Cancer researchers have traditionally used the mouse and the rat as staple model organisms. These animals are very short-lived, reproduce rapidly and are highly prone to cancer. They have been very ...useful for modelling some human cancer types and testing experimental treatments; however, these cancer-prone species offer little for understanding the mechanisms of cancer resistance. Recent technological advances have expanded bestiary research to non-standard model organisms that possess unique traits of very high value to humans, such as cancer resistance and longevity. In recent years, several discoveries have been made in non-standard mammalian species, providing new insights on the natural mechanisms of cancer resistance. These include mechanisms of cancer resistance in the naked mole rat, blind mole rat and elephant. In each of these species, evolution took a different path, leading to novel mechanisms. Many other long-lived mammalian species display cancer resistance, including whales, grey squirrels, microbats, cows and horses. Understanding the molecular mechanisms of cancer resistance in all these species is important and timely, as, ultimately, these mechanisms could be harnessed for the development of human cancer therapies.
Naked mole-rat (NMR), the longest-living rodent, produces very-high-molecular-mass hyaluronan (vHMM-HA), compared to other mammalian species. However, it is unclear if exceptional polymer length of ...vHMM-HA is important for longevity. Here, we show that vHMM-HA (>6.1 MDa) has superior cytoprotective properties compared to the shorter HMM-HA. It protects not only NMR cells, but also mouse and human cells from stress-induced cell-cycle arrest and cell death in a polymer length-dependent manner. The cytoprotective effect is dependent on the major HA-receptor, CD44. We find that vHMM-HA suppresses CD44 protein-protein interactions, whereas HMM-HA promotes them. As a result, vHMM-HA and HMM-HA induce opposing effects on the expression of CD44-dependent genes, which are associated with the p53 pathway. Concomitantly, vHMM-HA partially attenuates p53 and protects cells from stress in a p53-dependent manner. Our results implicate vHMM-HA in anti-aging mechanisms and suggest the potential applications of vHMM-HA for enhancing cellular stress resistance.
Aging is a global decline of physiological functions, leading to an increased susceptibility to diseases and ultimately death. Maximum lifespans differ up to 200-fold between mammalian species. ...Although considerable progress has been achieved in identifying conserved pathways that regulate individual lifespan within model organisms, whether the same pathways are responsible for the interspecies differences in longevity remains to be determined. Recent cross-species studies have begun to identify pathways responsible for interspecies differences in lifespan. Here, we review the evidence supporting the role of anticancer mechanisms, DNA repair machinery, insulin/insulin-like growth factor 1 signaling, and proteostasis in defining species lifespans. Understanding the mechanisms responsible for the dramatic differences in lifespan between species will have a transformative effect on developing interventions to improve human health and longevity.
It is important to understand molecular mechanisms responsible for longevity of naturally long-lived species to develop safe and effective antiaging treatments and improve human health.
Novel anticancer mechanisms have been identified in several long-lived species including elephants, naked mole rats, and blind mole rats.
Long-lived species evolved more efficient DNA repair machinery by upregulating the expression or altering the sequences of DNA repair genes.
Long-lived species alter telomere-binding proteins to protect telomeres.
Perturbation of the insulin/IGF-1 signaling pathway may contribute to longevity of long-lived mouse strains, small dog breeds, long-lived rodents, and Brandt’s bats.
Naked mole rats improve translational fidelity, increase the expression of chaperones, and augment proteasome activity and autophagy to maintain proteostasis.
Transposable elements (TEs) are major components of eukaryotic genomes. However, the extent of their impact on genome evolution, function, and disease remain a matter of intense interrogation. The ...rise of genomics and large-scale functional assays has shed new light on the multi-faceted activities of TEs and implies that they should no longer be marginalized. Here, we introduce the fundamental properties of TEs and their complex interactions with their cellular environment, which are crucial to understanding their impact and manifold consequences for organismal biology. While we draw examples primarily from mammalian systems, the core concepts outlined here are relevant to a broad range of organisms.
DNA double-strand breaks (DSBs) are dangerous lesions that can lead to potentially oncogenic genomic rearrangements or cell death. The two major pathways for repair of DSBs are nonhomologous end ...joining (NHEJ) and homologous recombination (HR). NHEJ is an intrinsically error-prone pathway while HR results in accurate repair. To understand the origin of genomic instability in human cells it is important to know the contribution of each DSB repair pathway. Studies of rodent cells and human cancer cell lines have shown that the choice between NHEJ or HR pathways depends on cell cycle stage. Surprisingly, cell cycle regulation of DSB repair has not been examined in normal human cells with intact cell cycle checkpoints. Here we measured the efficiency NHEJ and HR at different cell cycle stages in hTERT-immortalized diploid human fibroblasts. We utilized cells with chromosomally-integrated fluorescent reporter cassettes, in which a unique DSB is introduced by a rare-cutting endonuclease. We show that NHEJ is active throughout the cell cycle, and its activity increases as cells progress from G1 to G2/M (G1 < S < G2/M). HR is nearly absentin G1, most active in the S phase, and declines in G2/M. Thus, inG2/M NHEJ is elevated, while HR is on decline. This is in contrastto a general belief that NHEJ is most active in G1, while HR isactive in S, G2 and M. The overall efficiency of NHEJ was higherthan HR at all cell cycle stages. We conclude that human somaticcells utilize error-prone NHEJ as the major DSB repair pathway atall cell cycle stages, while HR is used, primarily, in the S phase.
Mice deficient for SIRT6 exhibit a severely shortened lifespan, growth retardation, and highly elevated LINE1 (L1) activity. Here we report that SIRT6-deficient cells and tissues accumulate abundant ...cytoplasmic L1 cDNA, which triggers strong type I interferon response via activation of cGAS. Remarkably, nucleoside reverse-transcriptase inhibitors (NRTIs), which inhibit L1 retrotransposition, significantly improved health and lifespan of SIRT6 knockout mice and completely rescued type I interferon response. In tissue culture, inhibition of L1 with siRNA or NRTIs abrogated type I interferon response, in addition to a significant reduction of DNA damage markers. These results indicate that L1 activation contributes to the pathologies of SIRT6 knockout mice. Similarly, L1 transcription, cytoplasmic cDNA copy number, and type I interferons were elevated in the wild-type aged mice. As sterile inflammation is a hallmark of aging, we propose that modulating L1 activity may be an important strategy for attenuating age-related pathologies.
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•SIRT6 KO mice accumulate L1 cDNA, triggering interferon response via cGAS pathway•Wild-type aged mice accumulate L1 cDNA and display type I interferon response•Reverse-transcriptase inhibitors rescue type I interferon response and DNA damage•Reverse-transcriptase inhibitors extend lifespan and improve health of SIRT6 KO mice
Simon et al. show that LINE1 retrotransposon elements are derepressed in aged and progeroid mice. Cytoplasmic accumulation of LINE1 cDNA copies induced a type I interferon response, through the cGAS DNA sensing pathway, resulting in pathological inflammation. Inhibiting L1 replication significantly improved the health and lifespan of aged mice.
Mammals have evolved a remarkable diversity of ageing rates. Within the single order of Rodentia, maximum lifespans range from 4 years in mice to 32 years in naked mole rats. Cancer rates also differ ...substantially between cancer-prone mice and almost cancer-proof naked mole rats and blind mole rats. Recent progress in rodent comparative biology, together with the emergence of whole-genome sequence information, has opened opportunities for the discovery of genetic factors that control longevity and cancer susceptibility.
Sirtuin 6 (SIRT6) is a mammalian homolog of the yeast Sir2 deacetylase. Mice deficient for SIRT6 exhibit genome instability. Here, we show that in mammalian cells subjected to oxidative stress SIRT6 ...is recruited to the sites of DNA double-strand breaks (DSBs) and stimulates DSB repair, through both nonhomologous end joining and homologous recombination. Our results indicate that SIRT6 physically associates with polyadenosine diphosphate (ADP)—ribose polymerase 1 (PARP1) and mono-ADP-ribosylates PARP1 on lysine residue 521, thereby stimulating PARP1 poly-ADP-ribosylase activity and enhancing DSB repair under oxidative stress.
The naked mole rat (Heterocephalus glaber) displays exceptional longevity, with a maximum lifespan exceeding 30 years. This is the longest reported lifespan for a rodent species and is especially ...striking considering the small body mass of the naked mole rat. In comparison, a similarly sized house mouse has a maximum lifespan of 4 years. In addition to their longevity, naked mole rats show an unusual resistance to cancer. Multi-year observations of large naked mole-rat colonies did not detect a single incidence of cancer. Here we identify a mechanism responsible for the naked mole rat's cancer resistance. We found that naked mole-rat fibroblasts secrete extremely high-molecular-mass hyaluronan (HA), which is over five times larger than human or mouse HA. This high-molecular-mass HA accumulates abundantly in naked mole-rat tissues owing to the decreased activity of HA-degrading enzymes and a unique sequence of hyaluronan synthase 2 (HAS2). Furthermore, the naked mole-rat cells are more sensitive to HA signalling, as they have a higher affinity to HA compared with mouse or human cells. Perturbation of the signalling pathways sufficient for malignant transformation of mouse fibroblasts fails to transform naked mole-rat cells. However, once high-molecular-mass HA is removed by either knocking down HAS2 or overexpressing the HA-degrading enzyme, HYAL2, naked mole-rat cells become susceptible to malignant transformation and readily form tumours in mice. We speculate that naked mole rats have evolved a higher concentration of HA in the skin to provide skin elasticity needed for life in underground tunnels. This trait may have then been co-opted to provide cancer resistance and longevity to this species.
Abstract
SIRT6 is critical for activating transcription of Nuclear factor (erythroid-derived 2)-like 2 (NRF2) responsive genes during oxidative stress. However, while the mechanism of SIRT6-mediated ...silencing is well understood, the mechanism of SIRT6-mediated transcriptional activation is unknown. Here, we employed SIRT6 separation of function mutants to reveal that SIRT6 mono-ADP-ribosylation activity is required for transcriptional activation. We demonstrate that SIRT6 mono-ADP-ribosylation of BAF170, a subunit of BAF chromatin remodeling complex, is critical for activation of a subset of NRF2 responsive genes upon oxidative stress. We show that SIRT6 recruits BAF170 to enhancer region of the Heme oxygenase-1 locus and promotes recruitment of RNA polymerase II. Furthermore, SIRT6 mediates the formation of the active chromatin 10-kb loop at the HO-1 locus, which is absent in SIRT6 deficient tissue. These results provide a novel mechanism for SIRT6-mediated transcriptional activation, where SIRT6 mono-ADP-ribosylates and recruits chromatin remodeling proteins to mediate the formation of active chromatin loop.