The adaptive immune system that we are all born with is structurally unsound for long term use. Even if we did not accumulate any of the known forms of cellular and molecular damage thought to cause degenerative aging, the adaptive immune system would still grind itself down into a state of continual malfunction. In this it is unusual: absent damage, a liver or a heart would continue to function as well as it did in youth far beyond the present human life span.
Why would the immune system fail even absent damage? From a mechanistic standpoint - and simplifying a complex situation considerably - it fails because it has a limited supply of new T cells in adulthood, but is programmed to assign some of its T cells to remembering every new threat that it encounters. Some threats, such as otherwise largely harmless herpesviruses like CMV, are exceedingly persistent and come back again and again. Eventually there are too many memory T cells and not enough naive T cells capable of attacking new pathogens or destroying senescent and precancerous cells. The outcome is frailty: inability to resist diseases, a greater toll on the body due to cellular senescence, and a rising risk of cancer.
(There are other structural issues, such as the fact that the immune system falls into a state of chronic low-level activation, producing inflammation: it is on alert, imposing the costs of inflammation on the body, but at the same time ever more ineffective at actually doing anything useful while being on alert. But for the same of this discussion, I'll skip over that, as it may be more of a consequence of forms of low-level tissue damage that accompanies aging rather than an inherent property resulting from the composition and activities of the immune system).
I thought I'd point out a couple of papers from the research community presently focused on T cell dynamics and the aging of the immune system, all from a recent issue of Experimental Gerontology. As you take a look, bear in mind that there are many plausible near-future ways in which these problems of the aging immune system might be addressed, some of which are already well within the capabilities of the research community. For example, we might regularly treat old people with infusions of immune cells grown from their own stem cells. Or we might aim to rejuvenate the thymus through tissue engineering: it atrophies in early adulthood, and restoring it would provide a flow of new immune cells created in the body. Another option is to target and destroy the excess population of memory cells. Many are useless, duplicates fixated on CMV or other non-threatening targets. Targeted cell killing technologies under development by the cancer research community are well suited to this task.
All in all there are many options, and most are either presently possible or a bare few years away - if there is just sufficient funding and interest in moving forward to rejuvenation the aged immune system. There is far from any sort of unified consensus on what approach to take, however, or even that the sketch I provided above is in fact an important part of the overall picture. You might see the first of the papers below, for example, in which the authors propose that promising results for thymic restoration in mice will probably not translate to humans. Other researchers are much more interested in developing drugs to manipulate the organization and activities of the immune system than in targeted destruction of excess memory cells or cell therapies to deliver new immune cells. So it goes - this is par for the course in any field.
The ability of the human immune system to repel infections is drastically diminished with age. Elderly individuals are more susceptible to new threats and are less able to control endogenous infections. The thymus, which is the sole source of new T cells, has been proposed as a target for regenerative efforts to improve immune competence, as thymic activity is dramatically reduced after puberty.
In this review, we review the role of the thymus in the maintenance of T cell homeostasis throughout life and contrast the differences in mice and humans. We propose that in humans, lack of thymic T cell generation does not explain a decline in T cell receptor diversity nor would thymic rejuvenation restore diversity. Initial studies using next generation sequencing are beginning to establish lower boundaries of T cell receptor diversity. With increasing sequencing depth and the development of new statistical models, we are now in the position to test this model and to assess the impact of age on T cell diversity and clonality.
When encountering foreign antigens, naïve T cells become activated and differentiate into effector and memory T cells. They represent therefore the primary source to mount an immune response against pathogens or tumors. Recent evidence of both quantitative and qualitative alterations of naïve T cells has accumulated in aged mice, indicating that the successful generation of primary T cell responses from the naïve T cell pool may be compromised with old age.
However, the vast majority of the data supporting compromised naïve T cell priming efficacy with old age have been produced in animal models, and the situation is much less clear in humans. In the elderly, the involution of the thymus and the associated decline in thymic output result in a decreased number of naïve T cells, which is partially compensated by homeostatic proliferation. Emerging evidence suggest that alterations of the TCR repertoire diversity and intrinsic defects of old CD4+ naïve T cells may impact on their responsiveness to antigenic stimulation. Increasing focus on the study of naïve T cells (in particular CD8+) in old humans are needed to fill the gaps in our understanding of reduced cellular immunity with aging.
Aging leads to reduced immunity, especially adaptive responses. A key deficiency is the poor ability to mount robust antibody response. Although intrinsic alterations in B cells with age are in part responsible, impaired CD4 T cell help makes a major contribution to the poor antibody response. Other CD4 effector responses and memory generation are also impaired.
We find delayed and reduced development of CD4 T follicular help (Tfh) cells in aged mice in response to influenza infection with reduction of long-lived plasma cells. We summarize strategies to circumvent the CD4 T cell defect in aged, including adjuvants and proinflammatory cytokines. We find that we can strongly enhance responses of aged naïve CD4 T cells by using Toll-like receptor (TLR) activated dendritic cells (DC) [and] that this leads to improved [antibody responses].