Abstract

Many age-associated changes in the human hematopoietic system have been reproduced in murine models; however, such changes have not been as robustly explored in rats despite the fact these larger rodents are more physiologically similar to humans. We examined peripheral blood of male F344 rats ranging from three to twenty-seven months of age and found significant age-associated changes with distinct leukocyte population shifts. We report CD25+ CD4+ population frequency is a strong predictor of healthy aging, generate a model using blood parameters, and find rats with blood profiles that diverge from chronologic age indicate debility; thus, assessments of blood composition may be useful for non-lethal disease profiling or as a surrogate measure for efficacy of aging interventions. Importantly, blood parameters and DNA methylation alterations, defined distinct juncture points during aging, supporting a non-linear aging process. Our results suggest these inflection points are important considerations for aging interventions. Overall, we present rat blood aging metrics that can serve as a resource to evaluate health and the effects of interventions in a model system physiologically more reflective of humans.

Data availability

The data that support the findings of this study are available in the Supplementary Material and Supplementary Tables of this article. The DNA methylation raw data is available via GEO Accession (GSE161141). FCS files have been uploaded to FlowRepository (FR-FCM-Z59K)

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Hagai Yanai

    Flow Cytometry Core, National Institute on Aging, Baltimore, United States
    For correspondence
    hagai.yanai@nih.gov
    Competing interests
    The authors declare that no competing interests exist.
  2. Christopher Dunn

    Flow Cytometry Core, National Institute on Aging, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7899-0110
  3. Bongsoo Park

    Epigenetics and Stem Cell Unit, National Institute on Aging, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Christopher Coletta

    Computational Biology and Genomics Core, National Institute on Aging, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Ross A McDevitt

    Comparative Medicine Section, National Institute on Aging, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3722-9047
  6. Taylor McNeely

    Epigenetics and Stem Cell Unit, National Institute on Aging, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Michael Leone

    Epigenetics and Stem Cell Unit, National Institute on Aging, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Robert P Wersto

    Flow Cytometry Core, National Institute on Aging, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Kathy A Perdue

    Comparative Medicine Section, National Institute on Aging, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Isabel Beerman

    Epigenetics and Stem Cell Unit, National Institute on Aging, Baltimore, United States
    For correspondence
    isabel.beerman@nih.gov
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7758-8231

Funding

National Institutes of Health (Intramural NIA)

  • Isabel Beerman

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All experimental procedures were conducted in accordance with the Guide for the Care and Use of Laboratory Animals and approved by the NIA Animal Care and Use Committee (ASP 467-CMS-2018 and 469-TGB-2022)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

Metrics

  • 1,204
    views
  • 228
    downloads
  • 3
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Hagai Yanai
  2. Christopher Dunn
  3. Bongsoo Park
  4. Christopher Coletta
  5. Ross A McDevitt
  6. Taylor McNeely
  7. Michael Leone
  8. Robert P Wersto
  9. Kathy A Perdue
  10. Isabel Beerman
(2022)
Male rat leukocyte population dynamics predict a window for intervention in aging
eLife 11:e76808.
https://doi.org/10.7554/eLife.76808

Share this article

https://doi.org/10.7554/eLife.76808

Further reading

    1. Evolutionary Biology
    2. Genetics and Genomics
    Julie N Chuong, Nadav Ben Nun ... David Gresham
    Research Article

    Copy number variants (CNVs) are an important source of genetic variation underlying rapid adaptation and genome evolution. Whereas point mutation rates vary with genomic location and local DNA features, the role of genome architecture in the formation and evolutionary dynamics of CNVs is poorly understood. Previously, we found the GAP1 gene in Saccharomyces cerevisiae undergoes frequent amplification and selection in glutamine-limitation. The gene is flanked by two long terminal repeats (LTRs) and proximate to an origin of DNA replication (autonomously replicating sequence, ARS), which likely promote rapid GAP1 CNV formation. To test the role of these genomic elements on CNV-mediated adaptive evolution, we evolved engineered strains lacking either the adjacent LTRs, ARS, or all elements in glutamine-limited chemostats. Using a CNV reporter system and neural network simulation-based inference (nnSBI) we quantified the formation rate and fitness effect of CNVs for each strain. Removal of local DNA elements significantly impacts the fitness effect of GAP1 CNVs and the rate of adaptation. In 177 CNV lineages, across all four strains, between 26% and 80% of all GAP1 CNVs are mediated by Origin Dependent Inverted Repeat Amplification (ODIRA) which results from template switching between the leading and lagging strand during DNA synthesis. In the absence of the local ARS, distal ones mediate CNV formation via ODIRA. In the absence of local LTRs, homologous recombination can mediate gene amplification following de novo retrotransposon events. Our study reveals that template switching during DNA replication is a prevalent source of adaptive CNVs.

    1. Developmental Biology
    2. Evolutionary Biology
    Hope M Healey, Hayden B Penn ... William A Cresko
    Research Article

    Seahorses, pipefishes, and seadragons are fishes from the family Syngnathidae that have evolved extraordinary traits including male pregnancy, elongated snouts, loss of teeth, and dermal bony armor. The developmental genetic and cellular changes that led to the evolution of these traits are largely unknown. Recent syngnathid genome assemblies revealed suggestive gene content differences and provided the opportunity for detailed genetic analyses. We created a single-cell RNA sequencing atlas of Gulf pipefish embryos to understand the developmental basis of four traits: derived head shape, toothlessness, dermal armor, and male pregnancy. We completed marker gene analyses, built genetic networks, and examined the spatial expression of select genes. We identified osteochondrogenic mesenchymal cells in the elongating face that express regulatory genes bmp4, sfrp1a, and prdm16. We found no evidence for tooth primordia cells, and we observed re-deployment of osteoblast genetic networks in developing dermal armor. Finally, we found that epidermal cells expressed nutrient processing and environmental sensing genes, potentially relevant for the brooding environment. The examined pipefish evolutionary innovations are composed of recognizable cell types, suggesting that derived features originate from changes within existing gene networks. Future work addressing syngnathid gene networks across multiple stages and species is essential for understanding how the novelties of these fish evolved.