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Aging leads to dysfunctional innate immune responses to TLR2 and TLR4 agonists.
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November 07 2018
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Source: Aging Clin Exp Res. 31(9):1185-1193
[PDF-1.29 MB]
Details:
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Alternative Title:Aging Clin Exp Res
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Personal Author:
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Description:Background:
Sepsis is more common in the elderly. TNFα is recognized as an important mediator in sepsis and Toll like receptors (TLRs) play an important role in initiating signaling cascades to produce TNFα. Little is known about how innate immunity is altered in healthy human aging that predisposes to sepsis.
Aims & Methods:
We tested the hypothesis that aging dysregulates the innate immune response to TLR 2 and 4 ligands. We performed whole blood assays on 554 healthy subjects aged 40–80 yrs. TNFα production was measured at baseline and after stimulation with the TLR2 agonists: peptidoglycan, lipoteichoic acid, Pam3CysK, Zymosan A and the TLR4 agonist lipopolysaccharide (LPS). In a subset of subjects (n=250), we measured Toll-like receptor (TLR) 2, 4 and MyD88 expression using real-time PCR.
Results & Discussion:
We measured a 2.5% increase per year in basal secretion of TNFα with aging (n=554 p=0.02). Likewise, TNFα secretion was increased with aging after stimulation with peptidoglycan (1.3% increase/yr; p=0.0005) and zymosan A (1.1% increase/yr p=0.03). We also examined the difference between baseline and stimulated TNFα for each individual. We found that the increases were driven by the elevated baseline levels. In fact, there was a diminished stimulated response to LPS (1.9% decrease/yr; p=0.05), Lipoteichoic acid (2.1% decrease/yr p=0.03), and Pam3CysK (2.6% decrease/yr p=0.0007). There were no differences in TLR or MyD88 mRNA expression with aging, however, there was an inverse relationship between TLR expression and stimulated TNFα production.
Conclusions:
With aging, circulating leukocytes produce high levels of TNFα at baseline and have inadequate responses to TLR2 and TLR4 agonists. These defects likely contribute to the increased susceptibility to sepsis in older adults.
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Source:
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Pubmed ID:30402800
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Pubmed Central ID:PMC6504629
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Document Type:
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Funding:R01 AG053553/NIA NIH HHS/National Institute on Aging/United States ; R01 OH008539/NIOSH CDC HHS/National Institute for Occupational Safety and Health/United States ; R01 OH008539/OH/NIOSH CDC HHS/United States ; R01OH008539/NIOSH CDC HHS/National Institute for Occupational Safety and Health/United States ; I01 CX000434/CSRD VA/Clinical Science Research & Development/United States ; ... More +
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Volume:31
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Issue:9
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