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Aging is the single greatest risk factor for developing chronic disease. Compared to younger adults, the elderly are at increased risk of infection and experience greater morbidity and mortality upon infection [1]. Similarly, the elderly also have poor vaccine responses, making them more susceptible to vaccine-preventable disease such as influenza or varicella zoster (causative agent in chickenpox and shingles) viruses, even when they have been vaccinated [2]. Central to this susceptibility is the functional deterioration of systemic immunity, or “immune senescence.” This term encompasses the collective loss of immune protection during aging and includes atrophy of the thymus leading to decreased naïve T cell output, an increased proportion of experienced lymphocytes contributing to adaptive immune memory but limiting responses to novel targets, an increased proportion of myeloid cells released from the bone marrow, and impaired functions of multiple existing immune cell types. Immune senescence is also characterized by functional dysregulation in immune cells at the cellular and molecular levels, ultimately leading to increased infection susceptibility and poor vaccination responses in the elderly as discussed in detail throughout this chapter.

Underlying many deficiencies in immunity is a chronic proinflammatory state. Many age-related diseases are driven by and promote increased inflammation, and elevated circulating inflammatory markers such as CRP, TNFα, and IL-6 correlate with age-related conditions including atherosclerosis [3] and frailty [4]. Importantly, even clinically healthy elderly individuals exhibit elevated inflammatory cytokines in serum [5]. While the precise source and cause of inflammation during aging is still unknown, this so-called “inflammaging” state contributes to the onset of multiple comorbidities in the elderly, including but not limited to Alzheimer’s disease, cardiovascular disease, muscle wasting, and immune senescence [6], making older adults a uniquely challenging patient population. Here, we will focus on the impact of inflammation on dysregulation of innate immune responses and relevant tissue microenvironments that influence immune cellular function.