Shared genetic and epigenetic changes link aging and cancer

Abstract

Aging is a universal biological process that increases the risk of multiple diseases including cancer. Growing evidence shows that alterations in the genome and epigenome, driven by similar mechanisms, are found in both aged cells and cancer cells. In this review, we detail the genetic and epigenetic changes associated with normal aging and the mechanisms responsible for these changes. By highlighting genetic and epigenetic alterations in the context of tumorigenesis, cancer progression, and the aging tumor microenvironment, we examine the possible impacts of the normal aging process on malignant transformation. Finally, we examine the implications of age-related genetic and epigenetic alterations in both tumors and patients for the treatment of cancer.

Keywords: aging; cancer; epigenetics; genetics; tumor microenvironment.

Figure 1.. Age-related changes in non-malignant cells in the tumor microenvironment alter cancer cell behavior.

Fibroblasts are a principal non-malignant component of the tumor microenvironment. As fibroblasts are exposed to sources of DNA damage including UV radiation, oxidative stress, and the aging process, and this accumulating damage is marked by the presence of 7,8-dihydro-8-oxo-2′-deoxyguanosine (8-oxo-dG). In addition, the base-excision repair protein APE-1 is downregulated with age, further increasing the susceptibility to DNA damage. These fibroblasts can undergo cellular senescence. Senescent cells are characterized by the presence of senescence-associated heterochromatin foci (SAHF), specialized domains of heterochromatin that contribute to the silencing of proliferation-promoting genes and adopt a senescence-associated secretory phenotype (SASP) which has been shown to promote tumor growth by increasing cancer cell susceptibility to DNA damage and activation of oncogenic signaling. The end result can either be paracrine senescence of cancer cells, though the promotion of a slow-cycling cancer cell phenotype is associated with highly invasive, therapy-resistance cells, or enhancement of cancer cell proliferation.

Figure 2.. Sirtuins, histone modifications, and the regulation of chromatin and gene transcription.

SIRT1, SIRT2, and SIRT6 are involved in regulating chromatin remodeling. SIRT1 can deacetylate H3K9, H3K56, H1K26, and H4K16. It can also deacetylate the transcription factors SOX2, Myc, and Oct4. SIRT2 deacetylates H3K56, H4K16, and H3K18 and can stabilize Myc through alterations in Myc ubiquitination. SIRT6 deacetylates H3K9 and H3K56 and can repress the transcription of MYC.

Figure 3.. Classical and alternative nonhomologous end-joining (NHEJ) pathways.

After the formation of a double-strand break, the classical (left) or the alternative (right) nonhomologous end-joining pathways repair DNA damage through break recognition, end binding/synapsis, end processing, and final ligation of DNA. Proteins marked with a yellow star have been shown to have decreased expression during aging.

Figure 4.. Age-related epigenetic changes and their effects on tumorigenesis.

(A-D) Aging is characterized by multiple alterations in the epigenome including (A) loss of histones and heterochromatin, (B) an increased frequency of non-canonical, variant histones, (C) a change in the balance of activating and repressing histone modifications, and (D) global DNA hypomethylation among others. These changes have been implicated in tumor growth and progression through the alteration of gene expression, genomic instability, and an increase in immune checkpoint molecule expression in cancer cells (inset box).