Dysregulation of human Toll-like receptor function in aging
Research highlights
► Dysregulation of Toll-like receptor function occurs in aging humans. ► Adjustment for potential confounding factors is critical in human aging studies. ► Both impaired and inappropriate persistence of TLR function occur in aging humans. ► Transcriptional and post-transcriptional mechanisms contribute to TLR dysregulation.
Introduction
Interest in understanding the effects of aging on host defense against infection is driven in part by the realities of current and future demographic trends. In particular, next year represents a watershed moment in the demographics of the United States: in 2011, the first members of the post-World War II baby boom generation (extending from 1946 to 1965) will turn 65. The number of individuals over age 65 estimated to grow to over 72 million by 2030—19% of the population and more than double the number in 2005 (Population Division, US Census Bureau, 2008). This “Gray Tsunami” lends particular urgency to understanding mechanisms associated with aging that may affect the health of older individuals. Although individuals over age 65 currently comprise approximately 12% of the population, they account for over 35% of visits to general internists, 34% of prescription drug use, 50% of hospital stays, and 90% of nursing home residents (Cherry et al., 2007).
It has long been evident that older individuals are at increased risk for morbidity and mortality from infectious diseases (Yoshikawa, 1997). While it is likely that comorbid conditions contribute to the observed increase in mortality (e.g. relative tissue ischemia from vascular disease exacerbating intestinal tract inflammatory disorders), it is clear that impaired host defenses associated with aging also contribute to increased morbidity and mortality. Substantial progress has been made in understanding of the consequences of aging on adaptive immunity (reviewed elsewhere in this issue); by contrast, the effects of aging on the innate immune system remain incompletely understood (Kovacs et al., 2009, Panda et al., 2009). However, recent studies indicate that aging influences the function of pattern recognition receptors mediating innate immunity. Here we review the progress made in our understanding of age-associated alterations in Toll-like receptors (TLR) expression and function, focusing on reports in humans.
Section snippets
Overview of Toll-like receptors, pattern recognition receptors of the innate immune system
Innate immunity is mediated by a network of cell types, including monocytes/macrophages, natural killer (NK) and natural killer T (NKT) cells, dendritic cells, eosinophils and basophils. Activation of the innate immune system in general results in diverse cellular processes including phagocytosis and the elaboration of mediators such as reactive oxygen and nitrogen species, defensins, complement, and pro-inflammatory cytokines and chemokines that mediate the initial host response to pathogens.
Earlier studies focusing on LPS stimulation of PBMCs
A number of studies initially evaluated the effects of aging on LPS-mediated cytokine responses by human monocytes. Some of those studies were conducted even before TLR4 was characterized as a component of the LPS receptor (van Duin and Shaw, 2007). These studies are in general conflicting, as some studies show an age-related increase in LPS-induced cytokine secretion (Clark and Peterson, 1994), while others show unchanged or decreased secretion (Delpedro et al., 1998, Gon et al., 1996, Mariani
Potential mechanisms underlying age-associated TLR dysfunction
As discussed above, recent studies have implicated specific signaling pathways in alterations in TLR function in the context of human aging. These include decreased PI3-kinase activity in MDDCs (associated with increased PTEN phosphorylation) (Agrawal et al., 2007) and an impairment in downregulation of STAT1 phosphorylation in macrophages (Kong et al., 2008). Both of these events result in increased TLR-dependent cytokine production in aging, and while the basis for these alterations in
TLR polymorphisms in aging
Responses to TLR ligands may also be influenced by single nucleotide polymorphisms (SNPs) within TLR genes, though the impact of such SNPs in the context of aging remains unclear. While it is likely that TLR SNPs favoring survival and fitness for reproduction may be subject to evolutionary selection in young individuals, SNPs in older individuals are less likely to undergo such selective pressure. Thus, a SNP resulting in, for example, enhanced function of a TLR and improved host innate immune
TLR agonists and antagonists
Alterations in TLR function in older adults are particularly relevant in view of the increased development and use of TLR agonists and antagonists as pharmacological agents (reviewed in Hennessy et al., 2010). Because at present there is little information on the efficacy of such agents in the context of aged individuals, we will provide a selective overview focused on conditions of potential relevance to human aging. In this regard, several TLR agonists are being used as vaccine
Acknowledgments
Work by the authors was supported in part by the NIH (N01-AI-50031 and U19-AI-089992). S.R.J. was supported by NIH T32AG1934. A.P. is a Brookdale Leadership in Aging Fellow.
References (87)
- et al.
A universal epitope-based influenza vaccine and its efficacy against H5N1
Vaccine
(2009) Toll signaling pathways in the innate immune response
Curr. Opin. Immunol.
(2000)- et al.
Response to systemic endotoxemia among humans bearing polymorphisms of the Toll-like receptor 4 (hTLR4)
Clin. Immunol.
(2006) - et al.
Vaccination in the elderly: an immunological perspective
Trends Immunol.
(2009) - et al.
Cytokine production and aging: overproduction of IL-8 in elderly males in response to lipopolysaccharide
Mech. Ageing Dev.
(1994) - et al.
Peripheral blood dendritic cells and monocytes are differently regulated in the elderly
Clin. Immunol.
(2007) - et al.
Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans
Mech. Ageing Dev.
(2007) - et al.
Overproduction of monokines by leukocytes after stimulation with lipopolysaccharide in the elderly
Exp. Gerontol.
(2002) - et al.
Inflammatory processes in Alzheimer's disease
J. Neuroimmunol.
(2007) - et al.
Potent immunogenicity and efficacy of a universal influenza vaccine candidate comprising a recombinant fusion protein linking influenza M2e to the TLR5 ligand flagellin
Vaccine
(2008)