A Popular Science Overview of the Development of Senolytic Therapies
This popular science article is a decent introduction to the still young field of senolytic therapies to selectively destroy senescent cells in aged tissues. That said, the author fails to note any of the numerous senolytic programs other than those of the Mayo Clinic and Unity Biotechnology - which represent an increasingly small portion of the field as a whole. The accumulation of lingering senescent cells is one of the contributing causes of aging; these errant cells secrete a potent mix of signals that spur chronic inflammation, change cellular behavior for the worse, and destructively remodel tissue structure. Senolytic therapies have been demonstrated in mice to turn back the progression of numerous age-related diseases, and results from early human trials have been promising.
Many researchers now view senescence as a beneficial process that evolved as a developmental and cancer prevention mechanism, but one that came with a tradeoff of the damage senescent cells can cause as they accumulate with age. There are still many unanswered questions about how these cells function, but it is already clear to scientists in the field that senescent cells influence a range of age-related pathologies, at least in rodents. Genetic ablation of senescent cells reduces the number of atherosclerotic plaques in mice, improves cartilage development in mouse models of osteoarthritis, boosts bone strength in murine models of osteoporosis, and even staves off neurodegenerative symptoms in models of Alzheimer's disease. These findings have a number of scientists thinking: If clearing senescent cells had such beneficial effects on health, could drugs be developed to do just that?
James Kirkland's group at the Mayo Clinic had started to search for senolytic agents long before the scientific community was convinced of senescent cells' role in aging, but it took him years to work out a good strategy to identify them. In the mid-2000s, his team tried developing toxins or antibodies that target senescent cells, but none of these approaches succeeded in killing senescent cells while sparing non-senescent ones. In 2013, it occurred to Kirkland's team to target the molecular machinery known to be used by senescent cells to defy death. The cells must have those mechanisms in place to avoid undergoing the apoptotic processes that would typically follow exposure to the high levels of harmful proteins they are producing, the team reasoned. Using a bioinformatics approach, the researchers identified several anti-apoptotic pathways that are upregulated in senescent cells, including certain pathways used by malignant B cells to avoid apoptosis and cause lymphoma.
They then screened for approved drugs and natural products that targeted those pathways and thus selectively killed senescent cells. To the group's surprise, two compounds appeared very effective in killing senescent cells in vitro as well as in mice: dasatinib, approved in the US to treat certain leukemias and lymphomas, and quercetin, which is used as a nutritional supplement. "I thought we'd have to screen millions of compounds to get drugs that regulate senescence." But it took fewer than 50 drugs to get the first hits.