LAUSR

MicroRNAs (miRNAs) are short noncoding RNAs that control nearly all aspects of plant and animal development. Each miRNA acts as a sequence-specific guide to direct an Argonaute protein to a target mRNA for silencing [1]. As with most genes, the expression of individual miRNAs fluctuates during development; however, global downregulation of miRNAs often occurs in aged animals [2–6]. Nonetheless, individual miRNAs have important roles in aging and can both shorten and extend lifespan [4, 7]. While studies exploring the roles of miRNAs in longevity have largely focused on individual miRNAs or essential miRNA biogenesis factors, it is possible that different branches of the pathway have distinct roles in regulating core cellular processes associated with aging. In this issue, Aalto and colleagues [8] discover that in Caenorhabditis elegans the 2 main arms of the miRNA pathway have opposite roles in regulating lifespan. Of the approximately 25 Argonautes in C. elegans, only 3—alg-1, alg-2, and alg-5—are dedicated exclusively to the miRNA pathway [9–11]. alg-1 and alg-2 are largely redundant with one another, and loss of function in either but not both is permissible. alg-5 appears to define a distinct branch of the miRNA pathway that acts in the germline [11]. Much is known about the roles of the miRNA-associated Argonautes in development, but less is known about their specific functions in adult animals. To better understand the roles of the miRNA-associated Argonautes in postdevelopmental aging, Aalto and colleagues [8] examined the expression of alg-1 and alg-2 during the first 5 days of adulthood. ALG-1 levels rapidly declined during aging, while ALG-2 levels remained steady. A recent study by Inukai and colleagues [2] also identified a decline in alg-1 expression as animals aged and a critical role for alg-1 in regulating global miRNA levels in aged animals. These results suggest that alg-1 likely has a central role in aging, while alg-2 may have a more specialized role. How does loss of alg-1 or alg-2 impact C. elegans’ longevity? Because of their sequence-relatedness and overlapping roles in many processes, one would predict that ALG-1 and ALG-2 function redundantly in aging as well and thus might act synergistically to control lifespan. Surprisingly, Aalto and colleagues [8] discovered that alg-1 mutants are short lived, consistent with previous studies [7], whereas alg-2 mutants are long lived. Aalto and colleagues [8] then asked what effect loss of both alg-1 and alg-2 activity has on lifespan. The authors circumvented the lethality of the double mutant by treating alg-2 mutants with RNAi during a late larval stage just before adulthood. Not surprisingly, alg-1 RNAi negated the extended lifespan of alg-2 mutants. Interestingly, alg-1 depletion led to a greater reduction in lifespan in alg-2 mutants than in wild-type, suggesting that alg-1 and alg-2 have overlapping roles in cellular processes important for healthy aging despite their opposite roles in longevity. What causes alg-2 mutants to have extended lifespans while alg-1 mutants die prematurely? Aalto and colleagues [8] tested whether miRNAs known to extend lifespan are associated with