Dietary restriction and other lifespan extending pathways converge at the activation of the downstream effector takeout

(DR), reduced food uptake without malnutrition, is the most universal intervention known to extend animal lifespan, from invertebrates to mammals [1]. However, despite impressive progress in identifying the key components of the DR pathway, many proximal effectors of DR induced longevity remain unknown to date [1]. One central obstacle in the search for such mechanisms is that DR causes a myriad of transcriptional and physiological changes that are either not – or only indirectly – related to its positive effects on lifespan. For example, DR often increases lifespan at the expense of fertility [1]. In turn, the inability to filter out non-longevity effects of DR might impede the development of therapeutic compounds that mimic DR without causing unwanted side effects. For instance, while manipulation of dietary methionine can uncouple the phenotypic association between DR induced longevity and decreased fertility [2-3], whether and how such pleiotropic effects of DR are functionally separable at the molecular level is currently not understood. In this May issue of AGING, Bauer and colleagues now make a major step towards identifying those downstream effectors of DR that specifically affect longevity [4]. To find the genetic key players that mediate lifespan extension upon DR, Bauer et al. used comparative whole genome expression profiling by searching for genes whose expression patterns overlap between DR treatment and two signaling states that are functionally related to DR but that do not affect fertility, activation of Sir2 and inactivation of p53 in the fly brain. Using this approach the authors identified a small set of shared transcriptional changes in 21 genes (20 genes up-and one downregulated) that are involved in chromatin structure or maintenance, circadian rhythm, neural acti-Commentary vity, detoxification and chaperone activity, muscle maintenance, immunity, growth factor activity, and nutrient storage. To further narrow this list, Bauer et al. performed qPCR for these genes in four additional long-lived mutants (Indy and Rpd3, both implicated in DR; the insulin receptor substrate chico; and the G protein-coupled receptor methuselah). Remarkably, the authors found a single gene, takeout (to), to be robustly upregulated in all seven longevity promoting conditions examined. Next, to confirm that to is a specific effector downstream of DR and other longevity pathways, Bauer et al. overexpressed to in adult neurons, pericerebral fat body and abdominal fat tissue and found that these manipulations extend lifespan in both females and males. Moreover, long-lived flies overexpressing to exhibited upregulation of nine genes …