimed at reversing the molecular features of dermal aging. One such target for aging reversal is collagen degradation or turnover. SA1-III is a decapeptide (Ac-Met-Gly-Lys-Val-Val-Asn-Pro-Thr-Gln-Lys-NH2), also known as KP1, formally derived from the C-terminal portion of serpin A1, an agent known as a physiological inhibitor of neutrophil elastase, and has been the subject of laboratory and clinical studies determining its effects on modulation of collagen turnover as well as the treatment of age-associated changes of the face. This review aims to provide a bio-inspired approach focusing on the latest scientific studies that describe the compound, as well as a comprehensive appraisal of laboratory and clinical tests on skincare formulations enriched with sA1-III.

Cycloastragenol activation of telomerase improves β-Klotho protein level and attenuates age-related malfunctioning in ovarian tissues

Age-related deterioration in the reproductive capacity of women is directly related to the poor developmental potential of ovarian follicles. Although telomerase plays a key role in female fertility, TERT-targeting therapeutic strategies for age-related female infertility have yet to be investigated. This study elucidated the effect of Telomerase activation on mice ovaries and more specifically on Klb (β-Klotho) gene expression, which is linked to ageing, female hormonal regulation, and cyclicity. The homology-based 3D model of hTERT was used to predict its binding mode of Cycloastragenol (CAG) using molecular docking and molecular dynamics simulations. Based on docking score, simulation behavior, and interaction with hTERT residues it was observed that CAG could bind with the hTERT model. CAG treatment to primary cultured mouse granulosa cells and activation of telomerase was examined via telomerase activity assay (Mouse TE (telomerase) ELISA Kit) and telomere length by quantitative fluorescence in situ hybridization. CAG mediated telomerase also significantly improved β-Klotho protein level in the aged granulosa cells. To demonstrate that β-Klotho is telomerase dependent, the TERT was knocked down via siRNA in granulosa cells and protein level of β-Klotho was examined. Furthermore, CAG-mediated telomerase activation significantly enhanced the level of Klb and recovered ovarian follicles in the D-galactose (D-gal)-induced ovarian ageing mouse model. Moreover, Doxorubicin-induced ovarian damage, which changes ovarian hormones, and inhibit follicular growth was successfully neutralized by CAG activated telomerase and its recovery of β-Klotho level. In conclusion, TERT dependent β-Klotho regulation in ovarian tissues is one of the mechanisms, which can overcome female infertility.

Long-Term Aerobic Training Improves Mitochondrial and Antioxidant Function in the Liver of Wistar Rats Preventing Hepatic Age-Related Function Decline.

Most studies on the effects of physical exercise have focused on its influence on muscle tissue, forgetting its interference in liver function. Ageing leads to the progressive impairment of hepatic functions. Several biochemical and bioenergetics parameters were determined to test the impact of a lifelong aerobic training program in the hepatic age-related and the development of an adaptative response. Liver samples were collected from 28 male Wistar rats (4-week-old, 159.4 ± 11.9 g at the beginning of the protocol), randomly distributed into two groups: non-exercised or exercised and submitted to a treadmill exercise program (60 min/day, 5 days/week, at 70% of maximal running speed), for 24 (n = 9) or 54 weeks (n = 10). A maximal running speed test was performed to determine the training speed. Antioxidant enzyme activity, cellular redox status, oxidative stress, mitochondrial respiratory chain enzymes and respiratory activity were performed in liver samples. Lifelong exercise decreased the age-associated decline in mitochondrial dysfunction, increasing the respiratory rate in state 2 (mitochondrial respiration stimulated by the substrate in the absence of added ADP) (p = 0.03) and citrate synthase enzymatic activity (p = 0.007). Complex II (p < 0.0001) and IV (p < 0.001) showed a decrease in enzymatic activity. Ageing-related oxidative stress was also attenuated by physical exercise, as showed by the increase in first-line defense antioxidant enzymes (superoxide dismutase (p = 0.07) and catalase (p = 0.03)), decreased lipid peroxidation levels (p = 0.864 for total fraction, p = 0,27 for mitochondrial fraction) and higher glutathione reduced/oxidized ratio (p = 0.02). According to our results, the regular practice of exercise can prevent the liver’s mitochondrial dysfunction and loss of antioxidant system efficacy that may arise from ageing, highlighting the benefit of lifelong aerobic exercise in preventing age-related hepatic impairment and associated diseases.

Nutrition for Older Adults.

The world population is aging rapidly. Japan has the oldest population in the world, with 28% of the current population aged 65 y or older. Maintaining good nutrition is important for preventing age-related deterioration in health. Physical activity levels, energy intake, and weight tend to decrease with age. Decreased food intake increases the risk of undernutrition due to the inadequate intake of essential nutrients. The proportion of the older population that is malnourished ranges from 1% to 5% among independent older adults living in the community, and increases to 30% to 50% among residents of care institutions. Among older adults, the risk of death increases with increasing leanness. In Japan, the government pays considerable attention to the prevention of adverse health effects related to obesity among young and middle-aged adults, although the adverse health effects related to undernutrition and being underweight among older adults have been overlooked. In addition to providing nutrients, eating has important psychological and social benefits. Therefore, there is a need to pay attention to the diet and nutritional needs of older adults in Japan in order to promote and maintain their physical and mental health.

Aging Fibroblasts Adversely Affect Extracellular Matrix Formation via the Senescent Humoral Factor Ependymin-Related Protein 1

Skin senescence is characterized by a decrease in extracellular matrix and the accumulation of senescent fibroblasts in the dermis, and their secretion of humoral factors. Ependymin-related protein 1 (EPDR1) is involved in abnormal fibroblast metabolism and collagen deposition, however, its relation to skin aging is unclear. We investigated whether and how EPDR1 is involved in age-related dermal deterioration. When young dermal fibroblasts and senescent cells were co-cultured in a semipermeable membrane separation system, the young fibroblasts showed decreased gene expression of collagen type I α1 chain (COL1A1) and elastin, and increased expression of matrix metalloproteinase (MMP)1 and MMP3. Senescence marker expression and EPDR1 production were increased in the culture medium of senescent cells. Treatment of young fibroblasts with recombinant EPDR1, enhanced matrix-related gene expression and suppressed COL1A1 expression, whereas EPDR1 knockdown had the opposite effects. EPDR1 gene and protein expression were increased in aged skin, compared to young skin. These results suggest that senescent cells affect nearby fibroblasts, in part through EPDR1 secretion, and exert negative effects on matrix production in the dermis. These results may lead to the discovery of potential candidate targets in the development of skin anti-aging therapies.

A postpartum enriched environment rescues impaired cognition and oxidative markers in aged mice with gestational inflammation.

Previous studies have shown that gestational inflammation can accelerate age-associated cognitive decline (AACD) in maternal mice; enriched environments (EEs) have been reported to protect normally aging mice from AACD and improve mitochondrial function. However, it is unclear whether the nitrosative stress-related proteins tet methylcytosine dioxygenase 1 (TET1) and S-nitrosoglutathione reductase (GSNOR) are involved in the accelerated aging process of gestational inflammation and whether EEs can slow this process. In this study, CD-1 female mice on the 15th day of pregnancy were injected with bacterial lipopolysaccharide (50μg/kg; LPS group) or an equivalent amount of normal saline (CON group) from the abdominal cavity for 4 consecutive days. Twenty-one days after delivery, half of the LPS-treated mice were randomly selected for EE until the end of the behavioral experiment (LPS-E group). When the female rats were raised to 6 months and 18 months of age, the Morris water maze (MWM) was used to detect spatial learning and memory ability; RT-PCR and Western blots were used to measure the mRNA and protein levels of hippocampal TET1 and GSNOR. As for the control group, compared with 6-month-old mice, the spatial learning and memory ability of 18-month-old mice decreased, and the hippocampal TET1 and GSNOR mRNA and protein levels were decreased. Gestational inflammation exacerbated these age-related changes, but an EE alleviated the effects. Pearson's correlation analysis indicated that performance during the learning and memory periods in the MWM correlated with the levels of hippocampal TET1 and GSNOR. Our findings suggest that gestational inflammation accelerates age-related learning and memory impairments and that postpartum EE exposure could alleviate these changes. These effects may be related to hippocampal TET1 and GSNOR expression.

Milk fat globule membrane concentrate as a nutritional supplement prevents age-related cognitive decline in old rats: A lipidomic study of synaptosomes

Aging is associated with a decline in cognitive abilities, mainly in memory and executive functioning. A similar but premature deterioration in cognitive capacities is the hallmark of mild cognitive impairment, Alzeimer’s disease and dementia. The biochemical mechanisms that cause these neurodegenerative disorders are poorly understood. However, some evidence suggests that insufficient dietary intakes of some phospholipids could impact on brain function and increase the risk of future cognitive impairment and dementia. We evaluated the cognitive and biochemical effects of supplementation with a milk fat globule membrane (MFGM) concentrate in aged rats.We observed that, compared to control animals, MFGM supplemented rats showed enhanced spatial working memory, but both groups exhibited similar reference spatial learning and emotional memory abilities. No significant differences between BDNF levels in the hippocampus and frontal cortex of treated rats as compared to controls were found. The nootropic effects observed were accompanied by significant changes in the lipid composition of synaptic membranes. MFGM supplementation increased the levels of EPA and DHA acids as well as the plasmalogens content in the synaptosomes isolated from the hippocampus (Synapt-HP) and the frontal cortex (Synapt-FC). In addition enhanced levels of phosphatidyl serine (PS), particularly PS(18:1/18:1), and phosphatidyl inositol (PI) molecular species were observed in Synapt-HP and Synapt-FC of treated animals.Lipidomic analysis also revealed greater concentration of phosphatidyl ethanolamine (PE) molecular species containing very long-chain fatty acids and PE plasmenyls in Synapt-HP as well as an increase of the SM content in Synapt-FC from the MFGM group. Although further studies are needed to confirm the underlying mechanism (individual or synergistic), these results suggest that MFGM supplementation could be employed as a dietary implement to restore the proper cerebral concentration of some bioactive lipids and prevent or slow the progression of age-related cognitive impairment.

Effects of exercise types on white matter microstructure in late midlife adults: Preliminary results from a diffusion tensor imaging study.

Higher aerobic fitness during late midlife is associated with higher white matter (WM) microstructure. Compared with individuals engaged in irregular exercise, those who engage in regular aerobic exercise show higher fractional anisotropy (FA), a diffusion tenor imaging (DTI) measure that provides an index of WM microstructural integrity. However, whether other types of exercise, such as Tai Chi, can also facilitate WM changes in adults during late midlife remains unknown. The present study compares two types of exercise, Tai Chi and walking, with a sedentary control group, in order to examine the effects of exercise on WM microstructure and determine the regional specificity of WM differences. Thirty-six healthy adults between the ages of 55 and 65 years participated in the study. Based on the participants' exercise habits, they were allocated into three groups: Tai Chi, walking, or sedentary control. All participants were required to complete physical fitness measurements and completed magnetic reasoning imaging (MRI) scans. Our results revealed that the Tai Chi group exhibited a higher FA value in the left cerebral peduncle, compared to the sedentary control group. We also observed that both the Tai Chi and walking groups exhibited higher FA values in the right uncinate fasciculus and the left external capsule, in comparison to the sedentary control group. Increased FA values in these regions was positively correlated with higher levels of physical fitness measurements (i.e., peak oxygen uptake [VO2peak], muscular endurance/number of push-up, agility, power). These findings collectively suggest that regular exercise is associated with improved WM microstructural integrity, regardless of the exercise type, which could guide the development and application of future prevention and intervention strategies designed to address age-related cognitive impairments during late midlife.

Senescence of the immune defences and reproductive trade-offs in females of the mealworm beetle, Tenebrio molitor

In the theory of ageing, it has been assumed that ageing is associated with a decline in somatic defences, including the immune system, as a consequence of a trade-off with reproduction. While overall immunity suffers from age-related deterioration (immune senescence), the different components of the immune response appear to age differently. It is also likely that investment among the many arms of the immune system and reproduction with age is finely adjusted to the organisms' reproductive strategy. We investigated this possibility in females of Tenebrio molitor, a species of long-lived insect with reproductive strategies similar to those of long-lived mammals. We specifically tested the effects of immunological challenges imposed early or late in adult life on immune pathway activation as well as fertility early and late in life. We found complex patterns of changes in immune defences with age and age-specific immune challenges with contrasted relationships with female reproduction. While cellular and enzymatic defences showed signs of ageing, they did not trade-off with reproduction. By contrast, the induced antibacterial immune response was found to be unaffected by age and to be highly connected to female fecundity. These findings suggest that these immunological pathways have different functions with regard to female ageing in this insect species.

Regulation of aging by balancing mitochondrial function and antioxidant levels

Aging is the deterioration of physiological mechanisms that is associated with getting old. There is a link between aging and mitochondrial function. However, there is an unresolved relationship between ATP levels and aging. To address this issue, we administered febuxostat (FBX), an inhibitor of human xanthine oxidase (XO)/xanthine dehydrogenase (XDH), to C. elegans. We used C. elegans as a model to evaluate the effects of FBX and to challenge the enigma of the relationship between ATP and lifespan. In this study, we showed that FBX protects mitochondria and prevents age-related muscle deterioration in C. elegans. In addition, we showed that FBX administration could increase ATP levels without overloading the mitochondria while extending the lifespan. We also showed that the combination of FBX and an antioxidant as a protection against ROS prolongs lifespan more. We have shown that the antioxidant effects and increased ATP levels may lead to antiaging effects.

Carotid disease, cognition, and aging: time to redefine asymptomatic disease?

There is an increasing appreciation of the vascular contributions in the development of age-related cognitive impairment and dementia1,2. Identifying risk and maintaining cognitive health for successful aging is ever relevant in our aging population. Carotid disease, a well-established risk factor for stroke and often a harbinger of other vascular disease states, is also emerging as another vascular risk factor for age-related cognitive decline. When combined with vascular risk factors, the incidence of age-related carotid disease can be as high as 70%3,4. Historically, carotid disease has been dichotomized into two large groups in trial design, outcome measurements, and treatment decisions: symptomatic and asymptomatic carotid artery stenosis. The dichotomous distinction between asymptomatic and symptomatic carotid stenosis based on existing definitions may be limiting the care we are able to provide for patients classified as "asymptomatic" from their carotid disease. Medically, we now know that these patients should be treated with the same intensive medical therapy as those with "symptomatic" carotid disease. Emerging data also shows that hypoperfusion from asymptomatic disease may lead to significant cognitive impairment in the aging population, and it is plausible that most "age-related" cognitive changes may be reflective of vascular impairment and neurovascular dysfunction. While over the past 30years medical, surgical, and radiological advances have pushed the field of neurovascular disease to significantly reduce the number of ischemic strokes, we are far from any meaningful interventions to prevent vascular cognitive impairment. In addition to including cognitive outcome measures, future studies of carotid disease will also benefit from including advanced neuroimaging modalities not currently utilized in standard clinical imaging protocols, such as perfusion imaging and/or functional connectivity mapping, which may provide novel data to better assess for hypoxic-ischemic changes and neurovascular dysfunction across diffuse cognitive networks. While current recommendations advise against widespread population screening for asymptomatic carotid stenosis, emerging evidence linking carotid stenosis to cognitive impairment prompts us to re-consider our approach for older patients with vascular risk factors who are at risk for cognitive decline.

LC3-Associated Phagocytosis Is Impaired in Bone Marrow Macrophages during Ageing Leading to Defective Processing of Apoptotic Cells and Suppression of Sting Activation

Introduction Macrophage phagocytic function declines with ageing, with potential deleterious consequences on inflammation, immune response, maintenance of tissue health, and cancer. Paradoxically, we and others have found that with increasing age, macrophage number increases within the bone marrow (BM) microenvironment, supporting the hypothesis that the ageing macrophages are functionally impaired. Phagocytosis by mononuclear cells occurs through either an LC3-dependent or -independent mechanism. LC3-associated phagocytosis (LAP) is physiologically triggered by pathogens and cellular debris via interaction with phagocyte surface receptors, including T cell membrane protein 4 (TIM-4) and FcR. Here, we investigate whether age-related macrophage functional impairment is associated with LC3. Results BM was isolated from young (8-12 weeks) and aged (18-24 months) female C57Bl/6 mice and macrophages were analysed using flow cytometry and isolated via FACS. We show increased BM macrophage numbers in old BM (2 fold), but no difference in total phagocytic potential as measured by uptake of E.coli bioparticles or apoptotic debris, when compared to young. Furthermore, using immunofluorescent microscopy to visualise macrophage phagocytosis, we observed that the phagosomes generated in BM macrophages from aged animals did not recruit LC3, whereas in young animals LC3 was recruited. Consequently, macrophages from older animals accumulated large amounts of E.coli bioparticles and apoptotic bodies when compared to young macrophages. This suggests defective processing of the E.coli bioparticles by the phagosome once the phagosome has formed. To understand if this is due to lack of LC3 protein, we next compared gene expression and protein levels of LC3 in young and old animals. There was no loss in LC3 RNA or protein expression in macrophages from old and young. As we have recently reported that BM macrophage LAP mediates the stimulator of interferon genes (STING) pathway, we examined STING activation in old and young BM macrophages by measuring Gbp2, Irf7, and Ifit3 gene expression. Results showed a significant reduction in STING mediated gene expression in BM macrophages from aged mice compared to young. Summary These data suggest the decline in macrophage phagocytic function associated with age occurs because of a failure of LC3-mediated phagosome clearance. Furthermore, we hypothesise that the observed increase in BM macrophage numbers in older animals is, at least in part, a compensatory mechanism for the defective individual macrophage phagocytic processing seen, helping preserve overall BM phagocytic function.

Gut microbiome, cognitive function and brain structure: a multi-omics integration analysis

BackgroundMicrobiome-gut-brain axis may be involved in the progression of age-related cognitive impairment and relevant brain structure changes, but evidence from large human cohorts is lacking. This study was aimed to investigate the associations of gut microbiome with cognitive impairment and brain structure based on multi-omics from three independent populations.MethodsWe included 1430 participants from the Guangzhou Nutrition and Health Study (GNHS) with both gut microbiome and cognitive assessment data available as a discovery cohort, of whom 272 individuals provided fecal samples twice before cognitive assessment. We selected 208 individuals with baseline microbiome data for brain magnetic resonance imaging during the follow-up visit. Fecal 16S rRNA and shotgun metagenomic sequencing, targeted serum metabolomics, and cytokine measurements were performed in the GNHS. The validation analyses were conducted in an Alzheimer’s disease case–control study (replication study 1, n = 90) and another community-based cohort (replication study 2, n = 1300) with cross-sectional dataset.ResultsWe found protective associations of specific gut microbial genera (Odoribacter, Butyricimonas, and Bacteroides) with cognitive impairment in both the discovery cohort and the replication study 1. Result of Bacteroides was further validated in the replication study 2. Odoribacter was positively associated with hippocampal volume (β, 0.16; 95% CI 0.06–0.26, P = 0.002), which might be mediated by acetic acids. Increased intra-individual alterations in gut microbial composition were found in participants with cognitive impairment. We also identified several serum metabolites and inflammation-associated metagenomic species and pathways linked to impaired cognition.ConclusionsOur findings reveal that specific gut microbial features are closely associated with cognitive impairment and decreased hippocampal volume, which may play an important role in dementia development.

The time is now: regular exercise maintains vascular health in ageing women.

Although ageing impairs cardiovascular health in both men and women, the timeline is different between the sexes. This is at least partially attributed to the loss of oestrogen in women at midlife, in connection with menopause. Oestrogen has protective effects on the cardiovascular system, and menopause consequently leads to a rapid and significant declineincardiovascularhealth. Notably, oestrogeninteracts with its nuclear and membrane receptors leading to changes in proteins of importance for cardiovascular health. Skeletal muscle activity, which affects the expression of many of the same proteins as oestrogen, could potentially counteract the loss of oestrogen at menopause. The hypothesis that exercise can counteract the loss of oestrogen has been explored in several recent studies. It has been found that regular physical activity opposes the detrimental effects not only of ageing, but also of the menopausal transition, on cardiovascular health. Although, vascular benefits can be gained at allages, initiating physical activity at or soon after menopause may be more effective than at a later time point in life. Intuitively, it is easier to prevent decrements than attempting to regain lost vascular health. This idea is supported by evidence at the molecular level, suggesting that exercise-inducedactivationoftheoestrogen-related receptor-α pathwayismoreeffectivesoonafter menopause compared tolater. Together, although a decline incardiovascular health due to chronological ageing cannot be completely prevented, a physically active lifestyle mitigates age-related cardiovascular impairments. Importantly, regular physical activity through life should always be addressed as the biological norm.

Growth Hormone Stimulates Murine Macrophage Migration during Aging.

Age-related impairments in macrophage functions have important consequences for the health of the elderly population. The aging process is also accompanied by a reduction in several hormones, including growth hormone (GH). Previous studies have shown that this hormone can affect macrophage activity in young individuals; however, the biological effects of GH stimulation on macrophages during aging have not yet been elucidated. The aim of this work was to investigate the in vitro effects of GH on peritoneal macrophages from aged mice. Peritoneal macrophages isolated from young (4 months-old) and old (12-15 months-old) mice were treated in vitro with 100 ng/mL of GH for 24 hours. After treatment, cells were analysed for cell morphology, reactive oxygen species (ROS) production, expression of integrins, cell adhesion to extracellular matrix molecules, and migration in transwell chambers. Although GH-treated cells from old mice exhibited decreased ROS production, we did not observe the effects of GH on macrophage morphology or macrophage phagocytic activity in young and old mice-derived cell cultures. Macrophages from old mice had increased adhesion to laminin and fibronectin substrates, as did cells obtained from young mice treated with GH, but no change was observed in the expression of integrin receptors. Furthermore, cells from old mice exhibited increased migration compared to young mice and a significant increase in macrophage migration was observed under GH stimulation. Our results showed that GH can interfere with the motility of macrophages from old mice, advancing our understanding of the interactions between the immune and neuroendocrine systems during aging.