Senescence and the Aging Immune System as Major Drivers of Chronic Kidney Disease

Schroth, Johannes; Thiemermann, Christoph; Henson, Sian M.

doi:10.3389/fcell.2020.564461

Cited by 40 publications

(41 citation statements)

References 105 publications

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“…Furthermore, the SASP is not only a product of senescent cells, it also induces and reinforces senescence itself through paracrine and autocrine signaling mechanisms 34,95,96 . In light of this, it is thought that age-associated losses in immune competency in a chronically inflamed milieu may allow senescent cells to evade removal [97][98][99] , although this is not fully understood. Additionally, SASP signals confer senescent cells with resistance to immune-mediated clearance (for example, through upregulation of ligands such as HLA-E, which can inhibit CD8 + T cell and natural killer cell function 100 ).…”

Section: The Saspmentioning

confidence: 99%

Strategies for targeting senescent cells in human disease

et al. 2021

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Section: The Saspmentioning

confidence: 99%

Strategies for targeting senescent cells in human disease

et al. 2021

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“…130,142 Although exercise is one of most effective anti-frailty interventions, other therapeutic targets for frailty are being actively investigated (Figure 3). Given the senescent cell burden in CKD, 143,144 use of senolytics, drugs that selectively induce senescent cell removal, hold promise. Preclinical studies applying senolytics in mice both prevented and reduced physical dysfunction.…”

Section: J O U R N a L P R E -P R O O Fmentioning

confidence: 99%

Frailty in CKD and Transplantation

Lorenz

Kennedy

Rule

et al. 2021

Kidney International Reports

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“…Moreover, a low-grade inflammatory milieu is known to be present in the aged tissues, a condition named “inflammaging” ( Greene and Loeser, 2015 ; Rea et al, 2018 ). “Immunosenescence” is a related concept, in which the dysfunctional immune response in the elderly presents characteristics related to cellular senescence and promotes inflammation, thus playing a crucial role in inflammaging ( Sato and Yanagita, 2019 ; Schroth et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Acute Kidney Injury is Aggravated in Aged Mice by the Exacerbation of Proinflammatory Processes

et al. 2021

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Acute kidney injury (AKI) is more frequent in elderly patients. Mechanisms contributing to AKI (tubular cell death, inflammatory cell infiltration, impaired mitochondrial function, and prolonged cell-cycle arrest) have been linked to cellular senescence, a process implicated in regeneration failure and progression to fibrosis. However, the molecular and pathological basis of the age-related increase in AKI incidence is not completely understood. To explore these mechanisms, experimental AKI was induced by folic acid (FA) administration in young (3-months-old) and old (1-year-old) mice, and kidneys were evaluated in the early phase of AKI, at 48 h. Tubular damage score, KIM-1 expression, the recruitment of infiltrating immune cells (mainly neutrophils and macrophages) and proinflammatory gene expression were higher in AKI kidneys of old than of young mice. Tubular cell death in FA-AKI involves several pathways, such as regulated necrosis and apoptosis. Ferroptosis and necroptosis cell-death pathways were upregulated in old AKI kidneys. In contrast, caspase-3 activation was only found in young but not in old mice. Moreover, the antiapoptotic factor BCL-xL was significantly overexpressed in old, injured kidneys, suggesting an age-related apoptosis suppression. AKI kidneys displayed evidence of cellular senescence, such as increased levels of cyclin dependent kinase inhibitors p16ink4a and p21cip1, and of the DNA damage response marker γH2AX. Furthermore, p21cip1 mRNA expression and nuclear staining for p21cip1 and γH2AX were higher in old than in young FA-AKI mice, as well as the expression of senescence-associated secretory phenotype (SASP) components (Il-6, Tgfb1, Ctgf, and Serpine1). Interestingly, some infiltrating immune cells were p21 or γH2AX positive, suggesting that molecular senescence in the immune cells (“immunosenescence”) are involved in the increased severity of AKI in old mice. In contrast, expression of renal protective factors was dramatically downregulated in old AKI mice, including the antiaging factor Klotho and the mitochondrial biogenesis driver PGC-1α. In conclusion, aging resulted in more severe AKI after the exposure to toxic compounds. This increased toxicity may be related to magnification of proinflammatory-related pathways in older mice, including a switch to a proinflammatory cell death (necroptosis) instead of apoptosis, and overactivation of cellular senescence of resident renal cells and infiltrating inflammatory cells.

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Senescence and the Aging Immune System as Major Drivers of Chronic Kidney Disease

Cited by 40 publications

References 105 publications

Strategies for targeting senescent cells in human disease

Strategies for targeting senescent cells in human disease

Frailty in CKD and Transplantation

Acute Kidney Injury is Aggravated in Aged Mice by the Exacerbation of Proinflammatory Processes

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