Aging-Us最新文献

{"title":"Mikhail 'Misha' Blagosklonny's enduring legacy in geroscience: the hyperfunction theory and the therapeutic potential of rapamycin.","authors":"David A Barzilai","doi":"10.18632/aging.206189","DOIUrl":"10.18632/aging.206189","url":null,"abstract":"<p><p>The untimely passing of Dr. Mikhail \"Misha\" Blagosklonny has left a lasting void in geroscience and oncology. This review examines his profound contributions, focusing on his pioneering the Hyperfunction Theory and his advocacy for rapamycin, an mTOR inhibitor, as a therapeutic agent for lifespan extension. Contrary to traditional damage-centric models, the Hyperfunction Theory rejects damage accumulation as the primary driver of aging. Instead, it redefines aging as a quasi-programmed process driven by the persistent, excessive activity of growth-promoting pathways beyond their developmental roles, leading to age-related pathologies. We explore how Blagosklonny's insights predict rapamycin's ability to decelerate aging by modulating excessive mTOR signaling, supported by empirical evidence across multiple physiological systems, including immune, cardiovascular, cognitive, and oncologic health. His forward-thinking approach, advocating for the cautious clinical use of rapamycin and suggesting personalized, preventive, and combination therapy strategies, has catalyzed interest in translational geroscience. This review synthesizes Blagosklonny's legacy, presenting rapamycin as a foundational pharmacological intervention with potential in managing age-related decline and extending healthspan, and underlines his impact in shifting aging research from theoretical frameworks to actionable interventions. Blagosklonny's work remains an enduring inspiration, paving the way toward treating aging as a modifiable condition.</p>","PeriodicalId":55547,"journal":{"name":"Aging-Us","volume":"null ","pages":"1-15"},"PeriodicalIF":3.9,"publicationDate":"2025-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11810056/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142980452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Senolytic agent ABT-263 mitigates low- and high-LET radiation-induced gastrointestinal cancer development in <i>Apc</i>^1638N/+ mice.","authors":"Kamendra Kumar, Bo-Hyun Moon, Santosh Kumar, Jerry Angdisen, Bhaskar V S Kallakury, Albert J Fornace, Shubhankar Suman","doi":"10.18632/aging.206183","DOIUrl":"10.18632/aging.206183","url":null,"abstract":"<p><p>Exposure to ionizing radiation (IR), both low-LET (e.g., X-rays, γ rays) and high-LET (e.g., heavy ions), increases the risk of gastrointestinal (GI) cancer. Previous studies have linked IR-induced GI cancer to cellular senescence associated secretory phenotype (SASP) signaling. This study explores the potential of senolytic therapy to mitigate IR-induced GI carcinogenesis. Male <i>Apc</i>^1638N/+ mice were exposed to γ and ²⁸Si-ions (69 keV/μm) IR. Two months later, they were treated with the senolytic agent ABT-263 orally for 5 days/week until euthanasia, followed by tumor counting and biospecimen collection at five months post-exposure. Tumors were classified as adenoma or carcinoma by a pathologist. Serum cytokine levels were measured, and the markers of senescence (p16), SASP (IL6), and oncogenic β-catenin signaling were assessed using <i>in-situ</i> immunostaining of intestinal tissue. Both low- and high-LET radiation exposure led to an increased frequency of adenoma and carcinoma in <i>Apc</i>^1638N/+ mice, accompanied by increased cellular senescence, acquisition of SASP, and overexpression of BCL-XL protein in a subset of these cells. Furthermore, administration of ABT-263 resulted in the elimination of senescent/SASP cells, a decrease in pro-inflammatory cytokines (TNFRSF1B, CCL20, CXCL4, P-selectin, CCL27, and CXCL16) at the systemic level, and downregulation of β-catenin signaling that coincided with decreased GI cancer development. This study suggests a link between IR-induced senescent/SASP cell accumulation and GI cancer development. It also shows that the senolytic agent ABT-263 can regulate IR-induced inflammatory cytokines and carcinogenic mediators both systemically and in intestinal tissue. These findings support the potential of senolytic intervention to reduce IR-induced GI cancer risk.</p>","PeriodicalId":55547,"journal":{"name":"Aging-Us","volume":"16 ","pages":"97-115"},"PeriodicalIF":3.9,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11810060/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142962597","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The profile of oxidative stress markers (arachidonic and linoleic acid derivatives) in patients with benign prostatic hyperplasia in relation to metabolic syndrome.","authors":"Weronika Ratajczak, Kinga Walczakiewicz, Maria Laszczyńska, Krzysztof Chmielowiec, Joanna Palma, Arleta Drozd, Anna Lubkowska, Olimpia Sipak","doi":"10.18632/aging.206187","DOIUrl":"10.18632/aging.206187","url":null,"abstract":"<p><p>So far, it has been proven that benign prostatic hyperplasia (BPH) is strongly associated with inflammation resulting from, i.a. the presence of infectious agent, autoimmune disease, aging process and lipid disorders associated with metabolic syndrome (MetS). We analyzed the association between serum eicosanoides (HETE, HODE, lipoxins, prostaglandin, and leucotrien) in aging man with benign prostatic hyperplasia (BPH) and healthy controls. The study involved 219 men (with BPH, n = 144; healthy controls, n = 75). We assessed the content arachidonic and linoleic acid derivatives in the serum samples of the study participants using liquid chromatography (HPLC). The levels of: RvE1 (p < 0.001); LXA₄ 5S,6R,15R (p = 0.001); 10S,17R-DiDHA (p < 0.001); MaR1 (p = 0.002); 9S-HODE (p < 0.05); 15S-HETE (p < 0.05); 12S-HETE (p < 0.001); 5-oxoETE (p < 0.05) and 5-HETE (p < 0.001) were significantly higher in patients with BPH than in the control group. PGE2 (p = 0.007), LTB₄ (p < 0.001), and 18RS-HEPE (p < 0.001) were significantly higher in control group. We also analyzed the relationship between LXA₄ 5S,6R,15R serum levels of oxidative stress markers and concomitance of MetS. We noticed a relationship between levels and MetS (F1216 = 6.114965, p = 0.01). Our research results suggest that pro-inflammatory mediators and suppressors of inflammation are involved in the development of BPH, but their exact contribution has yet to be investigated.</p>","PeriodicalId":55547,"journal":{"name":"Aging-Us","volume":"16 ","pages":"116-130"},"PeriodicalIF":3.9,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11810064/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142959173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of DNA methylation clock algorithms applied to diverse tissue types.","authors":"Mark Richardson, Courtney Brandt, Niyati Jain, James L Li, Kathryn Demanelis, Farzana Jasmine, Muhammad G Kibriya, Lin Tong, Brandon L Pierce","doi":"10.18632/aging.206182","DOIUrl":"10.18632/aging.206182","url":null,"abstract":"<p><strong>Background: </strong>DNA methylation (DNAm) data from human samples has been leveraged to develop \"epigenetic clock\" algorithms that predict age and other aging-related phenotypes. Some DNAm clocks were trained using DNAm obtained from blood cells, while other clocks were trained using data from diverse tissue/cell types. To assess how DNAm clocks perform across non-blood tissue types, we applied DNAm algorithms to DNAm data generated from 9 different human tissue types.</p><p><strong>Methods: </strong>We generated array-based DNAm measurements for 973 samples from deceased tissue donors from the GTEx (Genotype Tissue Expression) project representing nine distinct tissue types: lung, colon, prostate, ovary, breast, kidney, testis, skeletal muscle, and whole blood. For all samples, we generated DNAm clock estimates for 8 epigenetic clocks and characterized these tissue-specific clock estimates in terms of their distributions, correlations with chronological age, correlations of clock estimates between tissue types, and association with participant characteristics.</p><p><strong>Results: </strong>For each clock, the mean DNAm age estimate varied substantially across tissue types, and the mean values for the different clocks varied substantially within tissue types. For most clocks, the correlation with chronological age varied across tissue types, with blood often showing the strongest correlation. Each clock showed strong correlation across tissues, with some evidence of some residual correlation after adjusting for chronological age. In lung tissue, smoking generally had a positive association with epigenetic age.</p><p><strong>Conclusions: </strong>This work demonstrates how differences in epigenetic aging among tissue types leads to clear differences in DNAm clock characteristics across tissue types. Tissue or cell-type specific epigenetic clocks are needed to optimize predictive performance of DNAm clocks in non-blood tissues and cell types.</p>","PeriodicalId":55547,"journal":{"name":"Aging-Us","volume":"16 ","pages":"67-96"},"PeriodicalIF":3.9,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11810061/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142928634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Treadmill intervention attenuates motor deficit with 6-OHDA-induced Parkinson's disease rat via changes in lipid profiles in brain and muscle.","authors":"Binar Panunggal, Tu-Hsueh Yeh, Shu-Ping Tsao, Chun-Hsu Pan, Wei-Ting Shih, Ya-Tin Lin, Amelia Faradina, Chia-Lang Fang, Hui-Yu Huang, Shih-Yi Huang","doi":"10.18632/aging.206181","DOIUrl":"10.18632/aging.206181","url":null,"abstract":"<p><p>One of the key hallmarks of Parkinson's disease is the disruption of lipid homeostasis in the brain, which plays a critical role in neuronal membrane integrity and function. Understanding how treadmill training impacts lipid restructuring and its subsequent influence on motor function could provide a basis for developing targeted non-pharmacological interventions for individuals living with early stage of PD. This study aims to investigate the effects of a treadmill training intervention on motor deficits induced by 6-OHDA in rats model of PD. PD was induced by injecting 6-hydroxy dopamine (6-OHDA) into the medial forebrain bundle (MFB). For 10 weeks, rats underwent treadmill training on a four-lane motorized treadmill. Motor function deficits were evaluated through behavioral tests. Lipidomic analysis was performed through ultrahigh-performance liquid chromatography-tandem mass spectrometry (UPLC MS/MS). Treadmill intervention significantly improved motor function and restored altered brain and muscle lipid profiles in PD rats. Among the lipid species identified in PD rats, brain abundance was highest for phosphatidylethanolamine (PE), correlating positively with the beam-walking scores; muscle abundance peaked with lysophosphatidylethanolamine (LysoPE), correlating positively with grip strength scores. In the brain, the levels of diacylglycerol (DG), triacylglycerol (TG), and lysophosphatidylcholine (PC) correlated positively with grip strength and rotarod scores, while only phosphatidylethanolamine (PE) linked to beam-walking scores. In the muscle, the levels of phosphatidylinositol (PI), lysophosphatidylethanolamine (PE), lysophosphatidic acid (PA), ceramide (Cer), and ganglioside were positively correlated with grip strength and rotarod scores. In conclusion, treadmill may protect the cortex, mitigating motor deficits via change lipid profiles in the brain and muscle.</p>","PeriodicalId":55547,"journal":{"name":"Aging-Us","volume":"16 ","pages":"232-250"},"PeriodicalIF":3.9,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11810068/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142928636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retraction of: CCNA2 and KIF23 are molecular targets for the prognosis of adenoid cystic carcinoma.","authors":"Yongbin Di, Haolei Zhang, Bohao Zhang, Tianke Li, Dan Li","doi":"10.18632/aging.206185","DOIUrl":"10.18632/aging.206185","url":null,"abstract":"","PeriodicalId":55547,"journal":{"name":"Aging-Us","volume":"16 22","pages":"13694"},"PeriodicalIF":3.9,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11723660/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142933660","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of frailty and chronic limb-threatening ischemia in patients on maintenance hemodialysis: a prospective cohort study.","authors":"Mu-Yang Hsieh, Chien-Ming Luo, Chi-Hong Cheng, Li-Pei Dai, Chiu-Hui Chen, Shao-Yuan Chuang, Chung-Wei Yang, Chih-Cheng Wu","doi":"10.18632/aging.206178","DOIUrl":"10.18632/aging.206178","url":null,"abstract":"<p><p>Chronic limb-threatening ischemia (CLTI) is a prevalent yet unpredictable complication among patients undergoing hemodialysis, and frailty is linked to adverse outcomes in this population. This study examined the influence of clinical factors on vascular events in patients undergoing hemodialysis. This multicenter prospective cohort study included patients undergoing maintenance hemodialysis since January 2008. The initial cohort consisted of 1,136 patients, 828 of whom successfully underwent a frailty test. CLTI events were recorded at 3-month intervals until December 31, 2022. The mean patient age was 67 years, and 48% were female. Overall, 34% of participants were frail, 38% pre-frail, and 28% not frail. Frailty phenotype was associated with age, female sex, low educational level, diabetes mellitus, and history of stroke. During a median follow-up of 1461 days, 104 patients experienced CLTI events (not frail, 6.5%; pre-frail, 11%; frail, 20%; <i>P</i> < 0.001). Frail patients had a higher risk of CLTI than those who were non-frail (hazard ratio (HR) 3.94; 95% confidence interval (CI) 2.22-6.99; <i>P</i> < 0.001). After multivariable adjustment for age and comorbidities, frailty remained significantly associated with CLTI (HR 3.26; 95% CI 1.76-5.85; <i>P</i> < 0.001). Conclusively, these findings highlight the risk of CLTI in frail patients undergoing hemodialysis.</p>","PeriodicalId":55547,"journal":{"name":"Aging-Us","volume":"null ","pages":"13676-13692"},"PeriodicalIF":3.9,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11723663/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142904118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction for: PTPRD mutation is a prognostic biomarker for sensitivity to ICIs treatment in advanced non-small cell lung cancer.","authors":"Zhixuan Ren, Li Wang, Chaohui Leng","doi":"10.18632/aging.206186","DOIUrl":"10.18632/aging.206186","url":null,"abstract":"","PeriodicalId":55547,"journal":{"name":"Aging-Us","volume":"16 22","pages":"13693"},"PeriodicalIF":3.9,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11723662/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142933659","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cell-type specific epigenetic clocks to quantify biological age at cell-type resolution.","authors":"Huige Tong, Xiaolong Guo, Macsue Jacques, Qi Luo, Nir Eynon, Andrew E Teschendorff","doi":"10.18632/aging.206184","DOIUrl":"10.18632/aging.206184","url":null,"abstract":"<p><p>The ability to accurately quantify biological age could help monitor and control healthy aging. Epigenetic clocks have emerged as promising tools for estimating biological age, yet they have been developed from heterogeneous bulk tissues, and are thus composites of two aging processes, one reflecting the change of cell-type composition with age and another reflecting the aging of individual cell-types. There is thus a need to dissect and quantify these two components of epigenetic clocks, and to develop epigenetic clocks that can yield biological age estimates at cell-type resolution. Here we demonstrate that in blood and brain, approximately 39% and 12% of an epigenetic clock's accuracy is driven by underlying shifts in lymphocyte and neuronal subsets, respectively. Using brain and liver tissue as prototypes, we build and validate neuron and hepatocyte specific DNA methylation clocks, and demonstrate that these cell-type specific clocks yield improved estimates of chronological age in the corresponding cell and tissue-types. We find that neuron and glia specific clocks display biological age acceleration in Alzheimer's Disease with the effect being strongest for glia in the temporal lobe. Moreover, CpGs from these clocks display a small but significant overlap with the causal DamAge-clock, mapping to key genes implicated in neurodegeneration. The hepatocyte clock is found accelerated in liver under various pathological conditions. In contrast, non-cell-type specific clocks do not display biological age-acceleration, or only do so marginally. In summary, this work highlights the importance of dissecting epigenetic clocks and quantifying biological age at cell-type resolution.</p>","PeriodicalId":55547,"journal":{"name":"Aging-Us","volume":"16 22","pages":"13452-13504"},"PeriodicalIF":3.9,"publicationDate":"2024-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11723652/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142933658","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impaired renal transporter gene expression and uremic toxin excretion as aging hallmarks in cats with naturally occurring chronic kidney disease.","authors":"Qinghong Li, James A Holzwarth, Bethany Smith, Sonia Karaz, Mathieu Membrez, Vincenzo Sorrentino, Stacie Summers, Julie Spears, Eugenia Migliavacca","doi":"10.18632/aging.206176","DOIUrl":"10.18632/aging.206176","url":null,"abstract":"<p><p>Aging leads to nephron senescence and chronic kidney disease (CKD). In cats, indoxyl sulfate (IxS) has been previously quantified and associated with CKD, and little is known about tubular transporters. Two cohorts of cats aged 6 to 21 years were enrolled. Cohort 1 included 41 colony cats with 28 control and 13 CKD cats. Cohort 2 had 30 privately-owned cats with 10 control and 20 CKD cats. In cohort 1, serum concentrations of IxS, trimethylamine N-oxide (TMAO), <i>p</i>-cresol sulfate (PCS), and phenyl sulfate were higher in CKD vs. control cats (all P<0.05). This observation was independently validated in cohort 2. Renal cortical and medullar tissues were collected from a third cohort of cats euthanized for humane reasons unrelated to the study. We provided the evidence that renal tubular transporter genes, OAT1, OAT4, OATP4C1, and ABCC2, but not OAT3, were expressed in the kidneys of cats, and their expressions were downregulated in CKD (all FDR<0.1). Cats and humans share 90.9%, 77.8%, and 82.5% identities in OAT1, OATP4C1, and ABCC2 proteins, respectively. In healthy cats, circulating TMAO and IxS are significantly correlated with age. Our study reveals impaired uremic toxin secretion and tubular transporter expression in cats with CKD.</p>","PeriodicalId":55547,"journal":{"name":"Aging-Us","volume":"16 ","pages":"13588-13607"},"PeriodicalIF":3.9,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11723653/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142900624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}