In previous posts I’ve discussed, mTOR: the mammalian target of rapamycin. Studies in a variety of species support TOR as an aging regulator. During periods of dietary restriction, TOR signaling affects processes involving mRNA translation, autophagy, stress signaling and response, and metabolism which in turn slows aging. A paper published in June 2010, provides more support for TOR as an aging modulator. I try to highlight some of the major/most interesting concepts, but this is a pretty detailed paper you may want to read for yourself.
With TOR, less is more: a key role for the conserved nutrient-sensing TOR pathway in aging.
Rapamycin is an immunosuppressive drug which inhibits TOR activity. TORC1 (TOR Complex 1), which plays a central role in TOR signaling network, is the specific TOR protein sensitive to rapamycin. TORC1 controls cell size, proliferation, and life span through several downstream pathways.
TOR Affects Growth Via Nutrient Sensing
TOR is sensitive to the reduction in nutrients across a wide array of species. During nutrient deprivation, TOR slows growth. In species modified to have reduced or no TOR signaling, development and growth is either comparable to that seen with nutrient deprived circumstances, or in some situations lacking TOR the lack of development is fatal.
TOR: Growth Factors and Stress
TORC1 can also be thought of as a signaling hub: receiving signals from a number a factors and in turn influencing multiple physiological responses. Because of this, TOR is thought of as a “growth checkpoint” -checking for favorable conditions and mediating growth in turn. Many of the cellular processes affects by TOR mediation are believed to influence life span.
TOR is not only sensitive to quantity of available nutrients, but the quality too. One powerful TOR inhibitor is the withdrawal of amino acids (the building blocks of protein). L-lucine is a major TOR activator, but L-tryptophan, L-phenylalanine, and L-arginine can also activator TORC1 when transported into a cell. TOR is also affect by cellular glucose levels. During a reduction in cellular energy, TOR signaling is reduced. Other growth factors such as IGF and insulin, can also modulate TOR activity. TORC1 is also sensitive to stress such as high temperature, hydrogen peroxide, and osmotic stress -all of which reduce or inactive TORC1.
TOR Signaling and Dietary Restriction
Dietary restriction (DR) is a commonly known way to slow aging across multiple species. DR not only slow the progression of many age related diseases, but it can also reduce or prevent cancer growth, neurodegeneration, and cardiovascular disease. TORC1 is thought to play a major role in the beneficial effects of DR.
In the genetically modified long lived Ames dwarf mouse, data support reduced TOR activity as a major factor in their long life span. Even non-modified mice administrated rapamycin in middle age saw a positive effect on life span.
Strong TORC1 inhibition early in life often yields damaging or fatal results, but TORC1 inhibition during adulthood can have the opposite effect and actually extend life.
Mediators of TORC1
Reduced protein synthesis as a result of inhibited TOR activity is one of the major factors in increasing life span across species. Restriction of dietary protein is known to have beneficial effects on life span, which is thought to be a result of reduced TOR activity due to reduced amino acid availability.
Also, the activation of S6 Kinase (a downstream process of TOR signaling) modulates protein synthesis and the inhibition of S6K has recently been found to also extend life in some species. Interestingly, female (but not male mice) lacking S6K have been observed to have longer life spans suggesting there may be a gender related component to TOR signaling and lifespan.
Final Thoughts:
Extensive evidence shows the nutrient and stress sensing of the TOR singling network as a major factor in mediating responses to dietary restriction. Results indicate reduced TOR signaling works to extend life span. This information could lead to the development of “anti-aging” drugs.
Future work will include further examination of TOR signaling and DR as an aging modulator in a variety of species, and will hopefully elucidate the link between diet and age-related diseases.
Neat diagram that I don't have access to. Bah.
