Motivation and Research Objectives
Ageing has a profound impact on human society and modern medicine, yet it remains a major puzzle of biology. Our group broadly aims to help understand the genetic, cellular, and molecular mechanisms of aging. Although our research integrates different strategies, its focal point is developing and applying experimental and computational methods that help bridge the gap between genotype and phenotype, a major challenge of the post-genome era, and help decipher the human genome and how it regulates aging and longevity.
In the long term, we would like our work to contribute to the development of interventions that preserve health and combat disease by manipulating the ageing process. By studying mechanisms of aging our work could also have an impact on diseases, like cancer and neurodegenerative diseases, for which age is a major risk factor. No other biomedical field has so much potential to improve human health as research on the basic mechanisms of ageing.
Current Research Projects
The complexity and multi-dimensional nature of the ageing process require that this biological problem be tackled using a combination of disciplines and approaches. Below is a list of strategies and methods we employ in our work. Ultimately, however, we believe it is the integration of these different approaches that will mostly enhance our knowledge of longevity and ageing, which is why we aim to develop our research in a highly collaborative and interdisciplinary environment.
Systems Biology of Ageing
"Biologists can be divided into two classes: experimentalists who observe things that cannot be explained, and theoreticians who explain things that cannot be observed." Aharon Katzir-Katchalsky
Many genes have been shown to regulate ageing in model systems. It is now necessary, however, to study how these genes interact and how they exert their influence as an aggregate to modulate the ageing process. For that purpose, we have been developing a number of bioinformatics resources to try to understand how the parts, the genes, influence the ageing process as a whole. Specifically, we developed the GenAge database, the first curated database of genes possibly related to human ageing and are now integrating GenAge with other types of data, such as gene expression profiles, protein-protein interactions (a protein-protein interaction network derived from GenAge is shown on the right), and phenotypic data. Our goal is to enhance our understanding of gene networks and transcriptional regulation during ageing and build better models of ageing that help guide experiments.
There is a lack of mathematical models of human ageing even at higher levels of abstraction. We would like to construct better mathematical representations of changes during the lifespan at the level of molecules, organelles, cells, and tissues and model how these affect each other to determine ageing and age-related diseases in whole organisms. In this context, we are developing a web portal of age-related changes at various biological levels. This new portal, entitled Digital Ageing Atlas, aims to serve as a platform for modeling aging, in particular for developing quantitative and integrative models and for developing system-level models of aging.
Dietary Manipulations of Ageing
Findings from model organisms show that ageing is surprisingly plastic and can be manipulated not only by genes (as indicated above) but also by diet. The best-studied dietary manipulation of ageing is caloric restriction (CR), which consists of restricting the food intake of organisms without triggering malnutrition and has been shown to retard ageing across multiple model organisms. We are taking advantage of genomic technologies, including next-generation sequencing, to characterize the molecular changes during CR and gain mechanistic insights about ageing and its modulation by diet. Moreover, we are employing integrative and system-level approaches to study the signaling pathways and identify key genes mediating the life-extending effects of CR. Understanding the underlying molecular and genetic mechanisms of CR and identifying key regulators may lead to drug discovery and development with unprecedented impact on human health.
Genomics of Complex Diseases
Because ageing impacts on so many diseases and genome analysis and interpretation have broad biomedical implications, we also have a great interest in the genomics of complex human diseases. By taking advantage of our expertise in genomics, bioinformatics, statistics and cell biology, we aim to help unravel the genetic and molecular mechanisms of complex human diseases. Given our group's interest in ageing, age-related diseases like cancer and neurological disorders are of particular interest. Our data-mining analyses have already revealed new candidate cancer-related genes which we are validating experimentally in vitro.
Cellular Models and Stem Cells
Cells are the fundamental building blocks of animals. It is clear that human ageing has a cellular component and that, for instance, some aspects of cell cycle regulation are related to the ageing process and crucial in many age-related diseases like cancer. Therefore, our work focuses considerably on cell biology and cell cycle regulation. Considering their therapeutic potential to ameliorate diseases of ageing, we are also interested in stem cells (see picture of human embryonic stem cells on the right).
Currently, we are working on a synthetic biology project using mouse embryonic stem cells (mESC). Our goal is to evolve/construct mESC that display cellular markers associated with organismal longevity, such as resistance to stress. One molecular technique we use is called short hairpin RNA (shRNA), which functions similarly to RNA interference (RNAi) to silence gene expression. This technology allows thousands of genes to be screened in a single experiment for their role in a given phenotype, in this case stress resistance, and select the most promising ones. Eventually, we may be able to use these stress-resistant mESC to create transgenic mice and assess whether it is possible to select for cellular biomarkers of longevity that have an impact at the organismal level.
Evolutionary and Comparative Genomics
One of the most striking observations (and mysteries) in the field of ageing research is the variety of ageing rates among similar species such as mammals or even primates. Clearly, the genome determines the features of each species' ageing process to a large extent. Understanding why and how evolution gives rise to genomes that result in similar organisms with vastly different paces of ageing has an enormous potential to provide biologically-significant clues about the genetics of ageing. Therefore, one of the aims of our work is to develop and implement computational high-throughput approaches, such as comparative genomics, to study the evolution of complex processes such as ageing. As more organisms are sequenced, it is becoming possible to obtain detailed models of genome evolution to, for example, identify candidate human longevity genes by searching for genes with unique signatures of selection.
Because longevity evolved in the human lineage, we are particularly interested in employing modern computational methods in primates to study the evolution, structure, and function of genes associated with ageing, which may shed light on the genetic changes that contributed to the evolution of human longevity. Ultimately, our goal is to understand why we are different from each other and from other species and what is the role of each DNA base in the genome in determining these differences, in particular in the context of ageing and age-related diseases.
Biology of Long-Lived Animals
Stemming from the above rationale for studying the biological underpinnings of species differences in longevity and ageing, we are interested in studying the unique genetics, physiology, and cell biology of long-lived animals. One of such animals is the naked mole-rat (Heterocephalus glaber, shown on the left), the longest-lived rodent not known to develop cancer. For example, studies of cells from the naked mole-rat have a great potential to provide clues regarding mechanisms, such as DNA repair, cell cycle, and stress response mechanisms, that have been associated with longevity and cancer resistance. We are also using next-generation sequencing platforms to unravel the longevity secrets of the naked mole-rat.
Naked mole-rat photo courtesy of Pittsburgh Zoo & PPG Aquarium.
Theoretical Biology of Ageing
"Discovery consists of seeing what everybody has seen and thinking what nobody has thought." Albert Szent-Gyørgyi
Lastly, we are interested in putting our findings and ideas together to address the big questions in gerontology and develop a coherent theoretical framework that explains ageing. One hypothesis we are particularly interested in is the idea that some developmental mechanisms shaped by evolution to optimize reproduction have an impact on ageing and age-related diseases. The free radical theory of ageing, for instance, can be interpreted in light of the roles of reactive oxygen species in development and cellular growth.
Our work on ageing is also of relevance to life history theory, which is encompasses the evolutionary theory of ageing. We are interested in refining the analytical framework that explains the relationship between growth, development, reproduction, and lifespan as well as investigating the causal basis of trade-offs between these traits. To this end and to serve as a tool for the comparative biology of ageing we developed AnAge, a database of ageing and life history in animals featuring over 4,000 species.