Dataset Information

Aging and pathological aging signatures of the brain: through the focusing lens of SIRT6.

ABSTRACT: Brain-specific SIRT6-KO mice present increased DNA damage, learning impairments, and neurodegenerative phenotypes, placing SIRT6 as a key protein in preventing neurodegeneration. In the aging brain, SIRT6 levels/activity decline, which is accentuated in Alzheimer's patients. To understand SIRT6 roles in transcript pattern changes, we analyzed transcriptomes of young WT, old WT and young SIRT6-KO mice brains, and found changes in gene expression related to healthy and pathological aging. In addition, we traced these differences in human and mouse samples of Alzheimer's and Parkinson's diseases, healthy aging and calorie restriction (CR). Our results define four gene expression categories that change with age in a pathological or non-pathological manner, which are either reversed or not by CR. We found that each of these gene expression categories is associated with specific transcription factors, thus serving as potential candidates for their category-specific regulation. One of these candidates is YY1, which we found to act together with SIRT6 regulating specific processes. We thus argue that SIRT6 has a pivotal role in preventing age-related transcriptional changes in brains. Therefore, reduced SIRT6 activity may drive pathological age-related gene expression signatures in the brain.

SUBMITTER: Stein D

PROVIDER: S-EPMC7993737 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Aging and pathological aging signatures of the brain: through the focusing lens of SIRT6.

Stein Daniel D Mizrahi Amir A Golova Anastasia A Saretzky Adam A Venzor Alfredo Garcia AG Slobodnik Zeev Z Kaluski Shai S Einav Monica M Khrameeva Ekaterina E Toiber Debra D

Aging 20210309 5

Brain-specific SIRT6-KO mice present increased DNA damage, learning impairments, and neurodegenerative phenotypes, placing SIRT6 as a key protein in preventing neurodegeneration. In the aging brain, SIRT6 levels/activity decline, which is accentuated in Alzheimer's patients. To understand SIRT6 roles in transcript pattern changes, we analyzed transcriptomes of young WT, old WT and young SIRT6-KO mice brains, and found changes in gene expression related to healthy and pathological aging. In addit ...[more]

PMID: 33690173

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Project description:BackgroundStudying structural brain aging is important to understand age-related pathologies, as well as to identify the early manifestations of the Alzheimer's disease (AD) continuum. In this study, we investigated the long-term trajectory of physiological and pathological brain aging in a large number of participants ranging from the 50s to over 80 years of age.ObjectiveTo explore the distinct brain regions that distinguish pathological brain aging from physiological brain aging using sophisticated measurements of cortical thickness.MethodsA total of 2,823 cognitively normal (CN) individuals and 2,675 patients with AD continuum [874 with subjective memory impairment (SMI), 954 with amnestic mild cognitive impairment (aMCI), and 847 with AD dementia] who underwent a high-resolution 3.0-tesla MRI were included in this study. To investigate pathological brain aging, we further classified patients with aMCI and AD according to the severity of cognitive impairment. Cortical thickness was measured using a surface-based method. Multiple linear regression analyses were performed to evaluate age, diagnostic groups, and cortical thickness.ResultsAging extensively affected cortical thickness not only in CN individuals but also in AD continuum patients; however, the precuneus and inferior temporal regions were relatively preserved against age-related cortical thinning. Compared to CN individuals, AD continuum patients including those with SMI showed a decreased cortical thickness in the perisylvian region. However, widespread cortical thinning including the precuneus and inferior temporal regions were found from the late-stage aMCI to the moderate to severe AD. Unlike the other age groups, AD continuum patients aged over 80 years showed prominent cortical thinning in the medial temporal region with relative sparing of the precuneus.ConclusionOur findings suggested that the precuneus and inferior temporal regions are the key regions in distinguishing between physiological and pathological brain aging. Attempts to differentiate age-related pathology from physiological brain aging at a very early stage would be important in terms of establishing new strategies for preventing accelerated pathological brain aging.

Project description:Gardnerella vaginalis has long been associated with bacterial vaginosis, a condition that increases the risk of women to preterm birth, sexually transmitted infections, and other adverse sequelae. However, G. vaginalis is also commonly found in healthy asymptomatic women of all ages. This raises the question if genetic differences among strains might distinguish potentially pathogenic from commensal strains. To disentangle the diversity of G. vaginalis, we invoked the concept of ecotypes-lineages of genetically and ecologically distinct strains within a named species-to better understand their evolutionary history and identify functional characteristics. We compared the genomes of G. vaginalis to six species in the closely related Bifidobacterium genus and found that G. vaginalis has a large accessory genome relative to Bifidobacterium, including many unique genes possibly involved in metabolism, drug resistance, and virulence. We then performed a comparative genomic analysis of 35 strains of G. vaginalis to infer a phylogeny based on the combined analysis of the core genome, using nucleotide substitution models, and the accessory genome, using gene gain/loss models. With the inferred tree topology, we performed comparisons of functional gene content among lineages that diverged at varying depths in the phylogeny and found significant differences in the representation of genes putatively involved in pathogenicity. Our functional enrichment analysis suggests that some lineages of G. vaginalis may possess enhanced pathogenic capabilities, including genes involved in mucus degradation like sialidases, while others may be commensal strains, lacking many of these pathogenic capabilities. The combined phylogenetic evidence and functional enrichment analysis allowed us to identify distinct ecotypes that have evolved in G. vaginalis as the result of the differential gene gain/loss for specific functions, including the capability to cause disease. We finally discuss how this analysis framework could be used to gain insight into the etiology of bacterial vaginosis and improve diagnosis.

Dataset Information

Aging and pathological aging signatures of the brain: through the focusing lens of SIRT6.

Publications

Aging and pathological aging signatures of the brain: through the focusing lens of SIRT6.

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