Fight Aging!

Rising numbers of senescent cells are one of the root causes of aging, a process that arises from the normal operation of youthful metabolism, yet results in accumulated damage and failure over time. Senescent cells generate signaling that degrades tissue function, breaks down and remodels tissue structure, spurs chronic inflammation, and alters the behavior of surrounding cells for the worse. Evidence shows their presence to be a contributing cause of a range of common fatal age-related conditions. In a youthful body, near all cells that become senescent and fail to self-destruct as a result are promptly eliminated by the immune system. In an aged body, the immune system is worn and degraded; as a consequence many more senescent cells survive to linger. We are machines of interacting, dependent parts. Damage and failure in one component speeds the onset of damage and decline in others. The age-related failure of the immune system is an important part of the acceleration of functional decline in later life.

Much of the current work on methods to selectively destroy senescent cells, and thus produce a narrow form of rejuvenation, is focused on pharmaceuticals. Given that the immune system is already capable of destroying senescent cells in the normal course of events, why not immunotherapies, however? I'm only aware of the one company working along those lines, SIWA Therapeutics, and I believe that their immunotherapy approach doesn't interact at all with the natural immunosurveillance of senescent cells. Is it possible to do better than this, to build on the existing evolved mechanisms to induce high levels of clearance even in old and damaged immune systems? Alternatively, could the general methods of immune rejuvenation currently under consideration (such as restoring the thymus, destroying malfunctioning or overspecialized immune cells, or inducing greater stem cell production of immune cells) result in youthful levels of senescent cell destruction?

Whilst there is currently little understanding concerning the mechanisms governing macrophage mediated recognition of senescent cells, the processes are probably not specific to senescent cells. Rather, the more characterised molecular mechanisms associated with macrophage recognition during cancer immunosurveillance and apoptotic cell clearance may also be pertinent for senescence surveillance. Apoptotic cells have been shown to preferentially express specific cell surface antigens which can be recognised by naturally occurring antibodies (IgMs) that enable phagocytosis by macrophages. As such, it can be speculated that senescent cells may also express specific cell surface antigens which would not only provide insights into the mechanisms mediating immune clearance, but would also provide a means to specifically identify senescent cells in tissues.

Surface expression of CD47 acts as a "don't eat me" signal, sending inhibitory signals through SIRPα, a receptor expressed on the surface of macrophage, ensuring that healthy cells are not inappropriately phagocytosed. Therefore, the downregulation of CD47 would be required for macrophages to target damaged "self" cells. One study has demonstrated that induction of tumour cell senescence via c-Myc inactivation leads to the downregulation of CD47 which consequently promoted tumour regression. Whether CD47 downregulation in this instance is a specific response to c-Myc inactivation or activation of the senescence program is unclear. It would make biological sense to downregulate CD47 during cell senescence to enable removal of damaged "self" cells, but further research is required.

Immunotherapeutic strategies already in development for combating cancer may one day be repurposed for targeting senescent cells for the alleviation of age-related diseases. In addition, identifying further molecular changes associated with senescent cells, especially cell-type specific alterations, would be advantageous for developing therapeutic approaches for targeting senescent cells. Since senescent cells can also be beneficial in the short term, the elimination of acute senescent cells could be problematic. Therefore, the identification of therapeutic targets specific to chronic senescence which are absent in acute senescent cells would be highly desirable.

One of the mechanisms by which natural killer (NK) cells specifically recognise and kill senescent cells is via the surface expression of NKG2D ligands. Since many tumour cells also express NKG2D ligands, such ligands have been suggested to be a useful target for immunotherapeutic approaches in cancer, and so could be adapted for senescent cell clearance. For example, the use of engineered immune cells such as chimeric antigen receptor (CAR) T cells to target specific molecules on cancer cells has great potential as an anti-cancer therapy. As such, it may be possible to target senescent cells by engineering T cells to express a NKG2D CAR which recognise NKG2D ligands on the surface of senescent cells.

An adaption of cancer vaccines could also be considered for boosting immune clearance of senescent cells. Although a universal biomarker of cell senescence has not been identified, the exposure of senescent cell membranes to immune cells may evoke an immune response to antigens not yet identified. In one approach, senescence vaccines would involve the isolation of senescence specific antigens (SSAs) which are then exposed to dendritic cells, professional antigen presenting cells. In response to SSA uptake, dendritic cells process and express these antigens on their cell surface which can then be recognised by T cells. T cell interaction with these antigens promotes T cell activation, differentiation, and ultimately killing of target cells.

Link: https://doi.org/10.1016/j.arr.2018.02.001