BA Mathematics, University of Cambridge, 1972.
MSc Applied Statistics, University of Oxford, 1973.
PhD Biology, University of Cambridge, 1983.
2004 - 2011 Director, Institute for Ageing and Health, Newcastle University
1993 - 1999 Professor of Biological Gerontology, University of Manchester
1988 - 1993 Head, Laboratory of Mathematical Biology, MRC National Institute for Medical Research, London
1981 - 1988 Staff Scientist, then Senior Staff Scientist (1987), Computing Laboratory, MRC National Institute for Medical Research, London.
1973 - 1981 Scientist, then Staff Scientist (1979), Statistics Section, National Institute for Biological Standards and Control, London.
Evolution and genetics of ageing
Starting in 1977, we suggested that a major contribution to understanding ageing can be achieved by linking the evolutionary and physiological approaches in a concept called the disposable soma theory. This predicts that:
ageing is due to evolved limitations in investments in somatic maintenance and repair, due to competing priorities of reproduction;
ageing therefore results from the accumulation during life of damage in cells and tissues;
multiple mechanisms contribute to ageing (since there are multiple forms of somatic maintenance, all of which are subject to the same optimality process);
the principal genes determining longevity and rate of senescence are genes specifying the levels of maintenance functions (e.g. DNA repair genes, antioxidant enzymes, stress proteins);
the ageing process is intrinsically stochastic, but that longevity is programmed, on the average, through the settings of genes of the type just considered;
maximum life span is not clock-driven but malleable, e.g. through modifying exposure to damage or enhancing somatic maintenance functions.
We currently use these ideas to explore life history evolution (eg evolution of menopause) and the optimal allocation of metabolic resources in varying environments (eg life extension through rodent calorie-restriction). Such models are important for understanding the genetic architecture of the life history and have major relevance for genome research on longevity. Recently, with Rudi Westendorp (University of Leiden), we reported in Nature the first evidence for a trade-off between human longevity and fertility. In collaboration with Ruth Mace (University College London) we are examining evolutionary models of the human life history using an extensive data set collected in West Africa.
In genome studies on human ageing, we pioneered novel approaches to the analysis of gene polymorphisms affecting human longevity in collaboration with Francois Schachter and Daniel Cohen (Centre d’Etude du Polymorphisme Humain), and we are now developing detailed models of genetic and non-genetic factors affecting human longevity. Emerging from the disposable soma theory, there is a growing recognition that the development of the senescent phenotype is strongly affected by intrinsic stochastic factors (chance), as well as by genes and environment. A major synthesis of this new perspective has recently been developed in collaboration with Caleb Finch (University of Southern California).
Mechanisms of cellular ageing
A central problem in experimental gerontology is to understand how cells accumulate damage during ageing and how age changes at the cell level produce age-related dysfunction and disease within tissues and organs. In collaboration with Chris Potten (Paterson Institute for Cancer Research), we recently obtained some of the first direct evidence of age changes occurring within tissue stem cells in the intestinal epithelium. These changes involve increased susceptibility to genotoxic agents (low-dose irradiation) and impaired regenerative capacity. We are currently investigating the molecular basis of these changes in terms of an altered cellular response to DNA damage, which appears to be delayed in the aged stem cells. In a different context, we showed that primary skin fibroblasts from long-lived mammalian species have greater intrinsic capacity to withstand a variety of stresses in vitro than cells from short-lived species. This confirms a key prediction of the disposable soma theory and points to the central role of cell maintenance and stress response systems in ageing and longevity.
Another key prediction of the disposable soma theory is that there is no single mechanism of cell ageing, but rather that multiple mechanisms operate together. We have developed this concept of a network theory of cellular ageing in a series of theoretical models that examine the major candidate mechanisms of cell ageing in an integrated way (collaboration with Axel Kowald, Humboldt University). The models allow us to explore in a precise, quantitative manner the interactions and synergism between different biochemical mechanisms of cellular ageing. They show not only how the network theory can explain much more of the experimental data than individual hypotheses alone, but also that during the course of the cell ageing process the individual mechanisms can assume relatively more or less importance at different times. This is being used to guide experimental studies within the Department on integrative mechanisms of cell ageing and heterogeneity in ageing cell cultures and tissues.
A major contribution has been to link the evolutionary and physiological approaches to studying the biology of ageing through the disposable soma theory. This theory predicts that:
(i) ageing is due to evolved limitations in investments in somatic maintenance and repair, due to competing priorities of reproduction,
(ii) ageing therefore results from the accumulation during life of damage in cells and tissues,
(iii) multiple mechanisms contibute to ageing (since there are multiple forms of somatic maintenance, all of which are subject to the same optimality process),
(iv) the principal genes determining longevity and rate of senescence are genes specifying the levels of maintenance functions (e.g. DNA repair genes, antioxidant enzymes, stress proteins),
(v) the ageing process is intrinsically stochastic, but that longevity is programmed, on the average, through the settings of genes of the type just considered, and
(vi) maximum life span is not clock-driven but malleable, e.g. through modifying exposure to damage or enhancing somatic maintenance functions.
The disposable soma theory arose from studies on mechanisms of somatic cell ageing and from asking why cells age. The prevailing view at the time the theory was first proposed, in 1977, was that ageing was programmed. However, the reasons for existence of a programme had been little considered. The disposable soma theory, with its early focus on linking the Why? and How? questions, helped to demonstrate the intrinsic weakness of programme theories and to alter the paradigm to one that focuses on mechanisms of longevity assurance.
A second major strand of my work has been to address the integrative mechanisms responsible for ageing. In 1984, I wrote a paper addressing the need for a unified theory of cell ageing which won the Heinz Karger prize (shared with Jim Smith of Baylor College of Medicine). My work in the 1970s with Holliday on the commitment theory of cell senescence demonstrated that the growth behaviour of cell populations needs to be understood in terms of the clonal dynamics of individual cells. This remains an important principle which is resurfacing in the new work on cell replicative senescence. In vivo, the relationship between cell and tissue changes has been addressed in recent work with Potten on the stem cells of the mouse intestinal wall. We showed that progressive change occurs in the morphology of this tissue with age and have identified altered functional properties of the tissue stem cells which may be responsible. We are now investigating the underlying molecular mechanisms of stem cell functional impairment.
A key element of my work on integrative mechanisms of cell ageing has been the development of a network theory that explicitly embraces multiple mechanisms of cell ageing and the cell defense network. With Kowald, I have developed a series of theoretical models of biochemical mechanisms of cell ageing that allow us to explore in a precise, quantitative manner the interactions and synergism between different biochemical mechanisms of cellular ageing. The models show not only how the theory can explain much more of the experimental data than individual hypotheses alone, but also that during the course of the ageing process the various mechanisms can assume relatively more or less importance at different times.
A central message from much of my work is the need to consider how the complex development of the senescent phenotype is the product of genes, environment, and intrinsic stochastic factors (chance). A major synthesis of this view has recently been undertaken in collaboration with Finch. The specific question of the mechanisms contributing to longevity has been considered from the perspective of human gene polymorphisms, in the identification of heritable trade-offs revealed in human genealogical data extending across nearly 10 centuries, and in a comparative study of cell stress resistance demonstrating that among mammals long-lived species have greater functional resistance of their cells to a variety of stressors than short-lived species.
Arising from my interest in accuracy in molecular processes and mechanisms of genome evolution, I developed an early interest in techniques for statistical analysis of DNA sequences, in particular the detection of sequence homologies. Novel methods for homology testing were developed. A related interest in the variation and molecular evolution of viral genome sequences lead to study of the effects on virus replication dynamics of so-called defective interfering viruses. This work attracted considerable interest and was the motivation for an EMBO Workshop on Variation and molecular evolution of viruses in 1992, of which I was main organizer, and which brought together leading virologists and mathematical biologists in this field.
My early work was in biological standization, chiefly in the area of blood coagulation and. I was entrusted with planning and directing a major 'wet' workshop involving multiple laboratories, which identified chief sources of variation in Factor VIII assay , and I carried out an early meta-analysis (before this term was coined) demonstrating a significant, systematic discrepancy between the two principal assay methods. I devised a novel system for international calibration of thromboplastins and developed a clinical scale, the international normalized ratio, for expressing results of prothrombin time tests in common units around the world. This is now the standard method for reporting prothrombin time ratios, which are essential laboratory measures in monitoring those on anticoagulant therapy, e.g. for atrial fibrillation.