The goal of Project 2 is to understand the molecular mechanisms responsible for longevity and cancer resistance of long-lived rodents. Naked mole rat is the longest-lived rodent species with the maximum lifespan of 32 years. Furthermore, naked mole rats are highly resistant to cancer. Since naked mole rats are related to the short-lived and cancer-prone laboratory rodents, they represent an ideal model for the studies of longevity and cancer resistance. We identified a novel mechanism of cancer-resistance in the naked mole rat termed early contact inhibition (ECl). Naked mole rat cells are hypersensitive to contact inhibition and arrest proliferation at low cell density. ECl is associated with induction of pi6'^'^^ (p16). We found that cells of the naked mole rat, as well as another long-lived rodent the blind mole rat, secrete large amounts of extremely high molecular weight hyaluronan (HMW-HA), which is required for ECl. The properties of HA depend on the polymer length, with longer polymers being more beneflcial. Remarkably, naked mole rat HA is over six times longer than mouse or human HA. We show that HMW-HA protects cells from oxidative stress and rehioval of HA causes naked mole rat cells to form tumors. Based on these findings, we hypothesize that that HMW-HA plays a key role in the naked mole rat longevity and cancer resistance.
Our aims are: (1) Determine signaling pathways leading from HA to cell cycle arrest and ECl. We will test the hypothesis that HMW-HA signaling via CD44 receptor activates expression of pi6, and identify intermediate signaling events. In collaboration with Project 4 we will identify genes from HA and pi6 signaling pathways that are activated by HMW-HA and examine their effect on cell cycle arrest in vivo. (2) Identify mechanisms responsible for cytoprotective properties of HMW-HA. We hypothesize that in addition to being an extracellular scavenger of ROS, HMW-HA triggers signaling events that either suppress apoptosis or activate intacellular antioxidant machinery. We will identify the targets of HA signaling, and test whether expression of naked mole rat HAS2 improves oxidative stress resistance in mice. In collaboration with Project 4 we will analyze the stress-signaling genes showing differential expression in the naked mole rat. In collaboration with Project 3 we will determine whether HA has anti-mutagenic effect. (3) Test whether beneficial effects of HMW-HA from the naked mole rat can be transferred to other mammals. We will use two approaches: generate transgenic mice expressing naked mole rat HAS2 or treat mice with hyaluronidase inhibitors. We will test whether these treatments improve mouse cancer and/or stress resistance.

Public Health Relevance

The naked mole rat is the longest living rodent with the maximum lifespan of 32 years. In addition to its longevity, the naked mole rat has an extraordinary resistance to cancer as tumors have never been observed in these rodents. The goal of Project 2 is to understand the mechanisms behind the extraordinary resistance to cancer in the naked mole rat. We expect that investigation of long-lived mammalian species will unravel mechanisms of cancer resistance and longevity that will be applied to extend human lifespan.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG047200-03
Application #
9057422
Study Section
Special Emphasis Panel (ZAG1)
Project Start
Project End
Budget Start
2016-05-01
Budget End
2017-04-30
Support Year
3
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Rochester
Department
Type
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Seluanov, Andrei; Gladyshev, Vadim N; Vijg, Jan et al. (2018) Mechanisms of cancer resistance in long-lived mammals. Nat Rev Cancer 18:433-441
Meer, Margarita V; Podolskiy, Dmitriy I; Tyshkovskiy, Alexander et al. (2018) A whole lifespan mouse multi-tissue DNA methylation clock. Elife 7:
Tian, Xiao; Doerig, Katherine; Park, Rosa et al. (2018) Evolution of telomere maintenance and tumour suppressor mechanisms across mammals. Philos Trans R Soc Lond B Biol Sci 373:
Zhou, Xuming; Sun, Di; Guang, Xuanmin et al. (2018) Molecular Footprints of Aquatic Adaptation Including Bone Mass Changes in Cetaceans. Genome Biol Evol 10:967-975
Piscitello, D; Varshney, D; Lilla, S et al. (2018) AKT overactivation can suppress DNA repair via p70S6 kinase-dependent downregulation of MRE11. Oncogene 37:427-438
Swovick, Kyle; Welle, Kevin A; Hryhorenko, Jennifer R et al. (2018) Cross-species Comparison of Proteome Turnover Kinetics. Mol Cell Proteomics 17:580-591
Sziráki, András; Tyshkovskiy, Alexander; Gladyshev, Vadim N (2018) Global remodeling of the mouse DNA methylome during aging and in response to calorie restriction. Aging Cell 17:e12738
Hébert, Jean M; Vijg, Jan (2018) Cell Replacement to Reverse Brain Aging: Challenges, Pitfalls, and Opportunities. Trends Neurosci 41:267-279
Lee, Sang-Goo; Mikhalchenko, Aleksei E; Yim, Sun Hee et al. (2017) Naked Mole Rat Induced Pluripotent Stem Cells and Their Contribution to Interspecific Chimera. Stem Cell Reports 9:1706-1720
Vijg, Jan; Dong, Xiao; Zhang, Lei (2017) A high-fidelity method for genomic sequencing of single somatic cells reveals a very high mutational burden. Exp Biol Med (Maywood) 242:1318-1324

Showing the most recent 10 out of 62 publications