The activity undertaken by many important genes is quite subtle and conditional. Simply raising or lowering the amount of protein produced by that gene is rarely as effective as hoped in initial studies, and can be entirely counterproductive. The important activities of any specific protein might be very tissue-specific, and thus thwarted by being altered globally, or they might depend on other proteins and circumstances. The tumor suppressor p53 is a good example of the type; more p53 activity at the right times and in response to the right signals can both extend life and reduce cancer risk in mice. On the other hand, generally increased p53 activity shortens life.
The p53 protein is a part of the complex and shifting tradeoffs made between suppression of cellular replication and encouragement of cellular replication. When there is a greater risk of cancer, when cells are damaged or the cellular environment is toxic, more p53 encourages both greater repair and resistance to cellular damage and a more aggressive removal of cells most at risk by forcing them into senescence. In the normal course of regeneration and tissue maintenance, however, too much p53 suppresses the efforts of the cells that should be replicating, speeding the onset of frailty and organ failure, and over time the presence of larger numbers of senescent cells also leads to an acceleration of the aging process. Senescent cells cause a great deal of harm when they are not efficiently destroyed, either by the immune system or through programmed cell death.
It has been a decade since researchers first demonstrated a way to selectively enhance p53 activity only when needed, producing extension of life in mice. Since then, I think most of the groups involved have been quite distracted by work on telomerase gene therapies, which started in earnest at around the same time and among many of the same researchers, but which has since consumed ever more of the available time and interest. You might recall a merger of these two lines of research in which mice with enhanced telomerase and enhanced p53 activity were found to balance out with a longer life span. Since then the telomerase research has forged ahead, as I'm sure you've all noticed, but I can't say that work on selective increase of p53 activity as a method of modestly slowing aging has advanced all that much at all. The papers today are covering essentially the same ground as was covered a decade ago, and still with little impetus towards building some form of therapy from this:
Cancer is the consequence of an aberrant gain of cellular fitness linked to the accumulation of stress and cellular damage of acute intensity. This damage occasionally provides aberrant advantages to certain cells, which can eventually lead to cancer development. The Ink4/Arf locus and p53 are regarded as the most relevant tumor suppressors based on their ubiquitous and frequent inactivation in human cancer. The Ink4/Arf locus encodes three tumor suppressor genes p15Ink4b, p16Ink4a, and p14Arf (p19Arf in mice). On one hand, p15Ink4b and p16Ink4a (called Ink4 hereafter) inhibit the formation of the cyclin-dependent kinases (CDK4 and CDK6) and cyclinD complexes during the G1 phase of the cell cycle. Hence, they prevent the transcription of genes involved in the transition to S phase, importantly the Rb/E2F1 pathway, so regulating cell cycle progression. On the other hand, Arf exerts its tumor suppressive action by inhibiting Mdm2, a ubiquitin ligase considered the major p53 regulator, thereby contributing to the activation and stabilization of p53.
The Ink4/Rb and Arf/p53 pathways are major sensors of stress that play a crucial role in early detection and elimination of cells that have suffered different types of stress including oncogene activation, DNA damage, oxidative stress, etc. While the activation of Ink4/Rb pathway induces reversible cell cycle arrest or irreversible cellular senescence-associated changes, the activation of p53 elicits a cellular response that might vary from restoration of cellular homeostasis by a transient blockade of the cell cycle to allow for DNA repair, senescence, or apoptosis. The activation of these responses depends in a complex manner, on the intensity of the triggering stress and on the cellular context. In agreement with this damage protective role, the individual or combinatory deletion of these genes promotes cancer susceptibility in multiple tissues and contexts. On the contrary, enhanced Ink4/Arf and p53 activity preserves mice from spontaneous or chemically induced cancers.
Although cancer and aging may seem opposite processes, they can be regarded as two different manifestations of the same underlying process, namely the accumulation of cellular damage. Moreover, cancer and aging may share common origins. There are several genetic or pharmacological manipulations that simultaneously modulate cancer and aging. These proofs demonstrate that cancer protection and longevity can be simultaneously modulated using different strategies and molecular mechanisms. In recent years, this is deepening the knowledge of the implications that the Ink4/Rb and Arf/p53 pathways have on the management of cellular damage associated with the aging process. The observation that several manipulations simultaneously modulate longevity and cancer protection establishes an interesting parallel with the expression of members of the Ink4/Rb and Arf/p53 pathways, which are silent or very low during development and postnatal life, while progressively increase from adulthood to old age in a broad range of tissues and species.
There is little additional information regarding p53 and aging in human, yet there is no evidence of a pro-aging function. Indeed, it has been documented that p53 is not involved in human premature aging disorders such as Hutchinson-Gilford Progeria, and it has been postulated that well-preserved p53-mediated responses are likely a key factor contributing to protection from diseases and cancer in centenarians. The above raises the possibility that Ink4/Rb and Arf/p53 pathways might have a role in aging. Thus, stress conditions cause an accumulation of DNA damage at the cellular level. Ultimately, it leads to the final activation of the Ink4/Rb and Arf/p53 pathways in order to achieve various adaptive responses to this situation. Amidst such responses is the transient block of the cellular cycle to try to repair the damage, inducing a state of senescence, or even apoptosis. Therefore, the empowerment of Ink4/Rb and Arf/p53 pathways might play an important role not only on surveillance and suppression of tumors, but also on the accumulation of cellular damage and aging. Therefore, it is reasonable to surmise that Ink4/Rb and Arf/p53 play a role also in the response to age-associated chronic stress and consequently affects aging. As activation of the Ink4/Rb and Arf/p53 pathways triggers a protective mechanism against tumor-induced stresses, they could also have anti-aging activity by alleviating the load of age-associated damage.
Significant efforts have been made to determine the impact of Ink4/Rb and Arf/p53 tumor suppressor pathways. While their protective function against cancer is firmly established, their role in aging remains controversial. In mice, it has been demonstrated that modest increases of regulated Arf/p53 activity are anti-aging while deregulated activation of p53 promotes aging. These observations are not in conflict per se and indicate that the activity of Arf/p53 could be beneficial or detrimental for aging depending on their intensity and regulation. It has recently been demonstrated that these effects are mediated through the activity of stem cells, indicating the concept of a reciprocal trade between tumor suppression, aging, and stem cell biology. Based on this, we postulate a model by which high or deregulated Arf/p53 impacts on lifespan by a decline in tissue stem cell regenerative function, but modest and regulated increases in Arf/p53 result in systemic organismal benefits ameliorating stem cell aging and maintaining tissue homeostasis. Additional work is necessary to establish the detail role and mechanism of action of p16Ink4a in aging and stem cell biology.