Tissue aging: the integration of collective and variant responses of cells to entropic forces over time

Todhunter, Michael E.; Sayaman, Rosalyn W.; Miyano, Masaru; LaBarge, Mark A.

doi:10.1016/j.ceb.2018.05.016

Cited by 25 publications

(21 citation statements)

References 59 publications

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“…Taken together, these results indicate that changes in gene expression variance and cell-cell heterogeneity with age depend on cell identity. These results do not contradict previous observations of increased variation with age in some cell identities and contexts (Enge et al 2017;Martinez-Jimenez et al 2017), but rather suggest a nuanced view of changes in noise as a hallmark of aging at the single-cell level (Supplemental Note 5; Todhunter et al 2018).…”

Section: Changes In Cell-cell Variation With Age Depend On Cell Identitysupporting

confidence: 56%

Murine single-cell RNA-seq reveals cell-identity- and tissue-specific trajectories of aging

et al. 2019

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Aging is a pleiotropic process affecting many aspects of mammalian physiology. Mammals are composed of distinct cell type identities and tissue environments, but the influence of these cell identities and environments on the trajectory of aging in individual cells remains unclear. Here, we performed single-cell RNA-seq on >50,000 individual cells across three tissues in young and old mice to allow for direct comparison of aging phenotypes across cell types. We found transcriptional features of aging common across many cell types, as well as features of aging unique to each type. Leveraging matrix factorization and optimal transport methods, we found that both cell identities and tissue environments exert influence on the trajectory and magnitude of aging, with cell identity influence predominating. These results suggest that aging manifests with unique directionality and magnitude across the diverse cell identities in mammals. 2

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Section: Changes In Cell-cell Variation With Age Depend On Cell Identitysupporting

confidence: 56%

Murine single-cell RNA-seq reveals cell-identity- and tissue-specific trajectories of aging

et al. 2019

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“…Likewise, multivariate differences in gene expression between cells are not resolved due to the focus on mean dispersion values. Increased gene expression variance may reflect a global change in transcriptional noise, perhaps due to loss of regulatory control, as suggested in previous aging studies [93].…”

Section: Resultsmentioning

confidence: 85%

“…Taken together, these results indicate that changes in gene expression variance and cell-cell heterogeneity with age are not universal and depend on cell identity. This suggests a more nuanced view of the notion that an increase in noise is a defining hallmark of aging at the single cell level [34, 93].…”

Section: Resultsmentioning

confidence: 99%

A murine aging cell atlas reveals cell identity and tissue-specific trajectories of aging

Kimmel

Penland

Rubinstein

et al. 2019

Preprint

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Background: Aging is a pleiotropic process affecting many aspects of organismal and cellular 1 physiology. Mammalian organisms are composed of a constellation of distinct cell type and state 2 identities residing within different tissue environments. Due to technological limitations, the study 3 of aging has traditionally focused on changes within individual cell types, or the aggregate changes 4 across cell types within a tissue. The influence of cell identity and tissue environment on the trajectory 5 of aging therefore remains unclear.6Results: Here, we perform single cell RNA-seq on >50,000 individual cells across three tissues in 7 young and aged mice. These molecular profiles allow for comparison of aging phenotypes across cell 8 types and tissue environments. We find transcriptional features of aging common across many cell 9 types, as well as features of aging unique to each type. Leveraging matrix factorization and optimal 10 transport methods, we compute a trajectory and magnitude of aging for each cell type. We find that 11 cell type exerts a larger influence on these measures than tissue environment. 12Conclusion: In this study, we use single cell RNA-seq to dissect the influence of cell identity and 13 tissue environment on the aging process. Single cell analysis reveals that cell identities age in unique 14 ways, with some common features of aging shared across identities. We find that both cell identities 15 and tissue environments exert influence on the trajectory and magnitude of aging, with cell identity 16 influence predominating. These results suggest that aging manifests with unique directionality and 17 magnitude across the diverse cell identities in mammals. 18 Introduction 19Aging is a gradual process of functional and homeostatic decline in living systems. This decline results in increased 20 mortality risk and disease prevalence, eventually resulting in death. Aging appears to be a conserved feature of 21 eukaryotic biology, affecting organisms as phylogenetically diverse as the single celled S. cerevisiea, the eutelic 22 nematode C. elegans, mice, and humans [45, 63, 91]. Despite the near universal nature of the aging process, the 23 underlying causes of aging are poorly understood. Aging phenotypes have been observed and hypotheses have been 24 proposed for more than a hundred years [97, 50, 37, 64], but we do not yet know the cellular and molecular players 25 that cause aging or how they differ between biological contexts. Both the fundamental nature of aging and its negative 26 effects provide motivation to enumerate these players and establish causal relationships among aging phenotypes. 27Mammalian aging phenotypes manifest at the organismal, tissue, cellular, and molecular levels [100]. Extensive 28 research has produced catalogs of aging phenotypes at the physiological level, providing functional and behavioral 29 * Equal Contribution † Current Address: DuPont Nutrition and Biosciences, 200 Powder Mill Rd, Wilmington, DE, 19803 PREPRINT hallmarks of age related decline. Likewi...

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“…Epigenetic patterns differ between stem-like and differentiated cell types, but it is unclear how lineage-specific and somatic stem cells are altered during postnatal maturation, aging, and as a function of environmental exposures (Meissner et al, 2008). Furthermore, despite technological advancements in mapping epigenetic landscapes, the epigenetic factors that drive tissue maturation and aging remain largely undefined (Todhunter et al, 2018).…”

Section: The Case For a Pediatric Cell Atlasmentioning

confidence: 99%

The Pediatric Cell Atlas: Defining the Growth Phase of Human Development at Single-Cell Resolution

et al. 2019

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Single-cell gene expression analyses of mammalian tissues have uncovered profound stage-specific molecular regulatory phenomena that have changed the understanding of unique cell types and signaling pathways critical for lineage determination, morphogenesis, and growth. We discuss here the case for a Pediatric Cell Atlas as part of the Human Cell Atlas consortium to provide single-cell profiles and spatial characterization of gene expression across human tissues and organs. Such data will complement adult and developmentally focused HCA projects to provide a rich cytogenomic framework for understanding not only pediatric health and disease but also environmental and genetic impacts across the human lifespan.

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Tissue aging: the integration of collective and variant responses of cells to entropic forces over time

Cited by 25 publications

References 59 publications

Murine single-cell RNA-seq reveals cell-identity- and tissue-specific trajectories of aging

Murine single-cell RNA-seq reveals cell-identity- and tissue-specific trajectories of aging

A murine aging cell atlas reveals cell identity and tissue-specific trajectories of aging

The Pediatric Cell Atlas: Defining the Growth Phase of Human Development at Single-Cell Resolution

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