I love a parade. This week we’ve focused on a flurry of recent developments in the sirtuin field, specifically the regulation of Sirt1 by senescence and other factors. The fun continues today.

Sirt1 gets a lot of attention, and is unquestionably the best-studied of the human homologs of the canonical yeast SIR2 gene. SIR2 was originally identified in yeast as a Silent Information Regulator, a member of a multi-gene complex involved in repression of the silent mating type loci and in telomeric silencing. In the early 90s, Leonard Guarente‘s lab discovered that SIR2 also governs the replicative lifespan of yeast, allowing biogerontologists to deploy what the late Ira Herskowitz called the “awesome power of yeast genetics” into the field of aging. Since then, sirtuins (as the metazoan homologs of SIR2 are called: “sir-two-ins”) have been shown to regulate lifespan in worms, flies, and the mouse. Most of these studies have focused on Sirt1.

Recent work from the Guarente lab (in collaboration with Fred Alt‘s group) turns the spotlight on another member of the sirtuin family: Sirt4, a mitochondrial protein. From Haigis et al.

Sir2 is an NAD-dependent deacetylase that connects metabolism with longevity in yeast, flies, and worms. Mammals have seven Sir2 homologs (SIRT1–7). We show that SIRT4 is a mitochondrial enzyme that uses NAD to ADP-ribosylate and downregulate glutamate dehydrogenase (GDH) activity. GDH is known to promote the metabolism of glutamate and glutamine, generating ATP, which promotes insulin secretion. Loss of SIRT4 in insulinoma cells activates GDH, thereby upregulating amino acid-stimulated insulin secretion. A similar effect is observed in pancreatic β cells from mice deficient in SIRT4 or on the dietary regimen of calorie restriction (CR). Furthermore, GDH from SIRT4-deficient or CR mice is insensitive to phosphodiesterase, an enzyme that cleaves ADP-ribose, suggesting the absence of ADP-ribosylation. These results indicate that SIRT4 functions in β cell mitochondria to repress the activity of GDH by ADP-ribosylation, thereby downregulating insulin secretion in response to amino acids, effects that are alleviated during CR.

While the authors don’t focus on aging, their paper draws connections between a sirtuin, the mitochondria, and calorie restriction — an aging trifecta, even before one considers the ramifications for diabetes (oft-mentioned in discussions of progeroid syndromes in humans) and insulin/insulin-like growth factor signaling (critically important to the genetic control of lifespan in many organisms).

Something interesting I noticed, off the main story but especially relevent to aging issues: Mitochondrial ox/phos generates reactive oxygen species (ROS), and these ROS wander out into the rest of the cell to wreak havoc. This is a cell-autonomous feature, in the sense that a single cell’s mitochondria generate ROS that then damage macromolecules in that specific cell (or possibly in the nearest neighbors).

In the mitochondria of the pancreatic β cells, SIRT4 downregulates glutamate dehydrogenase and thereby throttles amino-acid-stimulated insulin secretion. Since insulin is one of the primary ways that the body communicates with itself, we have an example of a non-cell-autonomous mitochondrial function pertaining to aging.

Breathtakingly, there are five other sirtuins in human that have barely been studied. Watch this space for further developments.

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