Fight Aging!

These past few years, researchers have produced several demonstrations of extended life and reduced cancer rates in mice through the use of various gene therapy combinations involving increased telomerase expression and extra copies of cancer suppression genes such as P53. You can find an overview of this research and pointers to a review paper back in last year's archives.

A few years ago, a Spanish research team created transgenic mice that lived significantly longer than normal by combining increased p53 with increased telomerase. p53 is a cancer suppressor that under usual circumstances reduces the ability of stem cells to replace worn cells in aging tissue - less cell proliferation means a lower chance of cancer over time, but also faster aging as the tissues of the body wear and fail more readily. More telomerase, on the other hand, achieves the opposite end: dynamic, longer lasting cells that also produce way more cancers in the course of their more energetic operations. This, in any case, is the consensus view of how these elements work in the biochemistry of mammals.

The researchers recently published results for the next stage of their research program: taking the modifications that had been transgenic to date and instead applying them as gene therapies to adult mice.

That was last year. The latest update to arrive this month has the researchers trying out calorie restriction (CR) on their transgenic telomerase-enhanced (TgTERT) mice, with a wild-type (WT) control group. Apparently calorie restriction somewhat synergizes with the effects of additional telomerase, and thus calorie restricted TgTERT mice live longer than their ad libitum peers. Beyond that, this is also a study of how calorie restriction impacts telomere dynamics, finding that it delays the characteristic erosion of telomeres with age - which is consistent with the body of research showing calorie restriction to slow almost all other measurable aspects of aging.

Telomerase Reverse Transcriptase Synergizes with Calorie Restriction to Increase Health Span and Extend Mouse Longevity

First, we showed that the CR protocol used here was able to protect from the development of pathologies associated with aging in both WT and TgTERT mice, including insulin sensitivity and glucose intolerance, as well as protection from bone loss over time. In addition to protection from age-related pathologies, CR improved other aspects of mouse health such neuromuscular coordination in both genotypes. Together, these results indicate that the CR protocol used in this study was able to increase the "health span" of both WT and TgTERT mice.

In agreement with this, we observed a delayed onset of first deaths in the WT and TgTERT cohorts under CR. Interestingly, WT mice under CR showed a similar median longevity and similar onset of first deaths to that in TgTERT mice under a control diet, suggesting that TERT transgenic expression is partially the beneficial effects of CR.

By using longitudinal telomere length studies, we also describe here that CR delays telomere shortening associated to aging in blood cells from WT mice (PBLs), to an analogous degree to that observed associated to TERT over-expression. Other tissues, such as lung, kidney, bone marrow and muscle, also presented longer telomeres in mice under CR compared to those under the control diet. In agreement with a protection from telomere shortening associated with aging, we also observed that CR protected from telomere-originated DNA damage and chromosomal aberrations.

The trouble with ascribing causes and mechanisms to calorie restriction is that it does change everything. So autophagy researchers see it boosting autophagy, telomerase researchers see it changing telomere dynamics, fat metabolism researchers see it affecting fat metabolism, and so forth. So far I think that autophagy has a stronger claim than any other mechanism as being the dominant cause of calorie restriction benefits to health and longevity, if only because removal of mechanisms essential to autophagy has been shown to remove those benefits in some laboratory species. But there's still plenty of room for evidence and debate.