Multi-omic rejuvenation and lifespan extension upon exposure to youthful circulation

Heterochronic parabiosis (HPB) is known for its functional rejuvenation effects across several mouse tissues. However, its impact on the biological age of organisms and their long-term health remains unknown. Here, we performed extended (3-month) HPB, followed by a 2-month detachment period of anastomosed pairs. Old detached mice exhibited improved physiological parameters and lived longer than control isochronic mice. HPB drastically reduced the biological age of blood and liver based on epigenetic analyses across several clock models on two independent platforms; remarkably, this rejuvenation effect persisted even after 2 months of detachment. Transcriptomic and epigenomic profiles of anastomosed mice showed an intermediate phenotype between old and young, suggesting a comprehensive multi-omic rejuvenation effect. In addition, old HPB mice showed transcriptome changes opposite to aging, but akin to several lifespan-extending interventions. Altogether, we reveal that long-term HPB can decrease the biological age of mice, in part through long-lasting epigenetic and transcriptome remodeling, culminating in the extension of lifespan and healthspan.

• Publication year

  2021

• Venue

  bioRxiv

• Publication date

  2021-11-12

• Fields of study

  Biology, Medicine, Environmental Science

• Identifiers
  DOI 10.1101/2021.11.11.468258
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar

• No claims are published for this paper.

• No concepts are published for this paper.

• Molecular hallmarks of heterochronic parabiosis at single-cell resolution

  2022cited by this paper
• Asynchronous, contagious and digital aging

  2021cited by this paper
• Epigenetic clocks reveal a rejuvenation event during embryogenesis followed by aging

  2021cited by this paper
• Aged hematopoietic stem cells are refractory to bloodborne systemic rejuvenation interventions

  2021cited by this paper
• Transient non-integrative expression of nuclear reprogramming factors promotes multifaceted amelioration of aging in human cells

  2020cited by this paper
• Meteorin-like facilitates skeletal muscle repair through a Stat3/IGF-1 mechanism

  2020cited by this paper
• Sequence Analysis

  2020cited by this paper
• Reprogramming to recover youthful epigenetic information and restore vision

  2020cited by this paper
• Reversing age: dual species measurement of epigenetic age with a single clock

  2020cited by this paper
• Reversal of epigenetic aging and immunosenescent trends in humans

  2019cited by this paper
• Identification and Application of Gene Expression Signatures Associated with Lifespan Extension.

  2019influential reference
• A whole lifespan mouse multi-tissue DNA methylation clock

  2018influential reference
• Macrophage cells secrete factors including LRP1 that orchestrate the rejuvenation of bone repair in mice

  2018cited by this paper
• Partial reprogramming induces a steady decline in epigenetic age before loss of somatic identity

  2018cited by this paper
• A multi-tissue full lifespan epigenetic clock for mice

  2018cited by this paper
• Using DNA Methylation Profiling to Evaluate Biological Age and Longevity Interventions.

  2017influential reference
• Dynamics of epigenetic age following hematopoietic stem cell transplantation

  2017cited by this paper
• Peripheral inflammatory markers in Alzheimer’s disease: a systematic review and meta-analysis of 175 studies

  2017cited by this paper
• The Fountain of Youth: A Tale of Parabiosis, Stem Cells, and Rejuvenation

  2017cited by this paper
• Human umbilical cord plasma proteins revitalize hippocampal function in aged mice

  2017cited by this paper
• Preclinical Assessment of Young Blood Plasma for Alzheimer Disease.

  2016cited by this paper
• A single heterochronic blood exchange reveals rapid inhibition of multiple tissues by old blood

  2016cited by this paper
• Inflammation and Progression of CKD: The CRIC Study.

  2016cited by this paper
• Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice

  2014cited by this paper
• Alive and well? Exploring disease by studying lifespan.

  2014cited by this paper
• Systemic Regulation of the Age-Related Decline of Pancreatic β-Cell Replication

  2013cited by this paper
• featureCounts: an efficient general purpose program for assigning sequence reads to genomic features

  2013influential reference
• Rejuvenation of regeneration in the aging central nervous system.

  2012cited by this paper
• Pathobiology of Aging Mice and GEM

  2012cited by this paper
• Aging, rejuvenation, and epigenetic reprogramming: resetting the aging clock.

  2012cited by this paper
• The ageing systemic milieu negatively regulates neurogenesis and cognitive function

  2011cited by this paper
• Integrating diverse genomic data using gene sets

  2011cited by this paper
• expression analysis of digital gene expression data

  2010cited by this paper
• edgeR: a Bioconductor package for differential expression analysis of digital gene expression data

  2009influential reference
• Oxidative phosphorylation and aging.

  2006cited by this paper
• Reduced representation bisulfite sequencing for comparative high-resolution DNA methylation analysis

  2005cited by this paper
• From the Cover: Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles

  2005influential reference
• Survival characteristics and age-adjusted disease incidences in C57BL/6 mice fed a commonly used cereal-based diet modulated by dietary restriction.

  2002cited by this paper
• Physiological Migration of Hematopoietic Stem and Progenitor Cells

  2001cited by this paper
• The increase of IFN-gamma production through aging correlates with the expanded CD8(+high)CD28(-)CD57(+) subpopulation.

  2000influential reference
• DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development.

  1999cited by this paper
• Methionine restriction increases blood glutathione and longevity in F344 rats

  1994cited by this paper
• Residual blood volumes in organs of pregnant mice and fetuses.

  1979influential reference
• Experimental prolongation of the life span.

  1956cited by this paper

• High-dimensional Ageome Representations of Biological Aging across Functional Modules

  2024cites this paper
• Multi-omics characterization of partial chemical reprogramming reveals evidence of cell rejuvenation

  2024cites this paper
• Rejuvenation strategies share gene expression programs of reduced inflammation and downstream restored fatty acid metabolism

  2023cites this paper
• Distinct longevity mechanisms across and within species and their association with aging.

  2023cites this paper
• Nature of epigenetic aging from a single-cell perspective

  2023cites this paper
• Multi-omics characterization of partial chemical reprogramming reveals evidence of cell rejuvenation

  2023cites this paper
• Reversal of Biological Age in Multiple Rat Organs by Young Porcine Plasma Fraction

  2023cites this paper
• Heterochronic parabiosis: a valuable tool to investigate cellular senescence and other hallmarks of aging

  2022cites this paper
• Heterochronic parabiosis reprograms the mouse brain transcriptome by shifting aging signatures in multiple cell types

  2022cites this paper
• Biological age is increased by stress and restored upon recovery

  2022cites this paper