João Pedro de Magalhães

Meta-analysis of age-related gene expression profiles identifies common signatures of aging

MOTIVATION Numerous microarray studies of aging have been conducted, yet given the noisy nature of gene expression changes with age, elucidating the transcriptional features of aging and how these relate to physiological, biochemical and pathological changes remains a critical problem. RESULTS We performed a meta-analysis of age-related gene expression profiles using 27 datasets from mice, rats and humans. Our results reveal several common signatures of aging, including 56 genes consistently overexpressed with age, the most significant of which was APOD, and 17 genes underexpressed with age. We characterized the biological processes associated with these signatures and found that age-related gene expression changes most notably involve an overexpression of inflammation and immune response genes and of genes associated with the lysosome. An underexpression of collagen genes and of genes associated with energy metabolism, particularly mitochondrial genes, as well as alterations in the expression of genes related to apoptosis, cell cycle and cellular senescence biomarkers, were also observed. By employing a new method that emphasizes sensitivity, our work further reveals previously unknown transcriptional changes with age in many genes, processes and functions. We suggest these molecular signatures reflect a combination of degenerative processes but also transcriptional responses to the process of aging. Overall, our results help to understand how transcriptional changes relate to the process of aging and could serve as targets for future studies. AVAILABILITY http://genomics.senescence.info/uarrays/signatures.html. SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.

Human Ageing Genomic Resources: Integrated databases and tools for the biology and genetics of ageing

The Human Ageing Genomic Resources (HAGR, http://genomics.senescence.info) is a freely available online collection of research databases and tools for the biology and genetics of ageing. HAGR features now several databases with high-quality manually curated data: (i) GenAge, a database of genes associated with ageing in humans and model organisms; (ii) AnAge, an extensive collection of longevity records and complementary traits for >4000 vertebrate species; and (iii) GenDR, a newly incorporated database, containing both gene mutations that interfere with dietary restriction-mediated lifespan extension and consistent gene expression changes induced by dietary restriction. Since its creation about 10 years ago, major efforts have been undertaken to maintain the quality of data in HAGR, while further continuing to develop, improve and extend it. This article briefly describes the content of HAGR and details the major updates since its previous publications, in terms of both structure and content. The completely redesigned interface, more intuitive and more integrative of HAGR resources, is also presented. Altogether, we hope that through its improvements, the current version of HAGR will continue to provide users with the most comprehensive and accessible resources available today in the field of biogerontology.

The Human Ageing Genomic Resources: online databases and tools for biogerontologists

Aging is a complex, challenging phenomenon that requires multiple, interdisciplinary approaches to unravel its puzzles. To assist basic research on aging, we developed the Human Ageing Genomic Resources (HAGR). This work provides an overview of the databases and tools in HAGR and describes how the gerontology research community can employ them. Several recent changes and improvements to HAGR are also presented. The two centrepieces in HAGR are GenAge and AnAge. GenAge is a gene database featuring genes associated with aging and longevity in model organisms, a curated database of genes potentially associated with human aging, and a list of genes tested for their association with human longevity. A myriad of biological data and information is included for hundreds of genes, making GenAge a reference for research that reflects our current understanding of the genetic basis of aging. GenAge can also serve as a platform for the systems biology of aging, and tools for the visualization of protein–protein interactions are also included. AnAge is a database of aging in animals, featuring over 4000 species, primarily assembled as a resource for comparative and evolutionary studies of aging. Longevity records, developmental and reproductive traits, taxonomic information, basic metabolic characteristics, and key observations related to aging are included in AnAge. Software is also available to aid researchers in the form of Perl modules to automate numerous tasks and as an SPSS script to analyse demographic mortality data. The HAGR are available online at http://genomics.senescence.info.

A review and appraisal of the DNA damage theory of ageing

Given the central role of DNA in life, and how ageing can be seen as the gradual and irreversible breakdown of living systems, the idea that damage to the DNA is the crucial cause of ageing remains a powerful one. DNA damage and mutations of different types clearly accumulate with age in mammalian tissues. Human progeroid syndromes resulting in what appears to be accelerated ageing have been linked to defects in DNA repair or processing, suggesting that elevated levels of DNA damage can accelerate physiological decline and the development of age-related diseases not limited to cancer. Higher DNA damage may trigger cellular signalling pathways, such as apoptosis, that result in a faster depletion of stem cells, which in turn contributes to accelerated ageing. Genetic manipulations of DNA repair pathways in mice further strengthen this view and also indicate that disruption of specific pathways, such as nucleotide excision repair and non-homologous end joining, is more strongly associated with premature ageing phenotypes. Delaying ageing in mice by decreasing levels of DNA damage, however, has not been achieved yet, perhaps due to the complexity inherent to DNA repair and DNA damage response pathways. Another open question is whether DNA repair optimization is involved in the evolution of species longevity, and we suggest that the way cells from different organisms respond to DNA damage may be crucial in species differences in ageing. Taken together, the data suggest a major role of DNA damage in the modulation of longevity, possibly through effects on cell dysfunction and loss, although understanding how to modify DNA damage repair and response systems to delay ageing remains a crucial challenge.

How ageing processes influence cancer

The ageing of populations worldwide is leading to an unprecedented increase in cancer cases and fatalities. Understanding the links between cancer and ageing is therefore more important than ever. How the interplay of ageing-associated changes affects cancer initiation and progression is complex, however, and some ageing processes probably foster cancer development whereas others hinder it, possibly in a tissue-specific manner. In the emerging age of cancer, how can our growing understanding of the biology of ageing inform cancer biology?The ageing of populations worldwide is leading to an unprecedented increase in cancer cases and fatalities. Understanding the links between cancer and ageing is therefore more important than ever. How the interplay of ageing-associated changes affects cancer initiation and progression is complex, however, and some ageing processes probably foster cancer development whereas others hinder it, possibly in a tissue-specific manner. In the emerging age of cancer, how can our growing understanding of the biology of ageing inform cancer biology?

HAGR: the Human Ageing Genomic Resources

The Human Ageing Genomic Resources (HAGR) is a collection of online resources for studying the biology of human ageing. HAGR features two main databases: GenAge and AnAge. GenAge is a curated database of genes related to human ageing. Entries were primarily selected based on genetic perturbations in animal models and human diseases as well as an extensive literature review. Each entry includes a variety of automated and manually curated information, including, where available, protein–protein interactions, the relevant literature, and a description of the gene and how it relates to human ageing. The goal of GenAge is to provide the most complete and comprehensive database of genes related to human ageing on the Internet as well as render an overview of the genetics of human ageing. AnAge is an integrative database describing the ageing process in several organisms and featuring, if available, maximum life span, taxonomy, developmental schedules and metabolic rate, making AnAge a unique resource for the comparative biology of ageing. Associated with the databases are data-mining tools and software designed to investigate the role of genes and proteins in the human ageing process as well as analyse ageing across different taxa. HAGR is freely available to the academic community at http://genomics.senescence.info.

The Role of DNA Methylation in Aging, Rejuvenation, and Age-Related Disease

DNA methylation is a major control program that modulates gene expression in a plethora of organisms. Gene silencing through methylation occurs through the activity of DNA methyltransferases, enzymes that transfer a methyl group from S-adenosyl-L-methionine to the carbon 5 position of cytosine. DNA methylation patterns are established by the de novo DNA methyltransferases (DNMTs) DNMT3A and DNMT3B and are subsequently maintained by DNMT1. Aging and age-related diseases include defined changes in 5-methylcytosine content and are generally characterized by genome-wide hypomethylation and promoter-specific hypermethylation. These changes in the epigenetic landscape represent potential disease biomarkers and are thought to contribute to age-related pathologies, such as cancer, osteoarthritis, and neurodegeneration. Some diseases, such as a hereditary form of sensory neuropathy accompanied by dementia, are directly caused by methylomic changes. Epigenetic modifications, however, are reversible and are therefore a prime target for therapeutic intervention. Numerous drugs that specifically target DNMTs are being tested in ongoing clinical trials for a variety of cancers, and data from finished trials demonstrate that some, such as 5-azacytidine, may even be superior to standard care. DNMTs, demethylases, and associated partners are dynamically shaping the methylome and demonstrate great promise with regard to rejuvenation.

Cells discover fire: Employing reactive oxygen species in development and consequences for aging

The free radical theory of aging states that aging results from the accumulated damage caused by reactive oxygen species (ROS). Herein, we provide a critique of the theory that aims to point out the theorys weaknesses and put forward ideas for how future experiments must adjust to several emerging concepts. In the same way fire is dangerous and nonetheless humans learned how to use it, it now appears that cells evolved mechanisms to control and use ROS. The way ROS are used as signaling molecules in many crucial biological functions suggests ROS are not unwanted by-products of metabolism. We hypothesize that the connection between ROS and cellular processes like growth, proliferation, and apoptosis may explain why long-lived animals appear to have lower levels of ROS production: the longer development of long-lived animals may lead to lower steady state levels of ROS. With age, antioxidant systems become deregulated, just like so many other cellular components, and so oxidative damage occurs. Therefore, the production of ROS is not merely a cause of havoc but rather a complex and critical system whose disruption in disease and aging leads to oxidative damage. Potential roles of ROS in aging are discussed under this model.

Next-generation sequencing in aging research: Emerging applications, problems, pitfalls and possible solutions

Recent technological advances that allow faster and cheaper DNA sequencing are now driving biological and medical research. In this review, we provide an overview of state-of-the-art next-generation sequencing (NGS) platforms and their applications, including in genome sequencing and resequencing, transcriptional profiling (RNA-Seq) and high-throughput survey of DNA-protein interactions (ChIP-Seq) and of the epigenome. Particularly, we focus on how new methods made possible by NGS can help unravel the biological and genetic mechanisms of aging, longevity and age-related diseases. In the same way, however, NGS platforms open discovery not available before, they also give rise to new challenges, in particular in processing, analyzing and interpreting the data. Bioinformatics and software issues plus statistical difficulties in genome-wide studies are discussed, as well as the use of targeted sequencing to decrease costs and facilitate statistical analyses. Lastly, we discuss a number of methods to gather biological insights from massive amounts of data, such as functional enrichment, transcriptional regulation and network analyses. Although in the fast-moving field of NGS new platforms will soon take center stage, the approaches made possible by NGS will be at the basis of molecular biology, genetics and systems biology for years to come, making them instrumental for research on aging.

Insights into the Evolution of Longevity from the Bowhead Whale Genome

Summary The bowhead whale (Balaena mysticetus) is estimated to live over 200 years and is possibly the longest-living mammal. These animals should possess protective molecular adaptations relevant to age-related diseases, particularly cancer. Here, we report the sequencing and comparative analysis of the bowhead whale genome and two transcriptomes from different populations. Our analysis identifies genes under positive selection and bowhead-specific mutations in genes linked to cancer and aging. In addition, we identify gene gain and loss involving genes associated with DNA repair, cell-cycle regulation, cancer, and aging. Our results expand our understanding of the evolution of mammalian longevity and suggest possible players involved in adaptive genetic changes conferring cancer resistance. We also found potentially relevant changes in genes related to additional processes, including thermoregulation, sensory perception, dietary adaptations, and immune response. Our data are made available online (http://www.bowhead-whale.org) to facilitate research in this long-lived species.