Biology is complicated. We are built out of a million evolutionary optimizations, and evolution loves the reuse of component parts. Every newly evolved mechanism will quickly find its place in other evolved systems, while still being used in its original capacities. The human cell is a big cat's cradle of macromolecules, each with twenty-something different purposes, operating in interacting feedback loops and dynamically regulated processes.

When your research indicates that molecule A is the problem in medical condition B, you can be fairly sure that bluntly manipulating molecule A in order to treat B will completely mess up vital systems X, Y and Z.

A good example of this principle came to my attention today, in the form of PGC-1alpha, a protein that's right in the middle of all sorts of important processes. I put out a post a few days back, in fact, on research demonstrating the role of PGC-1alpha in calorie restriction and mitochondrial function.

So, you might think, another target to better recreate the beneficial effects of calorie restriction on health and longevity - without the dieting. Not so fast, now:

Researchers at Dana-Farber Cancer Institute have found a previously unknown molecular pathway in mice that spurs the growth of new blood vessels when body parts are jeopardized by poor circulation.

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Bruce Spiegelman, PhD, and his colleagues at Dana-Farber discovered that PGC-1alpha - a key metabolic regulatory molecule - senses a dangerously low level of oxygen and nutrients when circulation is cut off and then triggers the formation of new blood vessels to re-supply the oxygen-starved area - a process known as angiogenesis.

Blood vessel formation is not something to be tinkered with lightly - and that's just one of the many processes that PGC-1alpha is involved in.

This hyperconnectivity and reuse of processes, proteins and genes, this rampant complexity, is why aging researchers who focus on metabolic and genetic engineering - which is to say the bulk of the field - see healthy life extension as hard, and any meaningful progress in terms of additional decades as remote in the future. They believe the only viable way forward is to re-engineer our biology into something tougher and better, to slow the processes that cause damage and aging. I agree that this goal is a great challenge, and will likely still be a great and ongoing challenge when the era of hypercomputing and molecular manufacturing is upon us some decades from now.

Fortunately, a much better approach to complex systems exists: work with the examples you have. We have working examples of our biology in good health and operation. Similarly, we have examples that are age-damaged and failing. Rather than try to build some completely new complex biology to resist the ways in which age damages us, we should focus on identifying and reversing the specific differences between youthful metabolisms and age-damaged metabolisms.

Given the level of knowledge today, significant progress in reversing aging - repairing damage, reversing changes in metabolism - is much more plausible for the decades ahead than producing a new slow-aging human metabolism. In addition, any successful therapy that repairs some facet of the damage of aging in our metabolisms can be used over and over again by the same individual. Keep the damage beneath the level at which it causes the degeneration of aging, and you can continue to be healthy and youthful for so long as you please. This is obviously far more beneficial and valuable than a therapy that merely slows aging - slowing aging is of no use to the aged.

The greatest challenge in the scientific infrastructure and community of aging researchers today is to change the focus from slowing aging (slow, inefficient, producing less useful medical therapies) to repairing aging (more efficient, more rapid, producing more useful medical therapies). It is this challenge that spurs groups like the Methuselah Foundation and affiliated researchers. This may seem like an esoteric battle to some, but the future of life and health for everyone alive today depends upon it - which means that we should all pitch in and help.

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.

The present availability of funding for research into the mechanisms of longevity through calorie restriction (CR) continues to lead to important swaths of our biochemistry drawn forth from the darkness. A freely available paper in the latest Aging Cell makes the case for a specific lynchpin linking aging, changes in mitochondrial function and longevity increases due to calorie restriction. It's also a good introduction to present thought on how important mitochondria are to aging:

Mitochondria are the key organelle in substrate utilization and energy production. Transcriptional profiling studies demonstrate that genes involved in mitochondrial energy metabolism are coordinately up-regulated in multiple tissues with calorie restriction (CR), suggesting a change in dynamic of the electron transport system and a role for this alteration in mitochondrial metabolism in the mechanisms of CR. Biochemical analysis suggests that mitochondria from restricted tissues are functionally different from their control counterparts in terms of metabolism and composition

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Our understanding of the complexity of signalling pathways to and from the mitochondria is increasing, describing a network through which mitochondria may communicate functional status to the nucleus to impact cellular function. Metabolic reprogramming by CR may be central to the mechanism of lifespan extension, where changes in mitochondrial function confer an energetic shift that is conducive to increased cellular fitness, resulting in the promotion of longevity.

A number of research groups have put forward candidates for most important component of calorie restriction biochemistry - or at least most useful, for the purposes of near future therapeutic manipulation. Sirtris is still working on sirtuins, while other groups are digging deeper to find other vital genes, proteins and processes further down the chain. The authors of this paper are looking at PGC-1alpha, a biochemical that - like so many others - appears to be simultaneously involved in the regulation of all sorts of important cellular activities. Evolved systems favor component reuse and intertwined feedback loops, and cellular biochemistry is the prime example of the type. Very few forms of molecule inside a cell have just one purpose.

Mitochondrial function declines with age in humans, and a decline in the expression of components of the electron transport chain is a hallmark of aging across species

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There is evidence to suggest that CR induces specific pathways that promote longevity. For example, in yeast, CR and numerous low-intensity stressors associated with longevity activate a common pathway to influence lifespan. Here, we show that PGC-1alpha transcriptional activity is induced in the oxidative stress response and CR through a shared mechanism, suggesting that in mammals, regulation of mitochondrial function is a key element in both cellular survival and longevity. We propose that mitochondrial plasticity may be critical for maintaining cell viability and in orchestrating the program of aging retardation by CR, raising the possibility that loss of mitochondrial plasticity is an underlying cause of aging.

You might contrast this conclusion with another derived from discovering necessary biochemistry for longevity through calorie restriction:

Autophagy, an evolutionary conserved lysosomal degradation pathway, is induced under starvation conditions and regulates life span in insulin signaling C. elegans mutants. We now report that two essential autophagy genes (bec-1 and Ce-atg7) are required for the longevity phenotype of the C. elegans dietary restriction mutant (eat-2(ad1113) animals. Thus, we propose that autophagy mediates the effect, not only of insulin signaling, but also of dietary restriction on the regulation of C. elegans life span.

While one can speculate on the relationship between the degree of autophagic consumption of failing mitochondria and overall mitochondrial function, it seems clear that a complete picture of the biochemistry of calorie restriction is still a few years away. From where I stand, the greatest benefit of this research will likely be the increase in our detailed knowledge of mitochondrial biochemistry. The more we know, the more feasible mitochondrial repair strategies become for the reversal of aging. The weight of evidence for the role of mitochondrial damage and change in degenerating aging is plenty heavy enough to demand action; the question is how best to proceed. Some of the options are described below:

• Moving Mitochondria
• Can Damaged Mitochondria Repair Their DNA?
• Mitochondrial Protofection
• Xenotransplanting New Mitochondria
• MitoSENS Research at the Methuselah Foundation

So what is a SNP - a single nucleotide polymorphism - and why should you care? A quick definition:

A single nucleotide polymorphism (SNP, pronounced snip), is a DNA sequence variation occurring when a single nucleotide - A, T, C, or G - in the genome (or other shared sequence) differs between members of a species (or between paired chromosomes in an individual). For example, two sequenced DNA fragments from different individuals, AAGCCTA to AAGCTTA, contain a difference in a single nucleotide. In this case we say that there are two alleles : C and T. Almost all common SNPs have only two alleles.

Remember that a single gene is thousands of nucleotides long; SNPs are tiny differences considered in that scheme. However, in the same way that researchers - against initial skepticism - have been turning up single gene mutations that cause longevity for some time now, the community is starting to build the case for single SNPs that confer longevity benefits.

The common germline Arg72Pro polymorphism of p53 and increased longevity in humans:

A well known functional SNP in the tumor suppressor TP53 gene leads to increased longevity: in the Danish general population (n = 9219) homozygotes for the minor allele versus homozygotes for the major allele had an increase in median survival of 3 years. This is partly explained by increased survival after development of cancer or other diseases, in accordance with the observation that this Arg72Pro substitution in the p53 protein has important influence on cell death via increased apoptosis. Thus, the increased longevity may be due to a generally increased robustness after a diagnosis of any life-threatening disease.

In contrast to widespread skepticism on the importance of SNPs in humans, this gain-of-function p53 SNP of importance for cell repair mechanisms has a profound influence on longevity.

"Profound" here is in comparison to most examined SNPs, which appear to cause no meaningful differences. I imagine there will be other longevity SNPs uncovered in the future - there are tens of millions identified so far, and only a small fraction well studied. This particular SNP is another confirmation of the potential of p53 engineering for longevity:

• A New Look At p53, Cancer and Aging
• 50% Maximum Life Extension in Mice Via p53 and Telomerase

p53-related engineering looks to have at least as much potential as therapies based on the biochemistry of calorie restriction - which is to say not so much potential if you're already old. This is all about slowing rates of aging, not repairing the damaging of aging. This is why I favor quite different approaches to the engineering of human longevity.