Susceptibility of the aging lung to environmental injury

Abstract

With an ever-increasing number of elderly individuals in the world, a better understanding of the issues associated with aging and the environment is needed. The respiratory system is one of the primary interfaces between the body and the external environment. An expanding number of studies suggest that the aging pulmonary system (>65 years) is at increased risk for adverse health effects from environmental insult, such as by air pollutants, infection, and climate change. However, the mechanism(s) for increased susceptibility in this subpopulation are not well understood. In this review, we provide a limited but comprehensive overview of how the lung ages, examples of environmental exposures associated with injury to the aging lung, and potential mechanisms underlying the increased vulnerability of the aging lung to injury from environmental factors.

Figure 1. The Senescent Phenotype Induced by Multiple Stimuli

Mitotically competent cells respond to various stressors by undergoing cellular senescence. These stressors include dysfunctional telomeres, non-telomeric DNA damage, excessive mitogenic signals including those produced by oncogenes (which also cause DNA damage), non-genotoxic stress such as perturbations to chromatin organization and, probably, stresses with an as-yet-unknown etiology. The senescence response causes striking changes in cellular phenotype. These changes include an essentially permanent arrest of cell proliferation, development of resistance to apoptosis (in some cells), and an altered pattern of gene expression. The expression or appearance of senescence-associated markers such as senescence-associated β-galactosidase, p16, senescence-associated DNA-damage foci (SDFs) and senescence-associated heterochromatin foci (SAHFs) are neither universal nor exclusive to the senescent state and therefore are not shown. (Reprinted with permission from Campisi J et al, Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol. 2007 Sep;8(9):729–40.)

Figure 2. Sources and Consequences of DNA Damage

DNA damage can be induced by exogenous physical agents, by endogenous chemical genotoxic agents that are the products of metabolism, such as reactive oxygen species (ROS), or by spontaneous chemical reactions, such as hydrolysis. Examples of DNA damage are ultraviolet (UV)-induced photoproducts (left), interstrand and intrastrand crosslinks, bulky chemical adducts (purple sphere), abasic sites, and oxidative damage such as 8-oxoguanine (8-oxoG). The consequences of DNA damage are essentially twofold. After misrepair or replication of the damaged template, surviving cells may be subject to permanent changes in the genetic code in the form of mutations or chromosomal aberrations, both of which increase the risk of cancer. Alternatively, damage may interfere with the vital process of transcription or induce replication arrest, which may trigger cell death or cellular senescence, contributing to aging. Damage-induced cell death protects the body from cancer. G denotes guanine, and T thymidine. (Reprinted with permission from Jan H.J. Hoeijmakers. DNA Damage, Aging, and Cancer. N Engl J Med 2009;361(19): 1475–1485.)