The open access paper I'll point out today ties together a number of common themes in aging research. The authors propose that mitochondrial production of reactive oxygen species (ROS) is a significant cause of stochastic nuclear DNA damage, which in turn is a significant cause of cellular senescence. Those issues can then also disrupt mitochondrial function to increase ROS production, forming a feedback loop. In this view of the driving processes of aging, mitochondria are largely at fault for anything that can be pinned to rising levels of random mutations in nuclear DNA: cancer risk, cellular senescence, generally increased levels of cellular malfunction, and so forth.
An important caution regarding this paper is that the researchers used mice with a DNA repair deficiency in order to assemble their data. Such animals exhibit the appearance of accelerated aging, but it isn't in fact accelerated aging. It is usually an excess of cellular damage that isn't all that relevant in normal aging - any sort of global dysfunction in cells will tend to share high level similarities with aging, even if the damage is different. When it is significantly different, however, you usually can't learn much from it. So whether or not work in such mice is in fact useful in understanding normal aging depends very strongly on the low-level biochemical details in question. That can be hard to judge for those of us who are not life scientists.
The approach to the problem taken here sounds basically sensible as it is described below, but it nonetheless calls out for some form of confirming study in normal mice in order to rule out any peculiarity of DNA repair deficiency. One possibility would be to take one of the existing mitochondrially targeted antioxidant compounds and design a study that specifically evaluates reduced nuclear DNA mutation and reduced cellular senescence burden as a result of administration. Researchers have already run numerous studies in mice with these compounds, and some of that existing data might be helpful from this point of view. I note, however, that those studies didn't produce very large gains in life span where those gains were measured, which should perhaps temper our enthusiasm for this whole line of thought.
Cellular senescence was recently established to play a causal role in aging and many age-related diseases. Senescence is a programmed cell fate characterized by growth arrest, a metabolic shift, resistance to apoptosis and often a secretory phenotype. The senescent cell burden increases with age in virtually all vertebrates. In replicating human cells, shortened telomeres drive senescence. It has become increasingly clear that non-replicating cells also undergo senescence. However, in non-dividing cells, which are the majority of cells in mammalian organisms, the cause of senescence is not clear.
A variety of cellular stressors including genotoxic, proteotoxic, inflammatory, and oxidative have been implicated in driving senescence. However, senescence itself is associated with many of these cellular stressors, making it very difficult to decipher cause and effect. For example, DNA damaging agents definitively cause increased senescence (e.g. in cancer patients). Yet senescent cells are defined by persistent activation of the DNA damage response, increased expression of surrogate markers of DNA damage and are able to trigger genotoxic stress in neighboring cells. Therefore, in vivo, the importance of DNA damage as a driver of senescence and aging is debated.
Even less is known about endogenous DNA damage as a potential driver of senescence and aging. The vast majority of evidence implicating DNA damage in senescence comes from experiments implementing very high doses of environmental genotoxins such as ionizing radiation or doxorubicin. Also of note, all genotoxins damage not only DNA, but also all cellular nucleophiles including phospholipids, proteins, and RNA. Thus, it remains unknown whether physiological levels of spontaneous DNA damage is sufficient to drive cellular senescence.
A major source of endogenous DNA damage is reactive oxygen species (ROS) produced during mitochondrial-based aerobic metabolism. Some mitochondrial-derived ROS, such as H2O2, can diffuse throughout the cell, resulting in oxidative damage to lipids, proteins, RNA and DNA. Thus, mitochondrial dysfunction, which leads to an increase in ROS production, was proposed to be central to the aging process. However, this too remains controversial.
To address these gaps in knowledge, we utilized a genetic approach to increase endogenous nuclear DNA damage in mice. ERCC1-XPF is an endonuclease complex required for nucleotide excision repair, interstrand crosslink repair and the repair of a subset of DNA double-strand breaks. Mutations that mediate reduced expression of this enzyme cause accelerated aging in humans and mice. Genetic depletion of DNA repair mechanisms does not increase the amount of damage incurred, it simply accelerates the pace at which damage triggers a demonstrable physiological impact, affording an opportunity to investigate the role of endogenous nuclear DNA damage in driving senescence.
Here, we demonstrate that Ercc1-/Δ mice accumulate oxidative DNA damage and senescent cells more rapidly than age-matched wild-type (WT) controls, yet comparable to WT mice over two years of age. Surprisingly, we found that Ercc1-/Δ mice are also under increased oxidative stress. Increased ROS production and decreased antioxidant buffering capacity contributed to the oxidative stress, which was also observed in aged WT mice. Treatment of Ercc1-/Δ mice with a mitochondrial-targeted radical scavenger (XJB-5-131) was sufficient to suppress oxidative DNA damage, senescence, and age-related pathologies. These data demonstrate that damage of the nuclear genome arising spontaneously in vivo is sufficient to drive cellular senescence. Our data also demonstrate that endogenous DNA damage, as a primary insult, is able to trigger increased reactive oxygen species (ROS) and further oxidative damage in vivo.
By definition, the primary insult in untreated Ercc1-/Δ mice is unrepaired endogenous DNA damage to the nuclear genome. Not surprisingly, the Ercc1-/Δ mice accumulate senescent cells more rapidly than WT mice. This formally demonstrates that physiologically-relevant types and levels of endogenous DNA damage are able to trigger the time-dependent accumulation of senescent cells. Chronic administration of XJB-5-131 significantly reduced both oxidative DNA damage and senescence. The reduced level of senescent cells corresponded to a reduction in age-related morbidity. The observation that suppressing oxidant production is sufficient to decreases senescence indicates that reactive species are required to ultimately cause or maintain senescence in response to genotoxic stress.