Genome-wide RNA polymerase stalling shapes the transcriptome during aging

Gene expression profiling has identified numerous processes altered in aging, but how these changes arise is largely unknown. Here we combined nascent RNA sequencing and RNA polymerase II chromatin immunoprecipitation followed by sequencing to elucidate the underlying mechanisms triggering gene expression changes in wild-type aged mice. We found that in 2-year-old liver, 40% of elongating RNA polymerases are stalled, lowering productive transcription and skewing transcriptional output in a gene-length-dependent fashion. We demonstrate that this transcriptional stress is caused by endogenous DNA damage and explains the majority of gene expression changes in aging in most mainly postmitotic organs, specifically affecting aging hallmark pathways such as nutrient sensing, autophagy, proteostasis, energy metabolism, immune function and cellular stress resilience. Age-related transcriptional stress is evolutionary conserved from nematodes to humans. Thus, accumulation of stochastic endogenous DNA damage during aging deteriorates basal transcription, which establishes the age-related transcriptome and causes dysfunction of key aging hallmark pathways, disclosing how DNA damage functionally underlies major aspects of normal aging

First steps in developing the Dutch version of the Bayley III: Is the original Bayley III and its item sequence also adequate for Dutch children?

The Bayley Scales of Infant and Toddler Development [Bayley III, Bayley, N. (2006). The Bayley scales of infant and toddler development. San Antonio, TX: The Psychological Corporation] is currently developed and exclusively normed for American children. In this study, the appropriateness of the Bayley III item content and item sequence for Dutch children was evaluated. The translated version, the Bayley-III-NL was evaluated in two phases. In phase 1 (N=100), analyses showed that overall the item content seemed to be appropriate for Dutch children. In addition, the item sequence was found to be suitable for Dutch children. After phase 1, small adaptations were made to the instructions of a few items based on the experiences of the examiners to improve standardization in performance. In phase 2 (N=400), the findings of phase 1 were confirmed in a larger sample. It is concluded that Dutch norms can be based upon the current version of the Bayley-III-NL

First steps in developing the Dutch version of the Bayley III : Is the original Bayley III and its item sequence also adequate for Dutch children?

The Bayley Scales of Infant and Toddler Development [Bayley III, Bayley, N. (2006). The Bayley scales of infant and toddler development. San Antonio, TX: The Psychological Corporation] is currently developed and exclusively normed for American children. In this study, the appropriateness of the Bayley III item content and item sequence for Dutch children was evaluated. The translated version, the Bayley-III-NL was evaluated in two phases. In phase 1 (N=100), analyses showed that overall the item content seemed to be appropriate for Dutch children. In addition, the item sequence was found to be suitable for Dutch children. After phase 1, small adaptations were made to the instructions of a few items based on the experiences of the examiners to improve standardization in performance. In phase 2 (N=400), the findings of phase 1 were confirmed in a larger sample. It is concluded that Dutch norms can be based upon the current version of the Bayley-III-NL

Performance of Dutch Children on the Bayley III: A Comparison Study of US and Dutch Norms

Background The Bayley Scales of Infant and Toddler Development-third edition (Bayley-III) are frequently used to assess early child development worldwide. However, the original standardization only included US children, and it is still unclear whether or not these norms are adequate for use in other populations. Recently, norms for the Dutch version of the Bayley-III (The Bayley-III-NL) were made. Scores based on Dutch and US norms were compared to study the need for population-specific norms. Methods Scaled scores based on Dutch and US norms were compared for 1912 children between 14 days and 42 months 14 days. Next, the proportions of children scoring < 1-SD and < -2 SD based on the two norms were compared, to identify over- or under-referral for developmental delay resulting from non-population-based norms. Results Scaled scores based on Dutch norms fluctuated around values based on US norms on all subtests. The extent of the deviations differed across ages and subtests. Differences in means were significant across all five subtests (p < .01) with small to large effect sizes (ηp2) ranging from .03 to .26). Using the US instead of Dutch norms resulted in over-referral regarding gross motor skills, and under-referral regarding cognitive, receptive communication, expressive communication, and fine motor skills. Conclusions The Dutch norms differ from the US norms for all subtests and these differences are clinically relevant. Population specific norms are needed to identify children with low scores for referral and intervention, and to facilitate international comparisons of population data

Musculoskeletal senescence: a moving target ready to be eliminated

Aging is the prime risk factor for the broad-based development of diseases. Frailty is a phenotypical hallmark of aging and is often used to assess whether the predicted benefits of a therapy outweigh the risks for older patients. Senescent cells form as a consequence of unresolved molecular damage and persistently secrete molecules that can impair tissue function. Recent evidence shows senescent cells can chronically interfere with stem cell function and drive aging of the musculoskeletal system. In addition, targeted apoptosis of senescent cells can restore tissue homeostasis in aged animals. Thus, targeting cellular senescence provides new therapeutic opportunities for the intervention of frailty-associated pathologies and could have pleiotropic health benefits.The authors acknowledge support for MB from Dutch Cancer Society Grant UMCU-7141 awarded to PdK, and for EP and PMC from ERC-2016-AdG-741966 (STEM-AGING), SAF2015-67369-R, MDA and AFM. The DCESX/UPF is recipient of a ‘María de Maeztu’ Program for Units of Excellence in R&D MDM-2014-0370 (Government of Spain

Proportion of children with low scores based on US or Dutch norms.

<p>Note. Scaled scores of < 1SD correspond to scaled scores <7 indicating a low score which may reflect a developmental delay in the subtest domain and scaled scores of < 2SD correspond to scaled scores <4, which may indicate a severe delay in the domain examined.“</p><p>*p < .05;</p><p>** p < .01</p><p>Proportion of children with low scores based on US or Dutch norms.</p

Background characteristics of the sample.

<p>*’ ‘Low educational level’ refers to special education, primary school, or pre-vocational secondary education (< 12 years); ‘medium educational level’ refers to senior general secondary education, pre-university education, or secondary vocational education (13–16 years); ‘high educational level refers to higher professional education or university (17+ years).</p><p>** Refers to the percentages in the Dutch population based on information provided by the Central Bureau of Statistics (CBS; [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0132871#pone.0132871.ref012" target="_blank">12</a>]).</p><p>Background characteristics of the sample.</p

Average US and Dutch scaled scores in relation to age.

<p>Average US and Dutch scaled scores in relation to age.</p