22 February 2008. Autophagy is a process by which cells engulf and degrade their own damaged organelles and aggregated proteins. This self-cleaning feature is critical to the health of neurons, and its loss in the central nervous system is involved in age-related neurodegeneration (see ARF related news story). Defects in autophagy are seen in Alzheimer disease, and may be linked to enhanced accumulation of amyloid-β peptides (see review by Nixon, 2007).
A paper out in this week’s PNAS online connects autophagy with another health-promoting system, the longevity pathway controlled by sirtuins. Sirtuins, a family of NAD-dependent protein deacetylases activated by caloric restriction, seem to mediate the life-prolonging effects of that regimen in worms, flies, and yeast. In rodents, sirtuin activation by the red wine component resveratrol mimics the effects of caloric restriction, promoting not only a longer lifespan, but also extending health by warding off aging-related diseases.
How sirtuins prolong health is not clear, but the new study suggests they may function, at least in part, through stimulating autophagy. The work, from Frederick Alt of Harvard Medical School and Torin Finkel, at the National Heart, Lung and Blood Institute in Bethesda, Maryland, demonstrates that activation of one human sirtuin, Sirt1, can increase basal levels of autophagy and is required for stimulation of autophagy in response to starvation. The results show that both caloric restriction and sirtuin activity increase autophagy, a process that opposes the accumulation of damaged protein and organelles over time and thus may slow the aging process. The results also strengthen the prospect that sirtuin activators, under intense research for their life- and health-prolonging promise, could have application to neurodegenerative disease.
Cells use autophagy to degrade damaged mitochondria, which means that Sirt1 might regulate this process. That puts Sirt1 squarely in the driver’s seat of mitochondrial turnover, since the sirtuins also govern the generation of new mitochondria. The latter action of Sirt1 depends on the transcription factor PGC1α (Lagouge et al., 2006), which is the subject of another paper in this week’s Nature. Bruce Spiegelman and colleagues at Harvard Medical School demonstrate that PGC1α provides a major line of defense against hypoxia. PGC1α induces the angiogenic factor VEGF in response to low oxygen, but not through classical hypoxia-induced transcription factor HIF, but instead takes a previously unknown route via estrogen receptor-related proteins.
The results suggest new links between disparate pathways that have been implicated in stress, aging, and AD: sirtuins, autophagy, mitochondrial dynamics, and VEGF, a factor that stimulates both angiogenesis and neurogenesis. Taken together, the findings raise the prospect that the sirtuins might help protect against neurodegenerative disease via a host of other pathways that warrant more investigation.
The sirtuin study starts with an observation that boosting Sirt1 levels in cultured human cells stimulates autophagy. From there, first author In Hye Lee goes on to show that Sirt1, and more precisely its deacetylase activity, is necessary for cells to increase autophagy in response to starvation. The investigators further establish that essential proteins in the autophagy machinery (Atg-5, -7, and -8) interact with Sirt1. In the absence of Sirt1, the acetylation of these proteins increases dramatically. The results suggest that Sirt1 activity regulates autophagy activity in cells.
Noting that Sirt1-/- mice have some similarities to the Atg-5 knockout, which is deficient is autophagy, the investigators looked at autophagy in Sirt1 knockout mice. They found that embryos and neonates have decreased autophagy, accumulate abnormal organelles including mitochondria, and show energy depletion as indicated by activation of the energy-sensing kinase AMPK.
Atg-5 null mice die soon after birth, possibly because they lack an energy source between birth and their first meal. This is a time when normal mice derive energy from autophagy. Scientists can forestall death for this reason by supplying pyruvate to pregnant mothers as an alternative energy source. The researchers showed that Sirt1-/- pups also die within hours after birth, but can survive longer if their mothers consume pyruvate before birth.
The last result needs to be interpreted cautiously, the authors write, because pyruvate has many effects. However, they write, “The simplest explanation for our results is that a starvation-induced increase in Sirt1 activity stimulates the deacetylation of the autophagy machinery,” which allows the animals to tune their degree of autophagy to match cellular needs with metabolic status.
Further studies will be needed to find out to what extent the age-extending or neuroprotective activities of sirtuins are tied to their ability to regulate autophagy. Both pathways present potential targets for therapy: an activator of autophagy, rapamycin, has been shown to have benefits in an animal model of Huntington disease (see ARF related news story) and the sirtuin activator resveratrol works in models of chronic neurological diseases (see ARF related news story and Kim et al., 2007).
One important function of autophagy is clearing old and damaged mitochondria. Thus, the new work implicates Sirt1 in mitochondrial dynamics, but not for the first time. The sirtuin pathway regulates mitochondrial biogenesis, too, via activation of the transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator 1 α (PGC1α). Thus, sirtuins may be central players in the regulation of mitochondrial balance, the authors speculate.
The sirtuin link to PGC1α means they may also regulate the pleiotropic effects of this transcriptional coactivator. The study from the Spiegelman lab reveals a new function for PGC1α, showing that the factor plays a role in inducing angiogenesis in response to ischemia or nutrient deprivation in muscle. First author Zoltan Arany reports that blocking blood flow in mice induces VEGF and other angiogenic factors, and this requires the activation PGC1α. Surprisingly, the response is independent of the well-known hypoxia inhibitory factors, thought to be the primary pathway by which cells respond to hypoxia/ischemia. Instead, PGC1α acts via an orphan nuclear receptor, the estrogen-related receptor α. Thus, PGC1α activates what the authors call “a natural defense pathway” to protect ischemic tissue during hypoxia and nutrient deprivation. The new pathway may provide a novel therapeutic target for treating ischemic disease of the heart, brain and limbs,” they write. It will be important to probe the role of this new pathway in the brain, where VEGF is neuroprotective and stimulates the production of new neurons (see review by Greenberg and Jin, 2005).—Pat McCaffrey.
Lee IH, Cao L, Mostoslavsky R, Lombard DB, Bruns NE, Tsokos M, Alt F, Finkel T. A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. PNAS Early Edition, week of Feb 18, 2008. Abstract
Arany Z, Foo SY, Ma Y, Ruas JL, Bommi-Reddy A, Girnun G, Cooper M, Laznik D, Chinsomboon J, Rangwala SM, Baek KH, Rosenzweig A, Spiegelman BM. HIF-independent regulation of VEGF and angiogenesis by the transcriptional coactivator PGC-1α. Nature. 2008 Feb 21;451(7181):1008-12. Abstract