Senescent cells accumulate in tissues with age, a consequence of the normal operation of cellular biochemistry. While these cells can be beneficial in small numbers and for short period of times, such as while playing a role in wound healing, it is unfortunately the case that - when present in large numbers and lingering for years - the activities of these cells contribute meaningfully to the progression of age-related disease. Their signals and other secreted molecules generate chronic inflammation, corrode tissue structure, and alter the behavior of normal cells for the worse. Senescent cells are one of the causes of aging, in other words.
Progress in the means to safely remove these cells has led to numerous studies in the past few years in which senescent cells have been shown to contribute directly to many specific age-related conditions. This well illustrates that the fastest way to make progress in understanding any given cause of aging is to find a way to selectively remove it, and see what happens. In the research results I'll point out today, the authors look at the contribution of senescent cells to the development of osteoporosis. Encouragingly, they demonstrate that the condition can be partially reversed by removing these unwanted cells, at least in mice. Past evidence suggested that this would be the case, but here the proof is much more direct, more compelling.
What is osteoporosis? In a nutshell, it is the failure of tissue maintenance in bone. In older people bone becomes weak and fragile: failing bone, failing muscle, and a failing immune system are among the most obvious and troubling components of age-related frailty. Unlike the case for most other tissues, maintenance failure in osteoporosis is an imbalance between processes of destruction and processes of creation. Bone is maintained by osteoclasts, responsible for breaking down bone tissue, and osteoblasts, responsible for building it. There is a constant dynamic balance between the removal and deposition of bone in healthy individuals, but with age that balance tilts ever more towards the osteoclasts. This isn't the only contributing factor; consider for example the role of cross-links in weakening bone by altering the structural properties of its extracellular matrix independently of the activities of osteoblasts and osteoclasts. Imbalance is significant, however.
What upsets this balance? Inflammation is one candidate, and senescent cells are well known for their ability to generate chronic inflammation. Changes in vesicle-based cell signaling are also implicated, though it is unclear as to the degree to which senescent cells can be blamed here. There are plenty of papers examining more specific proteins, signals, and aspects of cell state in osteoblasts and osteoclasts, but these are very narrow slices of the problem and not all that illuminating. It is hard to place them in the bigger picture of cause and effect. It is likely that senescent cell clearance will be a widely available therapy for osteoporosis for quite some time before the effects of aging are fully understood in this one case.
It is very promising that the research community can now forge ahead with the destruction of senescent cells in animal studies and pin down their precise contribution to many varied conditions and processes of aging. Beyond the hope for therapies that might become accessible via medical tourism in the next few years, this is a time in which many new players may be drawn to the rejuvenation research field by the existence of real, working treatments targeting a cause of aging. Some will be convinced that repair approaches such as the SENS programs, that have incorporated senescent cell clearance as a goal for the past fifteen years, are the best way forward. More funding and more support are needed if we are to see the rest of the SENS agenda for rejuvenation therapies realized just as senescent cell clearance is being realized today.
Researchers have reported a causal link between senescent cells - the cells associated with aging and age-related disease - and bone loss in mice. Targeting these cells led to an increase in bone mass and strength. "While we know from previous work that the accumulation of senescent cells causes tissue dysfunction, the role of cell senescence in osteoporosis up to this point has been unclear. The novelty of this work for the bone field lies in the fact that, rather than targeting a bone-specific pathway, as is the case for all current treatments for osteoporosis, we targeted a fundamental aging process that has the potential to improve not only bone mass, but also alleviate other age-related conditions as a group."
In the study, researchers used multiple approaches to target senescent cells in mice with established bone loss between 20 and 22 months of age. That's the equivalent of over age 70 in humans. Approaches included using: (a) a genetic model where senescent cells can be killed off; (b) a pharmacological approach, where senolytic drugs eliminate senescent cells; and (c) a Janus kinase inhibitor - a drug that blocks the activity of Janus kinase enzymes - to eliminate the toxic products produced by senescent cells. "The effects of all three approaches on aging bone were strikingly similar. They all enhanced bone mass and strength by reducing bone resorption but maintaining or increasing bone formation, which is fundamentally different from all current osteoporosis drugs."
The benefits on bone found in elderly mice were not evident in younger mice. That, coupled with the finding that the senolytic drugs were effective when given only intermittently, supports the link between senescent cells and age-related bone loss. Researchers administered a senolytic drug combination (dasatinib and quercetin) once per month to eliminate senescent cells. "Even though this senolytic drug combination was only present in the mice for a couple of hours, it eliminated senescent cells and had a long-lasting effect. This is another piece of the mounting evidence that senolytic drugs are targeting basic aging processes and could have widespread application in treating multiple chronic diseases."
Aging is associated with increased cellular senescence, which is hypothesized to drive the eventual development of multiple comorbidities. Here we investigate a role for senescent cells in age-related bone loss through multiple approaches. In particular, we used either genetic (i.e., the INK-ATTAC 'suicide' transgene encoding an inducible caspase 8 expressed specifically in senescent cells) or pharmacological (i.e., 'senolytic' compounds) means to eliminate senescent cells. We also inhibited the production of the proinflammatory secretome of senescent cells using a JAK inhibitor (JAKi).
In aged (20- to 22-month-old) mice with established bone loss, activation of the INK-ATTAC caspase 8 in senescent cells or treatment with senolytics or the JAKi for 2-4 months resulted in higher bone mass and strength and better bone microarchitecture than in vehicle-treated mice. The beneficial effects of targeting senescent cells were due to lower bone resorption with either maintained or higher bone formation as compared to control mice. In vitro studies demonstrated that senescent-cell conditioned medium impaired osteoblast mineralization and enhanced osteoclast-progenitor survival, leading to increased osteoclastogenesis.
Collectively, these data establish a causal role for senescent cells in bone loss with aging, and demonstrate that targeting these cells has both anti-resorptive and anabolic effects on bone. Given that eliminating senescent cells and/or inhibiting their proinflammatory secretome also improves cardiovascular function, enhances insulin sensitivity, and reduces frailty, targeting this fundamental mechanism to prevent age-related bone loss suggests a novel treatment strategy not only for osteoporosis, but also for multiple age-related comorbidities.