Age-related Protein Research Articles

MRI‐based measure of dementia risk derived using machine learning is strongly associated with measures of longevity and biological age

AbstractBackgroundMachine learning and artificial intelligence methods have been applied to brain images to estimate measures of brain aging. However, only rarely have these measures been examined in the context of biologic age. Here, we investigated associations of an MRI‐based measure of dementia risk the Alzheimer’s disease pattern similarity (AD‐PS) scores with measures of longevity and biological age.MethodParticipants were those from visit 5 of the Atherosclerosis Risk in Community Study with cognitive status adjudication and MRI available. The AD‐PS score was estimated based on previously reported machine learning methods. We evaluated associations of the AD‐PS score with all‐cause mortality. Participants were stratified by AD‐PS tertiles and the analyses were adjusted for age, race, sex, hypertension and smoking. AD‐PS score was examined in association with 32 proteins reported to be associated with age. In these analyses, we used Bonferroni correction (α = 0.05,p<0.0016). Finally, associations with a deficit accumulation index(DAI) based on 38 health items was investigated. In both cases, linear regression models were adjusted for age, race and sex. Sensitivity analyses using only cognitively normal (CN) individuals were performed.ResultMortality – A total of 356 participants died within 8 years of follow‐up. The AD‐PS score was significantly associated(p<0.001) with time to all‐cause mortality. Participants in the lowest tertile had lower all‐cause mortality rate compared to those in the highest tertile (HR: 0.43;95% CI:0.31,0.60). The association remained significant when restricting the sample to only CN subjects (HR for lowest tertile:0.53; 95% CI:0.35,0.81, p = 0.0028).Age related proteins ‐ The AD‐PS scores were significantly associated (p<0.05, uncorrected) with 10 of the 32 proteins. Growth/differentiation factor 15(GDF‐15) and pleiotrophin remained significant after correction for multiple‐testing. Analysis of CN participants showed a subset of the same proteins to be significant (p<0.05,uncorrected) but only the GDF‐15 remained significant after correction for multiple‐testing.DAI ‐ A linear regression model showed a significant association between DAI and AD‐PS scores overall (coeff = 0.52; 95% CI:0.37‐0.67) and in the CN subset (coeff = 0.3,95% CI:0.13‐0.48).ConclusionWhile the AD‐PS scores were created as a measure of dementia risk, our analyses suggest that they could also be capturing brain aging.

P170 Trikafta® modulates release of extracellular vesicles in cystic fibrosis

Dysregulation of CFTR leads to chronic inflammation in Cystic Fibrosis (CF) airways. Extracellular vesicles (EVs) have emerged as an important biomarkers of disease. We previously reported elevated levels of EVs in CF with distinct age-related protein profiles. The levels of EVs and its associated proteins in CF in the presence of CF modulators Trikafta (elexacaftor, tezacaftor, ivacaftor), however remains unexplored. The study aims to characterise and study the effect of Trikafta on EVs and its associated protein targets in CF airway models and serum samples from patients with cystic fibrosis (PWCF). Bronchial brushings from CF patients were passaged and differentiated by air liquid interface (ALI) cultures. After 21 days, TEER was recorded and differentiation of mucociliary layer was confirmed with MUC5AC staining. Further the cultures were treated with Trikafta. EVs released into the apical and basal compartments before and after treatment were extracted by differential centrifugation and characterised by NTA and mass spectrometry (MS). The therapeutic restoration of CFTR was examined using immunoblotting. Serum samples from PWCF on Trikafta were also examined for EV release and content before and after 12 months treatment. After 21 days, of ALI culture. EVs were isolated before and after treatment with Trikafta showed a significant 1.5-fold decrease in EVs in both apical and basal compartments respectively (PWCF (Apical) Control: 4.2E+07 ± 3E+06; Treated 3.2E+07 ± 2E+06; (Basal) Control: 1.3E +08 ± 1.6E+07; Treated 8.1E+07 ± 5E+06) demonstrating that Trikafta treatment diminishes epithelial EV releases. MS based proteomics revealed unique EV protein fingerprints post Trikafta treatment for both epithelial EVs and serum EVs with changes in expression of immune proteins were observed. The study demonstrates that Trikafta can modulate EV release and content in PWCF demonstrating novel mechanisms by which CFTR modulators can regulate the inflammatory landscape in CF.

Cordyceps cicadae NTTU 868 Mycelia Fermented with Deep Ocean Water Minerals Prevents D-Galactose-Induced Memory Deficits by Inhibiting Oxidative Inflammatory Factors and Aging-Related Risk Factors.

Cordyceps cicadae, a medicinal fungus that is abundant in bioactive compounds such as N6-(2-hydroxyethyl)-adenosine (HEA) and polysaccharides, possesses remarkable anti-inflammatory, antioxidant, and nerve damage recovery properties. Deep ocean water (DOW) contains minerals that can be absorbed and transformed into organic forms by fungi fermentation. Recent studies have shown that culturing C. cicadae in DOW can enhance its therapeutic benefits by increasing the levels of bioactive compounds and minerals' bioavailibility. In this study, we investigated the effects of DOW-cultured C. cicadae (DCC) on brain damage and memory impairment induced by D-galactose in rats. Our results indicate that DCC and its metabolite HEA can improve memory ability and exhibit potent antioxidant activity and free radical scavenging in D-galactose-induced aging rats (p < 0.05). Additionally, DCC can mitigate the expression of inflammatory factors, such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS), thereby preventing brain aging. Furthermore, DCC showed a significant decrease in the expression of the aging-related proteins glial fibrillary acidic protein (GFAP) and presenilin 1 (PS1). By reducing brain oxidation and aging-related factors, DOW-cultured C. cicadae demonstrate enhanced anti-inflammatory, antioxidant, and neuroprotective effects, making it a promising therapeutic agent for preventing and treating age-related brain damage and cognitive impairment.

Gouqizi () seed oil reduces D-galactose induced inflammation in testis of rats Janus kinase 1/signal transducerand activator of transcription 1/nuclear factor-κB and.

To investigate the efficacy of Gouqizi () seed oil (FLSO) on D-gal induced inflammation in testis of rats and . In aging Sertoli cells (TM4 cells) induced by D-galactose (D-gal), the expression of upregulated aging-related proteins. The number of cells counted by cell counting kit (CCK)-8 assay showed a high number of cells disposed with FLSO at 50, 100 and 150 μg/mL compared to that for the aging model. , male Sprague-Dawley rats ( = 50, 8-week-old, 230-255 g) were randomly categorized into control, aging model, and FLSO (low-, medium-, and high-dose) groups. The expression of nuclear factor-κB (NF-κB) and its upstream factors [Janus kinase 1 (JAK1) and signal transducerand activator of transcription 1 (STAT1)] was detected by Western blot and immunofluorescence, related inflammatory factors quantified by enzyme-linked immunosorbent assay. Evaluation of testicular tissue by Johnsen score, the spermatogenic function was explored. The expression of interleukin-1β (IL-1β) ( < 0.05), IL-6 ( < 0.001), and tumor necrosis factor α (TNF-α) ( < 0.05) was decreased significantly, while that of heme oxygenase-1 (HO-1) ( < 0.001) and IL-10 ( < 0.05) was increased in cells disposed with FLSO 100 μg/mL. FLSO inhibited the expression of NF-B and declined p-p65/p65 ( < 0.01), as detected by Western blotting. In, the levels in serum of IL-1β ( < 0.001), IL-6 ( < 0.05), and TNF-( < 0.01) declined while IL-10 ( < 0.05) was upregulated post-FLSO treatment. In addition, the expression of JAK-1 and STAT1 increased significantly in testicular tissue of rats treated with FLSO as compared to the aging model of rats ( < 0.001), while the expression of NF-κB ( < 0.001) declined in the testis in the FLSO group, as assessed by immunofluorescence. The levels of inhibor B and testosterone in serum both increased (< 0.05). In conclusion, this study determined the protective effects of FLSO to tolerate inflammatory injury in the testis, indicating that FLSO alleviates inflammation JAK-1/STAT1/NF-κB pathway.

Comparison of Pairwise Venous and Fingertip Plasma Using Quantitative Proteomics Based on Data-Independent Acquisition.

Blood contains a great deal of health-related information and can be used to monitor human health status. Clinically, venous or fingertip blood is usually used for blood tests. However, the clinical application settings of the two sources of blood are unclear. In this study, the proteomes of pairwise venous plasma (VP) and fingertip plasma (FP) were analyzed, and the levels of 3797 proteins were compared between VP and FP. The Spearman's correlation coefficient for the relationship between protein levels of VP and FP ranges from 0.64 to 0.78 (p < 0.0001). The common pathways of VP and FP are related to cell-cell adhesion, protein stabilization, innate immune response, and complement activation, the classical pathway. The VP-overrepresented pathway is related to actin filament organization, while the FP-overrepresented pathway is related to the hydrogen peroxide catabolic process. ADAMTSL4, ADIPOQ, HIBADH, and XPO5 both in VP and FP are potential gender-related proteins. Notably, the VP proteome has a higher interpretation on age than the FP proteome, and CD14 is a potential age-related protein in VP but not in FP. Our study mapped the different proteomes between VP and FP, which can provide value for the standardization of clinical blood tests.

Extensive accumulation of misfolded protein aggregates during natural aging and senescence.

Accumulation of misfolded protein aggregates is a hallmark event in many age-related protein misfolding disorders, including some of the most prevalent and insidious neurodegenerative diseases. Misfolded protein aggregates produce progressive cell damage, organ dysfunction, and clinical changes, which are common also in natural aging. Thus, we hypothesized that aging is associated to the widespread and progressive misfolding and aggregation of many proteins in various tissues. In this study, we analyzed whether proteins misfold, aggregate, and accumulate during normal aging in three different biological systems, namely senescent cells, Caenorhabditis elegans, and mouse tissues collected at different times from youth to old age. Our results show a significant accumulation of misfolded protein aggregates in aged samples as compared to young materials. Indeed, aged samples have between 1.3 and 2.5-fold (depending on the biological system) higher amount of insoluble proteins than young samples. These insoluble proteins exhibit the typical characteristics of disease-associated aggregates, including insolubility in detergents, protease resistance, and staining with amyloid-binding dye as well as accumulation in aggresomes. We identified the main proteins accumulating in the aging brain using proteomic studies. These results show that the aged brain contain large amounts of misfolded and likely non-functional species of many proteins, whose soluble versions participate in cellular pathways that play fundamental roles in preserving basic functions, such as protein quality control, synapsis, and metabolism. Our findings reveal a putative role for protein misfolding and aggregation in aging.

A novel histological staging of hippocampal sclerosis that is evident in gray matter loss in vivo.

Hippocampal sclerosis of aging (HS) is defined by end-stage histological findings, strongly associated with limbic-predominant age-related TAR DNA-binding protein 43 (TDP-43) encephalopathy (LATE). We aimed to characterize features of early HS to refine the understanding of its role within combined pathology. We studied 159 brain donations from the multimodal Vallecas Alzheimer's Center Study. A staging system (0 to IV) was developed to account for HS progression and analyzed in relation to pre-mortem cognitive and magnetic resonance imaging (MRI) data. Our HS staging system displayed a significant correlation with disease duration, cognitive performance, and combined neuropathologies, especially with LATE. Two-level assessment along the hippocampal longitudinal axis revealed an anterior-posterior gradient of HS severity. In vivo MRI showed focally reduced hippocampal gray matter density as a function of HS staging. The association of this staging system with clinical progression and structural differences supports its utility in the characterization and potential in vivo monitoring of HS. The definition of hippocampal sclerosis of aging (HS) is currently limited to an end-stage pathological fingerprint. We characterize early HS histological features to define a complete staging system. The proposed staging displays a parallel but not identical progression to limbic-predominant age-related TAR DNA-binding protein 43 (TDP-43) encephalopathy (LATE). The proposed staging also reflects the expected demographic and cognitive differences associated with HS. In vivo magnetic resonance imaging (MRI) showed focal hippocampal gray matter loss as a function of HS staging.

Amonafide Induces HUVEC Senescence by Inhibiting Autophagy.

Amonafide (Amo), due to hematotoxicity and digestive tract symptoms, the clinical application of which is limited. Several studies have reported that chemotherapy side effects are closely related to cellular senescence accumulation. Our study aims to examine whether amonafide causes senescence in human umbilical vein endothelial cell (HUVEC) lines and investigate its mechanisms associated with senescence. The experiments of expression of genes and proteins associated with aging were carried out with HUVEC cell lines. The experiments were divided into a control group and an amonafide group with different days. The HUVEC senescence cells were detected by SA-β-Gal staining, Western blotting detected the protein levels of p16, p53, AMPK (Adenosine 5'-Monophosphate (AMP)-Activated Protein Kinase), mTOR (mechanistic Target of Rapamycin), p62, and LC3 (microtubule-associated protein1 light chain 3, MAP1LC3). Fluorescence detected the expression of mRFP (monomeric Red Fluorescent Protein)-GFP (Green Fluorescent Protein)-LC3 and LC3 puncta of HUVEC cells. RT-qPCR (Real-Time Quantitative Polymerase Chain Reaction) tested the expressions of p53, p21, IL (Interleukin)-1β, IL-6 (Interleukin-6), IL-8 (Interleukin-8), and MCP-1 (Monocyte Chemoattractant Protein-1). CCK-8 (Cell Counting Kit-8) assessed the HUVEC cell viability. Here, we reported that amonafide resulted in an increased proportion of SA-β-Gal positive cells, high expression of aging-related proteins (p53 p < 0.05; p16 p < 0.05), and aging-related genes (p53 p < 0.05; p21 p < 0.05; IL-1β p < 0.05; IL-6 p < 0.05; IL-8 p < 0.05; MCP-1 p < 0.05) on the 3rd day. Mechanistically, amonafide could cause an increase in the levels of the mTOR (p < 0.05) on days 1 and 3, and p62 protein (p < 0.05) on day 1, and a decline in LC3II (microtubule-associated protein1 light chain 3Ⅱ)/LC3I levels (p < 0.05) on day 3, which is associated with the regulation of senescence. Additionally, the viability of HUVECs (human umbilical vein endothelial cells) was significantly inhibited by amonafide starting with a concentration of 0.8 μm (p < 0.05). We first discovered that amonafide caused normal cellular senescence in our experiments. Amonafide-induced cellular aging by inhibiting autophagy and activating the mTOR pathway. The findings may offer new strategies for managing adverse reactions to amonafide.

Cepharanthine Inhibits Doxorubicin-Induced Cellular Senescence by Activating Autophagy via the mTOR Signaling Pathway.

Doxorubicin (Dox) is a clinical first-line broad-spectrum anticancer agent. A dose-dependent cardiotoxic and myelosuppressive response limits the clinical use of Dox. Recent research indicates that Dox-induced cardiotoxicity is associated with senescent cell accumulation and that antiaging therapy can alleviate aging-related disorders. Cepharanthine (Cep) is commonly used to treat various acute and chronic illnesses, including leukopenia, snakebites, dry mouth, and hair loss. Whether Cep alleviates Dox-induced senescence is unknown. The expression of genes and proteins associated with aging was examined using NIH3T3 cell lines. The experiments were divided into a control group, a Dox group, and a Cep group on different days. NIH3T3 senescent cells were detected by senescence-β-galactosidase (SA-β-Gal) staining, and Western blotting was used to detect the protein levels of p16, p53, AMP-activated protein kinase (AMPK), mammalian target of the rapamycin (mTOR), p62, and Light Chain 3 (LC3). Fluorescence was used to detect the expression of monomeric red fluorescence protein-green fluorescence protein-Light Chain 3 (mRFP-GFP-LC3) and LC3 puncta in NIH3T3 cells. Real-time quantitative reverse transcription polymerase chain reaction (RT‒qPCR) was used to test the expression of senescence-associated secretory phenotypes (SASP: Interleukin 6 (IL-6), Interleukin 1 beta (IL-1β), and Interleukin 8 (IL-8)). Cell Counting Kit-8 (CCK-8) was used to assess NIH3T3 cell viability. Here, we reported that Cep reversed the Dox-induced increase in the proportion of SA-β-Gal-positive cells and the high expression of aging-related proteins (p53, p < 0.05; p16, p < 0.05) and aging-related genes (IL-6, p < 0.05; IL-1β, p < 0.05; IL-8, p < 0.05) on the 3rd day. Mechanistically, Cep reduced the increase in the levels of phospho-mTOR (p < 0.05) on Days 1 and 3 and p62 protein (p < 0.05) caused by Dox on Day 1 and reversed the decline in LC3II/LC3I levels (p < 0.05) caused by Dox on Day 3, which is associated with the regulation of senescence. Additionally, the viability of NIH3T3 cells was significantly increased in the concentration range of 0.5-5 μM Cep (p < 0.05). We first found that Cep could suppress SA-β-Gal activity (p < 0.05) and the development of SASP. Additionally, in Cep-treated cells, Cep could restore autophagy dysfunction and suppress the mTOR signaling pathway. This research provides a new view on the mechanics of aging and autophagy and aids in developing novel antiaging drugs.

EARLY-LIFE PROTEIN TRANSLATION SPIKE DRIVES AGING VIA JUVENILE HORMONE/GERMLINE STEM CELL SIGNALING

Abstract Protein translation (PT) is high in early-adulthood across invertebrates, rodents, and humans but sharply declines thereafter. It has been implicitly assumed that elevated PT at young ages is beneficial to health and PT ends up dropping as a passive byproduct of aging. However, whether this holds true and how dynamic fluctuations in PT over time impact aging remain unknown. In Drosophila, we show that a transient PT spike in early-adulthood exerts long-lasting negative impacts on aging trajectories and proteostasis in later-life. Conversely, blocking the early-life PT spike robustly improves life-/health-span and prevents age-related protein aggregation. Further, greater early-life PT rise strongly predicts shorter future lifespan across fly strains and is observed in neurodegenerative disorders long before symptoms/pathologies appear. Proteomics-guided investigations revealed that during the early-adulthood PT rise, juvenile hormone triggers proteostatic dysfunction and drives aging via aggregation-prone large lipid transfer proteins. The early-life PT spike also transcriptionally represses stress responses essential for proteostasis maintenance and drives aging via germline stem cell signaling. Our findings suggest that PT is thereby suppressed after early-adulthood as an adaptive response to alleviate proteostatic burden, slow down aging, and optimize life-/health-span. We thus propose that the rise and fall in PT over time impact aging in the opposite direction from what was previously assumed. Our work provides a novel theoretical framework for understanding how lifetime PT dynamics regulate the onset of aging. Further, our study provides a foundation for future research, including whether high early-life PT spike is an early biological event driving neurodegeneration/age-related diseases.

Imaging Cataract-Specific Peptides in Human Lenses.

Age-related protein truncation is a common process in long-lived proteins such as proteins found in the ocular lens. Major truncation products have been reported for soluble and membrane proteins of the lens, including small peptides that can accelerate protein aggregation. However, the spatial localization of age-related protein fragments in the lens has received only limited study. Imaging mass spectrometry (IMS) is an ideal tool for examining the spatial localization of protein products in tissues. In this study we used IMS to determine the spatial localization of small crystallin fragments in aged and cataractous lenses. Consistent with previous reports, the pro-aggregatory αA-crystallin 66-80 peptide as well as αA-crystallin 67-80 and γS-crystallin 167-178 were detected in normal lenses, but found to be increased in nuclear cataract regions. In addition, a series of γS-crystallin C-terminal peptides were observed to be mainly localized to cataractous regions and barely detected in transparent lenses. Other peptides, including abundant αA3-crystallin peptides were present in both normal and cataract lenses. The functional properties of these crystallin peptides remain unstudied; however, their cataract-specific localization suggests further studies are warranted.

Association of Stroke and Cerebrovascular Pathologies With Scam Susceptibility in Older Adults

Scam susceptibility is associated with adverse financial and health outcomes, including an increased risk of cognitive decline and dementia. Very little is known about the role of cerebrovascular pathologies with scam susceptibility. To examine the association of diverse cerebrovascular pathologies (globally and regionally) with scam susceptibility. This clinical-pathological cohort study included participants from 2 ongoing studies of aging that began enrollment in 1994 and 1997. In 2010, participants were enrolled in the decision-making and behavioral economics substudy and were followed up for a mean (SD) of 3.4 (2.6) years prior to death. From 1365 older persons with clinical evaluations, 69 were excluded for having dementia at baseline. From 538 older persons who died, 408 had annual assessments for scam susceptibility, cardiovascular risk burden, and cognitive function and consented to brain donation for detailed neuropathologic examination. Data were analyzed from June 2021 through September 2022. Neuropathologic examination identified the presence of macroscopic and microscopic infarcts, atherosclerosis, arteriolosclerosis, cerebral amyloid angiopathy, and common neurodegenerative pathologies (Alzheimer disease, limbic-predominant age-related transactive response DNA-binding protein 43 encephalopathy, and Lewy bodies). There was a total of 408 participants. The mean (SD) age at death was 91 (6.1) years, the mean (SD) amount of education was 15.6 (3.1) years, and 297 (73%) were women. Participants included 4 Latino individuals (1%), 7 non-Latino Black individuals (2%), and 397 non-Latino White individuals (97%). The frequency of participants with macroscopic infarcts was 38% (n = 154), microinfarcts was 40% (n = 163), and moderate to severe vessel disease; specifically, atherosclerosis was 20% (n = 83), arteriolosclerosis was 25% (n = 100), and cerebral amyloid angiopathy was 35% (n = 143). In linear regression models adjusted for demographics and neurodegenerative pathologies, macroscopic infarcts were associated with greater scam susceptibility (estimate [SE], 0.18 [0.07]; P = .009). This association persisted after adjusting for cardiovascular risk burden and global cognition. Regionally, infarcts localized to the frontal, temporal, and occipital lobes and thalamus were associated with greater scam susceptibility. Neither arteriosclerosis, atherosclerosis, cerebral amyloid angiopathy, nor microinfarcts were associated with scam susceptibility. Cerebrovascular pathologies, specifically cerebral infarcts, is linked with greater scam susceptibility in older adults, independent of common neurodegenerative diseases such as Alzheimer disease. Future studies examining in vivo magnetic resonance imaging markers of cerebrovascular pathologies with scam susceptibility and related decision-making outcomes will be important.

Impact and Risk Factors of Limbic Predominant Age-Related TDP-43 Encephalopathy Neuropathologic Change in an Oldest-Old Cohort.

Limbic predominant age-related TAR DNA binding protein 43 (TDP-43) encephalopathy neuropathologic change (LATE-NC) is a prevalent degenerative pathology in the oldest-old who are the fastest-growing segment of our population with the highest rates of dementia. We aimed to determine the relationship between LATE-NC and cognitive impairment and to identify its potential risk factors by studying its relationship with common past medical histories in an oldest-old cohort. Participants from The 90+ Study with longitudinal evaluations and autopsy data were included. Dementia status and impairment in 5 main cognitive domains were determined at postmortem conferences leveraging all clinical and neuropsychological data blind to neuropathologic diagnosis. Medical history information was obtained from patients and their informants. LATE-NC and Alzheimer disease neuropathologic change (ADNC) were considered present in those with TDP-43 pathology in the hippocampus and/or neocortex and those with high likelihood of ADNC according to NIA-AA guidelines, respectively. We examined the association of degenerative pathologies with cognitive outcomes and multiple comparisons-adjusted relationship of medical history variables with LATE-NC and ADNC using logistic regressions adjusted for age at death, sex, and education. Three hundred twenty-eight participants were included in this study. LATE-NC was present in 32% of the participants. It had a significant association with the presence of dementia (OR 2.8, 95% CI 1.7-4.6) and impairment in memory (OR 3.0, 95% CI 1.8-5.1), language (OR 2.6, 95% CI 1.6-4.3), and orientation (OR 3.5, 95% CI 2.1-5.9). The association with impaired orientation was unique to LATE-NC, and the strength and significance of the other associations were comparable to ADNC. Furthermore, we found that history of osteoarthritis (OR 0.37, adjusted 95% CI 0.21-0.66) and hypertension (OR 0.52, adjusted 95% CI 0.28-0.98) were associated with a reduced likelihood of LATE-NC, but not ADNC. Our results suggest that LATE-NC is a prevalent degenerative pathology in the oldest-old and has significant associations with dementia and impairment in cognitive domains with magnitudes that are comparable to ADNC. We also found that past medical histories of hypertension and osteoarthritis were associated with a lower likelihood of LATE-NC. This might help identify upstream mechanisms leading to this important pathology.

Mechanism of Thymus Rejuvenation in Elderly Macaques.

Senile thymus atrophy is an important factor leading to decreased immune function. Repairing the atrophic thymus tissue structure, rebuilding immune function, and replenishing the number of exogenous stem cells may be ideal methods. In this study, bone marrow mesenchymal stem cells were intravenously infused into elderly macaques. We found that thymus volume was substantially increased, some thymus tissue regeneration was observed, the degree of thymus tissue fibrosis decreased, collagen fiber deposition decreased, cortical and medulla structures emerged gradually, the number of apoptotic cells decreased significantly, and the expression of apoptosis-related proteins decreased. For the effects of stem cell therapy on aging-related genes, we performed transcriptomic analysis of thymus tissue. The results show the expression pattern of the tissue transcriptome tended to be similar to the thymus expression pattern in young macaques compared with the elderly group, reverse aging-related proteins. Based on the results, it is suggested that stem cell therapy is an ideal method to prevent or reverse the aging of the thymus.

β-elemene induced apoptosis and senescence of triple-negative breast cancer cells through IGF1/IGF1R pathway

Purposeβ-elemene has a wide range of anticancer effects and can be used in a variety of cancer types. This study mainly explored its mechanism of action on TNBC cells and provided theoretical basis for the treatment of TNBC. MethodsFirstly, TNBC cells were treated with different concentrations of β-elemene, and screened out an appropriate concentration for subsequent research. Then, through the bioinformatics website, predicted genes that have a binding relationship with β-elemene. Then, the overexpression vector of the selected gene was transfected into the cell. The effects of β-elemene and its target genes on the proliferation and apoptosis of TNBC cells were detected by CCK-8, Edu assay, and flow cytometry, and the senescence of cells was determined by SA-β-gal experiment. Western blotting was used to detect the expression of apoptosis and aging-related proteins. Resultsβ-elemene inhibited TNBC cell viability and proliferation in a concentration-dependent manner, and induces apoptosis and senescence. Through the screening of candidate genes, IGF1 was finally determined to be an effective target gene of β-elemene. The expression level of IGF1 was decreased in cells treated with β-elemene. Overexpression of IGF1 significantly alleviated ability of β-elemene to inhibit cell viability, proliferation, and induced cell apoptosis and senescence. In addition, β-elemene inhibited the expression of IGF1R and Bcl-2, and promoted the expression of Cleaved Caspase-3 and senescence-related proteins (p27, p16, p53 and p21), and these effects were reversed by overexpression of IGF1. Conclusionβ-elemene induced apoptosis and senescence of triple-negative breast cancer cells through IGF1/IGF1R pathway.

Plasma proteome profiling of healthy individuals across the life span in a Sicilian cohort with long-lived individuals.

The study of healthy human aging is important for shedding light on the molecular mechanisms behind aging to promote well‐being and to possibly predict and/or avoid the development of age‐related disorders such as atherosclerosis and diabetes. Herein, we have employed an untargeted mass spectrometry‐based approach to study age‐related protein changes in a healthy Sicilian plasma cohort including long‐lived individuals. This approach confirmed some of the previously known proteins correlated with age including fibulin‐1, dystroglycan, and gamma‐glutamyl hydrolase. Furthermore, our findings include novel proteins that correlate with age and/or with location and uric acid, which could represent a unique signature for healthy aging.

Quantitative Acetylomics Reveals Dynamics of Protein Lysine Acetylation in Mouse Livers During Aging and Upon the Treatment of Nicotinamide Mononucleotide

Lysine acetylation is a reversible and dynamic post-translational modification that plays vital roles in regulating multiple cellular processes including aging. However, acetylome-wide analysis in the aging process remains poorly studied in mammalian tissues. Nicotinamide adenine dinucleotide (NAD+), a hub metabolite, benefits health span at least in part due to the activation of Sirtuins, a family of NAD+-consuming deacetylases, indicating changes in acetylome. Here, we combine two antibodies for the enrichment of acetylated peptides and perform label-free quantitative acetylomic analysis of mouse livers during natural aging and upon the treatment of beta-nicotinamide mononucleotide (NMN), a NAD+ booster. Our study describes previously unknown acetylation sites and reveals the acetylome-wide dynamics with age as well as upon the treatment of NMN. We discover protein acetylation events as potential aging biomarkers. We demonstrate that the life-beneficial effect of NMN could be partially reflected by the changes in age-related protein acetylation. Our quantitative assessment indicates that NMN has mild effects on acetylation sites previously reported as substrates of Sirtuins. Collectively, our data analyze protein acetylation with age, laying critical foundation for the functional study of protein post-translational modification essential for healthy aging and perhaps disease conditions.

Blood transcriptome analysis revealing aging gene expression profiles in red panda.

The red panda is an endangered forest species distributed on the edge of the Qinghai Tibet Plateau. The species has been conserved in ex-situ in many countries and its survival is threatened by many diseases. Its immune system is vulnerable to age-associated alterations, which accumulate and result in a progressive deterioration that leads to an increased incidence of diseases. We identified 2,219 differentially expressed genes (DEGs) between geriatric (11–16 years) and adult individuals (4–8 years), and 1690 DEGs between adults and juveniles (1 year). The gene expression and functional annotation results showed that the innate immunity of red pandas increases significantly in geriatric individuals, whereas its change remains unclear when comparing adults and juveniles. We found that the adaptive immunity of red pandas first increased and then decreased with age. We identified CXCR3, BLNK, and CCR4 as the hub genes in the age-related protein–protein interaction network, which showed their central role in age-related immune changes. Many DNA repair genes were down-regulated in geriatric red pandas, suggesting that the DNA repair ability of the blood tissue in geriatric red pandas is significantly reduced. The significantly up-regulated TLR5 in geriatric individuals also suggests the possibility of enhancing the vaccination immune response by incorporating flagellin, which could be used to address decreased vaccine responses caused by age-related declines in immune system function. This work provides an insight into gene expression changes associated with aging and paves the way for effective disease prevention and treatment strategies for red pandas in the future.

Evaluating the effects of mitochondrial autophagy flux on ginsenoside Rg2 for delaying D-galactose induced brain aging in mice

BackgroundAging is an inevitable gradual process of the body, which can cause dysfunction or degeneration of the nervous or immune system, thus becoming a critical pathogenic factor inducing neurodegenerative diseases. Previous reports have confirmed that saponins (ginsenosides) derived from Panax ginseng. C.A. Meyer exerted obvious memory-enhancing and anti-aging effects, and the simpler the structure of ginsenosides, the better the biological activity. Ginsenoside Rg2 (Rg2) is a prominent and representative panaxatriol-type ginsenoside produced during ginseng processing, which has been reported to have pretty good neuroprotective activity. PurposeThe work was aimed at exploring the therapeutic effects and possible molecular mechanisms of Rg2 by establishing the subacute brain aging model induced by D-galactose (D-gal) in mice. MethodsThe anti-aging activity of G-Rg2 (10, 20 mg/kg for 4 weeks) was assessed using the D-gal induced brain aging model (800 mg/kg for 8 weeks). The Morris water maze (MWM) and histopathological analysis were used to evaluate the cognitive function and pathological changes of the brain in mice, respectively. The protein expression levels of p53, p21, p16ink4α, IL-6, CDK4, ATG3, ATG5, ATG7, LC3, p62, LAMP2, and TFEB were quantified through western blot analysis. The degree of mitochondrial damage and the number of mitochondrial autophagolysosomes in hippocampal neurons were monitored using TEM analysis. ResultsThe results showed that Rg2 could significantly restore D-gal-induced impaired memory function, choline dysfunction, and redox system imbalance in mice. Rg2 treatment also considerably decreased the over-expression of aging-related proteins such as p53/p21/p16ink4α induced by D-galactose, which demonstrated that Rg2 possessed good anti-aging activity. Meanwhile, Rg2 could evidently reduce the pathological changes caused by D-gal exposure. Moreover, the results from transmission electron microscopy and western blot analysis indicated that Rg2 could delay the brain aging induced by D-gal in mice via promoting the degradation of the autophagy substrate p62 while increasing the protein expression level of LAMP2/TFEB to maintain mitochondrial function. ConclusionThese results indicate that Rg2 could postpone brain aging by increasing mitochondrial autophagy flux to maintain mitochondrial function, which greatly enriched the research on the pharmacological activity of ginsenosides for delaying brain aging.

Anti-Aging Effect of Momordica charantia L. on d-Galactose-Induced Subacute Aging in Mice by Activating PI3K/AKT Signaling Pathway.

Anti-aging is a challenging and necessary research topic. Momordica charantia L. is a common edible medicinal plant that has various pharmacological activities and is often employed in daily health care. However, its anti-aging effect on mice and the underlying mechanism thereof remain unclear. Our current study mainly focused on the effect of Momordica charantia L. on d-galactose-induced subacute aging in mice and explored the underlying mechanism. UHPLC-Q-Exactive Orbitrap MS was applied to qualitatively analyze the chemical components of Momordica charantia L. ethanol extract (MCE). A subacute aging mice model induced by d-galactose (d-gal) was established to investigate the anti-aging effect and potential mechanism of MCE. The learning and memory ability of aging mice was evaluated using behavioral tests. The biochemical parameters, including antioxidant enzyme activity and the accumulation of lipid peroxides in serum, were measured to explore the effect of MCE on the redox imbalance caused by aging. Pathological changes in the hippocampus were observed using hematoxylin and eosin (H&E) staining, and the levels of aging-related proteins in the PI3K/AKT signaling pathway were assessed using Western blotting. The experimental results demonstrated that a total of 14 triterpenoids were simultaneously identified in MCE. The behavioral assessments results showed that MCE can improve the learning and memory ability of subacute mice. The biochemical parameters determination results showed that MCE can improve the activity of antioxidant enzymes and decrease the accumulation of lipid peroxides in aging mice significantly. Furthermore, aging and injury in the hippocampus were ameliorated. Mechanistically, the results showed a significant upregulation in the protein expression of P-PI3K/PI3K and P-AKT/AKT (p < 0.01), as well as a significant reduction in cleaved caspase-3/caspase-3, Bax and P-mTOR/mTOR (p < 0.01). Our results confirm that MCE could restore the antioxidant status and improve cognitive impairment in aging mice, inhibit d-gal-induced apoptosis by regulating the PI3K/AKT signaling pathway, and rescue the impaired autophagy caused by mTOR overexpression, thereby exerting an anti-aging effect.