Arguing a Mechanism for DNA Damage to Drive Aging
There is some debate over the degree to which accumulated nuclear DNA damage contributes to aging. Here researchers propose a class of mechanisms: "Aging is characterized by the inability of tissues to maintain homeostasis. This leads to an impaired response to stress and, as a consequence, an increased risk of morbidity and mortality. ... Aging is thought to be driven, at least in part, by the accumulation of stochastic damage in cells. ... However, the mechanism by which cellular damage drives aging is not known. The simplest model is that damage causes attrition of functional cells. But this is inadequate in light of emerging evidence that aging-related degenerative changes in old and damaged organisms can be delayed or reversed by circulating factors. These observations point instead toward the cellular response to damage being the key driver of aging. The transcription factor NF-κB is a central component of the cellular response to damage, stress, and inflammation ... Numerous studies report increased NF-κB activity with aging. ... Genetic depletion of NF-κB in the skin of transgenic mice reversed age-related gene expression and histologic changes, providing support for NF-κB activation playing a causal role in skin aging. ... it remains to be determined whether NF-κB activation drives systemic aging and whether NF-κB is a therapeutic target for attenuating and/or delaying aging-related degenerative changes. ... We found that NF-κB is stochastically activated in a variety of cell types with normal and accelerated aging and that genetic or pharmacologic inhibition of NF-κB activation delays the onset of numerous aging-related symptoms and pathologies. Inhibition of IKK/NF-κB activity reduced cellular senescence and oxidative damage, including DNA and protein damage, revealing that cellular stress responses promote further cellular damage. Our findings strongly suggest that inhibitors of the IKK/NF-κB pathway may delay damage and extend healthspan in patients with accelerated aging and chronic degenerative diseases of old age."