Heterochronic parabiosis induces stem cell revitalization and systemic rejuvenation across aged tissues

Ma, Shuai; Wang, Si; Ye, Yanxia; Ren, Jie; Chen, Ruiqing; Li, Wei; Li, Jiaming; Zhao, Lei; Zhao, Qian; Sun, Guoqiang; Jing, Ying; Zuo, Yuesheng; Xiong, Muzhao; Yang, Yuan‐Han; Wang, Qiaoran; Lei, Jinghui; Sun, Shuhui; Long, Xiao; Song, Moshi; Yu, Shuyang; Chan, Piu; Wang, Jianwei; Zhou, Qi; Belmonte, Juan Carlos Izpisúa; Qu, Jing; Zhang, Weiqi; Liu, Guanghui

doi:10.1016/j.stem.2022.04.017

Cited by 81 publications

(46 citation statements)

References 62 publications

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“…Recent single cell studies examining heterochronic parabiosis have concluded that aged HSCs are among the most dramatically altered transcriptionally following exposure to the young environment 31,32 . By overlapping our functional CRISPR KO screen hits with the genes differentially expressed in heterochronic parabiosis, we predicted that we may be able to infer some of the functional consequences of the reported genes expression changes in this rejuvenating condition.…”

Section: Resultsmentioning

confidence: 99%

Large-scale in vivo CRISPR screens identify SAGA complex members as a key regulators of HSC lineage commitment and aging

Haney

Shankar

Hsu

et al. 2022

Preprint

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The biological mechanisms that sustain the vast blood production required for healthy life remain incompletely understood. To address this knowledge gap, we developed an in vivo hematopoietic stem cell (HSC)-based large-scale CRISPR knockout screening platform to enable the genetic interrogation of hematopoiesis and broad aspects of immune cell function in vivo. Targeting ~7000 genes with this methodology, we discovered SAGA complex members Tada2b and Taf5l as key regulators of HSC lineage commitment. Loss of Tada2b or Taf5l inhibited hematopoiesis in vivo and was associated with upregulation of interferon response gene expression. SAGA complex member expression is significantly reduced in aged HSCs and upregulated with heterochronic parabiosis, suggesting a novel mechanism of age-associated hematopoietic decline and rejuvenation. Our study provides a rich functional genetics resource of hematopoiesis regulators accessible through a public interactive database (www.hematopoiesiscrisprscreens.com), a novel mechanism regulating age-related decline of hematopoiesis, and a new methodology with broad applications to systematically probe the development and functions of the lymphohematopoietic system.

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Section: Resultsmentioning

confidence: 99%

Large-scale in vivo CRISPR screens identify SAGA complex members as a key regulators of HSC lineage commitment and aging

Haney

Shankar

Hsu

et al. 2022

Preprint

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“…Indeed, a recent study shows that immune system aging alone drives solid organs and aging of the whole system. Consistently, parabiosis studies show that the young or old blood rejuvenates or ages many tissues and organs of the reciprocal recipients (Ma et al, 2022).…”

Section: Systems Biology and Ai In Aging Researchmentioning

confidence: 66%

“…Single-cell assays, including single-cell RNA-sequencing (scRNA-seq), and spatial transcriptomics enable us to study aging at the single-cell level, uncover heterogeneous cell populations, and decipher the spatial distribution of aged stem cells. Additionally, recent studies have found that heterochronic parabiosis rejuvenates adult stem cells in aged individuals, especially HSPCs (Ma et al, 2022;Pálovics et al, 2022;Wang et al, 2022a). Taken to-gether, stem cell aging is a central hallmark of aging, and strategies that target stem cell exhaustion during aging hold great promise for developing regenerative medicine and delaying aging and age-associated diseases.…”

Section: Discussionmentioning

confidence: 99%

The landscape of aging

Cai

Song

et al. 2022

Sci. China Life Sci.

Self Cite

158

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Aging is characterized by a progressive deterioration of physiological integrity, leading to impaired functional ability and ultimately increased susceptibility to death. It is a major risk factor for chronic human diseases, including cardiovascular disease, diabetes, neurological degeneration, and cancer. Therefore, the growing emphasis on “healthy aging” raises a series of important questions in life and social sciences. In recent years, there has been unprecedented progress in aging research, particularly the discovery that the rate of aging is at least partly controlled by evolutionarily conserved genetic pathways and biological processes. In an attempt to bring full-fledged understanding to both the aging process and age-associated diseases, we review the descriptive, conceptual, and interventive aspects of the landscape of aging composed of a number of layers at the cellular, tissue, organ, organ system, and organismal levels.

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“…Notably, adult stem cells, especially bone marrow HSPCs, are responsive to the changing milieu. Specifically, a list of factors, including CCL3 and YY1, has been identified as potent hits for HSPC rejuvenation [19].…”

Section: Regenerative Medicinementioning

confidence: 99%

Potential approaches for intervening aging

Shen¹,

Liu²,

Song³

2022

NSO

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Though immortality and regeneration were ludicrous and far-fetched in an age of ignorance and superstition, people have never stopped looking for the elixir of longevity. As a result of advancements in lifestyle and medical care, the average human life expectancy has risen in recent decades, along with the increasingly higher incidence of aging-related diseases. With the advance in biological techniques, our understanding of aging and aging-related diseases has expanded significantly. Molecular and cellular mechanisms that contribute to the aging process and age-related diseases can be classified into several categories, including genomic instability, telomere atrophy, epigenetic changes, loss of protein stability, dysregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell depletion, and impaired intercellular communication [1].Along with the diverse strategies that have been exploited to explain aging, our ideas of aging intervention have also grown rapidly and multiple potentially effective strategies have been investigated. Here, we summarize these approaches below, dividing them into the following categories: (1) pharmacological administration; (2) gene therapy; (3) regenerative medicine; and (4) immunogenic intervention. Pharmacological administrationSenescent cells release enormous amounts of inflammatory cytokines, immunomodulators, growth factors and proteases, which are known as senescence-associated secretory phenotypes (SASP). Exosomes and episomes carrying enzymes, microRNAs, DNA fragments, chemokines, and other physiologically active components can also be found in the SASP [2]. Given that SASP and SASP-secreting cells have been regarded as possible therapeutic targets to ameliorate inflammatory conditions in the elderly, senolytics referred to the agents that selectively kill senescent cells are gaining traction as a way to possibly slow down the aging process and ameliorate organ malfunction. As such, the first empirical senolytic combination that extends mouse lifespan includes dasatinib, originally developed to target oncogene-addiction in leukemia, and quercetin, which inhibits the mTOR pathway, among numerous others [3]. In humans, dasatinib 100 mg

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Heterochronic parabiosis induces stem cell revitalization and systemic rejuvenation across aged tissues

Cited by 81 publications

References 62 publications

Large-scale in vivo CRISPR screens identify SAGA complex members as a key regulators of HSC lineage commitment and aging

Large-scale in vivo CRISPR screens identify SAGA complex members as a key regulators of HSC lineage commitment and aging

The landscape of aging

Potential approaches for intervening aging

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