Researchers have discovered a new form of cellular senescence, created by engineering mitochondrial dysfunction in cell cultures and genetically altered mice. This is quite interesting in that both growing numbers of senescent cells and rising levels of mitochondrial damage are recognized as distinct contributions to degenerative aging, fundamental forms of tissue damage that occur as a side-effect of the normal operation of metabolism.
We shouldn't be at all surprised to find forms of aging-associate damage interacting with one another or spurring one another along. While there is an excellent catalog of fundamental damage, the enumerated differences between old tissue and young tissue, and there is a less comprehensive but still very good catalog of the ways in which we humans fall apart when we are old, linking these two catalogs together with detailed chains of cause and effect is a massive undertaking. The complex interactions that happen in between initial damage and final disease state are at present more a matter of blank space on the map than a matter of filled lines and connections. There are exceptions: the contribution of lipofusin accumulation to age-related retinal disease is fairly direct, for example. Most of the picture is far less clear, and looks like the situation for mitochondrial damage and cellular senescence, however: numerous conflicting sketches of what is thought to happen, chains of cause and consequence have many steps, and there is a lot of room for debate and discovery. The way in which aging progresses at the detail level is enormously complex, and a full understanding of aging in this sense would require a full understanding of the molecular biology of the cell in all of its states. This is a work in progress that researchers expect to remain in progress for decades yet.
What this means to many scientists is that those decades of work must take place before any real impact on the aging process can be produced. Full understanding before action is the mantra. There are other approaches, however: it would be much faster to start in on repairing forms of age-associated damage in laboratory animals and see what happens. That is a rapid path to both answers and the possibility of rejuvenation therapies, skipping over the expensive and time-consuming need to understand the huge blank spaces on the map. Getting to rejuvenation therapies more rapidly is the entire point of the SENS approach to aging, based on damage repair, and where SENS or SENS-like work has reached the stage of technology demonstrations in laboratory animals, as is the case for senescent cell clearance, it is pretty clear that meaningful health benefits are the outcome.
Returning to cellular senescence created by mitochondrial damage, the real question here is whether or not this exact situation is something that happens in the course of normal aging. It is very possible to create cell states in the laboratory that do not occur in a normal aged organism, or do occur but not to a significant degree. Fortunately for the knowledge-seekers among us this form of senescence is distinctive, so an answer to that question lies somewhere in the near future. That said, this is arguably one of the complexities buried in the progression of aging that can be skipped over on the way to human rejuvenation; if therapies are deployed to both repair mitochondrial damage and clear senescent cells, then does it matter how these two forms of damage build on one another? Not all that much. This is the power of the repair approach to treating aging. It side-steps an enormous amount of investigative work that would be required by other forms of research and development.
Researchers need to stop thinking of cellular senescence, now accepted as an important driver of aging, as a single phenotype that stems from genotoxic stress. Research now reveals that cellular senescence, a process whereby cells permanently lose the ability to divide, is also induced by signaling from dysfunctional mitochondria - and that the arrested cells secrete a distinctly different "stew" of biologically active factors in a process unrelated to the damaging free radicals that are created in mitochondria as part of oxygen metabolism. "We don't yet know how much this process contributes to natural aging. But we do think the findings are important in addressing mitochondrial diseases, and those age-related diseases, such as some forms of Parkinson's, which involve mitochondrial dysfunction."
The discovery was unexpected and was made by eliminating sirtuins, a class of proteins long linked to longevity, one by one in human cell cultures. "The senescent phenotype only occurred when we eliminated the mitochondrial sirtuins." In addition, the senescent cells secreted a different IL-1-dependent inflammatory arm - a major factor in the more familiar form of SASP. The authors dubbed this new phenomenon MiDAS - mitochondrial dysfunction-associated senescence. "For any disease that has a mitochondrial component this research adds a potential explanation for the real driver of the dysfunction - and it's not free radicals, which we ruled out in our study. Our finding suggest a new role for mitochondria when it comes to affecting physiology."
Cellular senescence permanently arrests cell proliferation, often accompanied by a multi-faceted senescence-associated secretory phenotype (SASP). Loss of mitochondrial function can drive age-related declines in the function of many post-mitotic tissues, but little is known about how mitochondrial dysfunction affects mitotic tissues. We show here that several manipulations that compromise mitochondrial function in proliferating human cells induce a senescence growth arrest with a modified SASP that lacks the IL-1-dependent inflammatory arm. Cells that underwent mitochondrial dysfunction-associated senescence (MiDAS) had lower NAD+/NADH ratios, which caused both the growth arrest and prevented the IL-1-associated SASP through AMPK-mediated p53 activation. Progeroid mice that rapidly accrue mitochondrial DNA mutations accumulated senescent cells with a MiDAS SASP in vivo, which suppressed adipogenesis and stimulated keratinocyte differentiation in cell culture. Our data identify a distinct senescence response and provide a mechanism by which mitochondrial dysfunction can drive aging phenotypes.