Fight Aging!

Cells become senescent in response to a variety of circumstances. The vast majority are cases of replicative senescence, somatic cells reaching the Hayflick limit. Cell damage and toxic environments also produce senescence, and senescent cells are also created as a part of the wound healing process. A senescent cell ceases replication and begins to secrete inflammatory and pro-growth signals, altering the nearby extracellular matrix and behavior of surrounding cells - even encouraging them to become senescent as well.

Near all senescent cells last a short time only, as they self-destruct or are removed by the immune system. When the presence of senescent cells is transient, their signals are a useful part of the processes of regeneration following injury. Cellular senescence also serves to lower the risk of cancer, ensuring that cells with significant DNA damage (or that might gain significant DNA damage due to a locally genotoxic environment) are prevented from replication. Senescent cells linger with age, however. In older tissues they last longer and are created in greater numbers, and their signals become very harmful when present for the long term. In this way, cellular senescence is an important cause of aging.

While compelling evidence has existed for decades for the accumulation of senescent cells to be a contributing cause of aging, this area of study has only comparatively recently found acceptance and significant funding. A decade ago near all work on senescent cells took place in the context of cancer, carried out by researchers who didn't think that senescence was all that relevant to aging at all. Cancers generate senescent cells by their very nature, and there is a complex relationship between cellular senescence and cancerous tissues. Senescence is an initially protective mechanism when the number of cells (cancerous and senescent) is small, locking down replication and summoning immune cells. Given established cancer tissue, or the burden of senescent cells in old tissues, then the inflammatory, pro-growth signaling of senescent cells instead encourages cancer growth and spread. Some cancers, particularly leukemias, even appear to aggressively generate more senescent cells in order to accelerate their growth.

Bone Marrow Senescence and the Microenvironment of Hematological Malignancies

Bone marrow (BM) disorders, including myeloproliferative neoplasm (MPN), myelodysplastic syndrome (MDS), leukemia, and multiple myeloma are largely diseases of the elderly and as our population ages their incidence will likely continue to increase and with it, disease associated mortality. Acute myeloid leukemia (AML), alone accounted for 85,000 deaths globally in 2016 and multiple myeloma caused 98,000 deaths. Hematopoietic malignancies including AML multiple myeloma, MPNs, and MDS are highly dependent on the bone marrow microenvironment for survival.

The BM is the primary hematopoietic organ in adults. It comprises of blood vessels, nerve tissue, and a heterogeneous population of cells that are either directly involved in the generation of blood cells or support the hematopoietic function of the tissue. Together, all the components of the BM tightly regulate normal hematopoiesis to ensure adequate production of mature blood cells. In blood cancers, however, this process is disrupted resulting in cytopenias and immunosuppression. In AML, this is thought to be instigated by leukemic cells directly blocking differentiation of normal hematopoietic stem cells (HSC), as well as the manipulation of other BM-derived cells (including macrophages, endothelial cells, fibroblasts, and adipocytes).

Cellular senescence is the irreversible arrest of cell proliferation. It is associated with the secretion of numerous pro-inflammatory cytokines, chemokines, proteases, and growth factors, known as the senescence-associated secretory phenotype (SASP). It occurs as a response to cellular damage and is thought to have evolved to both suppress development of cancer and to promote tissue repair and wound healing. In the short term the SASP plays an important role in recruiting immune cells to sites of cellular damage in order to promote tissue repair, limit tissue fibrosis, and clear senescent cells. However, it appears that this process becomes less effective with age and senescent cells gradually accumulate. Overall the senescent response becomes maladaptive and there is now increasing evidence that it contributes to a number of age-related phenotypes and pathologies. When it persists over time the SASP has paradoxically been shown to disrupt a number of cellular and tissue functions to create a pro-tumoral and chemotherapy-resistant environment.

Age related changes within the BM microenvironment contribute to the development of hematological malignancies. These changes can also affect disease progression and response to treatment, and this may contribute, for example, to poorer outcomes observed in older patients with AML, which are not sufficiently explained by the differences in adverse prognostic features. AML cells were shown to induce a senescent phenotype in BM stromal cells (BMSCs) resulting in the secretion of a SASP which supports the survival and proliferation of leukemic blasts. In vivo experiments, using the p16-3MR model of senescence, showed that leukemic blast derived superoxide induces p16INK4A driven senescence in BMSCs and that deletion of these senescent BMSCs slows tumor progression and prolongs animal survival.

mesenchymal stem cells which creates an environment that supports myeloma cells growth, although the exact relationship between the myeloma cells and the senescent mesenchymal stem cells remains to be explored further. However, as with a number of solid tumors it is becoming increasingly clear that a senescent microenvironment favors survival of malignant cells in the bone marrow. It remains yet to be determined whether an existing senescent environment, as is observed with increasing age, drives the development of these malignancies or whether in fact the expansion of clonal cell populations within the bone marrow microenvironment drives the senescent process, accelerates aging and impairs immunosurveillance and clearance of both senescent cells and pre-malignant cells. It is also possible that these two processes together create the senescent BM microenvironment that is observed both with increasing age and in BM malignancies.

However, as there is increasing evidence that senescence in the bone marrow microenvironment forms a fundamental part of the malignant phenotype, this raises the question whether targeting the "benign" senescent cells in the BM microenvironment could disrupt the supportive nature of the tumor microenvironment and as a result impair tumor survival.