The cancer suppressor gene p53 has proven to be the center of a fruitful area of study in aging research: it is a master controller or important component in many critical biological processes - such as cell division, and even autophagy. While levels of p53 expression were thought to operate as a sliding scale between more cancer and slower aging at one end versus less cancer and faster aging at the other, researchers have in recent years demonstrated clever ways around this evolutionary trade-off. So gene-engineered mice have been created that suffer less cancer and still live longer:
[Previous research] showed that a boost in p53 kept mice cancer free but also caused them to age more quickly. [But] in the new work, the normal regulatory mechanisms remain in place, so p53 is churned out only when needed. ... These mice produce more p53 protein when prompted to by cellular stress, such as DNA damage or lack of oxygen. As expected, mice with the extra copy of p53 had fewer tumours than regular mice, and their cells were less likely to turn cancerous when grown in a Petri dish. On average, the transgenic mice lived 16% longer than normal mice.
Telomerase causes more cancer. So that there is a tumor, it must activate telomerase, and if a mouse has more telomerase than the normal thing, for example, making transgenic mice, we know that it will have more tumors. What we have done is to use [transgenic mice expressing more p53 than usual], because p53 protects against cancer and extends life of the mice 18%, and added the gene of immortality, telomerase, and we [found] that these multitransgenic mice live an average on a 50% more, without cancer.
I notice that the advance publication queue for the open access AGING Journal currently contains a couple of very readable editorials on the history and present state of p53 research:
p53 continues to surprise biologists. For nearly a decade, it was thought to be an oncogene, only to be subsequently declared a potent tumor suppressor. Initially characterized as a transcriptional activator, we now know p53 is also a transcriptional repressor. And just as it seemed p53 activities were confined to the nucleus, it became apparent that p53 also functioned in the cytoplasm to regulate mitochondrial responses. As a tumor suppressor and regulator of hundreds of genes, it was perhaps not surprising that p53 was shown to regulate numerous cellular processes related to cancer - cell cycle progression, apoptosis, cellular senescence and DNA repair, among others. It was another surprise, however, to learn that p53 might also regulate aging.
Multiple lines of evidence from animal models suggest that a functional p53 pathway favors prolonged survival. Aging mice show a decrease in p53 activity correlated with increased tumor incidence as well as an overall reduction in longevity. On the other hand, mice with an extra gene dosage of Arf and p53 show significant tumor protection, decreased oxidative damage and delayed aging.
As the ability of p53 to increase longevity becomes more evident, we should consider the role of its negative regulator, Mdm2 ... it is very tempting to imagine that just a slight inhibition of Mdm2 function in cells could both prolong full tumor surveillance mechanisms of p53, and in some circumstances increase longevity. Numerous molecular inhibitors of Mdm2 are in various stages of development with the goal of reactivating p53 activity in cancer. The idea that controlled pharmacological modulation of Mdm2 function might also have positive consequences in extension of human lifespan could be an unexpected benefit and an additional incentive for design of new compounds targeting Mdm2.
Like many other lines of life science research, genetic modification of longevity in mice leads fairly directly to the possibility of metabolic manipulation via drugs in humans. This is the dominant paradigm in those portions of the aging research community where people are thinking about engineered longevity: figure out a way to slow down aging through drugs that can mimic the biochemistry of longevity observed in other mammals.