Longevity is in the genes: half of lifespan is heritable<\/p>\n <\/a><\/p>\n Lu had spent three years trying different approaches \u2014 and had failed. But this time looked different. Lu had introduced three genes into mouse eyes that should revert cells to a younger developmental state. And there under the microscope he thought he could see signs of new growth. Now, he was asking his labmate to confirm his suspicions. \u201cI was so nervous,\u201d says Lu, now a geneticist at the Whitehead Institute in Cambridge, Massachusetts.<\/p>\n When the verdict was in, Lu remembers jumping up and down and high-fiving his colleagues in the microscope room. Yet, he couldn\u2019t help but worry that the celebration might be short-lived.<\/p>\n Lu and his colleagues were among several teams trying to \u2018partially reprogram\u2019 cells to a younger state<\/a>. Now, seven busy years later, his discovery1<\/a> is the basis for a clinical trial set to start this year. It will be a pivotal test of a burgeoning field that has attracted researchers in academia and industry \u2014 as well as billions of dollars of private investment and the attention of Silicon Valley\u2019s tech elite. The trial will attempt to answer an evocative question: can old cells safely be made young again?<\/p>\n The answer, some say, could reshape the very concept of ageing. It could provide a way to rejuvenate old organs<\/a> \u2014 or, in its most extreme and optimistic formulation, the entire human body. Partial reprogramming also promises to write a new chapter for the foundational discovery, 20 years ago, that adult cells can be reprogrammed to an embryonic-stem-cell-like state<\/a>2<\/a>.<\/p>\n But risks loom just as large as the promises: push a cell too close to that stem-like state and it could lose its ability to function properly, and even become cancerous. \u201cWhen cells lose their identity, we know that comes with some forms of danger,\u201d says Tamir Chandra, who studies ageing at the Mayo Clinic in Rochester, Minnesota.<\/p>\n Rejuvenation factors<\/p>\n In 2006, Shinya Yamanaka, a stem-cell biologist then at Kyoto University in Japan, and his colleague discovered that four proteins known as transcription factors \u2014 later dubbed Yamanaka factors \u2014 could transform an adult cell into an induced pluripotent stem (iPS) cell that is capable of taking on new identities2<\/a>. The finding was hailed as breakthrough that could pave the way to stem-cell based therapies in which iPS cells are coaxed into adopting a certain fate and then injected into a patient. In February, regulators in Japan endorsed the approval of the first such iPS-cell-based therapies<\/a> \u2014 for severe heart failure and Parkinson\u2019s disease.<\/p>\n But some researchers wondered whether the Yamanaka factors might be put to another use. In 2010, Prim Singh, a chromatin biologist now at Nazarbayev University in Astana, Kazakhstan, and his colleague Fred Zacouto proposed that researchers could introduce the genes that encode the factors briefly, but then turn them off before cells become completely reset (see \u2018Turning back cellular time\u2019). Then, they suggested, the cells might become younger without losing their identity3<\/a>.<\/p>\n It was a difficult idea for some researchers to accept, Singh says: at the time, most were focused on exploring iPS cells<\/a>, not rejuvenation.<\/p>\n In 2016, another publication pushed the nascent field into the limelight. Juan Carlos Izpis\u00faa Belmonte, a stem-cell biologist then at the Salk Institute for Biological Studies in La Jolla, California, and his colleagues reported that they had temporarily and repeatedly turned the Yamanaka factors on and off in mice4<\/a>. This cyclic expression extended the lifespan of model animals with a condition called progeria, which causes accelerated ageing. In normal, old mice, the factors improved regeneration of damaged muscle and pancreatic tissue.<\/p>\n The next few years were a boon for partial reprogramming efforts in mice. Scientists applied Yamanaka factors to rejuvenate skin cells and reduce scar tissue5<\/a>, to boost muscle regeneration6<\/a> and to allow the heart cells to regenerate after injury7<\/a>, to name just a few examples. One study even suggested that cyclic expression of the Yamanaka factors in the brains of aged mice improved their performance on memory tests8<\/a>.<\/p>\n Different groups experimented with ways to make the Yamanaka factors safe. Some researchers cycled genes on and off, others turned them on only transiently, in the hope that they would not be active long enough to fully reprogram the cells. Although the approaches seemed to be safe in mice, doubts lingered about leaving cells with unknown potential in the body. \u201cI\u2019d argue that a dinosaur is not a good pet, even if you trained it very well,\u201d says Daniel Ives, chief executive of Shift Bioscience in Cambridge, UK.<\/p>\n How your brain controls ageing \u2014 and why zombie cells could be key<\/p>\n <\/a><\/p>\n![\"\"](\"https:\/\/media.nature.com\/w400\/magazine-assets\/d41586-026-01024-7\/d41586-026-01024-7_52232390.jpg\"\/)
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