Researchers have recently demonstrated a partial restoration of immune response in aged mice using a combination of existing Toll-like receptor agonists. This might be seen as a first step on the road to ways to reverse those aspects of immune system failure with age that depend more on misconfiguration rather than cellular damage.
The immune system declines with age for a variety of reasons, and this decline accounts for a great deal of the frailty of the elderly, vulnerable to infections that the young shrug off, and less able to eliminate precancerous cells. Some of these reasons involve the rising levels of damage to all tissues and cells that occurs with aging, while others are structural and inevitable due to the way in which the immune system works. Even absent cellular damage it would fail over the course of a lifetime. For example, the slow pace of immune cell replacement in adults means that the population of these cells is effectively limited, and in the adaptive immune system ever more of that population consists of memory T cells devoted to past threats rather than naive T cells needed to meet new threats. Most of those memory T cells are not even particularly helpful, being duplicates of one another that exist because of the recurring presence of viruses that cannot be cleared from the body, such as cytomegalovirus. Some form of targeted cell clearance should be a useful approach here, to free up space for new immune cells, and has in fact been demonstrated to produce benefits in the laboratory for other immune cell types.
At base this sort of thing is a programming and configuration problem. Cells are machines that operate according to their state and the chemical signals they receive. Removing the misconfigured cells is one way to deal with the problem, and only requires the ability to reliably identify and target the cells to be destroyed. Given better understanding of cells and their signals in any given tissue type or system in the body, it should also be possible to change cell behaviors for the better, however. This more complex strategy may be particularly applicable to the immune system, given that so much of its age-related dysfunction is a matter of misconfiguration rather than damage. So in this research, you might see the seeds of more complex and comprehensive reprogramming efforts in the future:
Immunosenescence is characterised by decline in both adaptive and innate immune functions. Innate immune responses are activated, mainly, by stimulation of Toll-like receptors (TLRs), the expression and function of which declines with age. Dendritic cells (DCs) from both young and aged individuals exhibit comparable activation in response to most TLR ligands, and are equally capable of direct and cross-presentation of antigens to T cells in vitro, underscoring the likely importance of TLR-induced DC activation in promoting adaptive immunity. TLR stimulation is therefore a promising strategy to enhance vaccine efficacy in the elderly. Combinations of TLR agonists may be especially effective, as demonstrated in animal models and clinical trials.
We previously showed that triggering of multiple TLRs, using a combined adjuvant for synergistic activation of cellular immunity (CASAC), incorporating polyI:C, interferon (IFN)-γ and MHC-class I and II peptides, results in potent cytotoxic T cell-mediated immunity in young mice. Optimization of the adjuvant formulation and investigation of mechanism of action were also performed. We now report the ability of CASAC to improve vaccination-induced responses in aged mice by promoting induction of antigen-specific cellular immunity to both foreign and self tumour-associated peptide antigens.
We have demonstrated that our combined molecular adjuvant CASAC effectively promotes functional antigen-specific CD8+ T cell responses to vaccination with peptides in aged mice, despite their immunosenescent phenotype. CASAC improved responses in aged mice not only to a highly immunogenic foreign antigen, but also to the tumour-associated self-antigen TRP-2 whose immunogenicity is being evaluated in clinical trials. Restoration of response to vaccination in immunosenescent aged mice by CASAC likely reflects the benefits of multiple TLR triggering on DC function and provision of IFN-γ could substitute for lack of IFN-γ from CD8+ memory cells during the early phase of immune response. Since CASAC comprises a combination of agents that individually are approved for human use, our findings suggest that a CASAC-based vaccination strategy may be amenable to rapid clinical translation, particularly against chronically experienced antigens such as persistent infections or tumour-associated antigens in older people.