Considering the Treatment of Oxidative Stress and Fibrosis in Aging

The presence of reactive oxidizing molecules in our tissues increases with age. These cause damage by reacting with proteins, all of which are important parts of the biological machinery in some portion of a cell. An oxidized protein has a different chemical structure and thus cannot perform its normal tasks. This contributes to disarray and dysfunction in a cell until the damaged protein is removed by quality control processes. High levels of oxidation are referred to as "oxidative stress," and this plays an important role in aging. It is, however, far from straightforward as to how this stress arises and then interacts with metabolic operations and damage repair systems, though mitochondria appear to play a number of important roles. It appears that oxidative stress is a later condition of aging, a fair way removed from primary causes, but a lot of researchers start at this point and consider how to intervene at this level:

Improved therapies for the treatment of idiopathic pulmonary fibrosis (IPF) and other fibrotic diseases are needed. It has been suggested that core pathways that mediate fibrosis in multiple organ systems may serve as targets for anti-fibrotic drug development, such as redox imbalance in the context of aging. Aging results in decreased resistance to multiple forms of stress, as well as increased susceptibility to numerous diseases. Progressive fibrosis is a hallmark of aging in various organ systems, including the liver, kidney, pancreas and lung. IPF, the most fatal and progressive fibrotic lung disease, disproportionately affects the elderly population and is now widely regarded as a disease of aging. The incidence and prevalence of IPF increase with age; two-thirds of IPF patients are older than 60 years at the time of presentation with a mean age of 66 years at the time of diagnosis. Further, the survival rate for IPF patients markedly decreases with age. Although the roles of specific aging hallmarks in the pathogenesis of IPF have not been fully elucidated, numerous studies implicate age-related alterations in cellular function in the pathogenesis of IPF.

Aging and fibrotic disease are both associated with cumulative oxidant burden, and lung tissue from IPF patients demonstrate "signatures" of chronic oxidative damage. The "oxidative stress theory" posits that a progressive and irreversible accumulation of oxidative damage caused by reactive oxygen species (ROS) impacts critical aspects of the aging process by contributing to impaired physiological function, increased incidence of disease, and a reduction in life span. Oxidative stress can lead to extensive modifications or damage to macromolecules including DNA, lipids and proteins and can also lead to increased production of cytokines. The lungs are particularly prone to insult and injury by oxygen free radicals given their direct exposure to the environment via inspired air. Further, environmental insults to lung may serve as a "second hit" which accelerate the aging process by promoting persistently elevated oxidative stress levels leading to increased susceptibility to disease. Oxidative stress may represent a core pathway by which other "damage" theories of aging are based. Examples include genomic instability as a result of DNA damage, and accumulation of glycated crosslinks during protein damage that can result in pathogenesis associated with cardiovascular and neurodegenerative disease. Recent studies of familial and sporadic cases of IPF have been associated with telomere shortening, further supporting the concept that IPF may represent an age-related degenerative disease process. The causes for the shortened telomeres in IPF patients without mutations in telomerase is currently unknown; however, oxidative stress represents one potential mechanism. A better understanding of the mechanisms that mediate oxidant-antioxidant imbalance in aging may be critical to the development of more effective therapeutic strategies.

Despite the well-recognized role of oxidative stress in fibrosis and aging, the ability to precisely target key mediators of this process has proved difficult. By definition, oxidative stress occurs when cellular ROS levels overwhelm the cellular antioxidant capacities, thus therapeutic strategies have been directed inhibiting oxidant generation as well as stimulating antioxidant capacity. A number of antioxidant therapeutic strategies have shown promise in various preclinical models, however, they have failed to demonstrate efficacy in the clinic. Although there may be several potential reasons for this observed lack of efficacy of anti-oxidants, one important consideration is the potential for ROS to function as redox signaling molecules for physiologic cell signaling. In fact, ROS may be viewed as "antagonistically pleiotropic" by mediating detrimental effects in the context of aging or an age-related disease. Based on its pleiotropic functions, it can be argued that targeting the primary enzymatic source of ROS (rather than anti-oxidant approaches) may offer a more promising strategy.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4791330/

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