A rat epigenetic clock recapitulates phenotypic aging and co-localizes with heterochromatin

Levine, Morgan E.; McDevitt, Ross A.; Meer, Margarita; Perdue, Kathy A; Francesco, Andrea Di; Meade, Theresa; Farrell, Colin; Thrush, Kyra; Wang, Meng; Dunn, Christopher; Pellegrini, Matteo; Cabo, Rafael de; Ferrucci, Luigi

doi:10.7554/elife.59201

Cited by 46 publications

(65 citation statements)

References 31 publications

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“…PC1 explained 25% of the variance in this sample. When applying an elastic net model to train a predictor of age, PCs beyond PC1 did not increase the robustness of the age prediction 65 . Thus, PC1 was used to represent the ageing signature and was standardized to have a mean = 0 and s.d.…”

Section: Methodsmentioning

confidence: 87%

Reprogramming to recover youthful epigenetic information and restore vision

Brommer

Tian

et al. 2020

Nature

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Ageing is a degenerative process that leads to tissue dysfunction and death. A proposed cause of ageing is the accumulation of epigenetic noise that disrupts gene expression patterns, leading to decreases in tissue function and regenerative capacity 1 – 3 . Changes to DNA methylation patterns over time form the basis of ageing clocks 4 , but whether older individuals retain the information needed to restore these patterns—and, if so, whether this could improve tissue function—is not known. Over time, the central nervous system (CNS) loses function and regenerative capacity 5 – 7 . Using the eye as a model CNS tissue, here we show that ectopic expression of Oct4 (also known as Pou5f1), Sox2 and Klf4 genes (OSK) in mouse retinal ganglion cells restores youthful DNA methylation patterns and transcriptomes, promotes axon regeneration after injury, and reverses vision loss in a mouse model of glaucoma and in aged mice. The beneficial effects of OSK-induced reprogramming in axon regeneration and vision require the DNA demethylases TET1 and TET2. These data indicate that mammalian tissues retain a record of youthful epigenetic information—encoded in part by DNA methylation—that can be accessed to improve tissue function and promote regeneration in vivo.

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Section: Methodsmentioning

confidence: 87%

Reprogramming to recover youthful epigenetic information and restore vision

Brommer

Tian

et al. 2020

Nature

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529

513

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“…flat vs. round walls) will have a profound impact on the path of the light transitioning into water. In many previous studies on zebrafish vision, the potential occurrence of stimulus artifacts had received little attention 12 , although superior container designs had already successfully been used for other fish species 25 . Here, we compare the occurring optical artifacts of three different containers for aquatic animals: a commonly used Petri dish lid (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The visual system extracts features from stimulus patterns, and, accordingly, visual neurons can respond to a range of features such as contrast, motion direction, spatial frequency, sizes, locations and shapes of the visual stimulus 5 , 7 – 11 . Therefore, presenting high quality visual stimulus patterns to the animal eyes is crucial for the investigation of visual functions and neural encoding 12 .…”

Section: Introductionmentioning

confidence: 99%

“…fish) gives rise to additional challenges, since an underwater environment is required during the experiments 20 , 23 . Electronics need to be kept outside of the water, and therefore visual stimuli are oftentimes blurred and distorted before they reach the animal eyes, which mainly results from light refraction and reflection and the associated geometrical optics at the air-container-water interfaces 12 , 24 . For example, during the presentation of global optic flow, the motion consistency across the visual field may be disrupted.…”

Section: Introductionmentioning

confidence: 99%

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Reduction of visual stimulus artifacts using a spherical tank for small, aquatic animals

Wang

Arrenberg

Hinz

et al. 2021

Sci Rep

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Delivering appropriate stimuli remains a challenge in vision research, particularly for aquatic animals such as zebrafish. Due to the shape of the water tank and the associated optical paths of light rays, the stimulus can be subject to unwanted refraction or reflection artifacts, which may spoil the experiment and result in wrong conclusions. Here, we employ computer graphics simulations and calcium imaging in the zebrafish optic tectum to show, how a spherical glass container optically outperforms many previously used water containers, including Petri dish lids. We demonstrate that aquatic vision experiments suffering from total internal reflection artifacts at the water surface or at the flat container bottom may result in the erroneous detection of visual neurons with bipartite receptive fields and in the apparent absence of neurons selective for vertical motion. Our results and demonstrations will help aquatic vision neuroscientists on optimizing their stimulation setups.

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“…In healthy humans, the cerebellum is epigenetically younger than the rest of the organism (44). Multi-tissue full lifespan epigenetic clocks have been set up for mice (15, 45) and more recently, for Fischer344 male rats (46).…”

Section: Discussionmentioning

confidence: 99%

HIPPOCAMPAL DNA METHYLATION, DNAm AGE AND SPATIAL MEMORY PERFORMANCE IN YOUNG AND OLD RATS

Chiavellini

Lehmann

Canatelli-Mallat

et al. 2021

Preprint

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In humans and rats, aging is associated with a progressive deterioration of spatial learning and memory. These functional alterations are correlated with morphological and molecular changes in the brain, particularly in the hippocampus. Here, we assessed the age-related changes in the DNA methylation (DNAm) landscape in the rat hippocampus and assessed the correlation of spatial memory performance with hippocampal DNAm age in young (2.6 mo.) and old (26.6 mo.) rats. Spatial memory performance was assessed with a modified version of the Barnes maze test. In order to evaluate learning ability as well as spatial memory retention, we assessed the time spent (permanence) by animals in goal sector 1 (GS1) and 3 (GS3) when the escape box was removed. The rat pan-tissue clock was applied to DNA methylation profiles of hippocampal tissue. The bisulfite converted genomic DNA was analyzed by Illumina Infinium HorvathMammalMethylChip40. The Horvath Mammal Methyl Chip40 assay provides quantitative measurements of DNA methylation for 22528 CpG dinucleotides that map to the Rattus norvegicus UCSC 6.0 genome. An enrichment pathway analysis revealed that neuron fate commitment, brain development, and central nervous system development were processes whose underlying genes were enriched in positively methylated CpGs. In the old rat hippocampi, the methylation levels of CpGs proximal to transcription factors associated with genes Pax5, Lbx1, Nr2f2, Hnf1b, Zic1, Zic4, Hoxd9; Hoxd10, Gli3, Gsx1 and Lmx1b, and Nipbl showed a significant regression with spatial memory performance. Regression analysis of different memory performance indices with hippocampal DNAm age was significant when data from young and old rats were taken together. The above results suggest that age-related hypermethylation of certain gene families, like Zic and Gli, may play a causal role in the decline in spatial memory in old rats. Hippocampal DNAm age seems to be a reliable index of spatial memory performance in young and old rats.

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A rat epigenetic clock recapitulates phenotypic aging and co-localizes with heterochromatin

Cited by 46 publications

References 31 publications

Reprogramming to recover youthful epigenetic information and restore vision

Reprogramming to recover youthful epigenetic information and restore vision

Reduction of visual stimulus artifacts using a spherical tank for small, aquatic animals

HIPPOCAMPAL DNA METHYLATION, DNAm AGE AND SPATIAL MEMORY PERFORMANCE IN YOUNG AND OLD RATS

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