The PTEN gene shows up in a number of places in aging research, and today's paper is a review of what is known of its relevance to the field. To pick a few items, PTEN appears to be involved in some of the processes and pathways that control nutrient sensing, and is thus of interest to researchers attempting to recreate the beneficial effects of calorie restriction via pharmaceuticals. It is also involved in regeneration and cancer as a governor that prevents excessive cell growth. In this context, PTEN suppression has been shown to enhance nerve regrowth in mice, but of course there are other, adverse consequences to turning off a cancer suppression gene should that be accomplished too broadly or for too long a period of time. Moving the dial in the other direction, researchers have found that increasing the amounts of protein generated from the PTEN gene reduces cancer incidence and extends life in mice.
To find a cancer suppressor that also extends life when present in larger amounts is actually somewhat unexpected. The (perhaps overly) simple view of cancer suppressor genes is that they act to reduce cellular replication, which in turn diminishes tissue maintenance more rapidly as aging progresses. The net result is mixed: less cancer, true, but also a shorter life span and greater incidence of frailty. This is the case for the general application of tumor suppressor gene p53, for example. But even for p53, it is possible to find more subtle ways to apply the increase, such as only generating more p53 in the situations where it is needed, rather than all the time. That can both extend life and reduce cancer. The unusual nature of PTEN is that more of it, applied globally, has this wholly beneficial effect, without the need for subtlety. The results from the first PTEN study of cancer and aging suggested that the observed slowing of aging in mice was a matter of altered fat metabolism: the mice were lean, energetic, and suffered lesser degrees of insulin resistance. It is known that visceral fat is important in aging, and in mice a significant increase in life span can even be obtained via the very blunt solution of surgical removal of that fat in adult life.
In humans, when compared to mice, lifestyle influences such as calorie restriction and the level of visceral fat tend to have similar short-to-mid-term effects on health, but lesser effects on longevity. Calorie restriction can reliably increase life span by 40% in mice, but in humans it is more likely to be somewhere near five years at most. We are long-lived for our size as mammals, and there are evolutionary arguments to explain why it is that low or high calorie intake and resulting levels of fat tissue have a smaller effect on life span in our species. Enhanced longevity in response to calorie restriction evolved because it increases survival in the face of famine. Famines are seasonal, however, and while a season is a sizable fraction of the mouse life span, it is small in comparison to a human life span - so only the mouse has the evolutionary pressure to evolve a very plastic lifespan, capable of living half as long again when there is little food.
This paper can be taken as an example of present opinions on aging and longevity at the more optimistic end of the portion of the research community that seeks to modestly slow aging by altering metabolism. This usually involves changing circulating levels of proteins important in core cellular processes such as replication or nutrient sensing, of which PTEN is one example. While it is always pleasant to see more researchers explicitly advocating extension of healthy life span as a goal, I have to say that I don't think that this high level strategy is the right approach. It is an expensive, slow road to small benefits. If we are to live significantly longer than past generations, that must be achieved through comprehensive repair of the cell and tissue damage that causes aging, not by altering our metabolism so as to slightly slow the pace at which that damage accumulates. In the near term of the next few decades, only the former can reverse the progression of aging, only the former is useful to people already old, and only the former can produce very large increases in healthy life span.
Phosphatase and tensin homolog deleted on chromosome 10 (PTEN, also known as MMAC1 and TEP1) was first discovered in 1997 by two independent groups and recognized as the long sought after tumor suppressor gene frequently lost on human chromosome 10q23. This locus is highly susceptible to mutation in human cancers: the frequency of mutations have been estimated to be 50%-80% in sporadic tumors such as glioblastomas, prostate cancers and endometrial carcinomas; and 30%-50% in lung, colon and breast tumors. PTEN is often associated with advanced cancers and metastases, due to loss of PTEN having been observed at its highest frequency in late stages of cancers. Together with p53, Ink4a and Arf, PTEN makes up the four most important tumor suppressors in mammals as evidenced by their overall high frequency of inactivation across a variety of cancer types. Because of this, it is vital to understand the mechanisms of how PTEN functions.
The main function of PTEN is to antagonize the PI3K/AKT pathway, thereby opposing the pathway's cell proliferative response and, more important to longevity, opposing AKT's downregulation of antioxidant genes and proteins. In concert with this function, PTEN has been reported to bind with another antioxidant gene, p53, and arresting the cell cycle whilst positively regulating protein dealing with DNA-damage. These functions serve not only to extend cellular longevity but also prevent deleterious DNA-damage that can lead to malignant tumors.
The purpose of the report is to serve as a comprehensive review of the links that have been made between PTEN and the potential effects it may have on ageing. It will cover various issues such the regulators of PTEN, the regulatory effects of PTEN, its cellular functions, its associations with cancer and its direct effects on longevity in the effort to understand the many and varied pathways that PTEN is a part of, and how these intricate and integral pathways are key to effecting longevity. While Ponce de León's dream of a fountain of youth may be unobtainable as of yet, this report will show that extended longevity is highly possible. This paper follows in the theme of recent papers which show the strides that anti-ageing research have made over recent years. PTEN has the potential the play a crucial role alongside these other studies as, beyond its documented ability to extend longevity, its function as a tumor repressor is vital to any lasting extended longevity to prevent the rise of tumors often associated with extended longevity.
To sum up a lengthy report: PTEN has significant implications for extending human longevity through its actions on DNA-damage reduction, antioxidant activity, caloric restriction, inhibition of replication and tumor suppression. The importance cannot be overstated as PTEN overexpression can assist a variety of maladies including weight-related diseases such as diabetes to age-related diseases such as Alzheimer's and Parkinson's. Its function as a tumor suppressor can maintain an anguish-free life. It is because of this variety and necessity of function that PTEN is a vital subject for further research. Through studies done on invertebrates and on mammals we have seen that the application of this knowledge is successful, that PTEN's effect on longevity is not merely theoretical but practical. That PTEN can enhance longevity is no longer questionable, but neither is it irrefutable. Before any final concluding statements can be made, human trials with PTEN transfection must first be done. The authors of this study are currently working on cell culture trials, which is only the first step.
PTEN alone cannot extend longevity indefinitely, however, as a past study demonstrated only a 9%-16% increase in longevity, and while this is a significant milestone, this is hardly the fountain of youth that Ponce de León dreamt of. This is not to say that such a dream may not happen, merely that PTEN alone would not accomplish it. Others presented findings that telomerase can reverse tissue damage in aged mice. This rejuvenative quality bodes well as a potential partner for PTEN, and its most important feature, that of telomere extension, could potentially extend longevity as long as needed. PTEN is well suited as a partner for telomerase due to its tumor suppressive quality. This is because of two reasons. Telomerase have been commonly associated with cancer and a tumor suppressor may prevent this. However, more importantly, the longer one lives, the probability of having cancer increases. It is PTEN's tumor suppressive quality that sets it apart from other recent studied genes such as SIRT1.
The variety of genes, proteins and enzymes being studied today show how the interconnectivity of the human system also necessitates a complex solution to longevity. Whether this is achieved through the main pathways of telomerase, SIRT1, PTEN or others remains to be seen. What must be done now is testing, and further testing, until an answer is found. With the importance of such work, it deserves no less. While human trials oblige a lengthy testing time, it is an inevitable obstacle that must be overcome if Pons de León's dream is to be fulfilled.