Lifespan Regulation Research Articles

Unveiling a novel serpinB2-tripeptidyl peptidase II signaling axis during senescence.

Tripeptidyl peptidase II (TPPII or TPP2) degrades N-terminal tripeptides from proteins and peptides. Studies in both humans and mice have shown that TPPII deficiency is linked to cellular immune-senescence, lifespan regulation and the aging process. However, the mechanism of how TPPII participates in these processes is less clear. In this study, we established a chemical probe-based assay and found that although the mRNA and protein levels of TPPII were not altered during senescence, its enzymatic activity was reduced in senescent human fibroblasts. We also showed that elevation of the levels of the serine protease inhibitor serpinB2 reduced TPPII activity in senescent cells. Moreover, suppression of TPPII led to elevation in the amount of lysosomal contents as in well as TPPI (TPP1) and β-galactosidase activities, suggesting that lysosome biogenesis is induced to compensate for the reduction of TPPII activity in senescent cells. Together, this study discloses a critical role of the serpinB2-TPPII signaling pathway in proteostasis during senescence. Since serpinB2 levels can be increased by a variety of cellular stresses, reduction of TPPII activity through activation of serpinB2 might represent a common pathway for cells to respond to different stress conditions. This article has an associated First Person interview with the first author of the paper.

Nutrient-Response Pathways in Healthspan and Lifespan Regulation.

Cellular, small invertebrate and vertebrate models are a driving force in biogerontology studies. Using various models, such as yeasts, appropriate tissue culture cells, Drosophila, the nematode Caenorhabditis elegans and the mouse, has tremendously increased our knowledge around the relationship between diet, nutrient-response signaling pathways and lifespan regulation. In recent years, combinatorial drug treatments combined with mutagenesis, high-throughput screens, as well as multi-omics approaches, have provided unprecedented insights in cellular metabolism, development, differentiation, and aging. Scientists are, therefore, moving towards characterizing the fine architecture and cross-talks of growth and stress pathways towards identifying possible interventions that could lead to healthy aging and the amelioration of age-related diseases in humans. In this short review, we briefly examine recently uncovered knowledge around nutrient-response pathways, such as the Insulin Growth Factor (IGF) and the mechanistic Target of Rapamycin signaling pathways, as well as specific GWAS and some EWAS studies on lifespan and age-related disease that have enhanced our current understanding within the aging and biogerontology fields. We discuss what is learned from the rich and diverse generated data, as well as challenges and next frontiers in these scientific disciplines.

Dopamine D1- and D2-like receptors oppositely regulate lifespan via a dietary restriction mechanism in Caenorhabditis elegans

BackgroundDespite recent progress in understanding the molecular mechanisms regulating aging and lifespan, and the pathways involved being conserved in different species, a full understanding of the aging process has not been reached. In particular, increasing evidence suggests an active role for the nervous system in lifespan regulation, with sensory neurons, as well as serotonin and GABA signaling, having been shown to regulate lifespan in Caenorhabditis elegans (C. elegans). However, the contribution of additional neural factors, and a broad understanding of the role of the nervous system in regulating aging remains to be established. Here, we examine the impact of the dopamine system in regulating aging in C. elegans.ResultsWe report that mutations of DOP-4, a dopamine D1-like receptor (D1R), and DOP-2, a dopamine D2-like receptor (D2R) oppositely affected lifespan, fast body movement span, reproductive lifespan, and developmental rate in C. elegans. Activation of D2R using aripiprazole, an antipsychotic drug, robustly extended both lifespan and healthspan. Conversely, inhibition of D2R using quetiapine shortened worm lifespan, further supporting the role of dopamine receptors in lifespan regulation. Mechanistically, D2R signaling regulates lifespan through a dietary restriction mechanism mediated by the AAK-2-DAF-16 pathway. The DAG-PKC/PKD pathway links signaling between dopamine receptors and the downstream AAK-2-DAF-16 pathway to transmit longevity signals.ConclusionsThese data demonstrated a novel role of dopamine receptors in lifespan and dietary restriction regulation. The clinically approved antipsychotic aripiprazole holds potential as a novel anti-aging drug.

Immunosuppression Induced by Brain-Specific HDAC6 Knockdown Improves Aging Performance in Drosophila melanogaster.

The online version contains supplementary material available at 10.1007/s43657-022-00045-2.

Endocrine Regulation of Lifespan in Insect Diapause.

Diapause is a physiological adaptation to conditions that are unfavorable for growth or reproduction. During diapause, animals become long-lived, stress-resistant, developmentally static, and non-reproductive, in the case of diapausing adults. Diapause has been observed at all developmental stages in both vertebrates and invertebrates. In adults, diapause traits weaken into adaptations such as hibernation, estivation, dormancy, or torpor, which represent evolutionarily diverse versions of the traditional diapause traits. These traits are regulated through modifications of the endocrine program guiding development. In insects, this typically includes changes in molting hormones, as well as metabolic signals that limit growth while skewing the organism’s energetic demands toward conservation. While much work has been done to characterize these modifications, the interactions between hormones and their downstream consequences are incompletely understood. The current state of diapause endocrinology is reviewed here to highlight the relevance of diapause beyond its use as a model to study seasonality and development. Specifically, insect diapause is an emerging model to study mechanisms that determine lifespan. The induction of diapause represents a dramatic change in the normal progression of age. Hormones such as juvenile hormone, 20-hydroxyecdysone, and prothoracicotropic hormone are well-known to modulate this plasticity. The induction of diapause—and by extension, the cessation of normal aging—is coordinated by interactions between these pathways. However, research directly connecting diapause endocrinology to the biology of aging is lacking. This review explores connections between diapause and aging through the perspective of endocrine signaling. The current state of research in both fields suggests appreciable overlap that will greatly contribute to our understanding of diapause and lifespan determination.

Interaction of transcription factor FoxO3 with histone acetyltransferase complex subunit TRRAP modulates gene expression and apoptosis

Forkhead box O (FoxO) transcription factors are conserved proteins involved in the regulation of life span and age-related diseases, such as diabetes and cancer. Stress stimuli or growth factor deprivation promotes nuclear localization and activation of FoxO proteins, which—depending on the cellular context—can lead to cell cycle arrest or apoptosis. In endothelial cells (ECs), they further regulate angiogenesis and may promote inflammation and vessel destabilization implicating a role of FoxOs in vascular diseases. In several cancers, FoxOs exert a tumor-suppressive function by regulating proliferation and survival. We and others have previously shown that FoxOs can regulate these processes via two different mechanisms: by direct binding to forkhead-responsive elements at the promoter of target genes or by a poorly understood alternative process that does not require direct DNA binding and regulates key targets in primary human ECs. Here, we performed an interaction study in ECs to identify new nuclear FoxO3 interaction partners that might contribute to FoxO-dependent gene regulation. Mass spectrometry analysis of FoxO3-interacting proteins revealed transformation/transcription domain–associated protein (TRRAP), a member of multiple histone acetyltransferase complexes, as a novel binding partner of FoxO family proteins. We demonstrate that TRRAP is required to support FoxO3 transactivation and FoxO3-dependent G1 arrest and apoptosis in ECs via transcriptional activation of the cyclin-dependent kinase inhibitor p27kip1 and the proapoptotic B-cell lymphoma 2 family member, BIM. Moreover, FoxO–TRRAP interaction could explain FoxO-induced alternative gene regulation via TRRAP-dependent recruitment to target promoters lacking forkhead-responsive element sequences.

SIRT1 attenuates neuroinflammation by deacetylating HSPA4 in a mouse model of Parkinson's disease

As a deacetylase, SIRT1 plays essential roles in various physiological events, from development to lifespan regulation. SIRT1 has been shown neuroprotective effects in neurodegeneration disorders such as Parkinson's disease (PD). However, the underlying molecular mechanisms are still not well understood. Here, we generated transgenic mice with increased expression of Sirt1 in the brain and examined the potential roles of SIRT1 in PD. Our data showed that SIRT1 repressed proinflammatory cytokine expression both in microglia and astrocytes. In MPTP induced PD model mice, lower levels of microglia and astrocyte activation were observed in SIRT1 transgenic mice. Moreover, the tyrosine hydroxylase (TH) loss in the substantia nigra pars compacta (SNpc) and striatum induced by MPTP was also attenuated by SIRT1. As a consequence, the behavioral defects induced by MPTP were largely prevented in SIRT1 transgenic mice. Mechanistically, SIRT1 interacts with heat shock 70 kDa protein 4 (HSPA4) and deacetylates it at 305, 351 and 605 lysine residues. This deacetylation modification induces the nuclear translocation of HSPA4 and thus to repress proinflammatory cytokine expression. On the contrary, mutated HSPA4, in which 305/351/605 lysine residues were replaced with arginine, was mainly localized in the cytoplasm and losses its repression on proinflammatory cytokine expression. Taken together, our data indicate that SIRT1 plays beneficial roles in PD model mice, which is likely due to, at least in part, its anti-inflammation activity in glial cells by deacetylating HSPA4. Furthermore, HSPA4 might be a druggable target for developing novel agents for treating neuroinflammation associated disorders such as PD.

Effects of Atomoxetine Hydrochloride on Regulation of Lifespan in Drosophila Model.

Nootropics (smart drugs) are used by students to enhance cognitive performance which have been reported times in recent years. However, some of the nootropics are central nervous system stimulants which are very likely to lead to addiction or complications such as vomiting and dizziness. Are there nootropics that can improve learning behavior while having potential positive effect on health? Here, we reported that Atomoxetine (ATX) has sex-specific effect on prolonging the life span of female Drosophila melanogaster. Further study indicated that ATX enhanced female resistance to heat stress and their vertical climbing ability, but it did decrease the number of eggs laid. ATX increased food-intake and sleep time both of females and males, and significantly reduced the 24h spontaneous activity of females and males. Our results present the sex dimorphic effect of ATX on life span regulation in Drosophila, and support further research on the beneficial role of ATX and the mechanisms in other animal models.

The Role of Nutrients in Maintaining Hematopoietic Stem Cells and Healthy Hematopoiesis for Life.

Nutrients are converted by the body to smaller molecules, which are utilized for both anabolic and catabolic metabolic reactions. Cooperative regulation of these processes is critical for life-sustaining activities. In this review, we focus on how the regulation of nutrient-driven metabolism maintains healthy hematopoietic stem cells (HSCs). For this purpose, we have examined the metabolic regulation of HSCs from two perspectives: (1) the control of intracellular metabolism by the balance of anabolic and catabolic reactions; and (2) the control of organismal metabolic status and hematopoiesis by dietary intake of nutrients. Critical roles of catabolic regulators in stem cell homeostasis are conserved in several types of tissues, including hematopoiesis. These catabolic signals are also major regulators of organismal lifespan in multiple species. In parallel, changes to nutrients via alterations to dietary intake affect not only an organism’s metabolic state but also the behavior of its stem cells. While the molecular mechanisms involved in these two aspects of nutrient function may not necessarily overlap, a deeper understanding of these phenomena will point to new avenues of medical research and may furnish new agents for improving human health care.

Genes and Longevity of Lifespan.

Aging is a complex process indicated by low energy levels, declined physiological activity, stress induced loss of homeostasis leading to the risk of diseases and mortality. Recent developments in medical sciences and an increased availability of nutritional requirements has significantly increased the average human lifespan worldwide. Several environmental and physiological factors contribute to the aging process. However, about 40% human life expectancy is inherited among generations, many lifespan associated genes, genetic mechanisms and pathways have been demonstrated during last decades. In the present review, we have evaluated many human genes and their non-human orthologs established for their role in the regulation of lifespan. The study has included more than fifty genes reported in the literature for their contributions to the longevity of life. Intact genomic DNA is essential for the life activities at the level of cell, tissue, and organ. Nucleic acids are vulnerable to oxidative stress, chemotherapies, and exposure to radiations. Efficient DNA repair mechanisms are essential for the maintenance of genomic integrity, damaged DNA is not replicated and transferred to next generations rather the presence of deleterious DNA initiates signaling cascades leading to the cell cycle arrest or apoptosis. DNA modifications, DNA methylation, histone methylation, histone acetylation and DNA damage can eventually lead towards apoptosis. The importance of calorie restriction therapy in the extension of lifespan has also been discussed. The role of pathways involved in the regulation of lifespan such as DAF-16/FOXO (forkhead box protein O1), TOR and JNK pathways has also been particularized. The study provides an updated account of genetic factors associated with the extended lifespan and their interactive contributory role with cellular pathways.

Sirt6 regulates lifespan in Drosophila melanogaster.

Sirt6 is a multifunctional enzyme that regulates diverse cellular processes such as metabolism, DNA repair, and aging. Overexpressing Sirt6 extends lifespan in mice, but the underlying cellular mechanisms are unclear. Drosophila melanogaster are an excellent model to study genetic regulation of lifespan; however, despite extensive study in mammals, very little is known about Sirt6 function in flies. Here, we characterized the Drosophila ortholog of Sirt6, dSirt6, and examined its role in regulating longevity; dSirt6 is a nuclear and chromatin-associated protein with NAD+-dependent histone deacetylase activity. dSirt6 overexpression (OE) in flies produces robust lifespan extension in both sexes, while reducing dSirt6 levels shortens lifespan. dSirt6 OE flies have normal food consumption and fertility but increased resistance to oxidative stress and reduced protein synthesis rates. Transcriptomic analyses reveal that dSirt6 OE reduces expression of genes involved in ribosome biogenesis, including many dMyc target genes. dSirt6 OE partially rescues many effects of dMyc OE, including increased nuclear size, up-regulation of ribosome biogenesis genes, and lifespan shortening. Last, dMyc haploinsufficiency does not convey additional lifespan extension to dSirt6 OE flies, suggesting dSirt6 OE is upstream of dMyc in regulating lifespan. Our results provide insight into the mechanisms by which Sirt6 OE leads to longer lifespan.

Regulation of fatty acid desaturase- and immunity gene-expression by mbk-1/DYRK1A in Caenorhabditis elegans

BackgroundIn the nematode Caenorhabditis elegans, longevity in response to germline ablation, but not in response to reduced insulin/IGF1-like signaling, is strongly dependent on the conserved protein kinase minibrain-related kinase 1 (MBK-1). In humans, the MBK-1 ortholog DYRK1A is associated with a variety of disorders, most prominently with neurological defects observed in Down syndrome. To better understand mbk-1’s physiological roles and their dependence on genetic background, we analyzed the influence of mbk-1 loss on the transcriptomes of wildtype and long-lived, germline-deficient or insulin-receptor defective, C. elegans strains by RNA-sequencing.Resultsmbk-1 loss elicited global changes in transcription that were less pronounced in insulin-receptor mutant than in germline-deficient or wildtype C. elegans. Irrespective of genetic background, mbk-1 regulated genes were enriched for functions in biological processes related to organic acid metabolism and pathogen defense. qPCR-studies confirmed mbk-1 dependent induction of all three C. elegans Δ9-fatty acid desaturases, fat-5, fat-6 and fat-7, in wildtype, germline-deficient and insulin-receptor mutant strains. Conversely, mbk-1 dependent expression patterns of selected pathogen resistance genes, including asp-12, dod-24 and drd-50, differed across the genetic backgrounds examined. Finally, cth-1 and cysl-2, two genes which connect pathogen resistance to the metabolism of the gaseous messenger and lifespan regulator hydrogen sulfide (H2S), were commonly suppressed by mbk-1 loss only in wildtype and germline-deficient, but not in insulin-receptor mutant C. elegans.ConclusionOur work reveals previously unknown roles of C. elegans mbk-1 in the regulation of fatty acid desaturase- and H2S metabolic-genes. These roles are only partially dependent on genetic background. Considering the particular importance of fatty acid desaturation and H2S for longevity of germline-deficient C. elegans, we propose that these processes at least in part account for the previous observation that mbk-1 preferentially regulates lifespan in these worms.

Characterization of hexose transporter genes in the views of the chronological life span and glucose uptake in fission yeast.

Fission yeast, Schizosaccharomyces pombe, possesses eight hexose transporters, Ght1~8. In order to clarify the role of each hexose transporter on glucose uptake, a glucose uptake assay system was established and the actual glucose uptake activity of each hexose transporter-deletion mutant was measured. Under normal growth condition containing 2% glucose, ∆ght5 and ∆ght2 mutants showed large and small decrease in glucose uptake activity, respectively. On the other hand, the other deletion mutants did not show any decrease in glucose uptake activity indicating that, in the presence of Ght5 and Ght2, the other hexose transporters do not play a significant role in glucose uptake. To understand the relevance between glucose uptake and lifespan regulation, we measured the chronological lifespan of each hexose transporter deletion mutant, and found that only ∆ght5 mutant showed a significant lifespan extension. Based on these results we showed that Ght5 is mainly involved in the glucose uptake in Schizosaccharomyces pombe, and suggested that the ∆ght5 mutant has prolonged lifespan due to physiological changes similar to calorie restriction.

Genetic basis of cardiovascular aging is at the core of human longevity

Aging is an archetypical complex process influenced by genetic and environmental factors. Genetic variants impart a gradient of effect sizes, albeit the effect sizes seem to be skewed toward those with small effect sizes. On one end of the spectrum are the rare monogenic premature aging syndromes, such as Hutchinson Gilford Progeria Syndrome, whereby single nucleotide changes lead to rapidly progressive premature aging. On the end of the spectrum is the complex, slowly progressive process of living to an arbitrary-defined old age, i.e., longevity. Whereas the genetic basis of rare premature aging syndromes has been elucidated, only a small fraction of the genetic determinants of longevity and life span, time from birth to death, have been identified. The latter point to the complexity of the process and involvement of myriad of genetic and non-genetic factors and hence, the diluted effect of each determinant on longevity. The genetic discoveries point to the involvement of the DNA damage and activation of the DNA damage response pathway, particularly in the premature aging syndromes. Likewise, the insulin/insulin-like growth factor 1/mTOR/FOXO pathways have emerged as major regulators of life span. A notable fraction of the genetic variants that are associated with life span is also associated with age-related cardiovascular diseases, such as coronary artery disease and dyslipidemia, which places cardiovascular aging at the core of human life span. The clinical impact of the discoveries pertains to the identification of the pathways that are involved in life span, which might serve as targets of interventions to prevent, slow, and even possibly reverse aging.

Linkage Guided Sequence Analysis Revealed a Novel Gene PKD1L2 for Adiponectin: The Long Life Family Study (LLFS)

Hospital-associated disability (HAD), defined as a loss of activities of daily living (ADLs) occurring during hospitalization, is a common complication among older adults. Delirium is also a common complication during hospitalization and is associated with multiple long-term sequelae. We sought to determine the effect of delirium and known covariates on the risk of incident HAD in hospitalized older adults. We examined electronic health record (EHR) data for 35,201 older adults ≥ 65 years of age admitted to the general inpatient (non-ICU) units of UAB Hospital from January 1, 2015 to December 31, 2019. Delirium was defined as a score ≥ 2 on the Nursing Delirium Screening Scale (NuDESC) during hospital admission, and HAD defined as a decline on the Katz ADL scale from hospital admission to discharge. Generalized linear mixed models were used to examine the association between delirium and HAD, adjusting for covariates and repeated observations for individuals with multiple admissions. We found that 21.2% of older adults developed HAD during their hospitalization and experienced higher delirium rates as compared to those not developing HAD (25.2% vs. 16.3%). Presence of delirium, medical comorbidity score, baseline cognitive status, and baseline ADL function were associated (all p <0.001) with incident HAD. Mediation analyses also showed that 8% of the effect of comorbidity on incident HAD was due to delirium (p < 0.001). Reducing rates of delirium can be one component of a comprehensive approach to reduce rates of HAD in older adults.

The Crucial Roles of Phospholipids in Aging and Lifespan Regulation.

Phospholipids are major membrane lipids that consist of lipid bilayers. This basic cellular structure acts as a barrier to protect the cell against various environmental insults and more importantly, enables multiple cellular processes to occur in subcellular compartments. Numerous studies have linked the complexity of membrane lipids to signal transductions, organelle functions, as well as physiological processes, and human diseases. Recently, crucial roles for membrane lipids in the aging process are beginning to emerge. In this study, we summarized current advances in our understanding of the relationship between membrane lipids and aging with an emphasis on phospholipid species. We surveyed how major phospholipid species change with age in different organisms and tissues, and some common patterns of membrane lipid change during aging were proposed. Further, the functions of different phospholipid molecules in regulating healthspan and lifespan, as well as their potential mechanisms of action, were also discussed.

Phosphate Restriction Promotes Longevity via Activation of Autophagy and the Multivesicular Body Pathway.

Nutrient limitation results in an activation of autophagy in organisms ranging from yeast, nematodes and flies to mammals. Several evolutionary conserved nutrient-sensing kinases are critical for efficient adaptation of yeast cells to glucose, nitrogen or phosphate depletion, subsequent cell-cycle exit and the regulation of autophagy. Here, we demonstrate that phosphate restriction results in a prominent extension of yeast lifespan that requires the coordinated activity of autophagy and the multivesicular body pathway, enabling efficient turnover of cytoplasmic and plasma membrane cargo. While the multivesicular body pathway was essential during the early days of aging, autophagy contributed to long-term survival at later days. The cyclin-dependent kinase Pho85 was critical for phosphate restriction-induced autophagy and full lifespan extension. In contrast, when cell-cycle exit was triggered by exhaustion of glucose instead of phosphate, Pho85 and its cyclin, Pho80, functioned as negative regulators of autophagy and lifespan. The storage of phosphate in form of polyphosphate was completely dispensable to in sustaining viability under phosphate restriction. Collectively, our results identify the multifunctional, nutrient-sensing kinase Pho85 as critical modulator of longevity that differentially coordinates the autophagic response to distinct kinds of starvation.

Insight into the interaction between the RNA helicase CGH-1 and EDC-3 and its implications

Previous studies indicated that the P-body components, CGH-1 and EDC-3 may play a crucial role in the regulation of lifespan in Caenorhabditis elegans. Homo sapiens DDX6 or Saccharomyces cerevisiae Dhh1p (CGH-1 in C. elegans) could form complexes with EDC3 (Edc3p in yeast), respectively, which is significant for translation inhibition and mRNA decay. However, it is currently unclear how CGH-1 can be recognized by EDC-3 in C. elegans. Here, we provided structural and biochemical insights into the interaction between CGH-1 and EDC-3. Combined with homology modeling, mutation, and ITC assays, we uncovered an interface between CGH-1 RecA2 domain and EDC-3 FDF-FEK. Additionally, GST-pulldown and co-localization experiments confirmed the interaction between CGH-1 and EDC-3 in vitro and in vivo. We also analyzed PATR-1-binding interface on CGH-1 RecA2 by ITC assays. Moreover, we unveiled the similarity and differences of the binding mode between EDC-3 and CAR-1 or PATR-1. Taken together, these findings provide insights into the recognition of DEAD-box protein CGH-1 by EDC-3 FDF-FEK motif, suggesting important functional implications.

ADDITION OF RAPAMYCIN AND YOUNG GRANULOSA CELLS TO IMPROVE IN VITRO OOCYTE MATURATION AND EUPLOIDY RATES IN OLDER REPRODUCTIVE AGE WOMEN: A PROSPECTIVE RANDOMIZED STUDY

The bi-directional communication between the oocyte and the granulosa/cumulus cells plays a key role in follicle and oocyte maturation. Rapamycin (sirolimus) is a macrolide immunosuppressant that inhibits the mechanistic target of rapamycin (mTOR) protein kinase, which is a regulator of lifespan, aging, and cellular senescence. Recent studies suggested that rapamycin may help improve oocyte development in aging women. In this study, we aimed to determine whether the incubation of immature (germinal vesicles (GV) stage) oocytes from older reproductive age women with rapamycin and/or granulosa cells (GCs) from young donors would affect maturation and euploidy rates.

Loss of Caenorhabditis elegans homologue of human MOB4 compromises life span, health life span and thermotolerance.

Mob1/phocein family proteins are conserved from yeast to mammals. Human has four MOB genes, MOB1, 2, 3 and 4. Human MOB1 protein, which is a component of the Hippo pathway, is involved in the inhibition of yes-associated protein (YAP1) through large tumor suppressor (LATS) kinases and plays a tumor suppressive role. In contrast, MOB4 activates YAP1. Caernorhabditis elegans (C. elegans) also has four MOB genes. Moreover, C. elegans has homologues of YAP1 (Ce_YAP-1) and LATS kinases (WTS-1). Nevertheless, our previous study revealed that the Hippo pathway is not conserved in C. elegans and that heat shock activates Ce_YAP-1. We also reported that Ce_YAP-1 is involved in the regulation of life span, healthy lifespan and thermotolerance. In this study, we raised a question whether and how C. elegans homologue of MOB4 (Ce_MOB-4) is involved in the regulation of Ce_YAP-1. Ce_MOB-4 is ubiquitously expressed in adult worms. This expression pattern is similar to that of Ce_YAP-1. mob-4 loss-of-function mutants show short life span, short health life span and compromise thermotolerance. However, heat shock activates Ce_YAP-1 in mob-4 mutant. In conclusion, the role of MOB4 in the activation of YAP1 is not conserved in C. elegans.