Alright, I got slightly side tracked today on this topic, and felt like writing. Enjoy my compulsions. :-)

The search for mechanisms behind Calorie Restriction has produced another promising possible explanation. The center of this finding is the mTOR (mammalian target of rapamycin) pathway. Rapamycin is an immunosuppressant drug used to help prevent transplanted organs from rejecting. The mTOR protein is encoded in the FRAP1 gene which regulates cell growth, proliferation, motility, survival, protein synthesis, and transcription. Rapamycin was known to extend lifespan in invertebrates, yeast, nematodes, and fruit-flies, and a study in 2009 found that mice given rapamycin lived 9-14% longer.

This paper found that the inhibition of the mTOR signaling pathway extended lifespan in mice of both genders, and these findings were reproduced at 3 different, independent research locations. All the mice were of the same genotype to avoid possible introduction of genetic variables. The researchers hypothesize that rapamycin may extend lifespan by either postponing death from cancer and/or retarding aging mechanisms. Also, an important note is these mice were started on the drug late in life (20 months of age), which makes this an especially significant finding. This discovery opens the way for further understanding on how the mTOR signaling pathway can affect lifespan, and the fact that the findings were seen in both genders at 3 separate research locations shows this is a major breakthrough toward understanding CR and aging mechanisms as well as developing aging therapies.

mTOR Discussion
Before I go into another publication, I want to further briefly discuss the mTOR signaling pathway. Decreased TOR activity slows aging. The drug rapamycin acts as an mTOR inhibitor, thus decreasing TOR activity. Certain dietary practices such as calorie restriction and methionine restriction are hypothesized to decrease mTOR activity, thus leading to increased longevity.

mTOR is affected by input from the insulin, growth factor (IGF-1 & IGF-2), and mitogen (substance that triggers cell division) pathways as well as cellular nutrient and energy levels. Several studies have connected these pathways and nutrient signaling to longevity in a variety of organisms. So, it appears the mTOR signaling pathway may be one of the keys to understanding the longevity effects of dietary practices and allow for anti-aging therapies further progress.

Many studies significantly correlate nutrient signaling to longevity. As certain nutrients are less available, stress pathways are induced and organisms live longer. Of the several pathways of interest (IGF-1, AMP kinase, protein kinase A, and TOR), inhibition of the TOR pathway has indicated the potential for widespread protection from a variety of age related diseases.

The TOR pathway is primarily activated by amino acids, and other sensors that activate the TOR pathway detect cellular energy stores. Interestingly, in both invertebrate and mammalian models, dietary restriction leads to reduced insulin/IGF-1 and TOR signaling. There are two TOR complexes, TORC1 and TORC2, and both are essential. TORC1, primarily activated by amino acid availability, coordinates protein synthesis when nutrients are abundant. TORC2 is mostly responsive to growth factors, insulin and IGF, and also facilitates “cross-talk” between the insulin signaling pathways and TOR signaling.  

TOR and Cancer, Vascular Disease, Metabolic Disease, and Neurodegeneration
Increased TOR activity is seen with a wide variety of cancers, and in mutations leading to increased TOR activity, higher cancer rates with decreased cancer survival rates are observed. Decreased mTOR signaling as a result of rapamycin results in cardioprotective benefits. The mTOR pathway has also been implicated in both Type 1 and Type 2 diabetes, and it also appears that chronic TOR activation leads to insulin resistance. The mTOR signaling pathway is not only linked to normal brain functioning, learning, and memory, but patients suffering from Huntington’s and Alzheimer’s disease may also benefit from mTOR signaling modulation. Note that all these benefits from reducing/modulating the mTOR signaling pathway are also seen in dietary restriction, *and* this is the only pathway to produce longevity across the 4 classifications: yeast, invertebrates, nematodes, and mammals.

The authors sum up this review by reminding the reader the role of TOR signaling in modulating immunity and the mechanism of rapamycin are still not well understood, and a better understanding of TOR signaling and immune system function may further our understanding of mTORs effect on lifespan and age-related diseases.

Further Discussion on the Inhibition of mTOR signaling.
The previous review mentioned that nutrients (primarily amino acids) were responsible for activating TORC1 while insulin primarily activated TORC2. Deeper digging (HERE and here) points to leucine as an enhancer of mTOR signaling. Note that leuine and other branched chain amino acids are favored by bodybuilders. The activation of the mTOR signaling pathway inhibits muscle breakdown, thus leading to higher gains. This makes me think twice about the remaining protein powder I have been meagerly using; maybe I’ll look for another source when it’s gone. I also find it humorous that just a year ago, I would have jumped though fiery hoops for muscle gains, but I am just now understanding the stress and probable damage I was doing to my body. Ironic, no? (Maybe this is why I am getting forehead wrinkles…lol…maybe…)

Once again, the issue of protein restriction is brought into play. While I am not jumping on the protein restriction band wagon to the extreme, I have put protein consumption on a lower priority level in my diet, and most days I consume around 20% as opposed to 30% a few months ago.