Gene regulation and DNA damage in the ageing human brain

Lu, Tao; Pan, Y. Albert; Kao, Shyan Yuan; Cheng, Li; Kohane, Isaac S.; Chan, Jennifer A.; Yankner, Bruce A.

doi:10.1038/nature02661

Cited by 1,707 publications

(1,628 citation statements)

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“…Downregulated genes were enriched in synaptic functions and biosynthetic processes (FDR‐corrected p < 0.05), whereas differentiation and proliferation‐related categories showed enrichment for the upregulated genes (FDR‐corrected p < 0.05). These results are consistent with the findings of earlier brain aging transcriptome studies (Lu et al, 2004; Naumova et al, 2012; Xue et al, 2007). Oddly, ossification‐related biological processes also showed significant enrichment for the upregulated genes.…”

Section: Resultssupporting

confidence: 93%

“…We analysed data from seven, published, microarray‐based studies of age‐related changes in RNA expression (Barnes et al, 2011; Berchtold et al, 2008; Colantuoni et al, 2011; Kang et al, 2011; Lu et al, 2004; Maycox et al, 2009; Somel et al, 2010, 2011 ). The data came from 22 different brain regions, and the ages of the donors ranged from 20 to 106 years (Figure 1a and Supporting Information Figure S1a).…”

Section: Resultsmentioning

confidence: 99%

“…Accompanied by the altered intercellular communication and synaptic loss, these changes bring about cognitive decline, neurodegeneration and memory loss (Salthouse, 2009). The biological processes showing a change in expression include pathways related to synaptic and cognitive functions as well as proteostasis (Lu et al, 2004), suggesting gene expression changes in the aging brain could be used as a surrogate to find drugs to target detrimental effects.…”

Section: Introductionmentioning

confidence: 99%

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Gene expression‐based drug repurposing to target aging

et al. 2018

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Aging is the largest risk factor for a variety of noncommunicable diseases. Model organism studies have shown that genetic and chemical perturbations can extend both lifespan and healthspan. Aging is a complex process, with parallel and interacting mechanisms contributing to its aetiology, posing a challenge for the discovery of new pharmacological candidates to ameliorate its effects. In this study, instead of a target‐centric approach, we adopt a systems level drug repurposing methodology to discover drugs that could combat aging in human brain. Using multiple gene expression data sets from brain tissue, taken from patients of different ages, we first identified the expression changes that characterize aging. Then, we compared these changes in gene expression with drug‐perturbed expression profiles in the Connectivity Map. We thus identified 24 drugs with significantly associated changes. Some of these drugs may function as antiaging drugs by reversing the detrimental changes that occur during aging, others by mimicking the cellular defence mechanisms. The drugs that we identified included significant number of already identified prolongevity drugs, indicating that the method can discover de novo drugs that meliorate aging. The approach has the advantages that using data from human brain aging data, it focuses on processes relevant in human aging and that it is unbiased, making it possible to discover new targets for aging studies.

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Section: Resultssupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Gene expression‐based drug repurposing to target aging

et al. 2018

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“…A pioneer study comparing postmortem human frontal cortex tissue samples between 30 individuals of different ages yielded 463 differentially expressed genes (Lu et al ., 2004). Despite the small sample size, results were replicated in subsequent experiments.…”

Section: Omics and Agingmentioning

confidence: 99%

“…In human brain tissue, oxidative stress/DNA repair and inflammation‐related genes were shown to be enriched in the set of differentially expressed genes between young and old individuals (Lu et al ., 2004). Enrichment analysis facilitates the identification of pathways that are important for the aging process.…”

Section: From Omics To Systems Biologymentioning

confidence: 99%

Integration of ‘omics’ data in aging research: from biomarkers to systems biology

et al. 2015

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SummaryAge is the strongest risk factor for many diseases including neurodegenerative disorders, coronary heart disease, type 2 diabetes and cancer. Due to increasing life expectancy and low birth rates, the incidence of age‐related diseases is increasing in industrialized countries. Therefore, understanding the relationship between diseases and aging and facilitating healthy aging are major goals in medical research. In the last decades, the dimension of biological data has drastically increased with high‐throughput technologies now measuring thousands of (epi) genetic, expression and metabolic variables. The most common and so far successful approach to the analysis of these data is the so‐called reductionist approach. It consists of separately testing each variable for association with the phenotype of interest such as age or age‐related disease. However, a large portion of the observed phenotypic variance remains unexplained and a comprehensive understanding of most complex phenotypes is lacking. Systems biology aims to integrate data from different experiments to gain an understanding of the system as a whole rather than focusing on individual factors. It thus allows deeper insights into the mechanisms of complex traits, which are caused by the joint influence of several, interacting changes in the biological system. In this review, we look at the current progress of applying omics technologies to identify biomarkers of aging. We then survey existing systems biology approaches that allow for an integration of different types of data and highlight the need for further developments in this area to improve epidemiologic investigations.

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A Randomized Trial of Beta Carotene Supplementation and Cognitive Function in Men<subtitle>The Physicians' Health Study II</subtitle>

Grodstein

Kang²,

Glynn³

et al. 2007

Arch Intern Med

169

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Background: Oxidative stress contributes to brain aging. Antioxidant treatment, especially over the long term, might confer cognitive benefits. Methods: We added cognitive testing to the Physicians' Health Study II (PHSII), a randomized trial of beta carotene and other vitamin supplements for chronic disease prevention. The PHSII is a continuation of the Physicians' Health Study (PHS), which had randomized male participants to low-dose aspirin and beta carotene. Participants include those continuing their original beta carotene assignment from the PHS, begun in 1982, and newer recruits randomized as of 1998. The beta carotene arm (50 mg, alternate days) was terminated; follow-up is ongoing for the remaining arms. Near the close of the beta carotene arm, we interviewed 5956 participants older than 65 years to assess general cognition, verbal memory, and category fluency. The primary end point was a global score averaging all tests (using z scores); the secondary end point was a verbal memory score combining results of 4 tests. We compared mean cognition among those assigned to beta carotene vs placebo. We separately examined new recruits and continuing participants. Results: Among 1904 newly recruited subjects (mean treatment duration, 1 year), cognition was similar across treatment assignments. Among 4052 continuing participants from the PHS (mean treatment duration, 18 years), the mean global score was significantly higher in the beta carotene group than in the placebo group (mean difference in z scores, 0.047 standard units; P=.03). On verbal memory, men receiving long-term beta carotene supplementation also performed significantly better than the placebo group (mean difference in z scores, 0.063; P=.007). Conclusion: We did not find an impact of short-term beta carotenesupplementationoncognitiveperformance,butlongterm supplementation may provide cognitive benefits.

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Gene regulation and DNA damage in the ageing human brain

Cited by 1,707 publications

References 24 publications

Gene expression‐based drug repurposing to target aging

Gene expression‐based drug repurposing to target aging

Integration of ‘omics’ data in aging research: from biomarkers to systems biology

A Randomized Trial of Beta Carotene Supplementation and Cognitive Function in Men<subtitle>The Physicians' Health Study II</subtitle>

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