Abstract
Aging is associated with a progressive decline in immune function (immunosenescence) resulting in an increased susceptibility to viral and bacterial infections. Here we show reduced expression of Toll-like receptor 1 (TLR1) in polymorphonuclear leukocytes (PMN) and an underlying age-dependent deficiency in PMN bioenergetics. In older (>65 years) adults, stimulation through TLR1 led to lower activation of integrins (CD11b and CD18), lower production of the chemokine IL-8, and lower levels of the phosphorylated signaling intermediate p38 MAP kinase than in PMN from younger donors (21-30 years). In addition, loss of CD62L, a marker of PMN activation, was reduced in PMN of older adults stimulated through multiple pathways. Rescue of PMN from apoptosis by stimulation with TLR1 was reduced in PMN from older adults. In seeking an explanation for effects of aging across multiple pathways, we examined PMN energy utilization and found that glucose uptake after stimulation through TLR1 was dramatically lower in PMN of older adults. Our results demonstrate a reduction in TLR1 expression and TLR1-mediated responses in PMN with aging, and reduced efficiency of bioenergetics in PMN. These changes likely contribute to reduced PMN efficiency in aging through multiple aspects of PMN function and suggest potential therapeutic opportunities.
Highlights
Aging is associated with a progressive decline in immune function -- termed immunosenescence -- that results in an increased susceptibility to viral and bacterial infections and decreased response to vaccines [1]
Samples that could be assessed within 2 hr of the blood collection were used, and to reduce the time to measurement, the expression of Toll-like receptors (TLRs) on polymorphonuclear leukocytes (PMN) was assessed by flow cytometry using a whole blood assay
The aim of the present study was to investigate TLRs on PMN from older adults to determine expression levels and functional efficiency of receptors that are key to triggering antimicrobial host defense responses [13, 14]
Summary
Aging is associated with a progressive decline in immune function -- termed immunosenescence -- that results in an increased susceptibility to viral and bacterial infections and decreased response to vaccines [1]. Aging of the innate immune system is complex in spanning multiple cell types, activation states, and tissue context, and, while incompletely understood, it is characterized by dysregulation and inappropriate persistence of inflammatory responses [1]. Studies of the cellular mechanisms of aging broadly suggest roles for the accumulation of reactive oxygen species (ROS) leading to damage of biomolecules [3], an age-associated decrease of autophagy that reduces clearance of damaged mitochondria and cellular proteins [4], an NFκB-dependent inflammatory state in the hypothalamus leading to immune-neuroendocrine decline [5], and dysregulation of glucose metabolism that may underlie many aspects of senescence and aging-related diseases [6]. PMN are the first immune cells to migrate to pathogen-infected sites, and release potent reactive oxygen and nitrogen www.impactaging.com
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