npj aging最新文献

{"title":"Hsa-miR-520d-5p promotes survival in human dermal fibroblasts exposed to a lethal dose of UV irradiation","authors":"Yoshitaka Ishihara, Satoshi Tsuno, Bingqiong Ping, Taichiro Ashizaki, Masahiro Nakashima, Keigo Miura, Yugo Miura, Taro Yamashita, Junichi Hasegawa, Norimasa Miura","doi":"10.1038/npjamd.2016.29","DOIUrl":"10.1038/npjamd.2016.29","url":null,"abstract":"We previously reported that hsa-miR-520d-5p is functionally involved in the induction of the epithelial–mesenchymal transition and stemness-mediated processes in normal cells and cancer cells, respectively. On the basis of the synergistic effect of p53 upregulation and demethylation induced by 520d-5p, the current study investigated the effect of this miRNA on apoptotic induction by ultraviolet B (UVB) light in normal human dermal fibroblast (NHDF) cells. 520d-5p was lentivirally transfected into NHDF cells either before or after a lethal dose of UVB irradiation (302 nm) to assess its preventive or therapeutic effects, respectively. The methylation level, gene expression, production of type I collagen and cell cycle distribution were estimated in UV-irradiated cells. NHDF cells transfected with 520d-5p prior to UVB irradiation had apoptotic characteristics, and the transfection exerted no preventive effects. However, transfection with 520d-5p into NHDF cells after UVB exposure resulted in the induction of reprogramming in damaged fibroblasts, the survival of CD105-positive cells, an extended cell lifespan and prevention of cellular damage or malfunction; these outcomes were similar to the effects observed in 520d-5p-transfected NHDF cells (520d/NHDF). The gene expression of c-Abl (Abelson murine leukemia viral oncogene homolog 1), ATR (ataxia telangiectasia and Rad3-related protein), and BRCA1 (breast cancer susceptibility gene I) in transfectants was transcriptionally upregulated in order. These mechanistic findings indicate that ATR-dependent DNA damage repair was activated under this stressor. In conclusion, 520d-5p exerted a therapeutic effect on cells damaged by UVB and restored them to a normal senescent state following functional restoration via survival of CD105-positive cells through c-Abl-ATR-BRCA1 pathway activation, p53 upregulation, and demethylation. As hsa-miR-520d-5p has an innovating effect of reversion of undifferentiated cancer cells to benign or normal status via a stemness-mediated process, we attempted to examine its reprogramming effect on differentiated normal cells (dermal fibroblasts). We found that miR-520d-5p has a restoration effect on fibroblasts exposed to lethal ultraviolet B irradiation and that it induced these cells to the mesenchymal status with CD105 expression. The therapeutic effect indicates that miR-520d-5p is deeply involved in DNA repair (non-canonical pathway against nuclear stress), and it may function as the main regulator in the response mechanism to fragmented DNA and severely damaged nucleic acids. Therefore, this study may pave the way to elucidating a new mechanism because miRNA may play a role in the biogenesis of cells that are getting lethal due to cell damage or aging.","PeriodicalId":94160,"journal":{"name":"npj aging","volume":"2 1","pages":"1-9"},"PeriodicalIF":0.0,"publicationDate":"2016-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/npjamd.2016.29","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35179792","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metformin decreases progerin expression and alleviates pathological defects of Hutchinson–Gilford progeria syndrome cells","authors":"Anne-Laure Egesipe, Sophie Blondel, Alessandra Lo Cicero, Anne-Laure Jaskowiak, Claire Navarro, Annachiara De Sandre-Giovannoli, Nicolas Levy, Marc Peschanski, Xavier Nissan","doi":"10.1038/npjamd.2016.26","DOIUrl":"10.1038/npjamd.2016.26","url":null,"abstract":"Hutchinson–Gilford progeria syndrome (HGPS) is a rare genetic disorder that causes systemic accelerated aging in children. This syndrome is due to a mutation in the LMNA gene that leads to the production of a truncated and toxic form of lamin A called progerin. Because the balance between the A-type lamins is controlled by the RNA-binding protein SRSF1, we have hypothesized that its inhibition may have therapeutic effects for HGPS. For this purpose, we evaluated the antidiabetic drug metformin and demonstrated that 48 h treatment with 5 mmol/l metformin decreases SRSF1 and progerin expression in mesenchymal stem cells derived from HGPS induced pluripotent stem cells (HGPS MSCs). The effect of metformin on progerin was then confirmed in several in vitro models of HGPS, i.e., human primary HGPS fibroblasts, LmnaG609G/G609G mouse fibroblasts and healthy MSCs previously treated with a PMO (phosphorodiamidate morpholino oligonucleotide) that induces progerin. This was accompanied by an improvement in two in vitro phenotypes associated with the disease: nuclear shape abnormalities and premature osteoblastic differentiation of HGPS MSCs. Overall, these results suggest a novel approach towards therapeutics for HGPS that can be added to the currently assayed treatments that target other molecular defects associated with the disease. A diabetes drug with a proven track record in the clinic may also offer an alternative treatment for a rare ''premature aging'' disorder. A genetic mutation in patients with Hutchinson-Gilford progeria syndrome (HGPS) produces a defective protein called progerin, which causes children to develop skeletal, cardiovascular and other symptoms normally seen in the elderly. Researchers led by Xavier Nissan at I-Stem in France have demonstrated that metformin triggers a biochemical ''switch'' that causes cells to decrease their production of progerin, and instead generate an alternative, non-toxic protein. Relative to untreated cells, metformin-treated cells were less prone to develop structural abnormalities or undergo premature maturation. Importantly, doctors have used metformin for over 20 years, suggesting that such a treatment approach should be safe for HGPS patients.","PeriodicalId":94160,"journal":{"name":"npj aging","volume":"2 1","pages":"1-7"},"PeriodicalIF":0.0,"publicationDate":"2016-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/npjamd.2016.26","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35179790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The first human clinical study for NMN has started in Japan","authors":"Kazuo Tsubota","doi":"10.1038/npjamd.2016.21","DOIUrl":"10.1038/npjamd.2016.21","url":null,"abstract":"","PeriodicalId":94160,"journal":{"name":"npj aging","volume":"2 1","pages":"1-1"},"PeriodicalIF":0.0,"publicationDate":"2016-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/npjamd.2016.21","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35179786","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deficiency of angiotensin-converting enzyme 2 causes deterioration of cognitive function","authors":"Xiao-Li Wang, Jun Iwanami, Li-Juan Min, Kana Tsukuda, Hirotomo Nakaoka, Hui-Yu Bai, Bao-Shuai Shan, Harumi Kan-no, Masayoshi Kukida, Toshiyuki Chisaka, Toshifumi Yamauchi, Akinori Higaki, Masaki Mogi, Masatsugu Horiuchi","doi":"10.1038/npjamd.2016.24","DOIUrl":"10.1038/npjamd.2016.24","url":null,"abstract":"The classical renin–angiotensin system (RAS), known as the angiotensin (Ang)-converting enzyme (ACE)/Ang II/Ang II type 1 (AT1) receptor axis, induces various organ damages including cognitive decline. On the other hand, the ACE2/Ang-(1–7)/Mas receptor axis has been highlighted as exerting antagonistic actions against the classical RAS axis in the cardiovascular system. However, the roles of the ACE2/Ang-(1–7)/Mas axis in cognitive function largely remain to be elucidated, and we therefore examined possible roles of ACE2 in cognitive function. Male, 10-week-old C57BL6 (wild type, WT) mice and ACE2 knockout (KO) mice were subjected to the Morris water maze task and Y maze test to evaluate cognitive function. ACE2KO mice exhibited significant impairment of cognitive function, compared with that in WT mice. Superoxide anion production increased in ACE2KO mice, with increased mRNA levels of NADPH oxidase subunit, p22phox, p40phox, p67phox, and gp91phox in the hippocampus of ACE2KO mice compared with WT mice. The protein level of SOD3 decreased in ACE2KO mice compared with WT mice. The AT1 receptor mRNA level in the hippocampus was higher in ACE2KO mice compared with WT mice. In contrast, the AT2 receptor mRNA level in the hippocampus did not differ between the two strains. Mas receptor mRNA was highly expressed in the hippocampus compared with the cortex. Brain-derived neurotrophic factor (BDNF) mRNA and protein levels were lower in the hippocampus in ACE2KO mice compared with WT mice. Taken together, ACE2 deficiency resulted in impaired cognitive function, probably at least in part because of enhanced oxidative stress and a decrease in BDNF. Angiotensin-converting enzyme 2 (ACE2), an enzyme that regulates a cellular pathway linked to blood pressure regulation, is found to play an important role in maintaining normal cognitive functions. Masatsugu Horiuchi and his colleagues from the medical school of Ehime University in Japan, using classical behavioral tests, compared the cognitive functions of mice without ACE2 with those of normal mice, and found impaired spatial learning and memory in the former. Among the ACE2-deficient mice, the researchers observed an increased production of free radicals and a decrease of an important learning-related nerve growth factor, which might explain their impaired cognitive functions. The study helps elucidate cognitive effects of the protective arm of the hormone system that regulates blood pressure, with potential applications in the prevention of cognitive decline in diseases such as hypertension and diabetes.","PeriodicalId":94160,"journal":{"name":"npj aging","volume":"2 1","pages":"1-8"},"PeriodicalIF":0.0,"publicationDate":"2016-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/npjamd.2016.24","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35179789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Increased oxidative phosphorylation in response to acute and chronic DNA damage","authors":"Lear E Brace, Sarah C Vose, Kristopher Stanya, Rose M Gathungu, Vasant R Marur, Alban Longchamp, Humberto Treviño-Villarreal, Pedro Mejia, Dorathy Vargas, Karen Inouye, Roderick T Bronson, Chih-Hao Lee, Edward Neilan, Bruce S Kristal, James R Mitchell","doi":"10.1038/npjamd.2016.22","DOIUrl":"10.1038/npjamd.2016.22","url":null,"abstract":"Accumulation of DNA damage is intricately linked to aging, aging-related diseases and progeroid syndromes such as Cockayne syndrome (CS). Free radicals from endogenous oxidative energy metabolism can damage DNA, however the potential of acute or chronic DNA damage to modulate cellular and/or organismal energy metabolism remains largely unexplored. We modeled chronic endogenous genotoxic stress using a DNA repair-deficient Csa−/−|Xpa−/− mouse model of CS. Exogenous genotoxic stress was modeled in mice in vivo and primary cells in vitro treated with different genotoxins giving rise to diverse spectrums of lesions, including ultraviolet radiation, intrastrand crosslinking agents and ionizing radiation. Both chronic endogenous and acute exogenous genotoxic stress increased mitochondrial fatty acid oxidation (FAO) on the organismal level, manifested by increased oxygen consumption, reduced respiratory exchange ratio, progressive adipose loss and increased FAO in tissues ex vivo. In multiple primary cell types, the metabolic response to different genotoxins manifested as a cell-autonomous increase in oxidative phosphorylation (OXPHOS) subsequent to a transient decline in steady-state NAD+ and ATP levels, and required the DNA damage sensor PARP-1 and energy-sensing kinase AMPK. We conclude that increased FAO/OXPHOS is a general, beneficial, adaptive response to DNA damage on cellular and organismal levels, illustrating a fundamental link between genotoxic stress and energy metabolism driven by the energetic cost of DNA damage. Our study points to therapeutic opportunities to mitigate detrimental effects of DNA damage on primary cells in the context of radio/chemotherapy or progeroid syndromes. A link between DNA damage and cellular metabolism could benefit patients with premature aging disorders and lead to safer cancer treatments. Cells consume considerable energy to repair the destructive effects of chemicals, radiation and aging on the chromosomes. Researchers led by James Mitchell of the Harvard T.H. Chan School of Public Health have found that the damage-induced activation of these pathways accelerates fat metabolism and boosts production of ATP, the cell’s energetic currency. This metabolic shift is beneficial for cellular health, and appears to be an important defense mechanism in premature aging disorders like Cockayne syndrome. The researchers hypothesize that interventions such as dietary restriction could help protect against the side effects of DNA damage from radio- or chemotherapy by switching cellular energy metabolism into a more efficient state.","PeriodicalId":94160,"journal":{"name":"npj aging","volume":"2 1","pages":"1-11"},"PeriodicalIF":0.0,"publicationDate":"2016-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/npjamd.2016.22","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35179788","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extracellular vesicle-associated Aβ mediates trans-neuronal bioenergetic and Ca2+-handling deficits in Alzheimer’s disease models","authors":"Erez Eitan, Emmette R Hutchison, Krisztina Marosi, James Comotto, Maja Mustapic, Saket M Nigam, Caitlin Suire, Chinmoyee Maharana, Gregory A Jicha, Dong Liu, Vasiliki Machairaki, Kenneth W Witwer, Dimitrios Kapogiannis, Mark P Mattson","doi":"10.1038/npjamd.2016.19","DOIUrl":"10.1038/npjamd.2016.19","url":null,"abstract":"Alzheimer’s disease (AD) is an age-related neurodegenerative disorder in which aggregation-prone neurotoxic amyloid β-peptide (Aβ) accumulates in the brain. Extracellular vesicles (EVs), including exosomes, are small 50–150 nm membrane vesicles that have recently been implicated in the prion-like spread of self-aggregating proteins. Here we report that EVs isolated from AD patient cerebrospinal fluid and plasma, from the plasma of two AD mouse models, and from the medium of neural cells expressing familial AD presenilin 1 mutations, destabilize neuronal Ca2+ homeostasis, impair mitochondrial function, and sensitize neurons to excitotoxicity. EVs contain a relatively low amount of Aβ but have an increased Aβ42/ Aβ40 ratio; the majority of Aβ is located on the surface of the EVs. Impairment of lysosome function results in increased generation of EVs with elevated Aβ42 levels. EVs may mediate transcellular spread of pathogenic Aβ species that impair neuronal Ca2+ handling and mitochondrial function, and may thereby render neurons vulnerable to excitotoxicity. A deadly game of cellular ‘tag’ might underlie the degenerative spread of damage between brain cells in Alzheimer’s patients. Mark Mattson from the National Institute on Aging in Maryland and colleagues investigated a hallmark of Alzheimer’s disease: the proliferation of tangled amyloid β protein clusters between brain cells. They found that small pouches of the outer membrane of brain cells—called extracellular vesicles-shuttled a particularly damaging form of amyloid β between cells. Extracellular vesicles were isolated from the fluid surrounding the brain in Alzheimer’s patients; when normal brain cells were exposed to these vesicles, cellular function in the exposed brain cells turned aberrant, occasionally leading to cell death. Understanding the propagation of Alzheimer’s disease pathology within the brain might uncover markers for detecting the disease earlier, and perhaps a window to intervene and halt the damage.","PeriodicalId":94160,"journal":{"name":"npj aging","volume":"2 1","pages":"1-11"},"PeriodicalIF":0.0,"publicationDate":"2016-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/npjamd.2016.19","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"57528193","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Time distortions in Alzheimer’s disease: a systematic review and theoretical integration","authors":"Mohamad El Haj, Dimitrios Kapogiannis","doi":"10.1038/npjamd.2016.16","DOIUrl":"10.1038/npjamd.2016.16","url":null,"abstract":"Time perception is an essential function of the human brain, which is compromised in Alzheimer’s disease (AD). Here, we review empirical findings on time distortions in AD and provide a theoretical framework that integrates time and memory distortions in AD and explains their bidirectional modulation. The review was based on a literature survey performed on the PubMed and PsycInfo databases. According to our theoretical framework, time distortions may induce decline in the ability to mentally project oneself in time (i.e., mental time travel), and consequently may contribute to an episodic memory compromise in AD. Conversely, episodic memory compromise in AD may result in a loss of the ability to retrieve information about time and/or the ability to project oneself in subjective time. The relationship between time distortions and memory decline in AD can be jointly attributed to hippocampus involvement, as this brain area supports both time perception and memory and is preferentially targeted by the neuropathological processes of AD. Clinical implications of time distortions are discussed and directions for future research are suggested.","PeriodicalId":94160,"journal":{"name":"npj aging","volume":"2 1","pages":"1-5"},"PeriodicalIF":0.0,"publicationDate":"2016-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/npjamd.2016.16","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35179873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"It takes two to tango: NAD+ and sirtuins in aging/longevity control","authors":"Shin-ichiro Imai, Leonard Guarente","doi":"10.1038/npjamd.2016.17","DOIUrl":"10.1038/npjamd.2016.17","url":null,"abstract":"The coupling of nicotinamide adenine dinucleotide (NAD+) breakdown and protein deacylation is a unique feature of the family of proteins called ‘sirtuins.’ This intimate connection between NAD+ and sirtuins has an ancient origin and provides a mechanistic foundation that translates the regulation of energy metabolism into aging and longevity control in diverse organisms. Although the field of sirtuin research went through intensive controversies, an increasing number of recent studies have put those controversies to rest and fully established the significance of sirtuins as an evolutionarily conserved aging/longevity regulator. The tight connection between NAD+ and sirtuins is regulated at several different levels, adding further complexity to their coordination in metabolic and aging/longevity control. Interestingly, it has been demonstrated that NAD+ availability decreases over age, reducing sirtuin activities and affecting the communication between the nucleus and mitochondria at a cellular level and also between the hypothalamus and adipose tissue at a systemic level. These dynamic cellular and systemic processes likely contribute to the development of age-associated functional decline and the pathogenesis of diseases of aging. To mitigate these age-associated problems, supplementation of key NAD+ intermediates is currently drawing significant attention. In this review article, we will summarize these important aspects of the intimate connection between NAD+ and sirtuins in aging/longevity control.","PeriodicalId":94160,"journal":{"name":"npj aging","volume":"2 1","pages":"1-6"},"PeriodicalIF":0.0,"publicationDate":"2016-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/npjamd.2016.17","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35179785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Macrophages in age-related chronic inflammatory diseases","authors":"Yumiko Oishi, Ichiro Manabe","doi":"10.1038/npjamd.2016.18","DOIUrl":"10.1038/npjamd.2016.18","url":null,"abstract":"Chronic inflammation is the common pathological basis for such age-associated diseases as cardiovascular disease, diabetes, cancer and Alzheimer’s disease. A multitude of bodily changes occur with aging that contribute to the initiation and development of inflammation. In particular, the immune system of elderly individuals often exhibits diminished efficiency and fidelity, termed immunosenescence. But, although immune responses to new pathogens and vaccines are impaired, immunosenescence is also characterized by a basal systemic inflammatory state. This alteration in immune system function likely promotes chronic inflammation. Changes in the tissue microenvironment, such as the accumulation of cell debris, and systemic changes in metabolic and hormonal signals, also likely contribute to the development of chronic inflammation. Monocyte/macrophage lineage cells are crucial to these age-associated changes, which culminate in the development of chronic inflammatory diseases. In this review, we will summarize the diverse physiological and pathological roles of macrophages in the chronic inflammation underlying age-associated diseases.","PeriodicalId":94160,"journal":{"name":"npj aging","volume":"2 1","pages":"1-8"},"PeriodicalIF":0.0,"publicationDate":"2016-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/npjamd.2016.18","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35179787","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gene expression signatures of human cell and tissue longevity","authors":"Inge Seim, Siming Ma, Vadim N Gladyshev","doi":"10.1038/npjamd.2016.14","DOIUrl":"10.1038/npjamd.2016.14","url":null,"abstract":"Different cell types within the body exhibit substantial variation in the average time they live, ranging from days to the lifetime of the organism. The underlying mechanisms governing the diverse lifespan of different cell types are not well understood. To examine gene expression strategies that support the lifespan of different cell types within the human body, we obtained publicly available RNA-seq data sets and interrogated transcriptomes of 21 somatic cell types and tissues with reported cellular turnover, a bona fide estimate of lifespan, ranging from 2 days (monocytes) to a lifetime (neurons). Exceptionally long-lived neurons presented a gene expression profile of reduced protein metabolism, consistent with neuronal survival and similar to expression patterns induced by longevity interventions such as dietary restriction. Across different cell lineages, we identified a gene expression signature of human cell and tissue turnover. In particular, turnover showed a negative correlation with the energetically costly cell cycle and factors supporting genome stability, concomitant risk factors for aging-associated pathologies. In addition, the expression of p53 was negatively correlated with cellular turnover, suggesting that low p53 activity supports the longevity of post-mitotic cells with inherently low risk of developing cancer. Our results demonstrate the utility of comparative approaches in unveiling gene expression differences among cell lineages with diverse cell turnover within the same organism, providing insights into mechanisms that could regulate cell longevity. Human tissue and cell types exhibit different gene signatures based on their cellular lifespans. Vadim Gladyshev and colleagues from Brigham and Women’s Hospital, Harvard Medical School, analyzed the gene expression patterns of 21 different cell types with cellular turnover times ranging from 2 days (white blood cells) to a lifetime (neurons). This turnover–defined as the balance between cell proliferation and death–has been shown to be a good estimate of cellular lifespan. The authors found that long-lived cell lineages, including those of the muscle and the brain, showed lower expression of genes involved in promoting cell division and maintaining genomic fidelity, consistent with a molecular path toward longevity. The finding that cells use lineage-specific strategies to alter their lifespans lays the groundwork for future therapies that promote human longevity by modifying gene expression profiles.","PeriodicalId":94160,"journal":{"name":"npj aging","volume":"2 1","pages":"1-8"},"PeriodicalIF":0.0,"publicationDate":"2016-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/npjamd.2016.14","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35179872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}