β2-microglobulin is a systemic pro-aging factor that impairs cognitive function and neurogenesis

Smith, Lucas K.; He, Yingbo; Park, Jeong‐Soo; Bieri, Gregor; Snethlage, Cedric E; Lin, Karin; Gontier, Géraldine; Wabl, Rafael; Plambeck, Kristopher E; Udeochu, Joe C.; Wheatley, Elizabeth; Bouchard, Jill; Eggel, Alexander; Narasimha, R.; Grant, Jacqueline L; Luo, Jian; Wyss‐Coray, Tony; Villeda, Saul

doi:10.1038/nm.3898

Cited by 407 publications

(391 citation statements)

References 41 publications

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“…Conversely, factors in old blood can drive aging of certain cell types and tissues in young mice. These blood-borne pro-geronic factors include the chemokine CCL-11 (24) and β-2 microglobulin (25). In addition to these identified geronic factors, it is likely there are other circulating factors that also play key, cell nonautonomous roles in aging.…”

Section: Autonomous and Non-autonomous Mechanisms Of Agingmentioning

confidence: 99%

Extracellular vesicles and aging

Robbins¹

2017

Stem Cell Investig.

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AgingIt is estimated that in the next 20 years, the number of individuals in the United States over the age of 65 will double, numbering more than 70 million individuals. Unfortunately, as we age there is an unavoidable and progressive loss of the ability to maintain tissue homeostasis under stress and an attrition of functional reserve. As a consequence, the incidence of numerous debilitating diseases increases nearly exponentially with age, including cardiovascular disease, neurodegeneration, diabetes, osteoarthritis, and osteoporosis. Over 90% of individuals >65 years of age have at least one chronic disease, while >70% have at least two. These chronic diseases account for 75% of our healthcare costs, amounting to approximately $3 trillion in costs last year alone. Indeed, chronic diseases of the elderly are the greatest healthcare burden in the United States and seriously impact the quality of life of a large segment of the population. Thus, there is a significant need to understand mechanisms driving aging and to develop novel therapeutics. Given the diverse roles of blood-borne EVs in modulating not only the immune response, but also angiogenesis and tissue regeneration, they likely play a key role in modulating the aging process. This review focuses on the role EVs could play in aging, their therapeutic application for extending healthspan and their potential for use as biomarkers of unhealthy aging. Abstract: Aging and the chronic diseases associated with aging place a tremendous burden on our healthcare system. As our world population ages dramatically over the next decades, this will only increase.Hence, there is a great need to discover fundamental mechanisms of aging to enable development of strategies for minimizing the impact of aging on our health and economy. There is general agreement that cell autonomous mechanisms contribute to aging. As cells accrue damage over time, they respond to it by triggering individual cell fate decisions that ultimately disrupt tissue homeostasis and thus increase risk of morbidity. However, there are numerous lines of evidence, including heterochronic parabiosis and plasma transfer, indicating that cell non-autonomous mechanisms are critically important for aging as well. In addition, senescent cells, which accumulate in tissues with age, can display a senescence-associated secretory phenotype (SASP) that contributes to driving aging and loss of tissue homeostasis through a non-cell autonomous mechanism(s). Given the diverse roles of blood-borne extracellular vesicles (EVs) in modulating not only the immune response, but also angiogenesis and tissue regeneration, they likely play a key role in modulating the aging process through cell non-autonomous mechanisms. The fact that senescent cells release more EVs and with a different composition suggests they contribute to the adverse effects of senescence on aging. In addition, the ability of EVs from functional progenitor cells to promote tissue regeneration suggests that stem cell-derived EVs could be used therapeutica...

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Section: Autonomous and Non-autonomous Mechanisms Of Agingmentioning

confidence: 99%

Extracellular vesicles and aging

Robbins¹

2017

Stem Cell Investig.

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“…Blau's laboratory has developed a transient modified mRNA approach to deliver TERT for only 48 h, which overcomes problems associated with constitutive retroviral delivery, and leads to a marked increase in telomere length and rescue of cell proliferative defects (Ramunas et al, 2015). Finally, Saul Villeda (UCSF, USA), who explores the mechanisms of brain ageing, used mouse parabiosis experiments to show that β2-microglobulin (B2M) is a brain ageing factor, the action of which is mediated by the MHC (Smith et al, 2015). Indeed, mice missing the H2-D b and H2-H b MHC alleles perform better in hippocampus-mediated spatial tasks, and decreasing B2M levels improves cognition in ageing mice.…”

Section: Senescence Regeneration and Ageingmentioning

confidence: 99%

Trends in tissue repair and regeneration

et al. 2017

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The 6th EMBO conference on the Molecular and Cellular Basis of Regeneration and Tissue Repair took place in Paestum (Italy) on the 17th-21st September, 2016. The 160 scientists who attended discussed the importance of cellular and tissue plasticity, biophysical aspects of regeneration, the diverse roles of injury-induced immune responses, strategies to reactivate regeneration in mammals, links between regeneration and ageing, and the impact of non-mammalian models on regenerative medicine.

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“…This is where heterochronic parabiosis, the surgical union between an adult and an old organism, can be used as a powerful platform to both isolate individual pro-and anti-geronic factors and to understand the complexity of ageing. The anti-geronic effects of heterochronic parabiosis have been demonstrated thoroughly in skeletal muscle [7], central nervous system [8][9][10][11], pancreatic b cell proliferation [12], cardiac tissue [13], bone repair [14] and systemic cholesterol turnover [15]. In some cases, single molecules or pathways were identified as playing a significant pro-or anti-geronic role in the aetiology of ageing in the reported tissue.…”

Section: Heterochronic Parabiosis As Means To Study Ageing and (Immunmentioning

confidence: 99%

“…in the case of impaired Schwann cell function [17], impaired T cell subset distribution [18], function [19] and thymic involution [18,20], and in the first two examples pro-geronic effects were noted in the adult animal. Regarding individual pro-geronic molecules, increased levels of CCL11 and b2m with age are associated with decreased brain functions [8,11] and increased b-catenin signalling was implicated in defects in bone repair [14].…”

Section: Heterochronic Parabiosis As Means To Study Ageing and (Immunmentioning

confidence: 99%

Homeostatic migration and distribution of innate immune cells in primary and secondary lymphoid organs with ageing

Nikolich‐Žugich

Davies

2017

Clinical and Experimental Immunology

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SummaryAgeing of the innate and adaptive immune system, collectively termed immune senescence, is a complex process. One method to understand the components of ageing involves dissociating the effects of ageing on the cells of the immune system, on the microenvironment in lymphoid organs and tissues where immune cells reside and on the circulating factors that interact with both immune cells and their microenvironment. Heterochronic parabiosis, a surgical union of two organisms of disparate ages, is ideal for this type of study, as it has the power to dissociate the age of the cell and the age of the microenvironment into which the cell resides or is migrating. So far, however, it has been used sparingly to study immune ageing. Here we review the limited literature on homeostatic innate immune cell trafficking in ageing in the absence of chronic inflammation. We also review our own recent data on trafficking of innate immune subsets between primary and secondary lymphoid organs in heterochronic parabiosis. We found no systemic bias in retention or acceptance of neutrophils, macrophages, dendritic cells or natural killer cells with ageing in primary and secondary lymphoid organs. We conclude that these four innate immune cell types migrate to and populate lymphoid organs (peripheral lymph nodes, spleen and bone marrow), regardless of their own age and of the age of lymphoid organs.

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β2-microglobulin is a systemic pro-aging factor that impairs cognitive function and neurogenesis

Cited by 407 publications

References 41 publications

Extracellular vesicles and aging

Extracellular vesicles and aging

Trends in tissue repair and regeneration

Homeostatic migration and distribution of innate immune cells in primary and secondary lymphoid organs with ageing

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