A High Level View of Efforts to Modulate Inflammaging and Immunosenescence of the Aged Immune System

Change and disruption in the immune system is an important component of degenerative aging. Broadly, the immune system becomes ever more inflammatory (inflammaging) while also becoming ever less effective (immunosenescence). The immune system is not only responsible for defending against invasive pathogens and destroying errant cells, but it is also tightly integrated into the normal processes of tissue maintenance and operation. When immune cells become inflammatory, they abandon the range of tasks needed to keep tissues functional. Short-term inflammation is necessary in response to injury and infection, but unresolved, chronic inflammation is a major issue, highly disruptive, and contributing to the onset and progression of many age-related conditions.

That immune aging is a major issue is widely recognized, and many research and development initiatives are aimed at restoration of at least some aspect of lost immune function: largely reduction of inflammation, but also restoration of immune capacity in defense against pathogens or clearance of cancerous and senescent cells. The most promising direct approaches involve (a) improvement of hematopoietic stem cell function, (b) restoration of the thymus to enable greater production of T cells, (c) clearance of misconfigured and damaged immune cell populations. Removing the stimuli for chronic inflammation should also prove helpful, such as via clearance of senescent cells.

Immune system modulation in aging: Molecular mechanisms and therapeutic targets

Inflammation is a key factor for the onset and progression of almost all chronic diseases affecting aged individuals, with immunosenescence and inflammaging being two relevant phenomena that modulate the immune system during aging. Therefore, identification and characterization of the molecular and cellular mechanisms underlying the immune system dysfunction will surely help to develop effective therapeutic strategies to prevent the negative outcomes of infectious diseases on aged individuals.

For that reason, several pharmacological and cellular/genetic strategies have been developed to slow down or reverse the deleterious effects of immunosenescence on health: (a) Induced pluripotent stem cells (iPSCs) have been employed to generate hematopoietic cells and/or various specific immune cells; (b) administration of cytokine and growth factor cocktails boosted macrophage function; (c) bone marrow transplantation is a widely used therapy for thymus regeneration; (d) the use of Cdc42 and BATF inhibitors or antioxidants enhances the number and function of lymphoid-biased hematopoietic stem cells; (e) inhibition of dual specific phosphatases 4 boosts memory CD4+ T-cell function; (f) administration of fibroblast growth factor 7 (FGF7) stimulates naive T-cell production and promotes the removal of dysfunctional cells, thereby restoring thymus function; and (g) administration of rapamycin improves CD8+ T-cell function.

Finally, a relevant non-pharmacological strategy that has been proven to enhance immunity is caloric restriction; it delays the accumulation of senescent T cells and stimulates thymopoiesis through the activation of IGF-1 and/or PPAR pathways. On the other hand, recent studies have unveiled the relevance of functional foods to ameliorate oxidative stress and inflammation and to improve the metabolism of lipids associated with metabolic diseases, via Nrf2 and/or NF-κB signaling pathways.

Some of the molecules/pathways that modulate immunosenescence have therapeutic potential. Owing to the crucial role of the activator protein 1 (AP-1) signaling pathway in macrophage-mediated inflammation, targeting of AP-1 has been approached to attenuate inflammation. Transfection of lentiviral siRNA against AP-1 in mice fed with high-fat diet resulted in the alleviation of systemic and hepatic inflammation. Interestingly, the use of rosiglitazone, a PPARγ agonist, was found to exert a positive effect on animals with sepsis, decreasing cell death and cardiac inflammation; furthermore, increased fatty acid oxidation and improved insulin resistance were also observed in human skeletal muscle. Since aging is a very complex process that involves different biological processes, therapies aimed to modulate inflammaging have to be focused on the synergic effect of more than one compound, to regulate simultaneously different pathways. For instance, a combinatory treatment using three different compounds, rapamycin, acarbose, and 17α-estradiol, converge on the regulation of both ERK1/2 and p38-MAPK pathways.