Sirtuins in hematological aging and malignancy

Abstract

Aging of the hematological system causes anemia, reduced immunity, and increased incidence of hematological malignancies. Hematopoietic stem cells (HSCs) play a crucial role in this process as their functions decline during aging. Sirtuins are a family of protein lysine modifying enzymes that have diverse roles in regulating metabolism, genome stability, cell proliferation, and survival, and have been implicated in mammalian aging and longevity. Here we provide an updated overview of sirtuins in aging research; particularly, how increased activity of SIRT1, SIRT3, or SIRT6 improves several aging parameters, and may possibly increase lifespan in mice. We review the literature on how sirtuins may play a role in HSC aging and hematological malignancies, and how key signaling pathways of HSCs may be affected by sirtuins. Among them, SIRT1 plays a critical role in chronic myelogenous leukemia, an age-dependent malignancy, and inhibition of SIRT1 sensitizes leukemic stem cells to tyrosine kinase inhibitor treatment and blocks acquisition of resistant oncogene mutations. In-depth understanding of sirtuins in HSC aging and malignancy may help design novel strategies to deter hematological aging and improve treatment of hematological malignancies.

Figure 1

Overview of sirtuins’ activities and functions in aging and mammalian lifespan. “No” denotes no effect or not yet been shown.

Figure 2

Schematic illustration of sirtuins, p53, and their regulation of hematopoietic stem cells. Sirtuins (SIRT1, 2, 7) suppress the acetylation of p53 directly by deacetylating Ac-p53 or indirectly by inhibiting acetyltransferases TIP60 and p300. As acetylation of p53 activates its function, suppression of p53 by sirtuins may lead to increased HSC number and function, accompanied by increased tumor incidence. In contrast, hyperacetylated and activated p53 decreases HSC number and function, but may reduce the chance of malignant transformation of HSCs.