An Outline of Some Calorie Restriction Mechanisms

Calorie restriction (CR), eating fewer calories while still obtaining all the necessary micronutrients, extends life in a wide range of species. In humans we know that it is tremendously beneficial to health. As a phenomenon it has been studied for the better part of a century, but only very rigorously over the past two decades, as it became possible to think about building drugs that achieved the same changes in metabolic processes but without the dieting. Calorie restriction is a great poster child for the sheer, exuberant complexity of metabolism: it isn't an exaggeration to say that a couple of billion dollars have been poured into understanding how it works over the past ten years or so, and we're not there yet. Even a small, tiny slice of the way in which our metabolism works in practice, like calorie restriction and its beneficial effects on health and longevity, requires this level of resources to start to get a handle on what's going on under the hood.

This sort of research process will become easier as the tools and techniques of biotechnology continue to improve rapidly in the years ahead, but the expense in time and money remains one of the reasons why I don't advocate for work on slowing aging through metabolic manipulation. That is a hard, slow, expensive path, and the end result will be of little use to people already old. We should be spending that effort on ways to repair the damage that causes aging as outlined by the SENS Foundation and others.

In any case, I noticed an interesting open access paper on calorie restriction that does a good job of pulling together a high level view of what is currently known, while introducing the ideas of the authors. This diagram is a good starting point:

It isn't unreasonable to say that over the long term calorie restriction changes pretty much everything in your metabolism, either directly (such as through nutrient sensing mechanisms) or indirectly (such as through losing metabolically active visceral fat). So pulling out the important threads from "well, everything changed" has been a long haul. Still, researchers have made good inroads through the traditional route of using genetic engineering to remove pieces of the machinery of life and then seeing what breaks. For example, autophagy seems to be required for calorie restriction to produce benefits.

But take a look at the paper:

Caloric restriction, that is limiting food intake, is recognized in mammals as the best characterized and most reproducible strategy for extending lifespan, retarding physiological aging and delaying the onset of age-associated diseases. The aim of this mini review is to argue that p53 is the connection in the abilities of both the Sirt-1 pathway and the TOR pathway to impact on longevity of cells and organisms. This novel, lifespan regulating function of p53 may be evolutionarily more ancient than its relatively recent role in apoptosis and tumour suppression, and is likely to provide many new insights into lifespan modulation.


But which pathway is indispensable for prolonged lifespan by CR, inhibiting TOR or activating sirtuins? Evidence has emerged that sirtuins and mTOR are involved in the same longevity pathway. Importantly, resveratrol, an activator of sirtuins, antagonizes the mTOR/S6K pathway. Therefore, the two notions that CR prolongs lifespan either by activating sirtuins or by deactivating TOR are, in fact, complementary: CR deactivates the mTOR pathway in part by activating Sirt-1.

p53 is of course a well known cancer suppressant, a part of the mechanisms that enforce the trade-off between cancer risk and life span. If your increasingly damaged stem cells remain more active, your tissues are better maintained in later life but you have an increased risk of cancer. If the stem cells become less active, then you deteriorate more rapidly, but with a lower risk of cancer. Levels of p53 form a part of the system that determines which side of that line you are on, rising and falling in response to damage to cells and their molecular machinery. Interestingly, suitable manipulations of p53 can break this balance and let you have your cake and eat it too: less cancer and more life. You might see these posts from the archive on that subject:

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