Aging Cell最新文献

{"title":"Epigenomic signature of accelerated ageing in progeroid Cockayne syndrome","authors":"Clément Crochemore,&nbsp;Claudia Chica,&nbsp;Paolo Garagnani,&nbsp;Giovanna Lattanzi,&nbsp;Steve Horvath,&nbsp;Alain Sarasin,&nbsp;Claudio Franceschi,&nbsp;Maria Giulia Bacalini,&nbsp;Miria Ricchetti","doi":"10.1111/acel.13959","DOIUrl":"10.1111/acel.13959","url":null,"abstract":"<p>Cockayne syndrome (CS) and UV-sensitive syndrome (UVSS) are rare genetic disorders caused by mutation of the DNA repair and multifunctional CSA or CSB protein, but only CS patients display a progeroid and neurodegenerative phenotype, providing a unique conceptual and experimental paradigm. As DNA methylation (DNAm) remodelling is a major ageing marker, we performed genome-wide analysis of DNAm of fibroblasts from healthy, UVSS and CS individuals. Differential analysis highlighted a CS-specific epigenomic signature (progeroid-related; not present in UVSS) enriched in three categories: developmental transcription factors, ion/neurotransmitter membrane transporters and synaptic neuro-developmental genes. A large fraction of CS-specific DNAm changes were associated with expression changes in CS samples, including in previously reported <i>post-mortem</i> cerebella. The progeroid phenotype of CS was further supported by epigenomic hallmarks of ageing: the prediction of DNAm of repetitive elements suggested an hypomethylation of <i>Alu</i> sequences in CS, and the epigenetic clock returned a marked increase in CS biological age respect to healthy and UVSS cells. The epigenomic remodelling of accelerated ageing in CS displayed both commonalities and differences with other progeroid diseases and regular ageing. CS shared DNAm changes with normal ageing more than other progeroid diseases do, and included genes functionally validated for regular ageing. Collectively, our results support the existence of an epigenomic basis of accelerated ageing in CS and unveil new genes and pathways that are potentially associated with the progeroid/degenerative phenotype.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"22 10","pages":""},"PeriodicalIF":7.8,"publicationDate":"2023-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.13959","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10178842","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intact mitochondrial function in the setting of telomere-induced senescence","authors":"Daniel I. Sullivan,&nbsp;Fiona M. Bello,&nbsp;Agustin Gil Silva,&nbsp;Kevin M. Redding,&nbsp;Luca Giordano,&nbsp;Angela M. Hinchie,&nbsp;Kelly E. Loughridge,&nbsp;Ana L. Mora,&nbsp;Melanie Königshoff,&nbsp;Brett A. Kaufman,&nbsp;Michael J. Jurczak,&nbsp;Jonathan K. Alder","doi":"10.1111/acel.13941","DOIUrl":"10.1111/acel.13941","url":null,"abstract":"<p>Mitochondria play essential roles in metabolic support and signaling within all cells. Congenital and acquired defects in mitochondria are responsible for several pathologies, including premature entrance to cellar senescence. Conversely, we examined the consequences of dysfunctional telomere-driven cellular senescence on mitochondrial biogenesis and function. We drove senescence in vitro and in vivo by deleting the telomere-binding protein TRF2 in fibroblasts and hepatocytes, respectively. Deletion of TRF2 led to a robust DNA damage response, global changes in transcription, and induction of cellular senescence. In vitro, senescent cells had significant increases in mitochondrial respiratory capacity driven by increased cellular and mitochondrial volume. Hepatocytes with dysfunctional telomeres maintained their mitochondrial respiratory capacity in vivo, whether measured in intact cells or purified mitochondria. Induction of senescence led to the upregulation of overlapping and distinct genes in fibroblasts and hepatocytes, but transcripts related to mitochondria were preserved. Our results support that mitochondrial function and activity are preserved in telomere dysfunction-induced senescence, which may facilitate continued cellular functions.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"22 10","pages":""},"PeriodicalIF":7.8,"publicationDate":"2023-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.13941","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10187590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deciphering RNA m6A regulation in aging: Perspectives on current advances and future directions","authors":"Zeming Wu,&nbsp;Jie Ren,&nbsp;Guang-Hui Liu","doi":"10.1111/acel.13972","DOIUrl":"https://doi.org/10.1111/acel.13972","url":null,"abstract":"<p>N⁶-methyladenosine (m⁶A) is a dynamic and reversible RNA modification that has emerged as a crucial player in the life cycle of RNA, thus playing a pivotal role in various biological processes. In recent years, the potential involvement of RNA m⁶A modification in aging and age-related diseases has gained increasing attention, making it a promising target for understanding the molecular mechanisms underlying aging and developing new therapeutic strategies. This Perspective article will summarize the current advances in aging-related m⁶A regulation, highlighting the most significant findings and their implications for our understanding of cellular senescence and aging, and the potential for targeting RNA m⁶A regulation as a therapeutic strategy. We will also discuss the limitations and challenges in this field and provide insights into future research directions. By providing a comprehensive overview of the current state of the field, this Perspective article aims to facilitate further advances in our understanding of the molecular mechanisms underlying aging and to identify new therapeutic targets for aging-related diseases.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"22 10","pages":""},"PeriodicalIF":7.8,"publicationDate":"2023-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.13972","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41230096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fingerstick blood assay maps real-world NAD+ disparity across gender and age","authors":"Pei Wang,&nbsp;Meiting Chen,&nbsp;Yaying Hou,&nbsp;Jun Luan,&nbsp;Ruili Liu,&nbsp;Liuqing Chen,&nbsp;Min Hu,&nbsp;Qiuliyang Yu","doi":"10.1111/acel.13965","DOIUrl":"https://doi.org/10.1111/acel.13965","url":null,"abstract":"<p>Nicotinamide adenine dinucleotide (NAD⁺) level has been associated with various age-related diseases and its pharmacological modulation emerges as a potential approach for aging intervention. But human NAD⁺ landscape exhibits large heterogeneity. The lack of rapid, low-cost assays limits the establishment of whole-blood NAD⁺ baseline and the development of personalized therapies, especially for those with poor responses towards conventional NAD⁺ supplementations. Here, we developed an automated NAD⁺ analyzer for the rapid measurement of NAD⁺ with 5 μL of capillary blood using recombinant bioluminescent sensor protein and automated optical reader. The minimal invasiveness of the assay allowed a frequent and decentralized mapping of real-world NAD⁺ dynamics. We showed that aerobic sport and NMN supplementation increased whole-blood NAD⁺ and that male on average has higher NAD⁺ than female before the age of 50. We further revealed the long-term stability of human NAD⁺ baseline over 100 days and identified major real-world NAD⁺-modulating behaviors.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"22 10","pages":""},"PeriodicalIF":7.8,"publicationDate":"2023-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.13965","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41229815","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex- and APOE-specific genetic risk factors for late-onset Alzheimer's disease: Evidence from gene–gene interaction of longevity-related loci","authors":"Serena Dato,&nbsp;Francesco De?Rango,&nbsp;Paolina Crocco,&nbsp;Stefano Pallotti,&nbsp;Michael E. Belloy,&nbsp;Yann Le?Guen,&nbsp;Michael D. Greicius,&nbsp;Giuseppe Passarino,&nbsp;Giuseppina Rose,&nbsp;Valerio Napolioni","doi":"10.1111/acel.13938","DOIUrl":"https://doi.org/10.1111/acel.13938","url":null,"abstract":"<p>Advanced age is the largest risk factor for late-onset Alzheimer's disease (LOAD), a disease in which susceptibility correlates to almost all hallmarks of aging. Shared genetic signatures between LOAD and longevity were frequently hypothesized, likely characterized by distinctive epistatic and pleiotropic interactions. Here, we applied a multidimensional reduction approach to detect gene–gene interactions affecting LOAD in a large dataset of genomic variants harbored by genes in the insulin/IGF1 signaling, DNA repair, and oxidative stress pathways, previously investigated in human longevity. The dataset was generated from a collection of publicly available Genome Wide Association Studies, comprising a total of 2,469 gene variants genotyped in 20,766 subjects of Northwestern European ancestry (11,038 LOAD cases and 9,728 controls). The stratified analysis according to <i>APOE</i>*4 status and sex corroborated evidence that pathways leading to longevity also contribute to LOAD. Among the significantly interacting genes, <i>PTPN1</i>, <i>TXNRD1</i>, and <i>IGF1R</i> were already found enriched in gene–gene interactions affecting survival to old age. Furthermore, interacting variants associated with LOAD in a sex- and <i>APOE</i>-specific way. Indeed, while in <i>APOE</i>*4 female carriers we found several inter-pathway interactions, no significant epistasis was found in <i>APOE</i>*4 negative females; conversely, in males, significant intra- and inter-pathways epistasis emerged according to <i>APOE</i>*4 status. These findings suggest that interactions of risk factors may drive different trajectories of cognitive aging. Beyond helping to disentangle the genetic architecture of LOAD, such knowledge may improve precision in predicting the risk of dementia and enable effective sex- and <i>APOE</i>-stratified preventive and therapeutic interventions for LOAD.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"22 9","pages":""},"PeriodicalIF":7.8,"publicationDate":"2023-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.13938","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"7004182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alterations of lipid-mediated mitophagy result in aging-dependent sensorimotor defects","authors":"Natalia Oleinik,&nbsp;Onder Albayram,&nbsp;Mohamed Faisal Kassir,&nbsp;F. Cansu Atilgan,&nbsp;Chase Walton,&nbsp;Eda Karakaya,&nbsp;John Kurtz,&nbsp;Alexander Alekseyenko,&nbsp;Habeeb Alsudani,&nbsp;Megan Sheridan,&nbsp;Zdzislaw M. Szulc,&nbsp;Besim Ogretmen","doi":"10.1111/acel.13954","DOIUrl":"10.1111/acel.13954","url":null,"abstract":"<p>The metabolic consequences of mitophagy alterations due to age-related stress in healthy aging brains versus neurodegeneration remain unknown. Here, we demonstrate that ceramide synthase 1 (CerS1) is transported to the outer mitochondrial membrane by the p17/PERMIT transporter that recognizes mislocalized mitochondrial ribosomes (mitoribosomes) via 39-FLRN-42 residues, inducing ceramide-mediated mitophagy. P17/PERMIT-CerS1-mediated mitophagy attenuated the argininosuccinate/fumarate/malate axis and induced <span>d</span>-glucose and fructose accumulation in neurons in culture and brain tissues (primarily in the cerebellum) of wild-type mice in vivo. These metabolic changes in response to sodium-selenite were nullified in the cerebellum of CerS1to/to (catalytically inactive for C18-ceramide production CerS1 mutant), PARKIN−/− or p17/PERMIT−/− mice that have dysfunctional mitophagy. Whereas sodium selenite induced mitophagy in the cerebellum and improved motor-neuron deficits in aged wild-type mice, exogenous fumarate or malate prevented mitophagy. Attenuating ceramide-mediated mitophagy enhanced damaged mitochondria accumulation and age-dependent sensorimotor abnormalities in p17/PERMIT−/− mice. Reinstituting mitophagy using a ceramide analog drug with selenium conjugate, LCL768, restored mitophagy and reduced malate/fumarate metabolism, improving sensorimotor deficits in old p17/PERMIT−/− mice. Thus, these data describe the metabolic consequences of alterations to p17/PERMIT/ceramide-mediated mitophagy associated with the loss of mitochondrial quality control in neurons and provide therapeutic options to overcome age-dependent sensorimotor deficits and related disorders like amyotrophic lateral sclerosis (ALS).</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"22 10","pages":""},"PeriodicalIF":7.8,"publicationDate":"2023-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.13954","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10060942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of abnormal C/EBPβ/α-Syn signaling pathway through activation of Nrf2 ameliorates Parkinson's disease-like pathology","authors":"Zefang Lin,&nbsp;Lixuan Huang,&nbsp;Qianqian Cao,&nbsp;Hanyue Luo,&nbsp;Wei Yao,&nbsp;Ji-chun Zhang","doi":"10.1111/acel.13958","DOIUrl":"10.1111/acel.13958","url":null,"abstract":"<p>Parkinson's disease (PD) is characterized by the formation of Lewy bodies (LBs) in the brain. These LBs are primarily composed of α-Synuclein (α-Syn), which has aggregated. A recent report proposes that CCAAT/enhancer-binding proteins β (C/EBPβ) may act as an age-dependent transcription factor for α-Syn, thereby initiating PD pathologies by regulating its transcription. Potential therapeutic approaches to address PD could involve targeting the regulation of α-Syn by C/EBPβ. This study has revealed that Nrf2, also known as nuclear factor (erythroid-derived 2)-like 2 (NFE2L2), suppresses the transcription of C/EBPβ in SH-SY5Y cells when treated with MPP⁺. To activate Nrf2, sulforaphane, an Nrf2 activator, was administered. Additionally, C/EBPβ was silenced using C/EBPβ-DNA/RNA heteroduplex oligonucleotide (HDO). Both approaches successfully reduced abnormal α-Syn expression in primary neurons treated with MPP⁺. Furthermore, sustained activation of Nrf2 via its activator or inhibition of C/EBPβ using C/EBPβ-HDO resulted in a reduction of aberrant α-Syn expression, thus leading to an improvement in the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) in mouse models induced by 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) and those treated with preformed fibrils (PFFs). The data presented in this study illustrate that the activation of Nrf2 may provide a potential therapeutic strategy for PD by inhibiting the abnormal C/EBPβ/α-Syn signaling pathway.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"22 10","pages":""},"PeriodicalIF":7.8,"publicationDate":"2023-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.13958","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10435090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Accelerated aging in mice with astrocytic redox imbalance as a consequence of SOD2 deletion","authors":"Konstantinos Tsesmelis,&nbsp;Gandhari Maity-Kumar,&nbsp;Dana Croner,&nbsp;Jasmin Sprissler,&nbsp;Miltiadis Tsesmelis,&nbsp;Tabea Hein,&nbsp;Bernd Baumann,&nbsp;Thomas Wirth","doi":"10.1111/acel.13911","DOIUrl":"https://doi.org/10.1111/acel.13911","url":null,"abstract":"<p>Aging of the central nervous system (CNS) leads to motoric and cognitive decline and increases the probability for neurodegenerative disease development. Astrocytes fulfill central homeostatic functions in the CNS including regulation of immune responses and metabolic support of neurons and oligodendrocytes. In this study, we investigated the effect of redox imbalance in astrocytes by using a conditional astrocyte-specific SOD2-deficient mouse model (SOD2^ako) and analyzed these animals at different stages of their life. SOD2^ako mice did not exhibit any overt phenotype within the first postnatal weeks. However, already as young adults, they displayed progressive motoric impairments. Moreover, as these mice grew older, they exhibited signs of a progeroid phenotype and early death. Histological analysis in moribund SOD2^ako mice revealed the presence of age-related brain alterations, neuroinflammation, neuronal damage and myelin impairment in brain and spinal cord. Additionally, transcriptome analysis of primary astrocytes revealed that SOD2 deletion triggered a hypometabolic state and promoted polarization toward A1-neurotoxic status, possibly underlying the neuronal and myelin deficits. Conclusively, our study identifies maintenance of ROS homeostasis in astrocytes as a critical prerequisite for physiological CNS aging.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"22 9","pages":""},"PeriodicalIF":7.8,"publicationDate":"2023-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.13911","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6994246","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Suppression of FOXO1 attenuates inflamm-aging and improves liver function during aging","authors":"Wanbao Yang,&nbsp;Da Mi Kim,&nbsp;Wen Jiang,&nbsp;Weiqi Ai,&nbsp;Quan Pan,&nbsp;Shahina Rahman,&nbsp;James J. Cai,&nbsp;Wesley A. Brashear,&nbsp;Yuxiang Sun,&nbsp;Shaodong Guo","doi":"10.1111/acel.13968","DOIUrl":"10.1111/acel.13968","url":null,"abstract":"<p>The liver is a key metabolic organ that maintains whole-body nutrient homeostasis. Aging-induced liver function alterations contribute to systemic susceptibility to aging-related diseases. However, the molecular mechanisms of liver aging remain insufficiently understood. In this study, we performed bulk RNA-Seq and single-cell RNA-Seq analyses to investigate the underlying mechanisms of the aging-induced liver function changes. We found that liver inflammation, glucose intolerance, and liver fat deposition were aggravated in old mice. Aging significantly increased pro-inflammation in hepatic macrophages. Furthermore, we found that Kupffer cells (KCs) were the major driver to induce pro-inflammation in hepatic macrophages during aging. In KCs, aging significantly increased pro-inflammatory levels; in monocyte-derived macrophages (MDMs), aging had a limited effect on pro-inflammation but led to a functional quiescence in antigen presentation and phagosome process. In addition, we identified an aging-responsive KC-specific (ARKC) gene set that potentially mediates aging-induced pro-inflammation in KCs. Interestingly, FOXO1 activity was significantly increased in the liver of old mice. FOXO1 inhibition by AS1842856 significantly alleviated glucose intolerance, hepatic steatosis, and systemic inflammation in old mice. FOXO1 inhibition significantly attenuated aging-induced pro-inflammation in KCs partially through downregulation of ARKC genes. However, FOXO1 inhibition had a limited effect on aging-induced functional quiescence in MDMs. These results indicate that aging induces pro-inflammation in liver mainly through targeting KCs and FOXO1 is a key player in aging-induced pro-inflammation in KCs. Thus, FOXO1 could be a potential therapeutic target for the treatment of age-associated chronic diseases.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"22 10","pages":""},"PeriodicalIF":7.8,"publicationDate":"2023-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.13968","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10388212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cooperative effects of SIRT1 and SIRT2 on APP acetylation","authors":"Na Li,&nbsp;Ning Bai,&nbsp;Xiong Zhao,&nbsp;Rong Cheng,&nbsp;Xuan Wu,&nbsp;Bo Jiang,&nbsp;Xiaoman Li,&nbsp;Mingli Xue,&nbsp;Hongde Xu,&nbsp;Qiqiang Guo,&nbsp;Wendong Guo,&nbsp;Mengtao Ma,&nbsp;Sunrun Cao,&nbsp;Yanling Feng,&nbsp;Xiaoyu Song,&nbsp;Zhuo Wang,&nbsp;Xiaoyu Zhang,&nbsp;Yu Zou,&nbsp;Difei Wang,&nbsp;Hua Liu,&nbsp;Liu Cao","doi":"10.1111/acel.13967","DOIUrl":"10.1111/acel.13967","url":null,"abstract":"<p>Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by amyloid-β (Aβ) deposition and neurofibrillary tangles. Although the NAD⁺-dependent deacetylases SIRT1 and SIRT2 play pivotal roles in age-related diseases, their cooperative effects in AD have not yet been elucidated. Here, we report that the SIRT2:SIRT1 ratio is elevated in the brains of aging mice and in the AD mouse models. In HT22 mouse hippocampal neuronal cells, Aβ challenge correlates with decreased SIRT1 expression, while SIRT2 expression is increased. Overexpression of SIRT1 prevents Aβ-induced neurotoxicity. We find that SIRT1 impedes SIRT2-mediated APP deacetylation by inhibiting the binding of SIRT2 to APP. Deletion of SIRT1 reduces APP recycling back to the cell surface and promotes APP transiting toward the endosome, thus contributing to the amyloidogenic processing of APP. Our findings define a mechanism for neuroprotection by SIRT1 through suppression of SIRT2 deacetylation, and provide a promising avenue for therapeutic intervention of AD.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"22 10","pages":""},"PeriodicalIF":7.8,"publicationDate":"2023-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.13967","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10032476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}