Genes linked to ageing: p53, sir-2, daf, IGF
Examinations of model organisms such as mice and other lower organisms has yielded results which suggest that certain genes can contribute to alterations in the rate of ageing (Perls, 2002). The P53 gene is one of these genes. The p53 gene creates a tumour suppressor protein that has many functions. These include its ability to induce cell cycle arrest or activate apoptosis in cells that can’t repair DNA damage or when certain oncogenes are activated. It is commonly referred to as the “guardian of the genome”, due to its ability to prevent genetically unstable cells from entering a cancerous state (Donehower, 2005). In many cases of cancer a mutated p53 gene is present.
Tyner et al (2002) over expressed the p53 protein in mice; the resultant phenotype showed that the mice had a decreased susceptibility to cancer, but the research group also noted that the mice had reduced longevity, and displayed symptoms very similar to ageing. This was backed up by research conducted by Luo et al (2001). He noted that sir-2 in Saccharomyces cerevisiae and Caenorhabditis elegans switches p53 off and when this occurs, he noticed increased longevity and an increase in cancer susceptibility in these model organisms.
Experimental research conducted on model organisms has allowed researchers to identify possible genetic variation’s that increase longevity by slowing down the ageing process. Perls et al (2002) stated that mutations in the daf genes (daf-2, daf-16, and daf-23) and the age-1 gene within Caenorhabditis elegans could increase life span up to 5 fold. These genes are activated when the C.elegans enters a hibernating state, also known as the dauer state. These genes are involved in the regulation of forming this hibernating state in C.elegans. In this state C.elegans can survive for up to 2 months on limited food supply, as opposed to non-hibernating C.elegans which survive for up to 3 weeks on sufficient food supply. Kimura et al (2007) stated that the IGF-1 receptor gene is the human equivalent of the daf-2 gene.
The insulin/IGF signalling pathway is responsible for regulating life span in c.elegans. The daf-16 protein is one the key players in this pathway. It is believed that it is one of the main targets for the daf-2 pathways. This can be proven through daf-16 mutants as daf-2 phenotypes are only seen when daf-16 is fully operational (Lin et al, 2001).It is thought that daf-2 shortens life span as it inhibits the production of the daf-16 protein (Lin et al 2001). Studies have shown that Daf16 mutants do not survive for very long (Nicole, 2007). A mutation in the human homologue of the daf gene’s would actually decrease longevity, so their role in human life span is not yet fully understood (Perls et al, 2001).
Holzenberger et al (2003) showed that female mice that were heterozygous for the IGF-1 receptor gene had a significantly longer life span, than control females. It is assumed that this is because mice that are heterozygous have an increased resistance to oxidative stress. However in males there was no significant difference. This study was criticised for its small sample sizes, so researchers claim that no solid conclusions can be drawn from this experiment (Lin et al, 2001).
