 It was also shown that INK4a/ARF deficient animals increase an age-related decline in T-cell responsiveness to CD3 and CD28, which is a hallmark of aging.Furthermore, neural stem cells from Bmi-1- deficient animals demonstrate increased INK4a/ARF expression and impaired regenerative potential.The phenotype; however, can be rescued by p16INK4a deficiency implying that while p16INK4a can potentially be used as a biomarker of physiologic, rather than chronologic age, it is also an effector of aging.