Abstract
Aging reflects long-term decline in physiological function and integrity. Changes arise at a variable pace governed by time-dependent and -independent mechanisms that are themselves complex, interdependent and variable. Molecular decay produces inferior cells that eventually dominate over healthy counterparts in tissues they comprise. In a form of biological entropy, progression from molecular through cellular to tissue level degeneration culminates in organ disease or dysfunction, affecting systemic health. To better understand time-independent contributors and their potential modulation, common biophysical bases for key molecular and cellular changes underlying age-related physiological deterioration must be delineated. This review addresses the potential contribution of cytomegalovirus (CMV)-driven T cell proliferation to cellular senescence and immunosenescence. We first describe molecular processes imposing cell cycle arrest, the foundation of cellular senescence, then focus on the unique distribution, phenotype and function of CMV-specific CD8+ T cells in the context of cellular senescence and “inflammaging”. Their features position CMV infection as a pathogenic accelerant of immune cell proliferation underlying immune senescence. In human immunodeficiency virus (HIV) infection, where increased inflammation and exaggerated anti-CMV immune responses accelerate immune senescence, CMV infection has emerged as a major factor in unhealthy aging. Thus, we speculate on mechanistic links between CMV-specific CD8+ T-cell expansion, immune senescence and prevalence of age-related disorders in HIV infection.
Highlights
Immunology and Infectious Diseases Program, Division of BioMedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, 300 Prince Philip Drive, St
Modest increases in pro-inflammatory cytokines like tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β consistently occur with age [4,19,34]
As CMV-specific CD8+ T cells undergo massive clonal proliferation, display an altered phenotype and are functionally abnormal, we suggest that cells within this population may illustrate the transition to in vivo replication driven senescence in T lymphocytes
Summary
From the Latin senescere, is defined as “to grow old”. In biological terms, the concept of senescing or becoming senescent originates from work by Hayflick et al, describing loss of replicative capacity or onset of replicative senescence in fibroblast cell cultures [1,2]. In concert with this environmental deterioration, transcriptional analysis of isolated p16-expressing tissue-resident cells indicates up-regulation of pathways producing locally and systemically active soluble factors such as interleukins, chemokines, growth factors, and proteases [22,23,24,25] Increased expression of these mediators in association with cell cycle arrest introduced the term “senescence-associated secretory phenotype” (SASP), to represent a prominent and proposed pathological feature of chronic cell senescence [3]. This senescence-associated reprogramming positions chronic senescent cells as accumulating sources of inflammatory and other soluble factors that alter microenvironments to exacerbate age-related deterioration within multiple tissues
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