Personal website of João Pedro de Magalhães
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"Discovery consists of seeing what everybody has seen and thinking what nobody has thought." — Albert Szent-Gyørgyi

My work is primarily related to the biology of human aging. I want to know why we age, which genes determine the pace and onset of aging, what mechanisms drive aging, and how can we develop interventions that ameliorate and eventually delay the human aging process. To this end I have employed a number of methods involving theoretical, experimental, and computational approaches.

I began my career as a researcher working on cellular models of aging, including replicative senescence and stress-induced cellular senescence (SIPS)^2,5,9. Progressively, I became more skeptic about the relevance to organismal aging of the current cellular models and methods used in gerontology^7,8. I still think that human aging has a cellular component⁸, and I would like to develop better methods to assess cellular aging in vivo.

Another old interest of mine is Werner syndrome. I did some preliminary work with Werner syndrome fibroblasts⁵, but I haven't been able to continue studying this fascinating disease the way I would have liked to. It's a research theme I would like to return to in the future.

In recent years, I've worked mostly at the computational and theoretical level. Aging is largely a genetically-determined process ³, and the fact similar species can age at radically different paces proves it. Therefore, the genomic information determines a species' rate of aging to a large extent. With the surge in information in the life sciences, and the inherited difficulties associated with traditional biomedical model systems used to study human aging, computational approaches offer a new and revolutionary set of data and data-mining methods for the study of the aging process⁴.

One component of my work is related to evolutionary models of aging. I've been trying to obtain a more detailed view to the evolution of human aging and life history. One of my earliest models involved the evolution of mammalian aging¹. Right now, I'm trying to apply modern computational approaches, such as comparative genomics, to gather new clues about the evolution of human aging. One project involved studying human disease-causing alleles in mitochondrial DNA across primates¹⁵. Although the results obtained from this work are mostly relevant in the context of population genetics to understand the evolution of genetic variants, such as polymorphisms and diseases, I speculate that some of my findings could be related to the evolution of human longevity and intelligence. Eventually, as the quantity and quality of genomic data increases, I hope to use comparative genomics to gather biologically-significant clues about the human aging process.

Due to necessity, one side project of mine is the development and enhancement of statistical methods for the study of aging. Previously, I've used the Gompertz function to evaluate whether a number of mouse strains are aging differently than controls¹². While this approach is not perfect, it does improve on assays simply looking at average lifespan. I hope to continue developing more accurate methods to assess rate of aging from demographic measurements.

Probably the biggest project I'm involved with is the Human Ageing Genomic Resources (HAGR), a collection of databases and tools for the study of aging¹¹. The two key components of HAGR are the GenAge and AnAge databases. GenAge is the first curated database of genes related to human aging. My aim in GenAge is not only to provide basic information about genes related to aging. Having a dataset of genes related to aging allows me to employ a number of data-mining algorithms and computational approaches to study aging from a genomic, proteomic, or evolutionary perspective. In one of our earliest works with GenAge, we investigated proteomic networks⁶, but now we want to take it one step further using different approaches and further data. AnAge is an aging-oriented animal database featuring over 3,000 species. Again, my main goal with AnAge is not just to have a repository of longevity records. Among other uses, AnAge allows us to study the factors associated with longevity across different taxa.

Obviously, I'm interested in addressing the big questions regarding human aging: Why do similar species age at different rates? What changes drive human aging? Why do we age? Some of my reviews have focused on these fundamental questions¹⁰. One hypothesis I'm interested in is the idea that aging is a consequence of developmental mechanisms¹³. The free radical theory of aging, for instance, can be interpreted in light of the roles of reactive oxygen species in development and growth¹⁶. I'm also interested in neurodegeneration and worked on a model linking brain development to cognitive aging¹⁴. In the future I would like to do experiments to test these hypotheses, probably in mice.

I am always looking for potential collaborators, so if any of these projects or ideas interest you, please contact me.

The list of references (reprints are available for download in my list of publications):

1. de Magalhães, JP and Toussaint, O (2002) "The evolution of mammalian aging." Experimental Gerontology 37(6):769-75.
2. de Magalhães, JP et al. (2002) "Stress-induced premature senescence in BJ and hTERT-BJ1 human fibroblasts." FEBS Letters 523(1-3):157-162.
3. de Magalhães, JP (2003) "Is mammalian aging genetically controlled?" Biogerontology 4(2):119-120.
4. de Magalhães, JP and Toussaint, O (2004) "How bioinformatics can help reverse engineer human aging." Ageing Research Reviews 3(2):125-141.
5. de Magalhães, JP et al. (2004) "No increase in senescence-associated ß-galactosidase activity in Werner-syndrome fibroblasts after exposure to H2O2" Annals of the New York Academy of Sciences 1019:375-378.
6. de Magalhães, JP and Toussaint, O (2004) "GenAge: a genomic and proteomic network map of human ageing." FEBS Letters 571(1-3):243-247.
7. de Magalhães, JP and Toussaint, O (2004) "Telomeres and telomerase: a modern Fountain of Youth?" Rejuvenation Research 7:126-132.
8. de Magalhães, JP (2004) "From cells to ageing: a review of models and mechanisms of cellular senescence and their impact on human ageing" Experimental Cell Research 300:1-10.
9. de Magalhães, JP et al. (2004) "Gene expression and regulation in H2O2-induced premature senescence of human foreskin fibroblasts expressing or not telomerase" Experimental Gerontology 39:1379-1389.
10. de Magalhães, JP (2005) "Open-minded scepticism: inferring the causal mechanisms of human ageing from genetic perturbations" Ageing Research Reviews 4:1-22.
11. de Magalhães, JP et al. (2005) "HAGR: the Human Ageing Genomic Resources" Nucleic Acids Research 33:D537-D543.
12. de Magalhães, JP et al. (2005) "The influence of genes on the aging process of mice: a statistical assessment of the genetics of aging" Genetics 169:265-274.
13. de Magalhães, JP and Church, GM (2005) "Genomes optimize reproduction: aging as a consequence of the developmental program" Physiology 20:252-259.
14. de Magalhães, JP and Sandberg, A (2005) "Cognitive aging as an extension of brain development: A model linking learning, brain plasticity, and neurodegeneration" Mechanisms of Ageing and Development 126:1026-1033.
15. de Magalhães, JP (2005) "Human disease-associated mitochondrial mutations fixed in nonhuman primates" Journal of Molecular Evolution 61:491-497.
16. de Magalhães, JP and Church, GM (2006) "Cells discover fire: Employing reactive oxygen species in development and consequences for aging" Experimental Gerontology 41:1-10.