scholarly journals Aging shapes the population-mean and ‐dispersion of gene expression in human brains

2016 ◽  
Author(s):  
Candice L. Brinkmeyer-Langford ◽  
Jinting Guan ◽  
Guoli Ji ◽  
James J. Cai
Keyword(s):  
Gene Expression ◽  
Age Groups ◽  
Tissue Expression ◽  
Brain Regions ◽  
Tissue Samples ◽  
Protein Coding ◽  
Age Related ◽  
Increased Risk ◽  
Neurotransmitter Transport ◽  
Human Brains

AbstractHuman aging is associated with cognitive decline and an increased risk of neurodegenerative disease. Our objective for this study was to evaluate potential relationships between age and variation in gene expression across different regions of the brain. We analyzed the Genotype-Tissue Expression (GTEx) data from 54 and 101 tissue samples across 13 brain regions in post-mortem donors of European descent aged between 20 and 70 years at death. After accounting for the effects of covariates and hidden confounding factors, we identified 1,446 protein-coding genes whose expression in one or more brain regions is correlated with chronological age at a false discovery rate of 5%. These genes are involved in various biological processes including apoptosis, mRNA splicing, amino acid biosynthesis, and neurotransmitter transport. The distribution of these genes among brain regions is uneven, suggesting variable regional responses to aging. We also found that the aging response of many genes, e.g., TP37 and C1QA, depends on individuals’ genotypic backgrounds. Finally, using dispersion-specific analysis, we identified genes such as IL7R, MS4A4E, and TERF1/TERF2 whose expressions are differentially dispersed by aging, i.e., variances differ between age groups. Our results demonstrate that age-related gene expression is brain region-specific, genotype-dependent, and associated with both mean and dispersion changes. Our findings provide a foundation for more sophisticated gene expression modeling in the studies of age-related neurodegenerative diseases.

scholarly journals Gene Expression Profile in Different Age Groups and Its Association with Cognitive Function in Healthy Malay Adults in Malaysia

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1611
Author(s):  
Nur Fathiah Abdul Abdul Sani ◽  
Ahmad Imran Zaydi Amir Amir Hamzah ◽  
Zulzikry Hafiz Abu Abu Bakar ◽  
Yasmin Anum Mohd Mohd Yusof ◽  
Suzana Makpol ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cognitive Decline ◽  
Cognitive Aging ◽  
Successful Aging ◽  
Expression Patterns ◽  
Age Groups ◽  
Genetic Network ◽  
Cross Sectional ◽  
Age Related ◽  
Age Related Cognitive Decline

The mechanism of cognitive aging at the molecular level is complex and not well understood. Growing evidence suggests that cognitive differences might also be caused by ethnicity. Thus, this study aims to determine the gene expression changes associated with age-related cognitive decline among Malay adults in Malaysia. A cross-sectional study was conducted on 160 healthy Malay subjects, aged between 28 and 79, and recruited around Selangor and Klang Valley, Malaysia. Gene expression analysis was performed using a HumanHT-12v4.0 Expression BeadChip microarray kit. The top 20 differentially expressed genes at p < 0.05 and fold change (FC) = 1.2 showed that PAFAH1B3, HIST1H1E, KCNA3, TM7SF2, RGS1, and TGFBRAP1 were regulated with increased age. The gene set analysis suggests that the Malay adult’s susceptibility to developing age-related cognitive decline might be due to the changes in gene expression patterns associated with inflammation, signal transduction, and metabolic pathway in the genetic network. It may, perhaps, have important implications for finding a biomarker for cognitive decline and offer molecular targets to achieve successful aging, mainly in the Malay population in Malaysia.

scholarly journals A pH-eQTL interaction at the RIT2-SYT4 Parkinson's disease risk locus in the substantia nigra

2020 ◽  
Author(s):  
Sejal Patel ◽  
Derek Howard ◽  
Leon French
Keyword(s):  
Gene Expression ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Human Brain ◽  
Disease Risk ◽  
Brain Regions ◽  
Dopamine Neurons ◽  
Postmortem Human Brain ◽  
Increased Risk

BACKGROUND: Parkinson's disease (PD) causes severe motor and cognitive disabilities that result from the progressive loss of dopamine neurons in the substantia nigra. The rs12456492 variant in the RIT2 gene has been repeatedly associated with increased risk for Parkinson's disease. From a transcriptomic perspective, a meta-analysis found that RIT2 gene expression is correlated with pH in the human brain. OBJECTIVE: To assess pH associations at the RIT2-SYT4 locus. METHODS: Linear models to examine two datasets that assayed rs12456492, gene expression, and pH in the postmortem human brain. RESULTS: Using the BrainEAC dataset, we replicate the positive correlation between RIT2 gene expression and pH in the human brain. Furthermore, we found that the relationship between expression and pH is influenced by rs12456492. When tested across ten brain regions, this interaction is specifically found in the substantia nigra. A similar association was found for the co-localized SYT4 gene. In addition, SYT4 associations are stronger in a combined model with both genes, and the SYT4 interaction appears to be specific to males. In the GTEx dataset, the pH associations involving rs12456492 and expression of either SYT4 and RIT2 was not seen. This null finding may be due to the short postmortem intervals (PMI) of the GTEx tissue samples. In the BrainEAC data, we tested the effect of PMI and only observed the interactions in the longer PMI samples. CONCLUSIONS: These previously unknown associations suggest novel mechanistic roles for rs12456492, RIT2, and SYT4 in the regulation of pH in the substantia nigra.

Age and outcome after aneurysmal subarachnoid hemorrhage: why do older patients fare worse?

1996 ◽  
Vol 85 (3) ◽  
pp. 410-418 ◽  
Author(s):  
Giuseppe Lanzino ◽  
Neal F. Kassell ◽  
Teresa P. Germanson ◽  
Gail L. Kongable ◽  
Laura L. Truskowski ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Subarachnoid Hemorrhage ◽  
Age Groups ◽  
Age Group ◽  
Content Type ◽  
Poor Outcome ◽  
Symptomatic Vasospasm ◽  
Age Related ◽  
Increased Risk ◽  
Fine Print

✓ Advanced age is a recognized prognostic indicator of poor outcome after subarachnoid hemorrhage (SAH). The relationship of age to other prognostic factors and outcome was evaluated using data from the multicenter randomized trial of nicardipine in SAH conducted in 21 neurosurgical centers in North America. Among the 906 patients who were studied, five different age groups were considered: 40 years or less, 41 to 50, 51 to 60, 61 to 70, and more than 71 years. Twenty-three percent of the individuals enrolled were older than 60 years of age. Women outnumbered men in all age groups. Level of consciousness (p = 0.0002) and World Federation of Neurological Surgeons grade (p = 0.0001) at admission worsened with advancing age. Age was also related to the presence of a thick subarachnoid clot (p = 0.0001), intraventricular hemorrhage (p = 0.0003), and hydrocephalus (p = 0.0001) on an admission computerized tomography scan. The rebleeding rate increased from 4.5% in the youngest age group to 16.4% in patients more than 70 years of age (p = 0.002). As expected, preexisting medical conditions, such as diabetes (p = 0.028), hypertension (p = 0.0001), and pulmonary (p = 0.0084), myocardial (p = 0.0001), and cerebrovascular diseases (p = 0.0001), were positively associated with age. There were no age-related differences in the day of admission following SAH, timing of the surgery and/or location, and size (small vs. large) of the ruptured aneurysm. During the treatment period, the incidence of severe complications (that is, those complications considered life threatening by the reporting investigator) increased with advancing age, occurring in 28%, 33%, 36%, 40%, and 46% of the patients in each advancing age group, respectively (p = 0.0002). No differences were observed in the reported frequency of surgical complications. No age-related differences were found in the overall incidence of angiographic vasospasm; however, symptomatic vasospasm was more frequently reported in the older age groups (p = 0.01). Overall outcome, assessed using the Glasgow Outcome Scale at 3 months post-SAH, was poorer with advancing age (p < 0.001). Multivariate analysis of overall outcome, adjusting for the different prognostic factors, did not remove the age effect, which suggests that the aging brain has a less optimal response to the initial bleeding. Age as a risk factor is a continuum; however, there seems to be a significant increased risk of poor outcome after the age of 60 years.

scholarly journals Quantifying Microsatellite Mutation Rates from Intestinal Stem Cell Dynamics in Msh2-Deficient Murine Epithelium

Genetics ◽  
2019 ◽  
Vol 212 (3) ◽  
pp. 655-665 ◽  
Author(s):  
Joseph Christopher ◽  
Ann-Sofie Thorsen ◽  
Sam Abujudeh ◽  
Filipe C. Lourenço ◽  
Richard Kemp ◽  
...  
Keyword(s):  
Stem Cell ◽  
Fold Increase ◽  
Mutation Rates ◽  
Wild Type ◽  
Cell Dynamics ◽  
Tissue Samples ◽  
Age Related ◽  
Increased Risk ◽  
Microsatellite Mutation ◽  
Risk Of Cancer

Microsatellite sequences have an enhanced susceptibility to mutation, and can act as sentinels indicating elevated mutation rates and increased risk of cancer. The probability of mutant fixation within the intestinal epithelium is dictated by a combination of stem cell dynamics and mutation rate. Here, we exploit this relationship to infer microsatellite mutation rates. First a sensitive, multiplexed, and quantitative method for detecting somatic changes in microsatellite length was developed that allowed the parallel detection of mutant [CA]n sequences from hundreds of low-input tissue samples at up to 14 loci. The method was applied to colonic crypts in Mus musculus, and enabled detection of mutant subclones down to 20% of the cellularity of the crypt (∼50 of 250 cells). By quantifying age-related increases in clone frequencies for multiple loci, microsatellite mutation rates in wild-type and Msh2-deficient epithelium were established. An average 388-fold increase in mutation per mitosis rate was observed in Msh2-deficient epithelium (2.4 × 10−2) compared to wild-type epithelium (6.2 × 10−5).

Marked Increase in Incident Gynecomastia: A 20-Year National Registry Study, 1998 to 2017

2020 ◽  
Vol 105 (10) ◽  
pp. 3134-3140 ◽  
Author(s):  
Trine Koch ◽  
Elvira V Bräuner ◽  
Alexander S Busch ◽  
Martha Hickey ◽  
Anders Juul
Keyword(s):  
Age Groups ◽  
Population Based ◽  
Incidence Rates ◽  
National Registry ◽  
Registry Study ◽  
Age Related ◽  
Danish Health ◽  
Increased Risk ◽  
National Patient ◽  
First Time

Abstract Context Gynecomastia, the proliferation of mammary glandular tissue in the male, is a frequent but little-studied condition. Available prevalence data are based on selected patient populations or autopsy cases with their inherent bias. Objective The objective of this work is to evaluate the age-related incidence and secular trends in gynecomastia in the general population. Design An observational, 20-year national registry study was conducted. Setting This population-based study used nationwide registry data. Participants Participants included all Danish males (age 0-80 years) with a first-time diagnosis of gynecomastia. Main Outcome Measures All Danish males (age 0-80 years) were followed up for incident diagnosis of gynecomastia in the Danish National Patient Registry from 1998 to 2017 using the International Codes of Diseases, 10th revision, and the Danish Health Care Classification System. Age-specific incidence rates were estimated. The hypothesis tested in this study was formulated prior to data collection. Results Overall, a total 17 601 males (age 0-80 years) were registered with an incident diagnosis of gynecomastia within the 20-year study period, corresponding to 880 new cases per year and an average 20-year incidence of 3.4 per 10 000 men (age 0-80 years). The average annual incidence was 6.5/10 000 in postpubertal males age 16 to 20 years and 4.6/10 000 in males age 61 to 80 years, with a respective 5- and 11-fold overall increase in these 2 age groups over the 20-year period. Conclusions The incidence of gynecomastia has dramatically increased over the last 20 years, implying that the endogenous or exogenous sex-steroid environment has changed, which is associated with other adverse health consequences in men such as an increased risk of prostate cancer, metabolic syndrome, type 2 diabetes, or cardiovascular disorders.

Changes in the Dynamic Stability of Walking in Active Healthy Older Adults Independent of Changes in Walking Speed

2008 ◽  
Author(s):  
Hyun Gu Kang ◽  
Jonathan B. Dingwell
Keyword(s):  
Older Adults ◽  
Young Adults ◽  
Dynamic Stability ◽  
Walking Speed ◽  
Age Groups ◽  
Leg Strength ◽  
Age Related ◽  
Increased Risk ◽  
Risk Of Falls ◽  
Walking Speeds

Older adults commonly walk slower, which many believe helps improve their walking stability. However, they remain at increased risk of falls. We investigated how differences in age and walking speed independently affect dynamic stability during walking, and how age-related changes in leg strength and ROM affected this relationship. Eighteen active healthy older and 17 younger adults walked on a treadmill for 5 minutes each at each of 5 speeds (80–120% of preferred). Local divergence exponents and maximum Floquet multipliers (FM) were calculated to quantify each subject’s responses to small inherent perturbations during walking. These older adults exhibited the same preferred walking speeds as the younger subjects (p = 0.860). However, these older adults still exhibited greater local divergence exponents (p&lt;0.0001) and higher maximum FM (p&lt;0.007) than young adults at all walking speeds. These older adults remained more unstable (p&lt;0.04) even after adjusting for declines in both strength and ROM. In both age groups, local divergence exponents decreased at slower speeds and increased at faster speeds (p&lt;0.0001). Maximum FM showed similar changes with speed (p&lt;0.02). The older adults in this study were healthy enough to walk at normal speeds. However, these adults were still more unstable than the young adults, independent of walking speed. This greater instability was not explained by loss of leg strength and ROM. Slower speeds led to decreased instability in both groups.

Evidence of Developmental Differences in Implicit Sequence Learning: An fMRI Study of Children and Adults

2004 ◽  
Vol 16 (8) ◽  
pp. 1339-1351 ◽  
Author(s):  
Kathleen M. Thomas ◽  
Ruskin H. Hunt ◽  
Nathalie Vizueta ◽  
Tobias Sommer ◽  
Sarah Durston ◽  
...  
Keyword(s):  
Implicit Learning ◽  
Sequence Learning ◽  
Premotor Cortex ◽  
Age Groups ◽  
Reaction Time Task ◽  
Memory Systems ◽  
Brain Regions ◽  
Developmental Differences ◽  
Implicit Sequence Learning ◽  
Age Related

Prevailing theories of implicit or unaware learning propose a developmental invariance model, with implicit function maturing early in infancy or childhood despite prolonged improvements in explicit or intentional learning and memory systems across childhood. Neuroimaging studies of adult visuomotor sequence learning have associated fronto-striatal brain regions with implicit learning of spatial sequences. Given evidence of continued development in these brain regions during childhood, we compare implicit sequence learning in adults and 7- to 11-year-old children to examine potential developmental differences in the recruitment of fronto-striatal circuitry during implicit learning. Participants performed a standard serial reaction time task. Stimuli alternately followed a fixed 10-step sequence of locations or were presented in a pseudorandom order of locations. Adults outperformed children, achieving a significantly larger sequence learning effect and showing learning more quickly than children. Age-related differences in activity were observed in the premotor cortex, putamen, hippocampus, inferotemporal cortex, and parietal cortex. We observed differential recruitment of cortical and subcortical motor systems between groups, presumably reflecting age differences in motor response execution. Adults showed greater hippocampal activity for sequence trials, whereas children demonstrated greater signal during random trials. Activity in the right caudate correlated significantly with behavioral measures of implicit learning for both age groups, although adults showed greater signal change than children overall, as would be expected given developmental differences in sequence learning magnitude. These results challenge the idea of developmental invariance in implicit learning and instead support a view of parallel developments in implicit and explicit learning systems.

Comparison of Clinical and Biologic Significance of WT1 Mutations in Populations of Older (≥60 years[y]) and Younger (<60 y) Adult Patients (Pts) with Cytogenetically Normal (CN) De Novo Acute Myeloid Leukemia (AML): a Cancer and Leukemia Group B (CALGB) Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 326-326
Author(s):  
Heiko Becker ◽  
Guido Marcucci ◽  
Kati Maharry ◽  
Michael D. Radmacher ◽  
Krzysztof Mrózek ◽  
...  
Keyword(s):  
Gene Expression ◽  
De Novo ◽  
Age Groups ◽  
Stem Cell Marker ◽  
Treatment Intensity ◽  
Prognostic Impact ◽  
Wild Type ◽  
Age Related ◽  
Exon 9 ◽  
Wt1 Mutation

Abstract Abstract 326 Mutations of the Wilms tumor (WT1) gene are found in ∼10% of younger (<60 years[y]) adult pts with de novo CN-AML and impact adversely on their outcome. The clinical significance of WT1 mutations has not yet been evaluated in older (≥60 y) CN-AML pts. Therefore, we analyzed frequency and clinical impact of WT1 mutations in the context of other molecular markers in a relatively large cohort of 243 pts ≥60 y (range, 60-83 y) with de novo CN-AML treated intensively on upfront cytarabine/daunorubicin-based CALGB protocols. Included pts were those with material available for analysis of WT1 mutation status and that of a panel of other validated molecular prognosticators including NPM1, FLT3 (ie, FLT3-ITD, FLT3-TKD) and CEBPA mutations, BAALC and ERG expression levels. Mutations in WT1 “hot spots” (exons 7 and 9) were assessed by DHPLC and sequencing. The results were compared with the findings in younger (18-59 y) CALGB pts (n=207) characterized molecularly in a similar fashion. Gene expression profiles in both populations were assessed centrally using Affymetrix U133 plus 2.0 microchip. Among the 243 older pts, 16 (7%) had WT1 mutations. Of those, 14 had single WT1 mutations in exon 7 [frameshift (n=8), nonsense (n=1), and missense (n=1)] or in exon 9 [missense (n=4)]; 1 pt had 2 frameshift mutations in exon 7, and 1 had 1 frameshift mutation in exon 7 and 1 missense mutation in exon 9. Compared with older WT1 wild-type pts, older WT1 mutated pts more often had FLT3-ITD (P<.001) and had lower hemoglobin (P=.01), and higher WBC (P=.03) and % blood blasts (P=.03). WT1 mutated pts had a trend for lower complete remission (CR) rates (50% v 70%, P=.16) and shorter OS (P=.08; Figure 1), but similar disease-free survival (DFS; P=.59; Figure 2) compared with WT1 wild-type pts. The frequency of WT1 mutations tended to be lower in older than younger pts (7% v 12%, P=.07). Mutation types and pretreatment clinical and molecular characteristics associated with WT1 mutations were similar between the two age groups. Despite differences in treatment intensity, there were no significant differences in younger v older WT1 mutated pts with regard to CR rates (P=.18), or OS (P=.68; Figure 1) or DFS (P=.66; Figure 2) durations. In contrast, younger WT1 wild-type pts had significantly higher CR rates (P<.001), and longer OS (P<.001; Figure 1) and DFS (P<.001; Figure 2) than older WT1 wild-type pts. Although associated with WT1 mutations in both the younger (P=.02) and older age groups, FLT3-ITD had no impact on CR rates (P=.28), or OS (P=.15) or DFS (P=.21) durations of all WT1 mutated pts after controlling for age-related treatment intensity. To provide insights into the molecular features associated with WT1 mutations we analyzed the whole cohort (younger and older) for genes differentially expressed (ie, P≤.001) between WT1 mutated and WT1 wild-type pts. A signature comprising 110 named genes was derived. Among the 71 upregulated genes in WT1 mutated pts, were those encoding the leukemia stem cell marker CD96 and the leukemia fusion protein partners PML and MLL. The most upregulated gene (6.2 fold) was GTSF1, which, like WT1, may be involved in germ cell development. Among the 39 genes downregulated in WT1 mutated pts, were those encoding SNRPN and SNURF, involved in pre-mRNA processing, and the insulin receptor and IRS2, upstream effectors of the PI3K/AKT pathway. In conclusion, WT1 mutations in older CN-AML pts are less frequent than in younger pts. While WT1 mutations independently associate with shorter OS and DFS in younger CN-AML pts, in older CN-AML pts they are only associated with trends for a worse CR rate and shorter OS. This difference appears due to the poor outcome of the older compared to younger WT1 wild-type pts, which reduced the prognostic impact of WT1 mutations in the former. Nevertheless, the outcome of pts with WT1 mutations is equally poor in older and younger pts regardless of differences in treatment, thereby suggesting that WT1 mutated CN-AML may constitute a distinct biologic entity across age groups. The unique gene expression signature associated with WT1 mutations could provide useful insights into WT1 mutation-driven leukemogenic mechanisms across age-related groups, and help in devising novel molecular targeted therapeutic approaches for this subtype of CN-AML. Disclosures: No relevant conflicts of interest to declare.

RNA sequencing analysis for profiling activation of cancer-associated molecular pathways.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e13032-e13032 ◽  
Author(s):  
Anton Buzdin ◽  
Andrew Garazha ◽  
Maxim Sorokin ◽  
Alex Glusker ◽  
Alexey Aleshin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Original Data ◽  
Tissue Expression ◽  
Molecular Pathways ◽  
Sequencing Analysis ◽  
Rna Seq ◽  
Sequencing Data ◽  
Healthy Human ◽  
Tissue Samples ◽  
Normal Tissues

e13032 Background: Intracellular molecular pathways (IMPs) control all major events in the living cell. They are considered hotspots in contemporary oncology because knowledge of IMPs activation is essential for understanding mechanisms of molecular pathogenesis in oncology. Profiling IMPs requires RNA-seq data for tumors and for a collection of reference normal tissues. However, there is a shortage now in such profiles for normal tissues from healthy human donors, uniformly profiled in a single series of experiments. Access to the largest dataset of normal profiles GTEx is only partly available through the dbGaP. In TCGA database, norms are adjacent to surgically removed tumors and may be affected by tumor-linked growth factors, inflammation and altered vascularization. ENCODE datasets were for the autopsies of normal tissues, but they can’t form statistically significant reference groups. Methods: Tissue samples representing 20 organs were taken from post-mortal human healthy donors killed in road accidents no later than 36 hours after death, blood samples were taken from healthy volunteers. Gene expression was profiled in RNA-seq experiments using the same reagents, equipment and protocols. Bioinformatic algorithms for IMP analysis were developed and validated using experimental and public gene expression datasets. Results: From original sequencing data we constructed the biggest fully open reference expression database of normal human tissues including 465 profiles termed Oncobox Atlas of Normal Tissue Expression (ANTE, original data: GSE120795). We next developed a method termed Oncobox for interrogating activation of IMPs in human cancers. It includes modules of expression data harmonization and comparison and an algorithm for automatic annotation of molecular pathways. The Oncobox system enables accurate scoring of thousands molecular pathways using RNA-seq data. Oncobox pathway analysis is also applicable for quantitative proteomics and microRNA data in oncology. Conclusions: The Oncobox system can be used for a plethora of applications in cancer research including finding differentially regulated genes and IMPs, and for discovery of new pathway-related diagnostic and prognostic biomarkers.

scholarly journals Synchronized age-related gene expression changes across multiple tissues in human and the link to complex diseases

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Jialiang Yang ◽  
◽  
Tao Huang ◽  
Francesca Petralia ◽  
Quan Long ◽  
...  
Keyword(s):  
Gene Expression ◽  
Complex Disease ◽  
Principal Component ◽  
Tissue Expression ◽  
Whole Body ◽  
Disease Genes ◽  
Related Gene ◽  
Tissue Specific ◽  
Age Related ◽  
Holistic Understanding

Abstract Aging is one of the most important biological processes and is a known risk factor for many age-related diseases in human. Studying age-related transcriptomic changes in tissues across the whole body can provide valuable information for a holistic understanding of this fundamental process. In this work, we catalogue age-related gene expression changes in nine tissues from nearly two hundred individuals collected by the Genotype-Tissue Expression (GTEx) project. In general, we find the aging gene expression signatures are very tissue specific. However, enrichment for some well-known aging components such as mitochondria biology is observed in many tissues. Different levels of cross-tissue synchronization of age-related gene expression changes are observed and some essential tissues (e.g., heart and lung) show much stronger “co-aging” than other tissues based on a principal component analysis. The aging gene signatures and complex disease genes show a complex overlapping pattern and only in some cases, we see that they are significantly overlapped in the tissues affected by the corresponding diseases. In summary, our analyses provide novel insights to the co-regulation of age-related gene expression in multiple tissues; it also presents a tissue-specific view of the link between aging and age-related diseases.

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