The immune system is inconveniently complicated. Aging is also inconveniently complicated. The overlap between the two is a particularly dark forest for the research community, with few well-tracked paths. The fine details of how exactly the immune system becomes dysfunctional with age, and the sizable variation in those details between individuals, will keep research teams occupied for decades to come. It seems very plausible that here, as elsewhere in the study of aging, effective rejuvenation therapies that turn back immune aging will precede a strong understanding of how they produce benefits.

For example, it is fairly clear that here are harmful populations of immune cells, and that selectively destroying them produces benefits in old individuals. Age-associated B cells accumulate over time to cause numerous issues. When the B cell population is entirely destroyed it is rapidly replaced, even in late life, with new cells that lack the harmful behaviors of their predecessors. Similarly, it is fairly clear that having too few naive T cells capable of tackling new threats is damaging to health. The supply and reserve of such cells diminish with age due to atrophy of the thymus and incapacity of hematopoietic stem cell populations. Restoring the thymus or hematopoietic activity has been shown to improve immune function.

In both of those cases, there is a surrounding halo of unknowns regarding how and why problem cells arise, or the thymus atrophies, or hematopoietic stem cells become damaged and quiescent. The types of treatment proposed are very much engineering solutions: cut the Gordian knot of a lack of knowledge by enacting what appears to be the best solution and examining the consequences. When it works well in animal models, trial it in humans, is the philosophy. The scientific community is made somewhat uncomfortable by this sort of approach, however. The scientific impulse is, correctly, always in the direction of greater knowledge and greater understanding of exactly how a system works, fails, or is repaired. But we cannot let that impulse rule to the exclusion of building rejuvenation therapies that can work now, to the extent that we can do so, in advance of a full and complete understanding of immune aging.

The conundrum of human immune system “senescence”

Here, we consider what we believe to be the especially confused and confusing case of the ageing of the human immune system, commonly referred to as “immunosenescence“. But what exactly is meant by this term? It has been used loosely in the literature, resulting in a certain degree of confusion as to its definition and implications. Here, we argue that only those differences in immune parameters between younger and older adults that are associated in some definitive manner with detrimental health outcomes and/or impaired survival prospects should be classed as indicators of immunosenescence in the strictest sense of the word, and that in humans we know remarkably little about their identity.

Demonstrating which changes of immune ageing are in fact associated with detrimental health outcomes and only then trying to restore them to an appropriate level may indeed be theoretically desirable. However, prior to establishing which are truly detrimental, rather than merely different in aged individuals, such intervention would be premature, and in some cases might be dangerous. One has to say that with this in mind most such efforts are indeed premature because we do not know which parameters to take as biomarkers reflecting these changes, and mistakenly attempting to “correct” adaptive changes would be undesirable. Hence, there is an argument in favour of attempts to classify such biomarkers of senescence in ageing in general, and even more challengingly in immunosenescence in particular, in order to generate actionable entities for treatment.

A consensus from published studies delineates one immune parameter consistently reported to be different between younger and older adults, namely the very low absolute and relative counts of naïve CD8+ T cells in the peripheral blood of older adults. This is not to say the older adults actually do possess fewer naïve T cells because data on the presence of immune cells in other organs are mostly lacking and most data pertain only to circulating cells. However, the expectation is that the whole-body number of CD8+ naïve T cells is indeed low, due to markedly reduced thymic output and cell mortality owing to a lifetime´s exposure to pathogens, agreeing with data from animal models. Reciprocally, it would be expected that because antigen-stimulated naïve cells differentiate into effector and memory cells, the latter would be increased in older adults, as also often reported. It is thus somewhat surprising that CD8+ memory cell accumulation in the blood of older adults is not universally reported. It has become apparent in the meantime that the accumulations of late-stage memory cells that are seen in older people are driven by persistent infection with cytomegalovirus (CMV), but apparently not by other herpesviruses or other pathogens. These sometimes disputed findings have been confirmed in systematic reviews.

Despite differences in many immune parameters between men and women, in the few studies examining this issue, the markedly lower levels of circulating CD8+ naïve T cells have been found in both sexes, further emphasising the universality of these findings. Intriguingly, although present, age-associated differences for CD4+ naïve T cells, B cells, and many aspects of innate immunity, especially dendritic cells (DCs) and neutrophils, are much less marked than for CD8+ T cells, one of the enduring mysteries in immunosenescence research. Again, it should be emphasized that the majority of immune cells resides in tissues and not in blood, and that the latter most likely does not reflect patterns of cell subset distribution elsewhere

Immune parameters assessed in cross-sectional studies clearly document multiple differences between younger and older populations. Animal studies as well as some more limited longitudinal studies in humans indicate that many of these differences are indeed likely to be intra-individual age- and environment-associated changes. Some immune signatures established as subject to distinct changes with age can be associated with important health outcomes such as frailty and responses to vaccination, and finally, with mortality. Many others are clearly hallmarks of the adaptation to exposures over the lifespan and continue to play a positive role in maintaining organismal integrity. Many may be informative only in the population in which they were assessed, and the search for truly universal age-associated changes in immune markers is ongoing. Whether these exist as reflections of ageing processes per se is open to question. Thus far, they mostly seem limited to reductions in numbers, proportions and the antigen receptor repertoire of peripheral blood naïve T cells and other immune cells. In turn, this reflects thymic involution at puberty and the degree of residual thymic function in later life, as well as possibly dysfunctional haematopoiesis and the poorly defined detrimental systemic milieu in older individuals which remains mysterious.