Introduction

Abstract

Survival for our hunterer-gatherer ancestors was a case of making sure you ate the lion before it ate you, that you could last for days between meals and that you could overcome a variety of enteric pathogens associated with lack of sanitation and consuming raw lion as a staple diet. Planning for old age really was not a primary concern and as a result we have been selected for a genotype that favours a rapid flight or fight response, a thrifty metabolism and a potent inflammatory response to infection. This genetic profile may well have suited life on the African plains, but has far-reaching consequences for healthy aging of humans in a world of plentiful food supplies, clean water and lions encountered only in safari parks. In this special issue of Aging Cell we focus upon the impact of a lifespan of more than three score years and 10 on innate immunity. The innate immune response is our first and most primitive defence against infection and as such will react rapidly to the threat from invading pathogens, both viral and microbial. The response consists of cellular and humoral elements and although early reports suggested that this aspect of immunity remained intact during aging, more recent comprehensive analyses have revealed subtle age-related alterations. These changes challenge the efficiency of the innate immune system and result in a baseline pro-inflammatory status, first proposed by Franceschi as ‘inflamm-aging’. The macrophage lineage is a major contributor to the pro-inflammatory cytokine milieu and the inflammatory basis of many age-related diseases is now becoming clear, including cardiovascular disease and Alzheimer's disease. In addition, the contribution of infection-related morbidity to the poor quality of life of the elderly is now abundantly clear and is likely to reflect a decline in innate immune status. The time is ripe therefore for a consideration of the current understanding of the modulation of innate immune responses as humans enter ‘the third age’, as well as for the identification of possible strategies to minimize the impact of an aging innate immune response. We have included here consideration of the role of microglial cells (brain-based macrophages) in neurodegeneration as well as the effect of aging on the response of macrophages to pathogens. Neutrophil bacteriocidal function has been considered from the viewpoint of a decline with aging, the negative impact of stress hormones and of functional senescence that develops through the short life of the neutrophil. Finally, compromised antiviral responses are discussed with respect to changes in NK and NK–T-cell function with age. The hope is that gerontologists will now recognize a modified innate immune response as a significant consequence of aging in humans that may be susceptible to prophylactic measures. Moreover, we hope to make clear that these changes make as important a contribution to age-related morbidity as the very well-documented changes in the adaptive immune system. J. M. Lord – Special Guest Editor Department of Immunology, Birmingham University Medical School, Birmingham B15 2TT, UK. Tel.: +44 121 414 4399 Fax: +44 121 414 3599 E-mail: J.M.Lord@bham.ac.uk