Reviewing the Development of Therapies to Target Cellular Senescence
Senescent cell accumulation is an important feature of aging, both for its contribution to the chronic inflammation of old age, as well as the disruption of tissue function that leads to age-related disease. Targeting senescent cells for destruction via senolytic drugs is an area of clinical development that is growing in popularity, but it isn't the only possible approach. This paper is interesting for its taxonomy of drugs and other compounds that either selectively destroy senescent cells, prevent cells entering senescence, or mute portions of the senescence-associated secretory phenotype (SASP) that causes harm to surrounding cells and tissues. These strategies will likely turn out to be widely divergent in risk and outcome; selective destruction still appears the best of them to my eyes. But read the whole paper, as the summary below isn't the point of it, but rather the list and categorization it provides.
Aging leads to a high burden on society, both medically and economically. Cellular senescence plays an essential role in the initiation of aging and age-related diseases. Recent studies have highlighted the therapeutic value of senescent cell deletion in natural aging and many age-related disorders. However, the therapeutic strategies for manipulating cellular senescence are still at an early stage of development. Among these strategies, therapeutic drugs that target cellular senescence are arguably the most highly anticipated. Many recent studies have demonstrated that a variety of drugs exhibit healthy aging effects.
Senolytics are agents that selectively induce the apoptosis of senescent cells. This type of drug can be classified into BCL family inhibitors, PI3K/AKT inhibitors, and FOXO regulators. The BCL family is composed of pro-apoptotic proteins and pro-survival proteins. The PI3K/AKT pathway is one of the pro-survival pathways in senescent cells. Studies have shown that phosphoinositide 3-kinase (PI3K) is involved in protecting cells against apoptosis. FOXOs controls cell functions such as growth, survival, metabolism, and oxidative stress. Studies have shown that FOXO4 can interact with p53, inhibit p53-mediated apoptosis, and thus maintain the vitality of senescent cells.
Another major feature of senescent cells is the acquisition of SASP. Drugs that target SASP, such as antioxidants, Wnt/β-catenin inhibitors, and Janus kinase (JAK) inhibitors, also have healthy aging effects since SASP is associated with a pro-inflammatory status and a faster aging rate.
I hope that the main stream therapies will come before reserachers start and finish whole careers on the subject, though