Recent Research into the Mechanisms of Calorie Restriction

A great deal of time and money in the aging research community is invested into gaining a full understanding of the mechanisms of calorie restriction: how exactly it extends life in most species and improves health. This is still a small field in comparison to the broader life sciences or medical research in general, of course. Nonetheless it is probably the case that billions of dollars have gone into these efforts in the past couple of decades, with the goal being the development of calorie restriction mimetic drugs, some way to safely and reliably replicate the benefits of calorie restriction without the dieting. So far a lot of new knowledge of metabolism and little of practical value has emerged, but that's the way that research goes - if it was certain to produce a given set of results, then it wouldn't be research.

I, and others, think that this is a sideshow, and there are far better lines of research that are far more likely to result in meaningful extension of human life, and at a lesser cost in time and money. Change on that front is slow in coming, however.

Calorie restriction has large health benefits: along with exercise, it produces effects in basically healthy people that far outweigh those of any presently widely available medical technology. So if it wasn't already the case that a person can obtain all of those benefits just by, you know, restricting calories, I'd probably be more in favor of work focused on calorie restriction mimetics and metabolic manipulation. But you can obtain the benefits just through a modicum of willpower and planning, and while significant in the scheme of what can be done today, this is a tiny, tiny set of benefits in comparison to what billions of dollars of research into the basis for human rejuvenation should attain. You can't diet your way to living to 100 with any great chance of success, but future medical technology will achieve that end and more - just not by replicating the beneficial effects of dieting.

Here are a couple of open access papers typical of the sort of work presently taking place on the genes and proteins known to be associated with calorie restriction:

Deletion of microRNA-80 Activates Dietary Restriction to Extend C. elegans Healthspan and Lifespan

Dietary restriction, limitation of calorie intake with maintained vitamin and mineral support, can extend lifespan and protect against diseases of age across many species. Elaboration of molecular mechanisms that control dietary restriction in simple animal models may therefore inform on strategies to activate health-promoting metabolism to help address clinical challenges associated with aging and age-associated disease.

We characterize a single Caenorhabditis elegans microRNA gene that keeps dietary restriction programs off when food is abundant. A mir-80 deletion exhibits beneficial features of dietary restriction regardless of food availability, including extended maintenance of mobility and cardiac-like muscle function later into life as well as lifespan extension. We identify three key longevity genes that are required for these benefits. We hypothesize that miR-80 is a core regulator by which diverse and intersecting metabolic pathways are coordinately regulated to respond to nutrient availability.

Increased expression of Drosophila Sir2 extends life span in a dose-dependent manner

Sir2, a member of the sirtuin family of protein dacetylases, deacetylates lysine residues within many proteins and is associated with lifespan extension in a variety of model organisms. Recent studies have questioned the positive effects of Sir2 on lifespan in Drosophila. Several studies have shown that increased expression of the Drosophila Sir2 homolog (dSir2) extends life span while other studies have reported no effect on life span or suggested that increased dSir2 expression was cytotoxic.

To attempt to reconcile the differences in these observed effects of dSir2 on Drosophila life span, we hypothesized that a critical level of dSir2 may be necessary to mediate life span extension. Using approaches that allow us to titrate dSir2 expression, we describe here a strong dose-dependent effect of dSir2 on life span. Using the two transgenic dSir2 lines that were reported not to extend life span, we are able to show significant life span extension when dSir2 expression is induced between 2 and 5-fold. However, higher levels decrease life span and can induce cellular toxicity. [Our] results help to resolve the apparently conflicting reports by demonstrating that the effects of increased dSir2 expression on life span in Drosophila are dependent upon dSir2 dosage.


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