The estimated “natural” life span of humans is ∼30 years, but improvements in working conditions, housing, sanitation, and medicine have extended this to ∼80 years in most developed countries. However, much of the population now experiences aging-associated tissue deterioration. 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.
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. Another drug, UBX1967, a BCL-2 family inhibitor specifically tailored for diseases of the aging eye, is also advancing to human testing. Multiple clinical trials treating diverse diseases of aging with senolytic drugs are expected to follow soon. This includes two-step cancer treatment approaches whereby malignant cells are first forced into a senescent state by one drug and then eliminated with a senolytic agent. 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.