Removing worn-out cells led to a dramatic increase in the median life span of mice. An interesting idea very different from conventional approaches, but a long way from human use.
If the results hold up in people, they could lead to an entirely new way to treat aging, says gerontology and cancer researcher Norman Sharpless at the University of North Carolina School of Medicine in Chapel Hill. Most prospective antiaging treatments would require people to take a drug for decades. Periodically zapping senescent cells might temporarily turn back the clock and improve health for people who are already aging, he says. “If this paper is right, I believe it will be one of the most important aging papers ever,” Sharpless says.
Senescent cells are ones that have ceased to divide and do their usual jobs. Instead, they hunker down and pump out inflammatory chemicals that may damage surrounding tissues and promote further aging. “They’re zombie cells,” says Steven Austad, a biogerontologist at the University of Alabama at Birmingham. ”They’ve outlived their usefulness. They’re bad.”
Cancer biologist Jan van Deursen of the Mayo Clinic in Rochester, Minn., and colleagues devised the strategy for eliminating senescent cells by making the cells commit suicide. A protein called p16 builds up in senescent cells, the researchers had previously discovered. The team hooked up a gene for a protein that causes cells to kill themselves to DNA that helps turn on p16 production, so that whenever p16 was made the suicide protein was also made.
The paper appears in Nature (behind their paywall)
Naturally occurring p16Ink4a-positive cells shorten healthy lifespan
Darren J. Baker, Bennett G. Childs, Matej Durik, Melinde E. Wijers, Cynthia J. Sieben, Jian Zhong, Rachel A. Saltness, Karthik B. Jeganathan, Grace Casaclang Verzosa, Abdulmohammad Pezeshki, Khashayarsha Khazaie, Jordan D. Miller & Jan M. van Deursen
Cellular senescence, a stress-induced irreversible growth arrest often characterized by expression of p16Ink4a (encoded by the Ink4a/Arf locus, also known as Cdkn2a) and a distinctive secretory phenotype, prevents the proliferation of preneoplastic cells and has beneficial roles in tissue remodelling during embryogenesis and wound healing. Senescent cells accumulate in various tissues and organs over time, and have been speculated to have a role in ageing. To explore the physiological relevance and consequences of naturally occurring senescent cells, here we use a previously established transgene, INK-ATTAC, to induce apoptosis in p16Ink4a-expressing cells of wild-type mice by injection of AP20187 twice a week starting at one year of age. We show that compared to vehicle alone, AP20187 treatment extended median lifespan in both male and female mice of two distinct genetic backgrounds. The clearance of p16Ink4a-positive cells delayed tumorigenesis and attenuated age-related deterioration of several organs without apparent side effects, including kidney, heart and fat, where clearance preserved the functionality of glomeruli, cardio-protective KATP channels and adipocytes, respectively. Thus, p16Ink4a-positive cells that accumulate during adulthood negatively influence lifespan and promote age-dependent changes in several organs, and their therapeutic removal may be an attractive approach to extend healthy lifespan.