The aged hematopoietic system promotes hippocampal‐dependent cognitive decline

Smith, Lucas K.; Verovskaya, Evgenia; Bieri, Gregor; Horowitz, Alana; Ungern‐Sternberg, Saskia N. I. von; Lin, Karin; Seizer, Peter; Passegué, Emmanuelle; Villeda, Saul

doi:10.1111/acel.13192

Cited by 17 publications

(17 citation statements)

References 29 publications

(36 reference statements)

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“…Exposure to a young circulatory system rejuvenates muscle regenerative capacity by activating satellite cells and restores the proliferative capacity of hepatic progenitors (42). Heterochronic parabiosis also affects neurogenesis and associated learning and memory, improving these capacities in old mice (43,58,59), while impairing them in young mice (60)(61)(62). CyPA (61) and chemokines including CCL11 (62) have been identified as negative regulators, while TIMP2 (58) and GPLD1 (59) were identified as positive regulators of these functions.…”

Section: Extracellular Vesicles As a Critical Regulatory Component For Mammalian Aging And Longevitymentioning

confidence: 99%

“…42 Heterochronic parabiosis also affects neurogenesis and associated learning and memory, improving these capacities in old mice, 43,58,59 while impairing them in young mice. [60][61][62] CyPA 61 and chemokines including CCL11 62 have been identified as negative regulators, while TIMP2 58 and GPLD1 59 were identified as positive regulators of these functions. Outside of parabiosis, studies have demonstrated that plasma extracted from exercised animals confers antiaging cognitive benefits 59 and that there are substantial changes to the plasma EV pool, including increased numbers of EVs during exercise in humans.…”

Section: Blood-based Antiaging Therapiesmentioning

confidence: 99%

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Friends and foes: Extracellular vesicles in aging and rejuvenation

Lananna

Imai

2021

FASEB BioAdvances

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Extracellular vesicles (EVs) are released by many different cell types throughout the body and play a role in a diverse range of biological processes. EVs circulating in blood as well as in other body fluids undergo dramatic alterations over an organism's lifespan that are only beginning to be elucidated. The exact nature of these changes is an area of active and intense investigation, but lacks clear consensus due to the substantial heterogeneity in EV subpopulations and insufficiencies in current technologies. Nonetheless, emerging evidence suggests that EVs regulate systemic aging as well as the pathophysiology of age-related diseases. Here, we review the current literature investigating EVs and aging with an emphasis on consequences for the maintenance of human healthspan. Intriguingly, the biological utility of EVs both in vitro and in vivo and across contexts depends on the states of the source cells or tissues. As such, EVs secreted by cells in an aged or pathological state may impose detrimental consequences on recipient cells, while EVs secreted by youthful or healthy cells may promote functional improvement. Thus, it is critical to understand both functions of EVs and tip the balance towards their beneficial effects as an anti-aging intervention. Accepted ArticleNo copyright is required Biogenesis of small versus large EVs occurs via divergent pathways that nonetheless involve some of the same regulatory molecules. Small EVs are generated by a secondary invagination of the luminal membrane of endosomes following endocytosis, forming multivesicular bodies (MVBs).These MVBs then fuse with the cellular outer plasma membrane, emptying their contents including the nascent small EVs into the extracellular space. In contrast, large EVs form by directly budding from the external cellular plasma membrane (15). Description of current knowledge regarding the biogenesis, uptake, and basic biological functions of EVs are beyond the scope of this review, but are reviewed in detail elsewhere (5,15). Importantly, EVs can serve as both local and long-range transport and intertissue signaling mechanisms for mRNA, miRNA, protein, and lipids and are a major source for cell-free DNA and RNA in humans (15)(16)(17)(18)(19)(20). In this review article, we will focus on the biological significance of EVs in the systemic regulation of mammalian aging and longevity and also in the pathogenesis of age-associated dysfunctions. II. Changes to extracellular vesicles with ageEV quantification: Recent evidence suggests that there are substantial changes to EVs with age.Nevertheless, the extent of these changes and whether they represent a cause or effect of aging remain largely unanswered questions in the field. Such changes could be viewed as potential boons to our understanding of the aging process as well as in our search for viable aging biomarkers in humans. Analysis of plasma from 74 humans including young (30-35 years old), middle-aged (40-55 years old), and old (55-64 years old) revealed gradually decreasing quantities of circu...

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Section: Extracellular Vesicles As a Critical Regulatory Component For Mammalian Aging And Longevitymentioning

confidence: 99%

Section: Blood-based Antiaging Therapiesmentioning

confidence: 99%

Friends and foes: Extracellular vesicles in aging and rejuvenation

Lananna

Imai

2021

FASEB BioAdvances

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“…Previously, heterochronic transplantation of marrow or HSCs in mice has been shown to affect (modulate) a variety of phenotypes 15–18 . Most recently, aged HSCs were found to induce circulating cyclophilin A, encoded by Ppia 19 , a gene ranked among the top differentially expressed across cell types exposed to aged blood (Extended Data Fig. 5).…”

Section: Cell Type-specific Differential Gene Expressionmentioning

confidence: 99%

Molecular hallmarks of heterochronic parabiosis at single cell resolution

Pálovics¹,

Keller

Schaum³

et al. 2020

Preprint

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Slowing or reversing biological ageing would have major implications for mitigating disease risk and maintaining vitality. While an increasing number of interventions show promise for rejuvenation, the effectiveness on disparate cell types across the body and the molecular pathways susceptible to rejuvenation remain largely unexplored. We performed single-cell RNA-sequencing on 13 organs to reveal cell type specific responses to young or aged blood in heterochronic parabiosis. Adipose mesenchymal stromal cells, hematopoietic stem cells, hepatocytes, and endothelial cells from multiple tissues appear especially responsive. On the pathway level, young blood invokes novel gene sets in addition to reversing established ageing patterns, with the global rescue of genes encoding electron transport chain subunits pinpointing a prominent role of mitochondrial function in parabiosis-mediated rejuvenation. Intriguingly, we observed an almost universal loss of gene expression with age that is largely mimicked by parabiosis: aged blood reduces global gene expression, and young blood restores it. Altogether, these data lay the groundwork for a systemic understanding of the interplay between blood-borne factors and cellular integrity.

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“…During aging there is an increase in the blood circulation of IL-6 and TNF-α, which also corresponds to a higher expression of these factors in the choroid plexus (CP) (Smith et al, 2018). Likewise, heterochronic reconstitution experiments have also recently indicated that old hematopoietic cells reduce hippocampal neurogenesis through increased levels of cyclophilin A, a SASP factor (Smith et al, 2020). Together, these changes may account for the accumulation of pro-aging SASP factors in the old blood, which are also likely to promote senescence induction at the vascular level, ultimately contributing to the deterioration of adult neurogenesis.…”

Section: The Aging Systemic Milieu: Blood-borne Effects On Neurogenesismentioning

confidence: 99%

Vascular Senescence: A Potential Bridge Between Physiological Aging and Neurogenic Decline

et al. 2021

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The adult mammalian brain contains distinct neurogenic niches harboring populations of neural stem cells (NSCs) with the capacity to sustain the generation of specific subtypes of neurons during the lifetime. However, their ability to produce new progeny declines with age. The microenvironment of these specialized niches provides multiple cellular and molecular signals that condition NSC behavior and potential. Among the different niche components, vasculature has gained increasing interest over the years due to its undeniable role in NSC regulation and its therapeutic potential for neurogenesis enhancement. NSCs are uniquely positioned to receive both locally secreted factors and adhesion-mediated signals derived from vascular elements. Furthermore, studies of parabiosis indicate that NSCs are also exposed to blood-borne factors, sensing and responding to the systemic circulation. Both structural and functional alterations occur in vasculature with age at the cellular level that can affect the proper extrinsic regulation of NSCs. Additionally, blood exchange experiments in heterochronic parabionts have revealed that age-associated changes in blood composition also contribute to adult neurogenesis impairment in the elderly. Although the mechanisms of vascular- or blood-derived signaling in aging are still not fully understood, a general feature of organismal aging is the accumulation of senescent cells, which act as sources of inflammatory and other detrimental signals that can negatively impact on neighboring cells. This review focuses on the interactions between vascular senescence, circulating pro-senescence factors and the decrease in NSC potential during aging. Understanding the mechanisms of NSC dynamics in the aging brain could lead to new therapeutic approaches, potentially include senolysis, to target age-dependent brain decline.

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The aged hematopoietic system promotes hippocampal‐dependent cognitive decline

Abstract: Exposure to the aging systemic milieu, through models such as heterochronic parabiosis, promotes cellular, molecular, and structural changes in the brain that lead to cognitive decline (Katsimpardi

Cited by 17 publications

References 29 publications

Friends and foes: Extracellular vesicles in aging and rejuvenation

Friends and foes: Extracellular vesicles in aging and rejuvenation

Molecular hallmarks of heterochronic parabiosis at single cell resolution

Vascular Senescence: A Potential Bridge Between Physiological Aging and Neurogenic Decline

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