Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention

Abstract

Aging is accompanied by remodeling of the immune system. With time, this leads to a decline in immune efficacy, resulting in increased vulnerability to infectious diseases, diminished responses to vaccination, and a susceptibility to age-related inflammatory diseases. An age-associated immune alteration, extensively reported in previous studies, is the reduction in the number of peripheral blood naïve cells, with a relative increase in the frequency of memory cells. These two alterations, together with inflamm-aging, are considered the hallmarks of immunosenescence. Because aging is a plastic process, it is influenced by both nutritional and pharmacological interventions. Therefore, the role of nutrition and of immunomodulation in immunosenescence is discussed, due to the multifactorial influence on these hallmarks. The close connection between nutrition, intake of bioactive nutrients and supplements, immune function, and inflammation demonstrate the key role of dietary strategies as regulators of immune response and inflammatory status, hence as possible modulators of the rate of immunosenescence. In addition, potential options for therapeutic intervention are clarified. In particular, the use of interleukin-7 as growth factor for naïve T cells, the function of checkpoint inhibitors in improving T cell responses during aging and, the potential of drugs that inhibit mitogen-activated protein kinases and their interaction with nutrient signaling pathways are discussed. Finally, it is suggested that the inclusion of appropriate combinations of toll-like receptor agonists may enhance the efficacy of vaccination in older adults.

Keywords: aging; immunomodulation; immunosenescence; immunotherapy; nutrition.

Figure 1

Schematic changes occur during aging. The immunosenescence in older people is characterized by thymic involution, altered T and B cell responses, altered naïve/memory ratio, increased serum levels of IgG and IgA, a chronic low grade inflammation, and a poor response to newly encountered microbial antigens, including vaccines. The reduced ability to respond to new antigens, the accumulation of memory T cells and the lingering level of low-grade inflammation “inflamm-aging”) are considered hallmarks of immunosenescence. See the text for the acronyms. increase; decrease.

Figure 2

Overview of the main strategies of immunomodulation. (A) In age-related diseases, in particular in some metastatic cancers, the use of the monoclonal antibody (such as Nivolumab, a PD-1 inhibitor) alone or in combination with other antagonists (PD-L1 antibody, like Atezolizumab) shows positive results on T cell activities in older adults. These cells became able to respond to the action of their inhibitory receptors with a recovery of cytotoxic activity. (B) In old models, with Lack of activity of CD8⁺, it is possible to rejuvenate CD8⁺ T cell responses in an autophagy dependent manner, using the polyamine compound spermidine. Spermidine induces autophagy and prolongs lifespan in model organisms. Moreover, in the CD8⁺/CD45RA⁺/CCR7⁻ T cells, a block at the level of MAPK p38 by sestrins causes age-related signaling defects. The knockout of sMAC restores T cell activity (antigen-specific proliferation and cytokine production) in older humans, and enhances responsiveness to influenza vaccination in old mice. (C) GATOR and RAG A/B GTPase make a sestrin-inhibitory complex that involves the mTOR pathway. In particular, sestrins stimulate the activation of AMPK (by an unknown mechanism), inhibiting mTORC1 signaling. In addition, mTOR inhibitors, i.e., rapamycin and everolimus, are promising treatments for several age-related pathologies, including immunosenescence, prolonging lifespan. A soft inhibition of mTOR could be beneficial for immune function in older adults, although mTOR activity inhibits autophagy, and involves a decrease in the percentage of PD-1 positive T cells. See the text for the acronyms.