Changes in DNA repair during aging

DNA is a precious molecule. It encodes vital information about cellular content and function. There are only two copies of each chromosome in the cell, and once the sequence is lost no replacement is possible. The irreplaceable nature of the DNA sets it apart from other cellular molecules, and makes it a critical target for age-related deterioration. To prevent DNA damage cells have evolved elaborate DNA repair machinery. Paradoxically, DNA repair can itself be subject to age-related changes and deterioration. In this review we will discuss the changes in efficiency of mismatch repair (MMR), base excision repair (BER), nucleotide excision repair (NER) and double-strand break (DSB) repair systems during aging, and potential changes in DSB repair pathway usage that occur with age. Mutations in DNA repair genes and premature aging phenotypes they cause have been reviewed extensively elsewhere, therefore the focus of this review is on the comparison of DNA repair mechanisms in young versus old

The Naked Mole Rat Genome Resource: facilitating analyses of cancer and longevity-related adaptations

Motivation: The naked mole rat (Heterocephalus glaber) is an exceptionally long-lived and cancer-resistant rodent native to East Africa. Although its genome was previously sequenced, here we report a new assembly sequenced by us with substantially higher N50 values for scaffolds and contigs. Results: We analyzed the annotation of this new improved assembly and identified candidate genomic adaptations which may have contributed to the evolution of the naked mole rat’s extraordinary traits, including in regions of p53, and the hyaluronan receptors CD44 and HMMR (RHAMM). Furthermore, we developed a freely available web portal, the Naked Mole Rat Genome Resource (http://www.naked-mole-rat.org), featuring the data and results of our analysis, to assist researchers interested in the genome and genes of the naked mole rat, and also to facilitate further studies on this fascinating species. Availability and implementation: The Naked Mole Rat Genome Resource is freely available online at http://www.naked-mole-rat.org. This resource is open source and the source code is available at https://github.com/maglab/naked-mole-rat-portal. Contact: [email protected]

The 2021 FASEB science research conference on NAD metabolism and signaling

publishedVersio

Lipidome determinants of maximal lifespan in mammals

Maximal lifespan of mammalian species, even if closely related, may differ more than 10-fold, however the nature of the mechanisms that determine this variability is unresolved. Here, we assess the relationship between maximal lifespan duration and concentrations of more than 20,000 lipid compounds, measured in 669 tissue samples from 6 tissues of 35 species representing three mammalian clades: primates, rodents and bats. We identify lipids associated with species’ longevity across the three clades, uncoupled from other parameters, such as basal metabolic rate, body size, or body temperature. These lipids clustered in specific lipid classes and pathways, and enzymes linked to them display signatures of greater stabilizing selection in long-living species, and cluster in functional groups related to signaling and protein-modification processes. These findings point towards the existence of defined molecular mechanisms underlying variation in maximal lifespan among mammals.The National Natural Science Foundation of China (grant 31420103920), Strategic Priority Research Program of the Chinese Academy of Sciences (grant XDB13010200), the National Natural Science Foundation of China (grant 91331203), the National One Thousand Foreign Experts Plan (grant WQ20123100078), the Bureau of International Cooperation, Chinese Academy of Sciences (grant GJHZ201313) and the Federal Targeted Program for Research and Development in Priority Areas of Advancement of the Russian Scientific and Technological Complex for 2014–2020 (the Ministry of Education and Science of the Russian Federation), grant № 14.615.21.0002, the Unique identifier of the agreement: RFMEFI61515×0002. Additional support was obtained from the European Research Council (advanced grant 294678 to GRL).http://www.nature.com/scientificreportsam2017Zoology and Entomolog

Adenoviral Vector Driven by a Minimal Rad51 Promoter Is Selective for p53-Deficient Tumor Cells

Background: The full length Rad51 promoter is highly active in cancer cells but not in normal cells. We therefore set out to assess whether we could confer this tumor-selectivity to an adenovirus vector. Methodology/Principal Findings: Expression of an adenovirally-vectored luciferase reporter gene from the Rad51 promoter was up to 50 fold higher in cancer cells than in normal cells. Further evaluations of a panel of truncated promoter mutants identified a 447 bp minimal core promoter element that retained the full tumor selectivity and transcriptional activity of the original promoter, in the context of an adenovirus vector. This core Rad51 promoter was highly active in cancer cells that lack functional p53, but less active in normal cells and in cancer cell lines with intact p53 function. Exogenous expression of p53 in a p53 null cell line strongly suppressed activity of the Rad51 core promoter, underscoring the selectivity of this promoter for p53-deficient cells. Follow-up experiments showed that the p53-dependent suppression of the Rad51 core promoter was mediated via an indirect, p300 coactivator dependent mechanism. Finally, transduction of target cells with an adenovirus vector encoding the thymidine kinase gene under transcriptional control of the Rad51 core promoter resulted in efficient killing of p53 defective cancer cells, but not of normal cells, upon addition of ganciclovir. Conclusions/Significance: Overall, these experiments demonstrated that a small core domain of the Rad51 promoter ca

Reuniting philosophy and science to advance cancer research

Cancers rely on multiple, heterogeneous processes at different scales, pertaining to many biomedical fields. Therefore, understanding cancer is necessarily an interdisciplinary task that requires placing specialised experimental and clinical research into a broader conceptual, theoretical, and methodological framework. Without such a framework, oncology will collect piecemeal results, with scant dialogue between the different scientific communities studying cancer. We argue that one important way forward in service of a more successful dialogue is through greater integration of applied sciences (experimental and clinical) with conceptual and theoretical approaches, informed by philosophical methods. By way of illustration, we explore six central themes: (i) the role of mutations in cancer; (ii) the clonal evolution of cancer cells; (iii) the relationship between cancer and multicellularity; (iv) the tumour microenvironment; (v) the immune system; and (vi) stem cells. In each case, we examine open questions in the scientific literature through a philosophical methodology and show the benefit of such a synergy for the scientific and medical understanding of cancer

Stem cell maintenance in naked mole rats and other longevity mechanisms in rodents

Thesis (Ph. D.)--University of Rochester. Department of Biology, 2018.This thesis investigated the stem cell biology of the longest-lived rodent the naked mole rat (Heterocephalus glaber, NMR), compared to the short-lived laboratory mouse. The NMR is one of only two eusocial mammals, shows extreme longevity with a maximum lifespan of 32 years and negligible age-associated degeneration. During aging, stem cells play a pivotal role in maintaining tissue homeostasis by replenishing damaged and dead cells with newly differentiated functional cells. Age-associated stem cell dysfunction is a driving force of aging. What stem cell capacity the NMR has and how the NMR maintains their stem cell pool is unknown. In this thesis, I comparatively studied the hematopoietic stem cell (HSC) properties in the NMR and the mouse. I employed BrdU label retention assays to label HSC and track the HSC turnover. I was able to show that the BrdU label-retaining cells were responsive to fluorouracil induced bone marrow injury. I have discovered that the NMR HSC localizes to a niche with extremely high levels of high molecular weight hyaluronic acid (HA), displays slow turnover and extreme quiescence, compared to the mouse HSC. I have demonstrated that the niche HA levels reversely relate to HSC reactive oxidative species (ROS) levels. In addition, overexpressing NMR HAS2 in mice reduces ROS in the HSC and expands the HSC pool by about 3-fold. I have also shown the inhibition of HA synthesis by 4-MU impaired hematopoiesis in NMRs. With these findings, I propose a model of HSC maintenance that highlights the key role of niche HA in maintaining the quiescent HSC pool. Additionally, I describe the NMR iPSC reprogramming done with extensive collaboration with Dr. Li Tan. We have found the NMR fibroblasts are resistant to both the mouse and the NMR defined factors induced reprogramming, either in primed or naïve culture conditions. We have screened factors enhancing reprogramming and found the large T antigen drastically increased iPSC reprogramming efficiency. We have found that the NMR fibroblasts have a more repressive Rb signal pathway and large T induces massive opening of more closed promoter regions in the NMR, compared to the mouse. These results suggest that NMR displays a more stable epigenome that resists iPSC reprogramming. In another study that I collaborated with Dr. Jorge Azpurua, we have discovered that the NMR shows about 10 times higher translation fidelity than the mouse. However, whether the translation fidelity correlates with species maximum lifespan is unknown. Thus, I examined translation fidelity in 17 rodent species with diverse maximum lifespans. I have found that the fidelity at the first and second codon positions strongly correlates with species maximum lifespan, and that correlation remains significant after phylogenetic correction. This finding suggests that translation fidelity plays a novel role in longevity. Lastly, I had been managing the NMR colonies during my study and developed strategies to improve the husbandry and breeding of captive NMR colonies. As breeding and keeping NMRs in captivity is challenging to researchers, the slow breeding and low survival of NMRs under laboratory condition limits the NMR research. I have optimized the colony setting which allows NMR colonies to settle down more rapidly and established different chambers for different functions. I have found that pairing young NMRs, but not younger than 2 years old, could result in higher successful rate of establishing new colonies. I have also successfully cross-fostered NMR pups in a foreign colony. All of these strategies will help researchers struggling with breeding NMRs in captivity