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Aging: miRacles of Longevity? (day 0) and middle-aged (day 10) wild-type and long-lived daf-2 insulin signaling mutants. Notably, the use The inventory of processes that miRNAs regulate has continued to expand of deep sequencing allowed the since their relatively recent discovery. A new study reveals not only that the discovery of 11 new miRNAs, several expression of miRNAs changes with age, but also that these miRNAs can of which share homology with act in both pro- and anti-longevity regulatory pathways. miRNAs in higher eukaryotes. Generally, miRNA expression declines with age. However, a small Coleen T. Murphy pathways that both extend and reduce group of the small RNAs showed lifespan, suggesting a more important particularly large changes in MicroRNAs (miRNAs), the endogenous role for miRNAs in the regulation of expression, and a few were 22-nucleotide non-coding RNAs aging than had been previously upregulated with age. Most of these that regulate expression through appreciated. miRNAs have not yet been translational repression or RNA The questions posed in the paper characterized fully, but let-7, one of the degradation, were first discovered by de Lencastre et al. [3] are whether founding miRNAs that is associated through their roles in regulating miRNA expression changes with age, with both late larval development [6] developmental decisions in and whether those miRNAs that and cancer [7], showed the greatest Caenorhabditis elegans [1]. Since then, change with age play a role in decrease with age. Fusion of the miRNAs have been found to be regulating longevity [3]. These two miRNA promoters to the gfp gene and remarkably well-conserved in plants questions had been previously analysis of GFP expression revealed and animals, including humans. The addressed in separate studies; that many of these age-regulated regulation of developmental timing, Ibanez-Ventoso et al. [4] used miRNAs are expressed primarily in neuronal asymmetry, germline cell microarrays to identify C. elegans the intestine, neurons, and somatic division, reprogramming of induced miRNAs that change with age, while gonad — all tissues that have been pluripotent stem cells, p53-induced cell Boehm and Slack [5] showed that the previously associated with the senescence, and cancer progression heterochronic development circuit regulation of aging [8]. are all controlled by miRNAs [2], and miRNAs lin-4 and lin-14 regulate Do these miRNAs actually regulate it is likely that even more functions of longevity post-developmentally. longevity, or are they merely passive miRNAs will be discovered. In a paper de Lencastre et al. [3] have markers of age? de Lencastre et al. [3] published in this issue of Current elaborated on these concepts, using used C. elegans knock-out Biology by de Lencastre et al. [3], deep sequencing to identify miRNAs consortium deletion mutants to show miRNAs are shown to act in regulatory that change with age, examining young that some of the miRNAs that were Dispatch R1077 upregulated with age also regulate TOR, heat shock factor, daf-12, dietary the kinetics of the responses may longevity. Specifically, three of the restriction, sir-2, mitochondrial explain the advantage of adding a miRNAs with large expression function, and germline stem cells) are regulatory layer that involves small increases with age had significant also affected, regulated, or linked by RNAs: the responses of bacterial effects on lifespan, including one, these miRNAs. small RNAs are less noisy [13] and miR-239, that increased longevity. The Is a developmental role necessary have different sensitivities than loss of a gene that has deleterious for miRNAs that affect longevity? Up protein-based regulators, which may effects on longevity (i.e., that is to this point, lin-4 and lin-14 were the make them more responsive than pro-aging) would be expected only miRNAs known to function in transcription factors to stressful to extend lifespan. For example, lifespan regulation, but these genes conditions [14]. While the details of loss-of-function mutants of daf-2, were first identified for their roles in eukaryotic miRNA regulation might which normally functions to inhibit developmental timing. The fact that differ from those of prokaryotic small the pro-longevity activity of the FOXO lin-4 and lin-14 regulate longevity RNAs, the regulatory logic employed transcription factor DAF-16, are post-developmentally does not rule by the miRNAs and their targets may be long-lived. Thus, miR-239 acts like out the possibility that lifespan conserved. It is interesting that daf-2, in that its loss extends lifespan regulation and development are prokaryotic small RNAs and eukaryotic and increases stress resistance, and normally connected. In fact, lin-4 was miRNAs both regulate stress its overexpression shortens lifespan. found to be regulated by daf-16 in responses (and old age could be The two miRNAs whose loss L1 arrest [9], further linking the two considered a stress), further shortens lifespan are perhaps more pathways. Therefore, it is important to suggesting parallels in their utility. unexpected. While one could chalk up ask whether every miRNA that affects Once the complement of upstream the short lifespans of these miR-71 longevity does so as a secondary role, regulators of miRNA expression and and miR-246 mutants simply to the while its primary role is the downstream targets of the miRNAs induction of a sickly state, the authors developmental. have been identified, mapping out went on to show that overexpression Previous studies had not uncovered these details could explain the of these two miRNAs increased any obvious developmental significance of using miRNAs to lifespan, suggesting that the two phenotypes for the miRNAs in regulate lifespan. genes normally promote longevity and question [10]; de Lencastre et al. [3] The high level of conservation from stress resistance. These miRNAs act assayed the miRNA mutants in greater C. elegans through humans suggests similarly to heat shock genes, which detail, but still found no obvious miRNAs may regulate aging in other are induced by stress and old age, and changes in developmental rates, organisms as well. miRNAs now appear are also required for long lifespan. reproductive timing, or progeny to play a role in biological decisions Thus, these miRNAs may be production. Although it is possible that from the earliest to the latest stages considered to be pro-longevity genes. there is a cell-specific phenotype yet of C. elegans’ life. Given their high Together, these data show that to be uncovered, or that there is conservation and ubiquity, what is the specific miRNAs can extend or shorten functional redundancy, the lack of likelihood that miRNAs don’t play a lifespan and act in stress resistance a gross developmental change similar role in humans as well? pathways. suggests the exciting possibility that One important question, then, is these miRNAs specifically regulate what are the targets of these miRNAs aging independently of development. References 1. Lee, R.C., Feinbaum, R.L., and Ambros, V. that induce longevity-related cellular This would be novel, since even well- (1993). The C. elegans heterochronic gene lin-4 responses? miR-239 and miR-71 known longevity regulators (e.g., daf-2, encodes small RNAs with antisense complementarity to lin-14. Cell 75, 843–854. likely function in the insulin/IGF-1 eat-2, and mitochondrial mutants) 2. Stefani, G., and Slack, F.J. (2008). Small signaling (IIS) pathway, because have obvious developmental non-coding RNAs in animal development. miR-239-mediated effects on longevity phenotypes. Nat. Rev. Mol. Cell Biol. 9, 219–230. 3. de Lencastre, A., Pincus, Z., Zhou, K., Kato, M., are dependent on daf-16, and loss of These results beg the question of Lee, S.S., and Slack, F. (2010). MicroRNAs daf-16 does not further shorten why post-reproductive aging would both promote and antagonize longevity in C. elegans. Curr. Biol. 20, 2159–2168. miR-71’s lifespan. The authors tested be regulated at all, a question that 4. Ibanez-Ventoso, C., Yang, M., Guo, S., the expression of members of the is currently unanswered for any Robins, H., Padgett, R.W., and Driscoll, M. insulin/IGF-1 signaling and cell-cycle pathway other than those that couple (2006). Modulated microRNA expression during adult lifespan in Caenorhabditis elegans. Aging checkpoint pathways, and found that reproduction to lifespan [11]. The Cell 5, 235–246. expression of pdk-1 and cdc-25.1, cellular and organismal mechanisms 5. Boehm, M., and Slack, F. (2005). A which both have predicted involved must also be determined; developmental timing microRNA and its target 0 regulate life span in C. elegans. Science 310, miRNA-binding sites in their 3 miRNAs might control the senescence 1954–1957. untranslated regions, is altered in of particular ‘rate-limiting’ cells or 6. Reinhart, B.J., Slack, F.J., Basson, M., Pasquinelli, A.E., Bettinger, J.C., Rougvie, A.E., the miR-71 mutant, while miR-239 tissues, or may play a role in the Horvitz, H.R., and Ruvkun, G. (2000). The appears to regulate insulin/IGF-1 coordination of the aging rates of 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis signaling pathway genes indirectly. different tissues. elegans. Nature 403, 901–906. miR-71 may serve as a link between the Why would miRNAs be useful in the 7. Bussing, I., Slack, F.J., and Grosshans, H. insulin and DNA-damage checkpoint regulation of longevity? Controlling (2008). let-7 microRNAs in development, stem cells and cancer. Trends Mol. Med. 14, longevity pathways. In the future, it response robustness may be one role 400–409. will be interesting to see whether for miRNAs, and it has been proposed 8. Kenyon, C.J. (2010). The genetics of ageing. Nature 464, 504–512. other longevity pathways that were that robustness may generally 9. Baugh, L.R., and Sternberg, P.W. (2006). not examined (such as those involving decrease with age [12]. Understanding DAF-16/FOXO regulates transcription of Current Biology Vol 20 No 24 R1078

cki-1/Cip/Kip and repression of lin-4 aging from somatic aging. PLoS Genet. 5, of gene regulation by small RNA. during C. elegans L1 arrest. Curr. Biol. 16, e1000789. PLoS Biol. 5, e229. 780–785. 12. Ibanez-Ventoso, C., and Driscoll, M. (2009). 10. Miska, E.A., Alvarez-Saavedra, E., Abbott, A.L., MicroRNAs in C. elegans aging: Molecular Lewis-Sigler Institute for Integrative Lau, N.C., Hellman, A.B., McGonagle, S.M., insurance for robustness? Curr. Genomics 10, Genomics and Dept. of Molecular Biology, Bartel, D.P., Ambros, V.R., and Horvitz, H.R. 144–153. Princeton University, Princeton, (2007). Most Caenorhabditis elegans 13. Mehta, P., Goyal, S., and Wingreen, N.S. (2008). microRNAs are individually not essential for A quantitative comparison of sRNA-based and NJ 08544, USA. development or viability. PLoS Genet. 3, e215. protein-based gene regulation. Mol. Syst. Biol. E-mail: [email protected] 11. Luo, S., Shaw, W.M., Ashraf, J., and 4, 221. Murphy, C.T. (2009). TGF-beta Sma/Mab 14. Levine, E., Zhang, Z., Kuhlman, T., and signaling mutations uncouple reproductive Hwa, T. (2007). Quantitative characteristics DOI: 10.1016/j.cub.2010.11.018

Eukaryotic Evolution: The Importance But how could so many, and seemingly functionally important, of Being Archaebacterial eubacterial genes take over an essentially archaebacterial cell? This conundrum led back to the ideas of Approximately half of all eukaryotic genes show signs of prokaryotic origin. endosymbiotic origins for eukaryotes. Genes derived from eubacteria are more abundant than those from Instead of the mitochondrion archaebacteria, but the latter are functionally more important. This supports representing a latecomer to an already archaebacteria as founding ancestors of the eukaryotic nucleus. established, post-archaebacterial, proto-eukaryotic lineage, perhaps the mitochondrial endosymbiosis was John M. Logsdon, Jr. gene duplications between the itself one — if not the — key initial eubacteria and the archaebacteria event in eukaryote evolution. This view How did eukaryotic cells arise from and it indicated that eukaryotes had a has gained ground following the prokaryotic ancestors? In particular, sister relationship with archaebacteria, clear rejection of the Archezoa from which lineage (or lineages) of instead of being their descendants hypothesis — the idea that some prokaryotes can we trace the origin of [9,10]. The hegemony of this so-called eukaryotic lineages diverged the eukaryote nuclear genome? Such ‘three domain’ tree (Figure 1) even led before the mitochondrial questions have puzzled biologists for to a renaming of these major domains endosymbiosis — with data showing decades. A recent study by Cotton and [11]: Bacteria (eubacteria), Archaea that all known eukaryotes either have McInerney [1] takes a fresh look at (archaebacteria), and Eukarya or previously had a mitochondrion [15]. the question by asking not only where (eukaryotes). With the mitochondrion present in eukaryotic genes came from, but As both eukaryotic and prokaryotic the common ancestor of eukaryotes, also how functionally important these genome sequences became available eukaryotic genomes would then easily genes are in relation to which type in the late 1990s, it looked as though be true chimeras: combining of prokaryote — eubacteria or these pressing questions of eukaryotic archaebacterial genetic infrastructure archaebacteria — they are derived from. origins could be answered. If with metabolic machinery from Initial hypotheses posited that the eukaryotes derived from an eubacteria. These ideas have eukaryotic cell arose through archaebacterium then many, if not re-emerged as apparently synthetic endosymbioses among bacteria [2]. most, eukaryotic genes should be views, exemplified by Lake’s ‘ring of These hypotheses have been traceable to archaebacteria. But this life’ hypothesis [16] that acknowledges supported by early studies that was not the case. Instead, of the multiple prokaryotic sources to the confirmed that mitochondria and many genes that could be traced eukaryotic lineage. Even more recent chloroplasts are derived from bacteria to prokaryotic sources, most were phylogenetic analyses take us back [3]. Archaebacteria — later recognized derived from eubacteria [12]. A possible to the eocyte hypothesis (now, to be a prokaryotic group separate solution to this conundrum was that ‘two-domain hypothesis’; Figure 1B) from the eubacteria [4] — were most eubacterial genes were derived and provide considerable (but perhaps postulated as possible ancestors for from post-endosymbiotic gene transfer not definitive) evidence that eukaryotes the eukaryotic nucleus. In 1984, the to the nucleus via the proteobacterial derive from within archaebacteria privileged status of archaebacteria was ancestor of the mitochondrion [13]. [17,18]. elevated further, when Lake et al. [5] This explanation was at least consistent In the end, gene phylogenies, proposed that eukaryotes derived from with previous phylogenetic studies however methodologically rigorous, a particular group of archaebacteria indicating that most ‘informational’ seem unable to definitively answer dubbed ‘eocytes’ (now referred to genes in eukaryotes — i.e., those whether one particular and if so which as ‘crenarchaeotes’). functioning in transcription, translation prokaryotic lineage was the major Although additional data supported and replication — were derived from foundation on which eukaryotes were the eocyte hypothesis for eukaryotic archaebacterial sources, whereas the built. By sheer numbers, eubacterial origins [6-8], the ensuing two decades more abundant ‘operational’ genes, genes are more important. But the witnessed the widespread acceptance e.g., those encoding metabolic archaebacterial genes with their strong of a different view of the tree of life. functions, came primarily from roles in the information economy of the This tree was now rooted by ancient eubacterial sources [14]. cell are arguably more important. But