Mechanisms Linking Mitochondria, Calorie Restriction and Longevity

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


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


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:


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