Proteins generated by the gene p16INK4a are thought to be a biomarker for aging, and in this open access paper a connection with calorie restriction (CR) is explored: "Epigenetic events are among the most striking mechanisms responsible for nutrition-related longevity, which is believed to dynamically regulate gene expression by primarily impacting two epigenetic codes, DNA methylation and histone modification. As evidence of this, the yeast protein silent information regulator 2 (Sir2) [is] a key determinant in CR-induced lifespan prolongation in yeast. In mammalians, SIRT1 is one of seven mammalian orthologs of Sir2, which has been extensively studied for its roles in chromatin remodeling and lifespan elongation. SIRT1 acts as a nutrient sensor involved in the regulation of various gene expressions as well as modulation of important signal transductions either directly or indirectly through its unique epigenetic effects, which ultimately influence the regulation of longevity. Our previous studies indicated that glucose restriction-induced DNA methylation alteration in the p16 promoter contributes to cellular lifespan extension. In this regard, epigenetic mechanisms are major molecular events which play a crucial role in CR-induced longevity. Therefore, we speculated that an aging-associated gene such as p16 may have a central position in epigenetic control of inhibition of cellular senescence and lifespan elongation in response to CR."