Breakthroughs in the longevity field over the past few decades have led to major shifts in how we attack the problem of aging. What have been the most important of these shifts in our perspectives, ...aims, and approaches that will likely guide future research?
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The biology and behavior of adults differ substantially from those of developing animals, and cell-specific information is critical for deciphering the biology of multicellular animals. Thus, adult ...tissue-specific transcriptomic data are critical for understanding molecular mechanisms that control their phenotypes. We used adult cell-specific isolation to identify the transcriptomes of C. elegans' four major tissues (or "tissue-ome"), identifying ubiquitously expressed and tissue-specific "enriched" genes. These data newly reveal the hypodermis' metabolic character, suggest potential worm-human tissue orthologies, and identify tissue-specific changes in the Insulin/IGF-1 signaling pathway. Tissue-specific alternative splicing analysis identified a large set of collagen isoforms. Finally, we developed a machine learning-based prediction tool for 76 sub-tissue cell types, which we used to predict cellular expression differences in IIS/FOXO signaling, stage-specific TGF-β activity, and basal vs. memory-induced CREB transcription. Together, these data provide a rich resource for understanding the biology governing multicellular adult animals.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The ability to inherit learned information from parents could be evolutionarily beneficial, enabling progeny to better survive dangerous conditions. We discovered that, after C. elegans have learned ...to avoid the pathogenic bacteria Pseudomonas aeruginosa (PA14), they pass this learned behavior on to their progeny, through either the male or female germline, persisting through the fourth generation. Expression of the TGF-β ligand DAF-7 in the ASI sensory neurons correlates with and is required for this transgenerational avoidance behavior. Additionally, the Piwi Argonaute homolog PRG-1 and its downstream molecular components are required for transgenerational inheritance of both avoidance behavior and ASI daf-7 expression. Animals whose parents have learned to avoid PA14 display a PA14 avoidance-based survival advantage that is also prg-1 dependent, suggesting an adaptive response. Transgenerational epigenetic inheritance of pathogenic learning may optimize progeny decisions to increase survival in fluctuating environmental conditions.
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•C. elegans transmit learned avoidance of P. aeruginosa for four generations•ASI and the TGF-β ligand daf-7 are required for transgenerational PA14 avoidance•Piwi/PRG-1 is required for transgenerational inheritance of P. aeruginosa avoidance•Transgenerational avoidance of P. aeruginosa provides fitness benefits to offspring
Worms can transmit avoidance behavior to their young for four generations, providing progeny with a mechanism to survive dangerous conditions.
Women's reproductive cessation is the earliest sign of human aging and is caused by decreasing oocyte quality. Similarly, C. elegans' reproduction declines in mid-adulthood and is caused by oocyte ...quality decline. Aberrant mitochondrial morphology is a hallmark of age-related dysfunction, but the role of mitochondrial morphology and dynamics in reproductive aging is unclear. We examined the requirements for mitochondrial fusion and fission in oocytes of both wild-type worms and the long-lived, long-reproducing insulin-like receptor mutant daf-2. We find that normal reproduction requires both fusion and fission, but that daf-2 mutants utilize a shift towards fission, but not fusion, to extend their reproductive span and oocyte health. daf-2 mutant oocytes' mitochondria are punctate (fissioned) and this morphology is primed for mitophagy, as loss of the mitophagy regulator PINK-1 shortens daf-2's reproductive span. daf-2 mutants maintain oocyte mitochondria quality with age at least in part through a shift toward punctate mitochondrial morphology and subsequent mitophagy. Supporting this model, Urolithin A, a metabolite that promotes mitophagy, extends reproductive span in wild-type mothers-even in mid-reproduction-by maintaining youthful oocytes with age. Our data suggest that promotion of mitophagy may be an effective strategy to maintain oocyte health with age.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Nutrients are necessary for life, as they are a crucial requirement for biological processes including reproduction, somatic growth, and tissue maintenance. Therefore, signaling systems involved in ...detecting and interpreting nutrient or energy levels-most notably, the insulin/insulin-like growth factor 1 (IGF-1) signaling pathway, mechanistic target of rapamycin (mTOR), and adenosine monophosphate-activated protein kinase (AMPK)-play important roles in regulating physiological decisions to reproduce, grow, and age. In this review, we discuss the connections between reproductive senescence and somatic aging and give an overview of the involvement of nutrient-sensing pathways in controlling both reproductive function and lifespan. Although the molecular mechanisms that affect these processes can be influenced by distinct tissue-, temporal-, and pathway-specific signaling events, the progression of reproductive aging and somatic aging is systemically coordinated by integrated nutrient-sensing signaling pathways regulating somatic tissue maintenance in conjunction with reproductive capacity.
Induced CREB activity is a hallmark of long-term memory, but the full repertoire of CREB transcriptional targets required specifically for memory is not known in any system. To obtain a more complete ...picture of the mechanisms involved in memory, we combined memory training with genome-wide transcriptional analysis of C. elegans CREB mutants. This approach identified 757 significant CREB/memory-induced targets and confirmed the involvement of known memory genes from other organisms, but also suggested new mechanisms and novel components that may be conserved through mammals. CREB mediates distinct basal and memory transcriptional programs at least partially through spatial restriction of CREB activity: basal targets are regulated primarily in nonneuronal tissues, while memory targets are enriched for neuronal expression, emanating from CREB activity in AIM neurons. This suite of novel memory-associated genes will provide a platform for the discovery of orthologous mammalian long-term memory components.
The cell biology of aging DiLoreto, Race; Murphy, Coleen T
Molecular biology of the cell,
2015-Dec-15, 2015-12-15, 20151215, Letnik:
26, Številka:
25
Journal Article
Recenzirano
Odprti dostop
One of the original hypotheses of organismal longevity posits that aging is the natural result of entropy on the cells, tissues, and organs of the animal--a slow, inexorable slide into ...nonfunctionality caused by stochastic degradation of its parts. We now have evidence that aging is instead at least in part genetically regulated. Many mutations have been discovered to extend lifespan in organisms of all complexities, from yeast to mammals. The study of metazoan model organisms, such as Caenorhabditis elegans, has been instrumental in understanding the role of genetics in the cell biology of aging. Longevity mutants across the spectrum of model organisms demonstrate that rates of aging are regulated through genetic control of cellular processes. The regulation and subsequent breakdown of cellular processes represent a programmatic decision by the cell to either continue or abandon maintenance procedures with age. Our understanding of cell biological processes involved in regulating aging have been particularly informed by longevity mutants and treatments, such as reduced insulin/IGF-1 signaling and dietary restriction, which are critical in determining the distinction between causes of and responses to aging and have revealed a set of downstream targets that participate in a range of cell biological activities. Here we briefly review some of these important cellular processes.
Reduced insulin/IGF-1-like signaling (IIS) extends C. elegans lifespan by upregulating stress response (class I) and downregulating other (class II) genes through a mechanism that depends on the ...conserved transcription factor DAF-16/FOXO. By integrating genome-wide mRNA expression responsiveness to DAF-16 with genome-wide in vivo binding data for a compendium of transcription factors, we discovered that PQM-1 is the elusive transcriptional activator that directly controls development (class II) genes by binding to the DAF-16-associated element (DAE). DAF-16 directly regulates class I genes only, through the DAF-16-binding element (DBE). Loss of PQM-1 suppresses daf-2 longevity and further slows development. Surprisingly, the nuclear localization of PQM-1 and DAF-16 is controlled by IIS in opposite ways and was also found to be mutually antagonistic. We observe progressive loss of nuclear PQM-1 with age, explaining declining expression of PQM-1 targets. Together, our data suggest an elegant mechanism for balancing stress response and development.
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•DAF-16 activates gene expression only through the DAF-16 binding element•PQM-1 activates gene expression through the DAF-16 associated element•PQM-1 and DAF-16 are nuclear in opposite IIS conditions and mutually antagonistic•PQM-1 exits the nucleus in old age, causing the expression of its targets to decline
A combination of computational and experimental approaches identifies the transcription factor PQM-1 as a new player in the worm DAF-2/insulin signaling pathway regulating longevity. PQM-1 regulates a subset of DAF-16/FOXO-responsive genes, but antagonizes DAF-16 and acts through a different response element in target genes.
Interventions that delay ageing mobilize mechanisms that protect and repair cellular components, but it is unknown how these interventions might slow the functional decline of extracellular matrices, ...which are also damaged during ageing. Reduced insulin/IGF-1 signalling (rIIS) extends lifespan across the evolutionary spectrum, and in juvenile Caenorhabditis elegans also allows the transcription factor DAF-16/FOXO to induce development into dauer, a diapause that withstands harsh conditions. It has been suggested that rIIS delays C. elegans ageing through activation of dauer-related processes during adulthood, but some rIIS conditions confer robust lifespan extension unaccompanied by any dauer-like traits. Here we show that rIIS can promote C. elegans longevity through a program that is genetically distinct from the dauer pathway, and requires the Nrf (NF-E2-related factor) orthologue SKN-1 acting in parallel to DAF-16. SKN-1 is inhibited by IIS and has been broadly implicated in longevity, but is rendered dispensable for rIIS lifespan extension by even mild activity of dauer-related processes. When IIS is decreased under conditions that do not induce dauer traits, SKN-1 most prominently increases expression of collagens and other extracellular matrix genes. Diverse genetic, nutritional, and pharmacological pro-longevity interventions delay an age-related decline in collagen expression. These collagens mediate adulthood extracellular matrix remodelling, and are needed for ageing to be delayed by interventions that do not involve dauer traits. By genetically delineating a dauer-independent rIIS ageing pathway, our results show that IIS controls a broad set of protective mechanisms during C. elegans adulthood, and may facilitate elucidation of processes of general importance for longevity. The importance of collagen production in diverse anti-ageing interventions implies that extracellular matrix remodelling is a generally essential signature of longevity assurance, and that agents promoting extracellular matrix youthfulness may have systemic benefit.
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DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Changes in biomechanical properties have profound impacts on human health. C. elegans might serve as a model for studying the molecular genetics of mammalian tissue decline. Previously, we found that ...collagens are required for insulin signaling mutants' long lifespan and that overexpression of specific collagens extends wild-type lifespan. However, whether these effects on lifespan are due to mechanical changes during aging has not yet been established. Here, we have developed two novel methods to study the cuticle: we measure mechanical properties of live animals using osmotic shock, and we directly perform the tensile test on isolated cuticles using microfluidic technology. Using these tools, we find that the cuticle, not the muscle, is responsible for changes in the “stretchiness” of C. elegans, and that cuticle stiffness is highly nonlinear and anisotropic. We also found that collagen mutations alter the integrity of the cuticle by significantly changing the elasticity. In addition, aging stiffens the cuticle under mechanical loads beyond the cuticle's healthy stretched state. Measurements of elasticity showed that long-lived daf-2 mutants were considerably better at preventing progressive mechanical changes with age. These tests of C. elegans biophysical properties suggest that the cuticle is responsible for their resilience.
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