Immunosenescence is the name given to the decline of immune system effectiveness with aging, a large component of the frailty that arises in later life. This decline is partially a result of a failing supply of new immune cells, and partially a result of a growing misconfiguration of the immune system as a whole, driven by life-long exposure to infections. On this second front, persistent infection by herpesviruses such as cytomegalovirus appears to be particularly problematic, the cause of large fractions of the immune cell population in an old individual becoming specialized and unable to react to new threats. This open access paper considers the potential role for cell therapies in reversing immunosenescence, with possibilities that go beyond merely generating and delivering new immune cells to the patient on a regular basis:
Human life expectancy has increased from 40 to 80 years of age just over the past 2 centuries largely due to medical advances. However, it is likely that the human immune system did not evolve to protect the host over such an extended lifespan. Immunosenescence is a term that describes the changes in the immune system that are seen in the aging population. The hallmarks of immunosenescence include a reduced capability to respond to new antigens, increased memory responses, and a lingering level of low-grade inflammation that has been termed "inflamm-aging." Decline of the immune system is associated with increased incidence of infection, immune disease, and cancer in the elderly. While immunosenescence is often described as a decline in the number and function of immune cells, myeloid cells have been shown to increase in the aged population and some secreted peptides are also expressed in greater amounts. Therefore, it is important to keep in mind that immunosenescence is more appropriately conceptualized as a change in the actions of the immune system, rather than an overall decline of all functions and constituents.
The immune system is generated and maintained by asymmetric division of multipotent haematopoietic stem cells (HSCs) in the bone marrow. The immune system has 2 arms, the innate and the adaptive systems, which work together to eliminate pathogens and neoplastic cells, respond to vaccination, and regulate processes such as tissue turn over and wound healing. Increasing evidence shows that HSCs themselves undergo age-related changes and have a limited replicative lifespan. HSC aging was demonstrated by serial transplantation of whole bone marrow, which only supported 4-6 rounds of transplantation, suggesting the possibility of stem cell exhaustion or replicative senescence. In addition, accumulation of DNA damage has a profound impact on HSCs, leading to loss of proliferation, diminished self-renewal, increased apoptosis, and subsequent exhaustion. Differentiation of the HSCs is also affected by aging, where HSCs committed to the myeloid lineage outnumber lymphoid cells in both mice and men.
Rejuvenating the HSCs might improve some of the dysfunction of both macrophages and T-cells, as well as many other cell types, observed in aging. Bone marrow transplantation from a young donor to an elderly patient could be used to rejuvenate the exhausted, aged progenitor pool. However, imperfect tissue matches often lead to rejection and even graft-vs.-host disease, a major hurdle to overcome in many fields of study. Induced pluripotent stem cells (iPSCs) could theoretically be used to generate HSCs from a patient's own cells, thereby eliminating donor-recipient mismatch. Techniques to differentiate HSCs from iPS cells exist, but efficiency and safety are major hurdles that this technology must yet overcome. In addition, genetic reprogramming will likely need to take place ex vivo to prevent collapse of organ function in the intermediate, undifferentiated cell state, so repopulation of tissue resident macrophages and lymphocytes will take several weeks or months from a single bone marrow transplantation. Also, effectiveness of rejuvenated HSCs would be limited by thymic output for T-cells and would likely not replace tissue resident macrophages, which are self-sustaining. However, repopulating the bone marrow with autologous iPSC-derived HSCs is a promising approach to rejuvenating the majority of immune system, especially the innate effector response.
The thymus begins to significantly deteriorate around 10 years of age in humans, and likely plays a role in the decline of the immune system, especially the diversity of the T-cell repertoire, during aging. Rejuvenating or somehow regulating thymic output is an intriguing approach to combat age-related decline of T-cells. Approaches to replacing or regenerating the thymus include tissue and cell transplantation. Transplantation of cultured thymic tissue from human cadavers into the kidney capsule of patients with DiGeorge syndrome successfully restored immune function for up to 10 years. However there are limitations to this approach for treating the aging population due to lack of donated tissue, invasive surgery, and tissue rejection. Regenerative medicine, including tissue engineering and cell and gene therapy, offer alternative approaches to replacing the thymus. Many groups have identified multipotent progenitors, termed thymic epithelial cells (TEC), that can grow into a 3-dimensional thymus and support normal T-cell development when transplanted into the kidney capsule. Human TECs have yet to be isolated in sufficient numbers, however protocols to push human embryonic stem cells toward TEC lineage are becoming consistently more efficient.