Today I noticed a recent paper in which the researchers tested a senolytic drug in the course of working on mechanisms relevant to the development of osteoporosis. Once they realized that cellular senescence might be involved in the development of osteoporosis, they put the drug to work in order to clear out senescent cells and see if that improved the picture. This is something we'll be seeing a lot more of in future research papers, whether in cell cultures or in animal models, and it certainly makes a great deal of difference to the quality of the evidence produced by a study. When researchers can address a specific cause of aging in a narrowly targeted way, rather than simply observing it, then it becomes a great deal easier to (a) show that the mechanism is in fact causing age-related disease, and (b) map the size of its effect.
The weakening of bone known as osteoporosis affects every older individual. It is, at root, an imbalance between the constantly ongoing activities of bone creation and absorption: too few osteoblasts creating bone and too many osteoclasts removing it. Any therapy that can reliably and safely tilt back the balance of activity towards creation should be helpful, but none of the approaches to date address the root causes. Instead, as is usually the case in modern medicine, researchers focus on proximate causes, trying to force cellular behavior back towards a more youthful pattern of activity without addressing the reasons why that pattern has changed. This is usually going to be hard to do well - as is any attempt to keep a damaged engine running without fixing the damage - which is why most present treatments for most age-related diseases are marginal at best.
Senescent cells accumulate with age, a lingering tiny minority of all such cells, the few that manage to evade destruction via programmed cell death or the immune system. They might be few in number, but those numbers grow over time and they cause great harm. These cells behave badly, generating signals that spur chronic inflammation, destructively remodel the extracellular matrix, and change the behavior of nearby cells for the worse as well. This adds up to produce failing organ function and disruption of vital processes such as tissue regeneration. Researchers have shown that removing senescent cells can fairly rapidly remove their malign influence as well, to some degree restoring tissue function and to some degree turning back the clock on measures of aging. Linking osteoporosis to increased numbers of senescent cells offers the hope of a better class of therapy for this condition, one that will arrive in clinics within the next few years. Numerous research groups and companies are presently involved in producing the means to selectively destroy these unwanted, harmful cells.
Old age is, by far, the most important risk factor for the development of osteoporosis. In bone biopsies from elderly men and women, the age-related loss of both cancellous and cortical bone is associated with decreased mean wall thickness - the histomorphometric hallmark of decreased bone formation. Loss of bone mass in aged rodents is associated with a decline in the number of osteoblasts, the cells responsible for the synthesis and mineralization of the bone matrix. Because osteoblasts are postmitotic cells with a short lifespan, they need to be constantly replaced with new ones. Osteoblasts arise from progenitors of mesenchymal origin, which express the transcription factors Runx2 and Osterix1 (Osx1).
The decline in the regenerative capacity of most tissues with old age has led to the idea that aging is due, at least in part, to increased cell senescence causing the loss of functional adult stem/progenitor cells. Cellular senescence is a process in which cells stop dividing and initiate a gene expression pattern known as the senescence-associated secretory phenotype (SASP). Several stimuli associated with aging promote senescence. Because the number of senescent cells increases in multiple tissues with aging, it has been widely assumed that senescence contributes to aging. Importantly, ablation of senescent cells using genetically modified mice prolongs lifespan and delays age-related pathologies in naturally aged mice or progeria models. We have recently shown that senescent cells induced by normal aging or ionizing radiation (IR) can be eliminated by administration of ABT263, a drug that kills senescent cells selectively; and clearance of senescent cells rejuvenates aged tissue stem and progenitor cells.
In both humans and rodents, the reduced osteoblast number in the aging skeleton has been attributed to changes in bone marrow-derived mesenchymal progenitors, including a decrease in the number of mesenchymal stem cells, defective proliferation/differentiation of progenitor cells, increased apoptosis, or increased senescence. However, it remains unclear whether the number of senescent osteoblast progenitors increases with old age. Moreover, the contribution of the decline in osteoblast progenitor number to the decrease in bone formation with age remains unknown because of the lack of methods to specifically identify and isolate mesenchymal progenitors. Therefore, the molecular mechanisms responsible for the decline in osteoblast number have remained elusive. To overcome these limitations, we generated a mouse model in which osteoblast progenitors are labeled with a red fluorescent protein (TdRFP) to facilitate their isolation by fluorescence-activated cell sorting (FACS) and examination of the effects of aging in freshly isolated cells. We present evidence that the decline in bone formation with age can be accounted for by a decrease in the number of osteoprogenitors due to DNA damage-induced cell senescence.
We report that the number of TdRFP-Osx1 cells, freshly isolated from the bone marrow, declines by more than 50% between 6 and 24 months of age in both female and male mice. Moreover, TdRFP-Osx1 cells from old mice exhibited markers of DNA damage and senescence. Bone marrow stromal cells from old mice also exhibited elevated expression of SASP genes, including several pro-osteoclastogenic cytokines, and increased capacity to support osteoclast formation. These changes were greatly attenuated by the senolytic drug ABT263. Together, these findings suggest that the decline in bone mass with age is the result of intrinsic defects in osteoprogenitor cells, leading to decreased osteoblast numbers and increased support of osteoclast formation.