Here, one of the leading researchers working on the biochemistry of senescent cells - and their relevance to aging - considers the state of development of senolytic therapies. These are treatments, largely small molecule drugs at this stage, but also including suicide gene therapies, immunotherapies, and more, that are capable of selectively destroying some fraction of the senescent cells present in old tissues. There is tremendous enthusiasm in the scientific and development communities for the potential to create significant degrees of rejuvenation via this approach. The results in mice are far and away more impressive and reliable than anything else that has yet been tried in the matter of aging and age-related disease. Simple one time treatments with senolytics lead to significant extension of life span and reversal of aspects of age-related disease. Leading researchers, of course, have to be far more muted when writing for scientific journals, so the tone here is more cautious than enthused.
Healthy aging is limited by a lack of natural selection, which favors genetic programs that confer fitness early in life to maximize reproductive output. There is no selection for whether these alterations have detrimental effects later in life. One such program is cellular senescence, whereby cells become unable to divide. Cellular senescence enhances reproductive success by blocking cancer cell proliferation, but it decreases the health of the old by littering tissues with dysfunctional senescent cells (SNCs). In mice, the selective elimination of SNCs (senolysis) extends median life span and prevents or attenuates age-associated diseases. This has inspired the development of targeted senolytic drugs to eliminate the SNCs that drive age-associated disease in humans.
SNCs produce a bioactive "secretome," referred to as the senescence-associated secretory phenotype (SASP). This can disrupt normal tissue architecture and function through diverse mechanisms, including recruitment of inflammatory immune cells, remodeling of the extracellular matrix, induction of fibrosis, and inhibition of stem cell function. Paradoxically, although cellular senescence has evolved as a tumor protective program, the SASP can include factors that stimulate neoplastic cell growth, tumor angiogenesis, and metastasis, thereby promoting the development of late-life cancers. Indeed, elimination of SNCs with aging attenuates tumor formation in mice, raising the possibility that senolysis might be an effective strategy to treat cancer.
Given that our knowledge of SNCs in vivo is limited, how should researchers identify senolytic drug targets? One strategy is to identify vulnerabilities shared by cancer cells and SNCs and then use tailored variants of anticancer agents to target such vulnerabilities to selectively eliminate SNCs. Although cancer therapeutics that interfere with cell division are unsuitable as senolytic drugs, agents that block the pathways that cancer cells rely on for survival might be worth pursuing as senolytics. For example, resistance to apoptosis (a form of programmed cell death) is a feature shared by cancer cells and SNCs. Proof-of-principle evidence for the effectiveness of this strategy comes from targeting the BCL-2 protein family members: BCL-2, BCL-XL, and BCL-W. These antiapoptotic proteins are frequently overexpressed in both cancer cells and SNCs. Two targeted cancer therapeutic agents, ABT-263 and ABT-737, have been shown to selectively eliminate SNCs in mice by blocking the interactions of BCL-2, BCL-XL, and BCL-W.
Senolytic drugs that inhibit targets originally discovered in oncology could yield promising first-generation drugs to treat humans. However, this strategy may not accomplish the long-term goal of developing ideal senolytics that selectively, safely, and effectively eliminate SNCs upon systemic administration. Efforts to identify such "next-generation" senolytics could nonetheless benefit from general principles that have been used in anticancer drug discovery. For instance, it will be important to focus drug development on age-associated degenerative diseases in which SNCs are clear drivers of pathophysiology and in which senolysis could be disease modifying (e.g., osteoarthritis and atherosclerosis).
As knowledge of the fundamental biology and vulnerabilities of SNCs expands, the rational design of targeted senolytics is expected to yield therapies to eliminate SNCs that drive degeneration and disease. This positive outlook is based on successes in oncology and because the main limitation of cancer therapies - the clonal expansion of drug-resistant cells - does not apply to SNCs. Additional confidence comes from the recent progress in bringing senolytic agents into clinical trials. The first clinical trial is testing UBX0101 for the treatment of osteoarthritis of the knee. Success in these first clinical studies is the next critical milestone on the road to the development of treatments that can extend healthy longevity in people.