The molecular mechanisms of ageing

Human genes are optimised for survival of the species and not the individual, except of course in the case of cancer cells, which seem to have somehow beaten the ageing curse. These phenomena have been studied since the 18th century and will again be the subject of discussion at the ICHG in a session co-chaired by Dr David Schlessinger of the National Institute on Aging in Baltimore and Dr David Thorburn of the Murdoch Children's Research Institute in Melbourne.

Dr Robin Holliday of the Australian Academy of Science (AAS) in Canberra will overview the biological reasons for ageing. Holliday, a former chief research scientist of CSIRO, was elected as a fellow of the AAS in 2004 but originally hails from the UK, where he did his undergraduate and PhD at Cambridge.

Holliday has since made fundamental contributions to molecular genetics, epigenetics and cell biology. He postulated the now accepted mechanism for genetic recombination in 1964, known as the Holliday Structure, which, despite recent revelations, remains the basis for our thinking and for subsequent developments in the field. Holliday also made landmark findings on DNA methylation and gene silencing in mammalian cells, significantly advancing our understanding of epigenetic regulation in development.

"At the end of the 20th century, scientists have revealed the biological causes of ageing ... and why different mammalian species have very different longevities," Holliday says. "Ageing is due to the eventual failure of the maintenance of the soma and this also means that there are multiple causes of ageing."

For each organism, resource management is balanced between investment in reproduction versus maintenance of proteins, DNA and cellular function. Holliday will discuss evidence comparing the efficiency of maintenance mechanisms and lifespan. He argues that the evolved structure of the mammalian body is incompatible with continuous survival and that the increased investment in resources that would be needed to maintain the soma indefinitely would reduce Darwinian fitness.

Reproductive ageing

Another focus of the session will be on reproductive ageing, with a presentation on ageing of oocyte, ovary and human reproduction from Dr Chris Ottolenghi of the National Institute on Aging in Baltimore.

Oocytes are responsible for transgenerational genetic transfer and yet from birth these cells start to deplete, until finally reproductive capacity is lost for that generation. Ottolenghi's group is interested in gene activity during follicle formation and maintenance, looking for defects that can limit reproductive lifespan.

Using a mouse knockout model, they have discovered an important role for the transcription factor Fox12 in both follicle formation and reproductive lifespan in females. Ottolenghi will discuss the recent findings from these genetic analyses, which he says provide an entry point for understanding developmental mechanisms that sustain reproduction and suggests a possible role for sex determination genes in cessation of female reproductive life.

IGF signalling

Martin Holzenberger from the Hopital Saint-Antoine in Paris will also focus on one of Holliday's 'multiple causes of ageing' in his talk on IGF signalling and ageing. Insulin-like growth factor (IGF) and insulin signalling are known regulators of lifespan in animals from yeast to mammals, whereby reduction of IGF/insulin signalling activity is associated with increased longevity. This mechanism appears to be evolutionary-conserved.

Decreased somatotropic function and resistance to oxidative stress emerged as possible mechanisms to explain these findings, and current interest lies in translating such results from in vitro and animal studies to human biology. Holzenberger will present the latest data on this area from experiments in both mice and human.

Mitochondrial damage over time has been associated with both ageing and degenerative disease. This theory is supported by a substantial amount of morphological, biochemical and genetic data, and recently, the first direct causal link was provided between mitochondrial DNA (mtDNA) mutations and ageing in mammals by Nils-Goran Larsson in Finland. His mtDNA mutator mice accumulate a substantial number of somatic mtDNA mutations over their lifetimes, prematurely age, and have a reduced lifespan.

Mitochondrial DNA and cancer

Dr Douglas Wallace from the University of California Irvine (UCI) will present on this topic at the ICHG. Wallace first developed his ongoing scientific interest in mitochondria and their DNA as a graduate student at Yale in the late 1960s, going on to show the nucleus-centred genetics field that mtDNA did indeed mutate and that it was maternally inherited. His discoveries virtually launched the field of mitochondrial genetics and Wallace is now recognised as one of the world's leading geneticists.

More recently, Wallace has been looking at the mtDNA mutations associated with several forms of cancer. "More than half of the cancer mutations are the same nucleotide changes as the adaptive polymorphisms associated with different human populations," Wallace says. "Hence, cancer cells may use the same mitochondrial adaptive strategies during their migrations as human populations have."

In his ICHG presentation, Wallace will show evidence of common mtDNA variants affecting our risk of various diseases. Wallace believes that individuals of today have inherited energetic imbalances from the adaptive mtDNA mutations of our ancestors, which, when combined with modern dietary caloric intake, are driving the modern epidemics of obesity, diabetes, neurodegenerative disease, cardiovascular disease and cancer.