In this study we have shown that in an adult Dutch population that lived under affluent conditions for their entire life, there is a gradual decline in the production of ex vivo LPS-induced anti-inflammatory IL-10 as well as pro-inflammatory TNF response with increasing age. A similar decline in IL-10 production was observed in the Ghanaian adults that have experienced a lifelong exposure to infectious pathogens. In contrast TNF responses to LPS remained unchanged and in response to co-stimulation with LPS and zymosan TNF production even significantly increased with age among Ghanaians.
There are several possible explanations for these data, as an age-related decline in the cytokine production capacity of the innate immune system may be intrinsically regulated, environmentally driven or be a result of selective survival. First, we believe that in the Dutch study population that lives in an affluent environment with low infectious exposure and where mortality rates up to the age of 80 years are low, intrinsic age-related effects play a pivotal role and explain the age-related decline in cytokine production. This includes an age-related lower expression of Toll-like receptors  and impaired function of all cells of the innate immune system [17–19] that together results in a lower production capacity of cytokines. We propose that the same intrinsic mechanism of senescence of the innate immune system would act in the Ghanaian population.
Second, it is possible that in the Ghanaian population continuous pathogen exposure accelerates ageing of the innate immune system. Although this hypothesis is yet to be proven, there are several indications that chronic infections can modulate innate immune function, including findings that chronic helminthic infections reduce TLR2 expression and our own observations that LPS-induced TNF and IL-10 responses were significantly enhanced in the Ghanaian compared to Dutch study populations. Interestingly, in patients with chronic Hepatitis C Virus (HCV) infections, the over-production of pro-inflammatory cytokines, in particular TNF has been shown to be likely due to a loss of TLR tolerance, a protective mechanism usually in place to limit inflammation. In mice it has been shown that with age this tolerance process is attenuated. Considering that TNF responses remained unchanged or increased with age in the Ghanaian population, we propose that if anything, our data do not support the hypothesis that a lifelong exposure to infections accelerates the age-related decline in innate immune responses, but on the contrary may drive pro-inflammatory responses.
Third, the age-related changes in cytokine production observed in the Ghanaian population may reflect the selective survival of individuals with immune responses that promote survival in adverse environmental conditions [21, 2, 22]. Previously, we have hypothesized that under adverse conditions people with enhanced pro-inflammatory immune responses may have greater survival potential than those with stronger anti-inflammatory responses . This may explain why IL-10 but not TNF responses decline with age in Ghana.
Inflammation has been suggested to be one of the mechanisms underlying pathogenesis of several age-associated diseases such as cardiovascular disease . Considering the emerging epidemic of chronic diseases in low-income countries , we therefore propose that this could well be explained by the here observed increase in pro-inflammatory versus decrease in anti-inflammatory responses in older age groups resulting from overstimulation or selective survival for this pro-inflammatory response pattern.
To our knowledge this is the first study looking at age-related changes in innate immune responses in populations aging under very diverse environmental conditions. A drawback of this study is that for the Dutch study population we did not have data in response to TLR ligands other than LPS. However, given the same patterns to different ligands in Ghana, we would expect no remarkable differences. In further research it should be tested whether the same trends will be observed in the Dutch population. Also age ranges were not completely alike including participants with a larger age-range in the Ghana population than in the Dutch cohort. Also there might be some uncertainty concerning the age of the participants in the highest age-category in the Ghanaian population, as these were perceived ages estimated based on face-value, life-history and mobility. We therefore grouped them as 60 plus. In addition, due to the cross-sectional nature of the study, we can not draw any final conclusions whether age-related changes in cytokine production is indeed an intrinsic phenomenon occurring over age, a result of selective survival and/or pathogen exposure.
In conclusion, in this study we demonstrated for the first time that in both in affluent and adverse environmental conditions there is an age-related decline in the IL-10 production capacity of the innate immune system. For TNF production, a similar decline was observed under affluent environmental conditions, but not under adverse environmental conditions. Lower production of cytokines seems an intrinsic phenomenon of the ageing process whereas chronic infections and/or selective survival may drive cytokine production towards pro-inflammatory responsiveness.