To answer any questions on immunity and ageing, we clearly need to have a means to measure immunosenescence. At the moment, we only have rather unrefined biomarkers which we believe may reflect detrimental effects of age. Traditionally, cross-sectional studies in industrialized countries have almost unanimously documented lower numbers and/or proportions of peripheral blood naïve CD8+ T cells in the elderly, whereas age-effects on CD4+ T cells have been harder to pin down. Reciprocally, memory CD8 + T cells are more numerous in the elderly, again with lesser and more discordant effects reported for CD4 + T cells [
1‐
3]. It has been the assumption that the greater susceptibility of the elderly than the young to novel infections reflects this lesser availability of naïve cells poised to recognize new antigens. To the best of my knowledge, however, this assumption has never been experimentally tested in humans.
Based on a series of prospective cohort studies of the very elderly in Sweden, the concept of an “immune risk profile” (IRP), however, has gained traction over the past decade. The IRP was found to be present in around 15% of 85-year-olds in the OCTO/NONA studies at baseline [
4,
5]. Follow-up of 2-, 4- and 6-year mortality revealed significantly higher all-cause mortality in the IRP group than in the majority of very elderly. The IRP was characterized by a relative deficit in the numbers and proportions of B cells, and an accumulation of CD8+ memory T cells tipping the CD4:CD8 ratio to less than unity (in contrast to the majority of elderly where the CD4:CD8 ratio
increases rather than decreasing). This accumulation of late-stage differentiated cells (double-negative for the costimulatory receptors CD27 and CD28) was responsible for the poor T cell proliferative responses to mitogens which was characteristic of the cluster of parameters constituting the IRP, as the majority of these cells were later found also to express KLRG-1 and CD57 (ie., double-positive for negative regulatory coreceptors). This phenotype, or more commonly simply CD8 + CD28-negative, is often taken to mark senescent cells; I would argue strongly against this, although some of them might indeed be senescent. Caution would indicate designating them only as “late-stage differentiated”. It should be noted here that the numbers and proportions of CD8+ naïve cells were NOT part of the IRP, being greatly reduced in both groups. Additionally, neither naive or memory CD4+ T cells featured in these studies as informative for all-cause mortality [
4,
5].
The final parameter of the original IRP was, remarkably, Cytomegalovirus seropositivity. Although this persistent herpesvirus infected 85 % of the whole elderly population, every individual in the IRP group was a carrier. Thus, CMV-seropositivity was a part of the IRP; however, most CMV-infected people were nonetheless not in the IRP, already clearly indicating that CMV is a contributing but not controlling factor [
6‐
9]. Studies of 2-, 4- and 6-year survival in these cohorts also revealed a second set of parameters,
independent of the IRP, but at least additive with the IRP, which associated with mortality. These factors were higher levels of the pro-inflammatory cytokine IL 6, associated with frailty and mortality in countless studies, together with measures of cognitive impairment. Because some of the literature refers to the “IRP” as also including IL 6, I stress here that the only studies documenting the original IRP did NOT include IL 6. Thus survival of people with lower IL 6 and not in the IRP was better than those with the IRP alone, or high IL 6 alone, and much better than people in the IRP who also had high IL 6 [
4,
5]. The literature also includes many papers referring to the presence or absence of the IRP in different populations and situations. Again, I emphasize that the only studies showing the IRP to be informative for mortality are the Swedish OCTO/NONA studies. Whether this is also true of other populations has not been tested. Moreover, we do not know at which calendar age the IRP may become predictive of mortality; very preliminary data suggests possibly 60 years of age [
10]. At much older ages, the IRP is again not predictive, in that no subjects surviving long enough are found to be in the IRP category, presumably due to selection of those who were [
11]. Consistent with this, we have recently completed a small-scale study of subjects in the Leiden 85-Plus study, which as the name suggests also started from a baseline of 85 [
12]. Here, we analyzed subjects at the age of 89 and found that only one was in the IRP. Thus, in the highly selected very elderly population, one would not necessarily expect to find anyone still in the risk group. Fascinatingly, in the Leiden 85-Plus study, we found that a
lower proportion of naïve CD8+ T cells and a
higher proportion of some CD8+ memory cell phenotypes was associated with longer survival on 8-year follow-up [
12]. Clearly, greater naïve cell capacity under these conditions was not associated with favourable outcome. We interpret these data to suggest that in a very elderly population presumably not exposed to many new pathogens, it is more important to maintain good memory responses rather than use reserves to meet new challenges that may never come. The finding that longer survival was also associated with in unopposed pro-inflammatory responsiveness to CMV antigens in vitro [
12] underlines the nature of the memory responses that we propose are essential to maintain in old age. Thus, these considerations emphasize that immune parameters associated with survival maybe very different in different populations at different ages. This makes it unlikely that general “one size fits all” biomarkers of immune ageing (or any other parameter for that matter) will be identified. A consensus view would be that low naïve cells, high memory cells and high pro-inflammatory states would mitigate against survival. However, it is clear that in certain cases, such as the example of the Leiden 85-Plus described above, the exact opposite seems to be true. Other exceptional populations, such as centenarians, may also need to be considered separately [
13‐
15].