Normal ageing is accompanied by increased organismal frailty, reflecting organ specific functional decline, with an associated increase in the likelihood of disease. The immune system undergoes significant decline with age, termed immunesenescence, which results in increased susceptibility to infection and reduced vaccination responses. Significant changes in the hormonal milieu also occur with age and it is clear that age-related changes in adrenal hormone secretion can impose a significant environmental effect on tissues in the ageing body, including the immune system. In humans the adrenopause results in a decline in the production of DHEA and DHEAS with age, while the production of cortisol is unaffected. Ageing is therefore accompanied by an increase in the cortisol:DHEAS ratio.
The immune suppressive effect of cortisol is well established, but evidence is now increasing for an immune enhancing role for dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulphate (DHEAS). We have reported recently that DHEAS is able to enhance the response of neutrophils to bacterial fMLP, significantly increasing superoxide generation. Moreover we showed that neutrophils were unique amongst leukocytes in expressing a transporter for sulphate steroids such as DHEAS and that the effect on neutrophil superoxide generation was mediated via direct activation of protein kinase C. As neutrophils are the dominant leukocyte in the circulation and are the first defence against rapidly dividing bacteria, DHEAS may represent a significant neutrophil priming agent able to overcome the suppressive effects of cortisol.
Our previous data has also shown that at times of stress (both emotional and physical) in the older adult the cortisol:DHEAS ratio is further increased and is associated with suppression of neutrophil function and increased risk of infection. We therefore propose that the age-related changes in the HPA axis contribute to immunesenescence and that this effect is enhanced at times of stress in old age.