Systematic expression profiling of innate immune genes defines a complex pattern of immunosenescence in peripheral and intestinal leukocytes

Abstract

Immunosenescence is characterized by a quantitative decline of adequate immune responses, which renders the elderly individual particularly susceptible to bacterial, viral and fungal pathogens. Whereas changes of the aging adaptive immune system (for example, reduced immunoglobulin secretion) have been extensively characterized, alterations of the innate immune system are still poorly understood. The aim of the present study was to systematically examine mRNA expression levels of innate immune genes and proinflammatory cytokines in peripheral and intestinal leukocytes of subjects of different ages. In both, whole blood samples and in colonic biopsies most of the Toll-like receptors (TLRs) and nucleotide-binding and oligomerization domain-like receptors (NLRs) transcript levels were significantly downregulated in elderly subjects (90-99 years). Older individuals, when compared to the younger, exhibited an increased expression and/or secretion of proinflammatory cytokines by peripheral and intestinal leukocytes as well as an increased level of nuclear factor-kB activation in colonic biopsies. The observed downregulation of TLRs and NLRs during the aging process may contribute to the lack of effective recognition of invading pathogens or the commensal flora. This effect results in aberrant secondary immune cell activation and could significantly contribute to morbidity and mortality at advanced age.

Genome‐wide miRNA signatures of human longevity

“…Possible explanations for the discrepant findings in our study and that of Noren Hooten et al (2010) may be differences in sample sizes (102 vs. four individuals), ages of the participants (maximum age 105 vs. 64.5 years), phenotypes (healthy aging vs. normal aging), and in the examined tissues (whole blood vs. blood mononuclear cells). Despite its heterogeneity of cell types, whole blood has been shown to be a suitable tissue for reliably monitoring expression changes related to human aging and diseases (McLoughlin et al, 2006;Rosenstiel et al, 2008;Keller et al, 2011). Nevertheless, given the changes in peripheral blood with the aging processes (Paganelli et al, 1992;Pawelec et al, 1997), we cannot rule out the possibility that the observed differential miRNA expression in LLI may also partially reflect alterations in their cell type composition.…”

Cellular senescence: A link between cancer and age-related degenerative disease?

“…Why this is so is not clear. One possibility is that the aging immune system, which shows both decrements and derangements in function [52, 53], becomes less capable of clearing senescent cells. In addition, the production of senescent cells may increase with age owing to an age-dependent acceleration of tissue damage – for example, increasing oxidative stress due to progressively more damaged and hence less functional mitochondria [54].…”

Age‐associated elevation in TLR5 leads to increased inflammatory responses in the elderly

“…The adaptive immune system is affected by aging, with a well-documented dysregulation in humoral as well as cell-mediated immune responses (McGlauchlen & Vogel, 2003; Linton & Dorshkind, 2004). Recent studies have begun to document the impact of aging on the innate immune system, but age-related deficits, especially in human subjects, remain incompletely defined (Rosenstiel et al , 2008; Shaw et al , 2010). …”