A couple of recent papers on calorie restriction caught my eye today - the standard fare for recent investigations, containing a little clarification, a little muddying of the waters. The behavior of metabolism is complex indeed, not to mention the large differences between species. All sorts of genes, mechanisms and pathways are involved in calorie restriction, and scientists are still in that portion of the discovery process that produces apparently contradictory information.

First off, a little more support for the interesting biomechanisms of calorie restriction - going beyond the benefits of less visceral fat - to be triggered by less methionine in the diet:

Dietary restriction (DR) lowers mitochondrial reactive oxygen species (ROS) generation and oxidative damage and increases maximum longevity in rodents. Protein restriction (PR) or methionine restriction (MetR), but not lipid or carbohydrate restriction, also cause those kinds of changes. However, previous experiments of MetR were performed only at 80% MetR, and substituting dietary methionine with glutamate in the diet.

In order to clarify if MetR can be responsible for the lowered ROS production and oxidative stress induced by standard (40%) DR, Wistar rats were subjected to 40% or 80% MetR without changing other dietary components. It was found that both 40% and 80% MetR decrease mitochondrial ROS generation and percent free radical leak in rat liver mitochondria, similarly to what has been previously observed in 40% PR and 40% DR.

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The results show that 40% isocaloric MetR is enough to decrease ROS production and oxidative stress in rat liver. This suggests that the lowered intake of methionine is responsible for the decrease in oxidative stress observed in DR.

Can human studies be too many years away? I imagine that producing a safe diet with much lower levels of methionine is not impossible, and that people out there in the calorie restriction community will hack away at that problem with more enthusiasm as the evidence mounts.

The second paper adds some additional facts and confusion to discussion of the role of autophagy in calorie restriction, and draws in other work on the TOR gene and calorie restriction.

A Role for Autophagy in the Extension of Lifespan by Dietary Restriction in C. elegans:

In many organisms, dietary restriction appears to extend lifespan, at least in part, by down-regulating the nutrient-sensor TOR (Target Of Rapamycin). TOR inhibition elicits autophagy, the large-scale recycling of cytoplasmic macromolecules and organelles.

In this study, we asked whether autophagy might contribute to the lifespan extension induced by dietary restriction in C. elegans. We find that dietary restriction and TOR inhibition produce an autophagic phenotype and that inhibiting genes required for autophagy prevents dietary restriction and TOR inhibition from extending lifespan. The longevity response to dietary restriction in C. elegans requires the PHA-4 transcription factor. We find that the autophagic response to dietary restriction also requires PHA-4 activity, indicating that autophagy is a transcriptionally regulated response to food limitation.

In spite of the rejuvenating effect that autophagy is predicted to have on cells, our findings suggest that autophagy is not sufficient to extend lifespan. Long-lived daf-2 insulin/IGF-1 receptor mutants require both autophagy and the transcription factor DAF-16/FOXO for their longevity, but we find that autophagy takes place in the absence of DAF-16. Perhaps autophagy is not sufficient for lifespan extension because although it provides raw material for new macromolecular synthesis, DAF-16/FOXO must program the cells to recycle this raw material into cell-protective longevity proteins.

It seems to me that a pressing next step in understanding the biomechanisms of calorie restriction is a definitive account of how autophagic and mitochondrial changes brought on by CR are linked.

What is wealth? Let me try a slightly non-standard answer to that question. Wealth is a measure of your ability to do what you would like to do, when you would like to do it - a measure of your breadth of immediately available choice. Therefore your wealth is determined by the resources you presently own, as everything requires resources.

For the sake of argument, let us say that your resources presently amount to a leather bag containing a hundred unmarked silver coins. Interestingly enough, by the "what would you like to do" measure, you are fantastically more wealthy than any given ancestor put in the same position of ownership. You have immensely greater choice. Clearly there is more to wealth-as-choice than present property. We must also consider the historical investment made into increasing choice, and into lowering the cost of specific - usually popular - choices. The engines of technology and open, free markets are turned by people to create new, better, cheaper choices. The choice to fly, the choice to remain alive with heart disease, the choice to avoid that heart disease.

Where do silver coins - or indeed, any other resources you might own - come from? Where does investment come from? After all, we don't come into this world with the proverbial silver implement between the teeth. No, we worked for those coins. We spent time and negotiated payment for that time. Why? Because time is valuable.

But time spent alive, measured in the ticking of heartbeats, is more than valuable - it is wealth itself, the source of all other measures of wealth. All property was created by someone, somewhere, taking their time. The creation and exchange of property is a way to make time fungible, transferrable, a more valuable resource. Time spent alive is the root of all property, all human action, and thus all wealth - both the silver in your pocket that provides for present choice, and the wealth of possible choices created by past investment.

Time is everything. How much have time you spent reading this far? Could you have been doing something more useful, more optimal from your perspective? We make these small evaluations constantly, because time is the most valuable thing we have.

We all go through engineering our cycles of property and time; how can we best optimize time to generate property that can be used to make our time more effective? We do this in small ways and large, but everyone does it. Some people do it so effectively they launch themselves into property escape velocity, exponentially increasing the effectiveness of their time and exploring the outer limits of what it means to maintain ownership of a great deal of property.

Interestingly, despite the grand importance of time as the absolute foundation of wealth, very little progress has been made in the most obvious optimization of all: creating property that can create more time. More heartbeats, more health, more time spent alive and active. Rejuvenation medicine, capable of repairing the damage of aging. Tissue engineering to generate replacements for worn organs. The cure for cancer. If you could do all that, then the much more productive form of escape velocity becomes possible - longevity escape velocity. Why strive to maintain an empire of property that will crumble to dust when the degenerations of age catch up with you when you could be that fit-looking guy having a blast swimming in the breakers every other Sunday for as long as you like?

Wealth is exactly time, and here we are, bordering the era of biotechnology for the repair of aging. Planning ahead for the best possible personal future starts with investment now. Think about it.