SUMMARY Many genes that affect replicative lifespan (RLS) in the budding yeast Saccharomyces cerevisiae also affect aging in other organisms such as C. elegans and M. musculus. We performed a systematic analysis of yeast RLS in a set of 4,698 viable single-gene deletion strains. Multiple functional gene clusters were identified, and full genome-to-genome comparison demonstrated a significant conservation in longevity pathways between yeast and C. elegans. Among the mechanisms of aging identified, deletion of tRNA exporter LOS1 robustly extended lifespan. Dietary restriction (DR) and inhibition of mechanistic Target of Rapamycin (mTOR) exclude Los1 from the nucleus in a Rad53-dependent manner. Moreover, lifespan extension from deletion of LOS1 is non-additive with DR or mTOR inhibition, and results in Gcn4 transcription factor activation. Thus, the DNA damage response and mTOR converge on Los1-mediated nuclear tRNA export to regulate Gcn4 activity and aging.

In Saccharomyces cerevisiae, 59 of the 78 ribosomal proteins are encoded by duplicated genes that, in most cases, encode identical or very similar protein products. However, different sets of ribosomal protein genes have been identified in screens for various phenotypes, including life span, budding pattern, and drug sensitivities. Due to potential suppressors of growth rate defects among this set of strains in the ORF deletion collection, we regenerated the entire set of haploid ribosomal protein gene deletion strains in a clean genetic background. The new strains were used to create double deletions lacking both paralogs, allowing us to define a set of 14 nonessential ribosomal proteins. Replicative life-span analysis of new strains corresponding to ORF deletion collection strains that likely carried suppressors of growth defects identified 11 new yeast replicative aging genes. Treatment of the collection of ribosomal protein gene deletion strains with tunicamycin revealed a significant correlation between slow growth and resistance to ER stress that was recapitulated by reducing translation of wild-type yeast with cycloheximide. Interestingly, enhanced tunicamycin resistance in ribosomal protein gene deletion mutants was independent of the unfolded protein response transcription factor Hac1. These data support a model in which reduced translation is protective against ER stress by a mechanism distinct from the canonical ER stress response pathway and further add to the diverse yet specific phenotypes associated with ribosomal protein gene deletions.T HE yeast ribosome consists of two subunits, the 40S (small) and 60S (large), which together contain four discrete rRNA species and 78 ribosomal proteins (RPs). In Saccharomyces cerevisiae, 59 of the 78 ribosomal proteins are encoded by a pair of paralogous genes, most of which arose through a genome-wide duplication event roughly 100 million years ago (Wolfe and Shields 1997). Only 12% of the duplicated genome remains, and of the paralogous gene pairs present, a majority of ribosomal proteins genes (RPGs) are in a class that exhibits little or even decelerated evolution (Kellis et al. 2004). Remarkably, 21 of the 59 RPG pairs encode identical proteins, and the others are highly similar (Supporting Information, Table S1). The prevalence of synthetic lethality among RPG paralogs indicates that the two protein products are generally redundant for at least one essential function (Dean et al. 2008).Despite the significant similarity among RPG paralogs, many reports have described differential effects of deleting only one, and such instances have been observed even in cases where the encoded protein product is identical (Briones et al. 1998). One explanation for this is that the two genes contribute different amounts of protein, and neither is alone sufficient to support wild-type growth. In the case of Rpl16, for example, expression of either RPL16A or RPL16B can rescue the growth defect of cells lacking RPL16B (Rotenberg et al. 1988). Consistently, the RPL16...

When unfolded proteins accumulate in the endoplasmic reticulum (ER), the unfolded protein response is activated. This ER stress response restores ER homeostasis by coordinating processes that decrease translation, degrade misfolded proteins, and increase the levels of ER-resident chaperones. Ribonuclease inositol-requiring protein-1 (IRE-1), an endoribonuclease that mediates unconventional splicing, and its target, the XBP-1 transcription factor, are key mediators of the unfolded protein response. In this study, we show that in Caenorhabditis elegans insulin/IGF-1 pathway mutants, IRE-1 and XBP-1 promote lifespan extension and enhance resistance to ER stress. We show that these effects are not achieved simply by increasing the level of spliced xbp-1 mRNA and expression of XBP-1's normal target genes. Instead, in insulin/IGF-1 pathway mutants, XBP-1 collaborates with DAF-16, a FOXO-transcription factor that is activated in these mutants, to enhance ER stress resistance and to activate new genes that promote longevity.aging | daf-2 | insulin signaling | unfolded protein response

Summary In C. elegans and Drosophila, removing germline stem cells increases lifespan. In C. elegans, this lifespan extension requires DAF-16, a FOXO transcription factor and DAF-12, a nuclear hormone receptor. To better understand the regulatory relationships between DAF-16 and DAF-12, we used microarray analysis to identify downstream genes. We found that these two transcription factors influence the expression of distinct but overlapping sets of genes in response to loss of the germline. In addition, we identified several new genes that are required for loss of the germline to increase lifespan. One, phi-62, encodes a conserved, predicted RNA binding protein. PHI-62 influences DAF-16-dependent transcription, possibly by collaborating with TCER-1, a putative transcription-elongation factor, and FTT-2, a 14-3-3 protein known to bind DAF-16. Three other genes encode proteins involved in lipid metabolism; one is a triacylglycerol lipase, and another is an acyl CoA reductase. These genes do not noticeably affect bulk fat storage levels; therefore, we propose a model in which they may influence production of a lifespan-extending signal or metabolite.

Context Depression and dementia are common in older adults and often co-occur, but it is unclear whether depression is an etiologic risk factor for dementia. Objective, Design, Setting and Participants To clarify the timing and etiology of the association, we examined depressive symptoms assessed in mid-life (1964–1973) and late-life (1994–2000) and the risks of dementia, Alzheimer’s disease (AD) and vascular dementia (VaD) (2003–2009) in a retrospective cohort study of 13,535 long-term Kaiser Permanente members. Depressive symptoms were categorized as none, mid-life only, late-life only or both. Cox proportional hazards models (age as time-scale) adjusted for demographics and medical comorbidities were used to examine depressive symptom category and risk of dementia, AD or VaD. Main Outcome Measure Any medical record diagnosis of dementia; Neurology clinic diagnosis of AD or VaD. Results Subjects had a mean (standard deviation) age of 81 (5) years in 2003; 58% were women and 25% were non-white. Depressive symptoms were present in 14.1% of subjects in mid-life only, 9.2% late-life only, and 4.2% both. Over 6 years, 23.1% were diagnosed with dementia (5.5% AD, 2.3% VaD). The adjusted hazard of dementia was increased by approximately 20% for mid-life depressive symptoms only (Hazard Ratio [95% confidence interval]: 1.19 [1.07, 1.32]), 70% for late-life symptoms only (1.72 [1.54, 1.92]), and 80% for both (1.77 [1.52, 2.06]). When we examined AD and VaD separately, subjects with late-life depressive symptoms only had a two-fold increase in AD risk (2.06 [1.67, 2.55]) whereas subjects with both mid-life and late-life symptoms had more than a three-fold increase in VaD risk (3.51 [2.44, 5.05]). Conclusions Depressive symptoms in mid-life or late-life are associated with an increased risk of developing dementia. Depression that begins in late-life may be part of the AD prodrome, while recurrent depression may be etiologically associated with increased risk of VaD.

SUMMARY Integrating stress responses across tissues is essential for survival of multicellular organisms. The metazoan nervous system can sense protein misfolding stress arising in different subcellular compartments and initiate cytoprotective transcriptional responses in the periphery. Several subcellular compartments possess a homotypic signal whereby the respective compartment relies on a single signaling mechanism to convey information within the affected cell to the same stress responsive pathway in peripheral tissues. In contrast, we find that the heat shock transcription factor, HSF-1, specifies its mode of transcellular protection via two distinct signaling pathways. Upon thermal stress, neural HSF-1 primes peripheral tissues through the thermosensory neural circuit to mount a heat shock response. Independent of this thermosensory circuit, neural HSF-1 activates the FOXO transcription factor, DAF-16, in the periphery and prolongs lifespan. Thus a single transcription factor can coordinate different stress response pathways to specify its mode of protection against changing environmental conditions.

Removal of the germ cells of C. elegans extends lifespan in part because signals from the somatic reproductive tissues activate the nuclear hormone receptor DAF-12.

Slowing down mRNA translation in either the cytoplasm or the mitochondria are conserved longevity mechanisms. Here, we found a non-interventional natural correlation of mitochondrial and cytoplasmic ribosomal proteins (RPs) in mouse population genetics, suggesting a translational balance between these two compartments. Inhibiting mitochondrial translation in C. elegans through mrps-5 RNAi repressed overall cytoplasmic translation. Transcriptomics integrated with proteomics revealed that this inhibition specifically reduced the translational efficiency (TE) of mRNAs required in growth pathways while increasing the TE of stress response mRNAs. The coordinated repression of cytoplasmic translation is dependent on atf-5/Atf4 and is conserved in mammalian cells upon inhibiting mitochondrial translation pharmacologically with the antibiotic doxycycline. Lastly, extending this in vivo, doxycycline repressed cytoplasmic translation and RP expression in the livers of germ-free mice. These data demonstrate that inhibiting mitochondrial translation initiates an atf-5/Atf4-dependent cascade leading to coordinated repression of cytoplasmic translation, which could be targeted to promote longevity. Keywords longevity / ribosomes / mitochondrial translation / cytoplasmic translation / translational balance Highlights • Mitochondrial and cytoplasmic RP levels balance in a natural stoichiometric ratio • Blocking mitochondrial ribosomes in worms and mice reduces cytoplasmic translation • This translational balance is ATF4/atf-5 dependent and conserved in human cells • Translational efficiency of RP transcripts changes in response to ratio requirement