Clinical strategies and animal models for developing senolytic agents

• Published in: Experimental gerontology 2015-08, Vol.68, p.19-25
• Main Authors: Kirkland, James L., Tchkonia, Tamara
• Format: Article
• Language: English
• Subjects: Aging - drug effects; Animals; Cellular senescence; Cellular Senescence - drug effects; Chronic Disease; Disabled Persons; Drug Discovery - methods; Healthspan; Humans; Models, Animal; Senescence-associated secretory phenotype; Senolytic
• ISSN: 0531-5565; 1873-6815
• DOI: 10.1016/j.exger.2014.10.012

Aging is associated with increasing predisposition to multiple chronic diseases. One fundamental aging process that is often operative at sites of the pathology underlying chronic age-related diseases is cellular senescence. Small molecule senolytic agents are being developed. For successful drug development: 1) appropriate animal models of human age-related diseases need to be devised. 2) Models have to be made in which it can be proven that beneficial phenotypic effects are actually caused through clearing senescent cells by putative senolytic agents, as opposed to “off-target” effects of these agents on non-senescent cells. 3) Models are needed to test efficacy of drugs and to uncover potential side effects of senolytic agents. Development of the optimal animal models and clinical trial paradigms for senolytic agents warrants an intensive effort, since senolytic agents, if successful in delaying, preventing, alleviating, or reversing age-related diseases as a group would be transformative. •Scenarios for proof-of-concept clinical studies of senolytic agents are proposed.•Animal models for testing candidate senolytics are considered.•Models are needed that reflect potential clinical applications of senolytic agents.•Animal models for determining dosing intervals and side effects will be important.•Whether senescent cell removal related to drugs is the cause of phenotype resolution must be proven.