Resveratrol: Breakfast of champions

Hot on the heels of the Sinclair lab’s recent publication demonstrating that resveratrol can extend the lifespan and preserve the health of mice eating an unhealthy diet (i.e., Western-style ad libitum high-calorie buffet), Johan Auwerx and colleagues have published their observations that this compound can prevent obesity and boost mitochondrial functions as well. From their very recent paper, Lagouge et al.:

Diminished mitochondrial oxidative phosphorylation and aerobic capacity are associated with reduced longevity. We tested whether resveratrol (RSV), which is known to extend lifespan, impacts mitochondrial function and metabolic homeostasis. Treatment of mice with RSV significantly increased their aerobic capacity, as evidenced by their increased running time and consumption of oxygen in muscle fibers. RSV’s effects were associated with an induction of genes for oxidative phosphorylation and mitochondrial biogenesis and were largely explained by an RSV-mediated decrease in PGC-1α acetylation and an increase in PGC-1α activity. This mechanism is consistent with RSV being a known activator of the protein deacetylase, SIRT1, and by the lack of effect of RSV in SIRT1-/- MEFs. Importantly, RSV treatment protected mice against diet-induced-obesity and insulin resistance. …

Not only are mice avoiding diet-related illness as they age, they appear to be reaping health benefits throughout the lifespan. These benefits are independent of any decrease in caloric intake, so it’s not a trivial case of resveratrol spoiling their appetite and pushing them into a calorie-restricted dietary regimen. It seems clear from the SIRT1 knockout results (and all of the pharmacology we already know about this molecule) that resveratrol is acting directly via Sirt1 activation.

The new study also adds a tantalizing bit of human relevance:

These pharmacological effects of RSV combined with the association of three Sirt1 SNPs and energy homeostasis in Finnish subjects implicates SIRT1 as a key regulator of energy and metabolic homeostasis.

In other words, naturally occurring variations in SIRT1 sequence confer differences in readouts of mitochondrial function, implying that the gene is an important factor even in a particular mammal much larger and longer-lived than mice (and, for most of us, much nearer and dearer to our hearts).

This is still a far cry from demonstrating the efficacy of resveratrol in human lifespan extension, but the mitochondrial-function experiments do suggest a series of functional assays that we could perform in human volunteer subjects: Assuming for the moment that the anti-diabetic, anti-obesity, pro-mitochondrial and anti-aging benefits all come from the same molecular function, then we might use the easiest and quickest measurement (exercise capacity) as a proxy for the others, and thereby begin to study pharmacokinetics and dosimetry of resveratrol in humans.