(A form of that compound eventually became UBX0101.) Another lead emerged from a drug screen conducted by Daohong Zhou, a cancer researcher now at the University of Florida at Gainesville, who in 2014 became a scientific cofounder of Unity. Unity’s first promising candidate came from Campisi’s lab, where researchers discovered that a small-molecule inhibitor of MDM2 called nutlin-3a had senolytic activity. “It’s a really hit-and-run approach,” says Paul Robbins, a molecular biologist at the University of Minnesota Medical School in Minneapolis. And whereas the rapid pace of cancer development usually necessitates giving high doses of drug on a frequent basis, senescence targeting often works at lower doses administered intermittently. But whereas a cancer drug must eliminate every last tumor cell to avoid disease recurrence, a senolytic can still be effective if it purges only a meaningful fraction. Now the goal was to find drug compounds capable of doing the same thing in people.Įarly leads mostly came from the world of oncology, where the aim is also to induce cell death. The van Deursen mice had lost their senescent cells through a trick of genetic engineering. They looped in Campisi, who was working on a similar transgenic mouse model for selective senescent cell destruction at the time, and Unity (initially known as Cenexys) was born. Within weeks of that report, van Deursen had teamed up with serial biotech entrepreneur Ned David. In the rapidly aging mice, the senescent ouster retarded many aspects of the usual fast-tracked tissue degeneration. Their paper detailed a transgenic strategy (devised by Kirkland and adapted from a technique 4 pioneered by Philipp Scherer, a fat-cell researcher now at the University of Texas Southwestern Medical Center in Dallas) for selectively purging mice of cells in stable replicative arrest by targeting a protein characteristic of senescence: the tumor suppressor p16 lnk4a (ref. But in 2011, van Deursen - working with a Mayo colleague, gerontologist James Kirkland - showed that one could simply do away with the senescent cells instead. To many researchers, suppressing the SASP seemed like the most obvious way of combating the ills of senescence to treat cancer and diseases of aging. Judith Campisi, a cell biologist at the Buck Institute for Research on Aging in Novato, California who led one of the three teams that first described this complex network of immune-modulating molecules, gave the phenomenon a name: the senescence-associated secretory phenotype, or SASP 3 (Fig. They kept tumors at bay, but also fueled the aging process through a toxic brew of secreted interleukins, chemokines, growth factors, enzymes and other molecules that were arousing local inflammation and damaging nearby cells. In the face of replicative stress, cells were thought to enter senescence as a way to avoid becoming malignant.īut in van Deursen’s mice, the cells seemed to have a dark side. The cells had stopped dividing, but refused to die.Īt the time, this zombie-like state of cellular existence - first described 2 by biogerontologist Leonard Hayflick and cytogeneticist Paul Moorhead at the Wistar Institute in 1961 - was chiefly understood as a defense mechanism against cancer. Instead, they just seemed to age prematurely 1.īy the time the mice were a few months old, their eyes were pocked with cataracts, their skin was wearing thin, their muscles were wasting away, and - conspicuously - their organs were chock-full of senescent cells, trapped in a state of long-term cell-cycle arrest like mosquitoes in amber. He expected the resulting chromosome instability to lead to tumor formation. In the early 2000s, van Deursen engineered a strain of mice with low levels of the mitotic checkpoint protein BubR1, which helps maintain the proper segregation of chromosomes during cell division. The idea of therapeutically targeting senescence traces its roots back to the laboratory of Jan van Deursen, a molecular biologist who directed the mouse transgenic and knockout core facility at the Mayo Clinic for over 20 years.
0 Comments
Leave a Reply. |