Fight Aging!

Cellular senescence contributes meaningfully to near all age-related conditions, judging by the research of the past few years. In only a very few cases has clearance of senescent cells failed to perform well as a basis for therapy. In just the past year, papers have been published on the role of senescent cells in twenty or more very different age-related conditions. In many cases, the researchers demonstrated that clearance of a sizable fraction of the senescent cells present in tissues, using one of the available senolytic mouse models or small molecule therapies, reversed the progression of the age-related condition under study. When it comes to the diseases of aging, senolytic therapies are about as close to a panacea as it is possible to be, at least in animal studies.

Cells become senescent constantly, largely somatic cells reaching the Hayflick limit on replication. Cells also become senescent in reaction to DNA damage, environmental toxicity, tissue injury, and the signaling of senescent neighbors, however. Senescence is useful in the short term, assisting regeneration and suppressing cancer risk. But not all senescent cells self-destruct or are removed by the immune system, and the processes of clearance appear to slow down and become less efficient with age. The numbers of lingering senescent cells grow throughout the body, and the inflammatory signaling produced by these cells, useful in the short-term, becomes very harmful when sustained over months and years.

Today I'll point your attention to an open access review paper that discusses cellular senescence as a contributing cause of osteoporosis. It isn't the only contributing cause, but it appears sufficient in and of itself to cause the loss of bone mass and strength. Osteoporosis is, at the high level, an imbalance between the number and activity of cells building bone (osteoblasts) and the number and activity of cells breaking down bone (osteoclasts). Both osteoblasts and osteoclasts are continually active, and bone tissue is constantly remodeled. In youth, these processes of creation and destruction are in balance. The inflammatory signaling of senescent cells helps to disrupt that balance, tipping it in favor of osteoclast activity.

Senile Osteoporosis: The Involvement of Differentiation and Senescence of Bone Marrow Stromal Cells

Senile osteoporosis is an age dependent bone disorder occurring both in men and women, which has become a worldwide health concern. The functional change of bone marrow stromal cells (BMSCs) has been demonstrated to contribute to senile osteoporosis, showing as BMSCs differentiate into fewer osteoblasts, but more adipocytes, and BMSCs become senescent. Besides the critical involvement of BMSCs in senile osteoporosis, BMSCs are also a favorite cell source for cell therapy and have been applied for osteoporosis treatment. Therefore, uncovering the underlying mechanisms of function changes of BMSCs during senile osteoporosis is important not only for better understanding the involvement of BMSCs in senile osteoporosis, but also for manipulating them for clinical applications.

Recent findings demonstrate that numerous transcriptional factors, signaling pathways, epigenetic regulations and other factors play key roles in regulating the differentiation and senescence of BMSCs, the alteration of which contributes to senile osteoporosis. Runx2 and PPARγ are two key transcription factors that are responsible for osteogenic differentiation and adipogenic differentiation of BMSCs, respectively. Decreased Runx2 expression and increased PPARγ results in senile osteoporosis. NRF2 and FOXP1 are two transcription factors related to the senescence of BMSCs by regulating antioxidant responsive genes. They are decreased with age, thus, leads to BMSCs senescence and bone loss. BMP signaling, Wnt signaling, and Notch signaling pathways all show dual roles in regulating osteogenic and adipogenic differentiation of BMSCs. They function either by targeting the downstream transcription factors, such as Runx2, PPARγ, or by cross-talking with each other.

Recently, p53/p21 and p16/Rb signaling pathways have been demonstrated to be involved in the senescence of BMSCs, which is one main cause of senile osteoporosis. These signaling pathways are activated by DNA damage or reactive oxygen species (ROS) accumulation and finally lead to cell senescence. Besides, BMP signaling and Wnt signaling also participate in inducing senescence of BMSCs by inducing ROS, triggering DNA damage or interacting with p53/p21 signaling. Moreover, epigenetic regulation also plays important role in regulating differentiation and senescence of BMSCs. The epigenetic regulation, such as DNA methylation and histone acetylation, regulates the differentiation and senescence of BMSCs by regulating the expression of transcription factors or disturbing the binding of transcription factors to specific gene's promoter. These findings provide an understanding of the molecular mechanisms underlying the altered differentiation and senescence of BMSCs during senile osteoporosis and provide potential targets or methods for treating senile osteoporosis.

Direct transplantation of normal BMSCs and elimination of senescent BMSCs both efficiently treat senile osteoporosis. Transplantation of normal allogeneic BMSCs into aged mice shows both prevention and treatment effects on senile osteoporosis. In addition, modification of the differentiation ability of BMSCs through targeting some genes can be applied for treating senile osteoporosis. More recently, elimination of senescent BMSCs has been demonstrated to be an effective therapeutic method for treating senile osteoporosis. All these findings strongly demonstrate that BMSCs can be applied for clinical treatment of senile osteoporosis by directly transplanting normal BMSCs, modifying differentiation of BMSCs, or eliminating senescent BMSCs. However, present findings are obtained from animal studies. Further clinical trials are needed.