Fight Aging!

Cells enter a senescent state constantly throughout life, largely as a result of reaching the Hayflick limit on cellular replication, but also due to damage and stress. Senescent cells cease to replicate and begin to secrete pro-inflammatory, pro-growth signals. This attracts the immune system to sites of potential concern, and in the case of physical injuries to tissue the signaling of senescent cells helps to coordinate repair. Senescent cells are normally cleared from tissues fairly quickly, being destroyed either by immune cells, or via programmed cell death mechanisms. With age, however, the pace of clearance slows and the pace of creation picks up as the body becomes more inflamed, stressed, and damaged.

Studies in mice make it clear that a burden of lingering senescent cells grows with age throughout the body, and that their secreted signals actively disrupt tissue structure and function when maintained for the long term, changing the behavior of other cells for the worse. Targeted destruction of senescent cells by first generation senolytic drugs, or the genetic engineering techniques that preceded those drugs, produces rapid rejuvenation. Life span is extended, measures of many different age-related diseases are reversed. This happens quite quickly. As one might expect, a great deal of attention is now focused on refining strategies for clearing senescent cells, both in academia and in biotech companies.

While the research and development communities are focused on working towards new, more selective senolytics, I think it worth noting that the cheap, safe senolytics that already exist receive far less attention than they should. The combination of dasatinib and quercetin has a good safety profile in clinical trials, and has been shown to clear senescent cells in humans to about the same degree as it does in mice. It can be prescribed off-label by physicians. One might expect a good deal more ongoing effort to prove that this is in fact reversing aging in humans than is actually taking place: only a few, slow academic clinical trials and little exploration of dosing. This is an area in which philanthropists might do a great deal of good by sponsoring low-cost, well-managed trials that are intended to prove that off-label approaches of this nature are actually as good as the animal data might indicate.

Senescent cells at the crossroads of aging, disease, and tissue homeostasis

The variation in senescent cell phenotypes creates some challenges in their elimination, as not every pathway may be shared between senescent cells, as is often observed during cancer. Furthermore, beneficial aspects of senescent cells create caveats for when and how they should be eliminated, as disruption of healing, developmental, or regenerative processes in pursuit of prevention or treatment of chronic diseases is less desirable. Thus, development of next-generation precision senolytic therapies that take advantage of potential distinctions between beneficial and detrimental senescent cells might improve safety by allowing selective clearance of those that drive the condition being treated.

Since current strategies focus on targeting pathways that promote cell survival, collateral damage to other cell types, as observed in the case of thrombocytopenia with the BCL-2 family inhibitor ABT-263, are a current target for improvement. Indeed, a modified version of ABT-263 that cannot be activated by platelets has removed one form of collateral damage, and others are currently in development.

One aspect of senescence that might be amenable to precision targeting is the temporal nature of acute vs. chronic senescence. Many beneficial aspects of senescence described thus far are transient in nature, and typically occur within a few days following induction/initiation of senescence, while chronic accumulation of senescent cells has been linked to interferon activation and age-related chronic disease. Therefore, perhaps the simplest way differentiating between beneficial and deleterious senescent cells may be by targeting effects that occur in chronic senescence and not during the more transient early response. This approach may improve outcomes in the future by improving the safety of senolytic use and more selectively only targeting those senescent cells that drive more degenerative chronic pathology.

Overall, identification of senescent cell types and their role in causing human disease will be invaluable in the creation of new senotherapeutics that might allow these contrasting phenotypes to be selectively targeted. This is a major potential benefit of the recently announced SenNet Consortium, which will map senescent cells in both murine and human tissues and help to catalog the diversity, abundance, spatial localization, and secretome of senescent cells in human and murine conditions. Beyond identification of senescent cell heterogeneity, these data will also help answer questions about translatability of findings between species, identify new biomarkers of senescence, and give indications about the origins of senescent cells across the lifespan.