I exaggerate in the title of this post, of course, but there is some truth in it. Certainly, a lot more attention is focused on the phenomenon of cellular senescence now that mouse life spans have been extended and aspects of aging have been reversed via clearance of senescent cells. The existence of several startup biotechnology companies aiming to bring senescent cell clearance treatments to the clinic is shining even more of a spotlight on this area. It has been something of a transformation. Five years ago, one of the few groups of researchers interested in this field struggled greatly to raise the funding for the pivotal study to prove that selectively removing senescent cells had a significant impact on health. Five years from now, every major research center will have a cellular senescence arm in the same way that they have a cancer arm today. It is that important to that many aspects of aging and age-related disease.
Cells become senescent when they reach the end of their replicative life span, or in response to damage, or a toxic environment. They cease to divide, and largely destroy themselves or are destroyed by the immune system. It is an evolutionary adaptation that serves, at least initially, to suppress cancer by removing those cells most at risk of uncontrolled replication. Unfortunately not all are destroyed. Some remain, and their numbers grow over the years, secreting a disruptive mix of signal molecules that causes chronic inflammation, corrodes surrounding tissue structures, changes the behavior of healthy cells for the worse, and no doubt more that is yet to be cataloged. Recently researchers have shown that senescent cells contribute directly to the progression of atherosclerosis, as well as declining lung function and loss of tissue elasticity in that organ. The inflammation angle on its own is enough to link greater numbers of senescent cell to an increased risk of most age-related diseases, and a worse prognosis for long-term health. Then, of course, there is the life span study showing extended life in mice as a result of senescent cell clearance.
Senescent cell accumulation is only one of the processes that cause degenerative aging. Fixing it via periodic selective destruction of these cells is only a narrow, partial rejuvenation. There is still everything else in the SENS rejuvenation research agenda to work through. Nonetheless, it is a great improvement over the present state of medicine to have senescence cell clearance therapies on the horizon. Given that senescent cells can be linked to near every age-related condition via at least inflammatory mechanisms, and given the greatly increased awareness of cellular senescence in far-flung parts of the research community that probably weren't paying all that much attention in the past, we are now seeing the first of what will no doubt prove to be a wide selection of efforts to link preexisting theories, data, and viewpoints on aging and age-related disease to what is known of the biochemistry of cellular senescence. I offer the open access paper quoted below as one example of the type, though I wouldn't take everything the authors have to say about oxidative stress in aging at face value. They mention the supporting evidence, but omit the equally numerous counterexamples that demonstrate the relationship between oxidative damage and aging to be far from simple.
The Free Radical or Oxidative Stress Theory of Aging postulates that reactive oxygen species (ROS) formed exogenously or endogenously from normal metabolic processes play a role in the aging process. The imbalance of pro-oxidants and antioxidants leads to an age-related accumulation of oxidative damage in macromolecules, resulting in a progressive loss in function and aging. Over the past three decades, the Oxidative Stress Theory of Aging has become one of the most popular theories to explain the biological/molecular mechanism underlying aging because several lines of evidence support the theory. First, the levels of oxidative damage to lipid, DNA, and protein have been reported to increase with age in a wide variety of tissues and animal models. Second, studies with animal models showing increased longevity are consistent with the Oxidative Stress Theory of Aging. Longer-lived animals show reduced oxidative damage and/or increased resistance to oxidative stress, e.g., dietary restriction in rodents and genetic manipulations that increase lifespan in invertebrates (C. elegans and Drosophila) and in mice. Thus, the observations that experimental manipulations that increase lifespan in invertebrates and rodents were correlated to increased resistance to oxidative stress or reduced oxidative damage provided strong support for the Oxidative Stress Theory of Aging. However, all of the experimental manipulations that increase lifespan also alter processes other than oxidative stress/damage; therefore, the increase in longevity in these animal models could arise through another mechanism.
Over the past two decades, our group has directly tested the role of oxidative damage/stress in aging by genetically manipulating the antioxidant status of a wide variety of antioxidant genes to increase or reduce the level of oxidative stress/damage and determine what affect these manipulations had on lifespan. Our research with 18 different genetic manipulations in the antioxidant defense system shows that only the mouse model null for Cu/Zn-superoxide dismutase (Sod1) had an effect on lifespan (in this case a decrease in lifespan) as predicted by the Oxidative Stress Theory of Aging. Because it has been reported that more than 70% of Sod1-/- mice developed liver hyperplasia and hepatocellular carcinoma later in life, it was initially believed that the 30% decrease in the lifespan of Sod1-/- mice was not due to accelerated aging but was the result of a dramatic increase in hepatocellular carcinoma, which is rare in C57BL/6 mice. In a more recent study, we found a similar 30% decrease in lifespan of the Sod1-/- mice; however, in our study, only about 30% of Sod1-/- mice developed hepatocellular carcinoma later in life. In addition, we showed that dietary restriction, which is a manipulation that retards aging in rodents, increased the lifespan of the Sod1-/- mice to that of normal, wild type (WT) mice. These data combined with studies showing that Sod1-/- mice exhibited various accelerated aging phenotypes (e.g., muscle atrophy and loss of fat mass, hearing loss, cataracts, skin thinning and delayed wound healing) lead us to conclude that the Sod1-/- mice exhibit accelerated aging. This then raised the question of why we observed a significant decrease in lifespan and accelerated aging in only the Sod1-/- mice and not in other mouse models with compromised antioxidant defense systems that showed changes in oxidative stress/damage.
Sod1-/- mice show a much higher level DNA oxidation (i.e., 8-oxo-dG levels) in tissues than any of the mouse models we have studied, which all have deficiencies in one or more of the antioxidant genes. In addition, DNA mutations have been reported to increase significantly in several tissues in Sod1-/- mice. Because the DNA damage response has been shown to play a central role in the generation of senescent cells and because it has been shown that clearance of senescent cells delays aging-associated disorders and increases lifespan in a progeroid mouse model as well as in normal, wild type (WT) mice, we hypothesized that the increased oxidative damage to DNA in tissues of Sod1-/- mice could activate the DNA damage response and drive cells into becoming senescent. To test our hypothesis, we measured various markers of cellular senescence in kidney tissue, a tissue that shows a significant increase in senescent cells with age. We compared kidney from young-adult and old WT mice and young-adult Sod1-/- mice fed ad libitum or a dietary restriction diet. Our data clearly demonstrate that the level of senescent cells is dramatically increased in the kidney of young-adult Sod1-/- mice compared to young-adult WT mice and are at a level comparable to old WT mice. In addition, we observed that the increase in cellular senescence observed in the Sod1-/- mice was attenuated by dietary restriction. Interestingly, the increase in cellular senescence in the Sod1-/- mice was correlated to increased circulating cytokines. Thus, our data suggest that increased cellular senescence could play a role in the accelerated aging phenotype we have observed in the Sod1-/- mice.