Vacuolar dynamics and replicative aging.

Often described as the counterpart of the mammalian lysosome, the yeast vacuole is the destination for cellular constituents targeted for degradation by autophagic processes. However, the vacuole serves other roles, for instance, as a regulator of cellular ion homeostasis and a storage reservoir for nutrients, metal ions and other metabolites.1 The vacuole is also dynamically regulated, both in number and size in response to environmental conditions, including those linked to replicative lifespan.1 For instance, nutrient restriction, which extends lifespan or the number of daughters that one mother can produce, causes yeast cells to undergo vacuolar fusion events, leading to one large vacuole in place of the 4–5 that normally exist under nutrient-replete conditions. In contrast, osmotic stress leads to enhanced fission and the production of several small vacuolar fragments. In a recent report, Gebre et al. examine the relationship between vacuolar fusion and longevity, finding that overexpression of Osh6, an oxysterol-binding protein that mediates membrane sterol deposition, enhances longevity.2 Several yeast genes are required for vacuolar fusion, and in their absence, yeast vacuoles appear as a multitude of vesicles. Among these are ERG6, which is required for ergosterol synthesis,3 and NYV1, which encodes a vacuolar SNARE complex component.4 Both of these genes are also required for lifespan extension by calorie restriction.5 Also required are the set of OSH genes; in the absence of all seven, vacuoles are fragmented.6 Gebre et al. tested whether overexpression of any OSH gene rescued defects of other fragmentation mutants, finding that elevated Osh6 levels restored fusion in a nyv1Δ background.2 Overexpression of Osh6 did not rescue the erg6Δ, presumably because these genes act in the same pathway involving sterol synthesis and vacuolar membrane deposition. They then showed that OSH6 overexpression led to extension of replicative lifespan. These findings point to Osh6 as having a specific role in modulating vacuolar membrane sterol content and a potential relationship between this function and longevity. Another piece of evidence that vacuolar fusion may be important for longevity in yeast comes from the observation that vacuolar membranes become disordered in replicatively old cells.2,5 Thus, enhanced fusion driven by Osh6 overexpression may help maintain vacuoles in a normal state later in the lifespan of a yeast cell. It remains unclear, however, why this matters, particularly since young yeast cells can proliferate normally with fragmented vacuoles. One possibility comes back to the starvation response, in which autophagy becomes important for survival, as fusion events promote mixing of autophagic cargoes with vacuolar enzymes. Genome-wide transcriptional studies suggest that old cells attempt to initiate a starvation response. If vacuolar fusion is important for autophagic flux under these conditions, then defects in this process may compromise continued yeast viability and proliferation. A related view would be that vacuolar fragmentation may be an indicator of altered lipid composition in vacuolar membranes resulting from age-related elevation of autophagosome-fusion events.5 Reduced TOR signaling enhances lifespan in a wide range of organisms including yeast.7 Recent studies show that the TORC1 complex localizes to the vacuolar membrane and mediates vacuole fragmentation.8,9 Gebre et al. speculate that elevated Osh6 levels may inhibit TORC1 function at the vacuolar membrane, tipping the balance toward fusion.2 Consistently, Osh6 overexpression failed to further enhance the long lifespan of a tor1Δ strain, suggesting that the two genetic interventions may be leading to lifespan extension through similar mechanisms. One final possibility that cannot be ruled out is that Osh6 overexpression may affect lifespan in part through vacuole-independent mechanisms, since Gebre found unexpectedly that expression of sterol synthesis genes was reduced under these conditions. Of course, many of these possible pathways are non-exclusive, and Osh6 overexpression may affect replicative aging through multiple mechanisms. Many yeast aging genes have been identified, and it is paramount that the field begins to understand why altered expression of these genes affects longevity. The study by Gebre et al. points to a role for the vacuole in longevity control and possibly link this organelle to calorie restriction and TOR signaling.2 A critical next step will be to determine how altered vacuolar dynamics impact aging.