Abstract
BackgroundDetermining the prerequisites for healthy aging is a major task in the modern world characterized by a longer lifespan of the individuals. Besides lifestyle and environmental influences genetic factors are involved as shown by several genome-wide association studies. Older individuals are known to have an impaired immune response, a condition recently termed “inflamm-aging”. We hypothesize that the induction of this condition in the elderly is influenced by the sensitivity of the innate immune system. Therefore, we investigated genetic variants of the Toll-like receptor (TLR) family, one of the major family of innate immune receptors, for association with age in two cohorts of healthy, disease-free subjects.ResultsAccording to sex we found a positive association of loss-of-function variants of TLR-1 and −6 with healthy aging with odds ratios of 1.54 in males for TLR-6 (249 S/S), and 1.41, 1.66, and 1.64 in females for TLR-1 prom., TLR-1 (248 S/S), and TLR-1 (602 S/S), respectively. Thus, the presence of these variants increases the probability of achieving healthy old age and indicates that a reduced TLR activity may be beneficial in the elderly.ConclusionsThis is the first report showing an association of TLR variants with age. While a loss of function of an important immune receptor may be a risk factor for acute infections as has been shown previously, in the setting of healthy ageing it appears to be protective, which may relate to “inflamm-aging”. These first results should be reproduced in larger trials to confirm this hypothesis.
Highlights
Determining the prerequisites for healthy aging is a major task in the modern world characterized by a longer lifespan of the individuals
Age-associated dysfunctions of human Toll-like receptor (TLR) have been described before: An age dependent decrease in TLR-1/2 heterodimer function determined by a lessened TNF-α- and IL-6-release upon stimulation as well as an overall decrease in cellular TLR-1 expression have been described for monocytes of the elderly [6]
We have recently shown that loss of function genotypes of TLR-1 (I602S) and TLR-6 (P249S) are protective in chronic inflammatory disease such as gastric cancer and atherosclerosis [17, 18]
Summary
Determining the prerequisites for healthy aging is a major task in the modern world characterized by a longer lifespan of the individuals. We investigated genetic variants of the Toll-like receptor (TLR) family, one of the major family of innate immune receptors, for association with age in two cohorts of healthy, disease-free subjects. The mechanism for a decreased immune response in the elderly is complex and affects the innate as well as the adaptive immune system. Decreased diversity of the antigen repertoire resulting in diminished T- and B-cell responses, and accumulation of functionally impaired memory lymphocytes i.e. have been described to impair the adaptive immunity of the elderly [1]. Functions of cells of the innate immune system may be affected in older age: Key functions of neutrophils, macrophages, dendritic cells, and NK cells, e.g. chemotaxis, phagocytosis, migration, and cytotoxicity are known to be reduced in the elderly [3, 4].
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