Epigenetic modifications correlated with aging and oncogenesis are changes in the pattern of DNA methylation and of histone modifications, and changes in the level of histone variants (H3.3, macroH2A, H2A.Z) and gene mutations. The sirtuins are a set of highly conserved protein deacetylases of particular significance to the aging process. Many cancer types are found to carry mutations in chromatin-modifying genes such as those encoding methyl or acetyl transferases, affecting the histone modifications of promoters and enhancers. The aging process and oncogenesis present a number of changes in the nuclear architecture. Mutations in the lamina-coding genes lead to premature aging syndromes. Mutations in remodeling complexes are found in different cancers. Modifications that affect the architectural protein binding sites at topologically associating domain (TAD) borders can cause the merging of neighboring TADs. The levels of short non-coding RNAs (sncRNAs) are altered in model organisms and are associated with cancer. Changes in the position of chromosome territories often occur in tumor cells. Nevertheless, cellular senescence, due mostly to the absence of telomerase, represents a mechanism of tumor suppression.