The practice of calorie restriction, consuming fewer calories while still obtaining optimal levels of dietary micronutrients, has been demonstrated to greatly improve measures of health in humans and slow the progress of near every measure of degenerative aging in numerous species in the laboratory. It extends life by up to 40% or so in mice and similarly in other short-lived species, but the effects on life span in comparatively long-lived primates appears to be more limited. Yet the health benefits and alterations to the operation of metabolism are very similar in mice and primates, providing a puzzle that will keep researchers occupied for some years to come, I expect.
Calorie restriction has been shown to slow the accumulation of DNA damage measured in aging, and evidence suggests that this is due to changes in the very complex array of DNA repair mechanisms hard at work in our cells. Calorie restriction also slows the pace at which senescent cells gather in tissues, and short-term calorie restriction can even modestly reduce the numbers of those cells present in older tissues. Senescent cells are those that have removed themselves from the cell cycle in reaction to damage or signals in the tissue environment associated with risk of damage, such that causes by excess heat and toxins. Some forms of DNA damage such as double-strand breaks can trigger cellular senescence; this process is considered to be an evolutionary adaptation to suppress the risk of cancer arising from just such damaged cells. However there are also harmful consequences, as senescent cells degrade surrounding tissues, spurring their neighbors to also become senescent. The growing presence of these cells directly contributes to many of the degenerative conditions of aging.
The research linked below uncovers a link between low nutrient environments in tissues, such as those created by calorie restriction, and more proficient DNA repair. It is no doubt far from the only contributing mechanism to the benefits of calorie restriction for DNA repair. The response to calorie restriction is enormously complex, touching on near every major area of research into metabolism, and as yet no complete model exists for even the better studied parts of the process:
Cells harbour genetic material in the form of DNA, which contains all the information required for the cell to function. Every time a cell divides this information has to be precisely copied so that the newly made cell receives a perfect replica in order that it, too, can function properly. The inheritance of damaged DNA, however, must be inhibited. In order to recognise altered DNA and prevent it from getting passed on to daughter cells, cells have developed surveillance mechanisms, or checkpoints. Checkpoints stop cells from dividing; thereby allowing more time for the cell to repair damaged genetic material. In some cases, however, the DNA cannot be efficiently repaired even though the checkpoints have been activated. If DNA damage persists for a very long time the cells may eventually turn the checkpoints off without waiting for the DNA to get repaired. This process, referred to as adaptation, may initially seem advantageous to the cell because it can finally grow again. "However, for the whole organism, adaptation is often dangerous, as the unrepaired DNA may lead to diseases such as cancer."
Molecular biologists have found a way to prevent cells from turning off the checkpoint and therefore increase the time available for repair, while at the same time preventing damaged DNA from getting passed to newly made cells. The researchers discovered that the amount of nutrients in the cellular environment is a major factor influencing this process. When cells with DNA damage are exposed to low levels of nutrients, they do not adapt and instead remain fully arrested with an active checkpoint. The same effect was observed when cells with DNA damage were treated with the drug "rapamycin", which inhibits metabolic signalling and therefore mimics nutrient starvation. "The cells that are in low nutrient conditions end up being much more viable, likely because they have waited for the damaged DNA to be repaired before starting to divide again. We believe that high nutrients are pushing cells to grow and proliferate even when the cells should not, e.g. with damaged DNA. Low nutrient conditions likely ensure that cells will only 'risk' dividing when the DNA has been completely repaired."
Cells challenged with DNA damage activate checkpoints to arrest the cell cycle and allow time for repair. Successful repair coupled to subsequent checkpoint inactivation is referred to as recovery. When DNA damage cannot be repaired, a choice between permanent arrest and cycling in the presence of damage (checkpoint adaptation) must be made. While permanent arrest jeopardizes future lineages, continued proliferation is associated with the risk of genome instability.
We demonstrate that nutritional signaling through target of rapamycin complex 1 (TORC1) influences the outcome of this decision. Rapamycin-mediated TORC1 inhibition prevents checkpoint adaptation via both Cdc5 inactivation and autophagy induction. Preventing adaptation results in increased cell viability and hence proliferative potential. In accordance, the ability of rapamycin to increase longevity is dependent upon the DNA damage checkpoint. The crosstalk between TORC1 and the DNA damage checkpoint may have important implications in terms of therapeutic alternatives for diseases associated with genome instability.