Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Researchers used the INK-ATTAC transgenic mouse model to investigate the physiological impact of naturally occurring senescent cells. They found that clearing p16Ink4a-positive cells in mice extended median lifespan and delayed tumorigenesis, while preserving organ function in the kidney, heart, and fat. These cells, which accumulate during adulthood, negatively influence lifespan and promote age-dependent changes in multiple organs. Therapeutic removal of these cells may be an attractive approach to extend healthy lifespan. The study showed that p16Ink4a-positive cells in fat tissue were cleared by the INK-ATTAC system, leading to improved fat tissue function and reduced age-related dysfunction. Clearance of these cells also reduced inflammation in fat, skeletal muscle, and kidney. In addition, the removal of p16Ink4a-positive cells improved cardiac function, reduced glomerulosclerosis in the kidney, and preserved cardiac stress tolerance. These findings suggest that p16Ink4a-positive cells contribute to age-related cardiac aging and kidney dysfunction. The study also found that the clearance of p16Ink4a-positive cells did not negatively impact healthspan or cause adverse effects in mice. However, the clearance was partial and tissue-selective, with some tissues like the liver and colon being refractory to clearance. The study highlights the complex role of senescent cells in aging and suggests that their therapeutic removal may be a promising strategy to extend healthy lifespan.Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Researchers used the INK-ATTAC transgenic mouse model to investigate the physiological impact of naturally occurring senescent cells. They found that clearing p16Ink4a-positive cells in mice extended median lifespan and delayed tumorigenesis, while preserving organ function in the kidney, heart, and fat. These cells, which accumulate during adulthood, negatively influence lifespan and promote age-dependent changes in multiple organs. Therapeutic removal of these cells may be an attractive approach to extend healthy lifespan. The study showed that p16Ink4a-positive cells in fat tissue were cleared by the INK-ATTAC system, leading to improved fat tissue function and reduced age-related dysfunction. Clearance of these cells also reduced inflammation in fat, skeletal muscle, and kidney. In addition, the removal of p16Ink4a-positive cells improved cardiac function, reduced glomerulosclerosis in the kidney, and preserved cardiac stress tolerance. These findings suggest that p16Ink4a-positive cells contribute to age-related cardiac aging and kidney dysfunction. The study also found that the clearance of p16Ink4a-positive cells did not negatively impact healthspan or cause adverse effects in mice. However, the clearance was partial and tissue-selective, with some tissues like the liver and colon being refractory to clearance. The study highlights the complex role of senescent cells in aging and suggests that their therapeutic removal may be a promising strategy to extend healthy lifespan.