Daan Pieren

178 Chapter 6 aged and Ercc1 -/ Δ 7 mice was partially dependent of mTOR activation. Treating Ercc1 -/ Δ 7 mice with rapamycin increased and/or preserved the proportion of naive T cells. Higher frequencies of naive T cells may lead to better memory T-cell mediated protection, as observed previously in rapamycin intervention studies [92,93]. The relatively minor effect of rapamycin treatment we observed on age-related T-cell changes does not necessarily imply that treatment with rapamycin is ineffective. One of the limitations of our study is that we used one dose of rapamycin, whereas it has been shown in lifespan studies that different doses of rapamycin lead to differing lifespan in WT mice [87,94]. This may indicate that different doses of rapamycin may affect T cells differently. Moreover, the lifespan of Ercc1 -/ Δ 7 mice is short compared to the lifespan of wild type mice. Therefore, the duration of rapamycin treatment in Ercc1 -/ Δ 7 mice was relatively short compared to other studies in wild type mice, which may have a different impact on T cells. The dose and duration of rapamycin that is administered and its effect on T cells therefore warrants future immune studies. Preventing intracellular DNA damage or results thereof over the course of life may help to improve immune protection at old age. THE SENSE IN BECOMING SENESCENT OR EXHAUSTED The general term ‘immunosenescence’ comprises all age-related changes that occur to the immune system, including those that occur in the T-cell population. Two hallmarks of immunosenescence that occur to T cells during aging are T-cell senescence and T-cell exhaustion. These terms are partly overlapping, as they both mark T cells with impaired functionality, such as reduced proliferative capacity. However, senescent T cells are mostly viewed as cells that express senescence-associated markers CD57, KLRG1, and γ H2AX (indicating DNA damage), whereas exhausted T cells have been characterized as T cells that constitutively express co-inhibitory receptors. The increase in senescent and exhausted T cells is a major topic in the field of immune aging. It is generally accepted that increased presence of senescent and exhausted T cells promotes viral persistence, susceptibility to infectious disease, and more severe disease following infection at older age. However, a final important factor to address is whether sustained expression of co-inhibitory markers by T cells could be beneficial to the host, within and outside the field of infectious diseases. What is the purpose of expression of these markers? And is it wise to interfere with these co-inhibitory markers to elicit stronger responses against vaccines and infectious diseases?