Daf-2

Last updated
abnormal dauer formation protein 2
Identifiers
Organism Caenorhabditis elegans
Symboldaf-2
Entrez 175410
RefSeq (mRNA) NM_065249.5
RefSeq (Prot) NP_497650.4
UniProt Q968Y9
Other data
Chromosome III: 2.99 - 3.03 Mb
Search for
Structures Swiss-model
Domains InterPro

The DAF-2 gene encodes for the insulin-like growth factor 1 (IGF-1) receptor in the worm Caenorhabditis elegans . DAF-2 is part of the first metabolic pathway discovered to regulate the rate of aging. [1] DAF-2 is also known to regulate reproductive development, resistance to oxidative stress, thermotolerance, resistance to hypoxia, and resistance to bacterial pathogens. [2] Mutations in DAF-2 and also Age-1 have been shown by Cynthia Kenyon to double the lifespan of the worms. [3] [4] In a 2007 episode of WNYC’s Radiolab, Kenyon called DAF-2 "the grim reaper gene.” [5]

Contents

Long-lived mutants

Long-lived DAF-2C. elegans mutants are resistant to the oxidizing agent paraquat and to UV light. [6] DAF-2 mutants also have a higher DNA repair capability than wild-type C. elegans. [6] Knockdown of the nucleotide excision repair gene Xpa-1 increases sensitivity to UV and reduces the life span of the long-lived mutants. These findings support the hypothesis that DNA damage has a significant role in the aging process. [6]

IGF-1 signal pathway

Insulin/IGF-1-like signaling is well-conserved evolutionarily across animal phyla, from single celled organisms to mammals. [7] DAF-2 is the only member of the insulin receptor family in C. elegans but it corresponds, in form and function, to multiple pathways in humans. The protein predicted from DAF-2's sequence is 35% identical to the human insulin receptor, which regulates metabolism; 34% identical to the IGF-1 receptor, which regulates growth; and 33% identical to the human insulin receptor–related receptor. [8] [9] In C. elegans, the insulin/IGF-1/FOXO pathway is initiated by changes in IGF-1 levels which cause IGF-1 receptors to start a phosphorylation cascade that deactivates the FOXO transcription factor, DAF-16. When not phosphorylated, DAF-16 is active and present in the nucleus. DAF-16 is responsible for up-regulating transcription of about 100 genes that code for cell protecting products such as heat shock proteins and antioxidants. [10] Genetic analysis reveals that the presence of functioning DAF-16 is required to produce the extended lifespan observed in DAF-2 knock-downs. [1] By silencing DAF-16, activation of DAF-2 receptors can ultimately compromise a cell’s ability to mitigate harmful environmental conditions. [7] In most eukaryotes, insulin activates DAF-2 signaling. However, both human insulin and insulin coded for by orthologous genes in C. elegans inhibit DAF-2 receptors in C. elegans. [11]

Role in C. elegans developmental stages

Caenorhabditis elegans, which progresses through a series of larval stages into a final reproductive adult, may instead enter a less metabolically active dauer diapause stage if food scarcity or overcrowding occurs before reaching adulthood. [10] Disabling DAF-2 arrests development in the dauer stage which increases longevity, delays senescence and prevents reproductive maturity. [11]

Diet’s interaction with the IGF-1 pathway

Research into the interaction between diet and the insulin/IGF-1 pathway has shown sugar intake to be negatively correlated with DAF-16 activity and longevity. One study found that glucose ingestion reduced the rate of dauer formation and shortened the life-spans of DAF-2 knock-downs to resemble that of normal C. elegans, suggesting that DAF-16 mediated gene expression associated with longevity is suppressed by glucose ingestion. Wild type C. elegans fed a diet that included 2% glucose showed reduced Daf-16 activity and lifespan was shortened by 20% compared to worms fed on glucose-free media. These findings raise the possibility that a low-sugar diet might have beneficial effects on life span in higher organisms. [12]

See also

Related Research Articles

<span class="mw-page-title-main">Insulin-like growth factor</span> Proteins similar to insulin that stimulate cell proliferation

The insulin-like growth factors (IGFs) are proteins with high sequence similarity to insulin. IGFs are part of a complex system that cells use to communicate with their physiologic environment. This complex system consists of two cell-surface receptors, two ligands, a family of seven high-affinity IGF-binding proteins, as well as associated IGFBP degrading enzymes, referred to collectively as proteases.

<i>Caenorhabditis elegans</i> Free-living species of nematode

Caenorhabditis elegans is a free-living transparent nematode about 1 mm in length that lives in temperate soil environments. It is the type species of its genus. The name is a blend of the Greek caeno- (recent), rhabditis (rod-like) and Latin elegans (elegant). In 1900, Maupas initially named it Rhabditides elegans. Osche placed it in the subgenus Caenorhabditis in 1952, and in 1955, Dougherty raised Caenorhabditis to the status of genus.

Calorie restriction mimetics (CRM), also known as energy restriction mimetics, are a hypothetical class of dietary supplements or drug candidates that would, in principle, mimic the substantial anti-aging effects that calorie restriction (CR) has on many laboratory animals and humans. CR is defined as a reduction in calorie intake of 20% to 50% without incurring malnutrition or a reduction in essential nutrients. An effective CRM would alter the key metabolic pathways involved in the effects of CR itself, leading to preserved youthful health and longer lifespan without the need to reduce food intake. The term was coined by Lane, Ingram, Roth of the National Institute on Aging in a seminal 1998 paper in the Journal of Anti-Aging Medicine, the forerunner of Rejuvenation Research. A number of genes and pathways have been shown to be involved with the actions of CR in model organisms and these represent attractive targets for drug discovery and for developing CRM. However, no effective CRM have been identified to date.

Dauer describes an alternative developmental stage of nematode worms, particularly rhabditids including Caenorhabditis elegans, whereby the larva goes into a type of stasis and can survive harsh conditions. Since the entrance of the dauer stage is dependent on environmental cues, it represents a classic and well studied example of polyphenism. The dauer state is given other names in the various types of nematodes such as ‘diapause’ or ‘hypobiosis’, but since the C. elegans nematode has become the most studied nematode, the term ‘dauer stage’ or 'dauer larvae' is becoming universally recognised when referring to this state in other free-living nematodes. The dauer stage is also considered to be equivalent to the infective stage of parasitic nematode larvae.

<span class="mw-page-title-main">Cynthia Kenyon</span> US molecular biologist

Cynthia Jane Kenyon is an American molecular biologist and biogerontologist known for her genetic dissection of aging in a widely used model organism, the roundworm Caenorhabditis elegans. She is the vice president of aging research at Calico Research Labs, and emeritus professor of biochemistry and biophysics at the University of California, San Francisco (UCSF).

<span class="mw-page-title-main">SHC1</span> Protein-coding gene in humans

SHC-transforming protein 1 is a protein that in humans is encoded by the SHC1 gene. SHC has been found to be important in the regulation of apoptosis and drug resistance in mammalian cells.

<span class="mw-page-title-main">FOXO3</span> Protein-coding gene in the species Homo sapiens

Forkhead box O3, also known as FOXO3 or FOXO3a, is a human protein encoded by the FOXO3 gene.

<span class="mw-page-title-main">FOXO4</span> Protein

Forkhead box protein O4 is a protein that in humans is encoded by the FOXO4 gene.

Gary Bruce Ruvkun is an American molecular biologist at Massachusetts General Hospital and professor of genetics at Harvard Medical School in Boston. Ruvkun discovered the mechanism by which lin-4, the first microRNA (miRNA) discovered by Victor Ambros, regulates the translation of target messenger RNAs via imperfect base-pairing to those targets, and discovered the second miRNA, let-7, and that it is conserved across animal phylogeny, including in humans. These miRNA discoveries revealed a new world of RNA regulation at an unprecedented small size scale, and the mechanism of that regulation. Ruvkun also discovered many features of insulin-like signaling in the regulation of aging and metabolism. He was elected a Member of the American Philosophical Society in 2019.

<span class="mw-page-title-main">Daf-16</span> Ortholog

DAF-16 is the sole ortholog of the FOXO family of transcription factors in the nematode Caenorhabditis elegans. It is responsible for activating genes involved in longevity, lipogenesis, heat shock survival and oxidative stress responses. It also protects C.elegans during food deprivation, causing it to transform into a hibernation - like state, known as a Dauer. DAF-16 is notable for being the primary transcription factor required for the profound lifespan extension observed upon mutation of the insulin-like receptor DAF-2. The gene has played a large role in research into longevity and the insulin signalling pathway as it is located in C. elegans, a successful ageing model organism.

David Gems is a British geneticist who studies the biology and genetics of ageing (biogerontology). He is Professor of Biogerontology at the Research Department of Genetics, Evolution and Environment, University College London and he is a co-founder and Research Director of the UCL Institute of Healthy Ageing. His work concerns understanding the underlying causes of aging. His research laboratory tests theories of aging and develops new ones using a short-lived animal model C. elegans.

In molecular biology mir-71 microRNA is a short RNA molecule. MicroRNAs function to regulate the expression levels of other genes by several mechanisms.

<span class="mw-page-title-main">Genetics of aging</span> Overview of the genetics of aging

Genetics of aging is generally concerned with life extension associated with genetic alterations, rather than with accelerated aging diseases leading to reduction in lifespan.

Host microbe interactions in <i>Caenorhabditis elegans</i>

Caenorhabditis elegans- microbe interactions are defined as any interaction that encompasses the association with microbes that temporarily or permanently live in or on the nematode C. elegans. The microbes can engage in a commensal, mutualistic or pathogenic interaction with the host. These include bacterial, viral, unicellular eukaryotic, and fungal interactions. In nature C. elegans harbours a diverse set of microbes. In contrast, C. elegans strains that are cultivated in laboratories for research purposes have lost the natural associated microbial communities and are commonly maintained on a single bacterial strain, Escherichia coli OP50. However, E. coli OP50 does not allow for reverse genetic screens because RNAi libraries have only been generated in strain HT115. This limits the ability to study bacterial effects on host phenotypes. The host microbe interactions of C. elegans are closely studied because of their orthologs in humans. Therefore, the better we understand the host interactions of C. elegans the better we can understand the host interactions within the human body.

The DAF-12 gene encodes the nuclear receptor of dafachronic acid in the worm Caenorhabditis elegans, with the NRNC Symbol NR1J1 as the homolog of nuclear hormone receptor HR96 in Drosophila melanogaster. DAF-12 has been implicated by Cynthia Kenyon and colleagues in the formation of Dauer larva.

The Daf-9 gene encodes a cytochrome p450 enzyme catalysis the generation of dafachronic acid in the worm Caenorhabditis elegans, with the CYP Symbol CYP22A1. After generation, dafachronic acid will binding it's nuclear receptor Daf-12 and has been implicated by Cynthia Kenyon and colleagues related to the formation of Dauer larva.

The DAF-1 gene encodes for a cell surface Enzyme-linked receptor of TGF-beta signaling pathway in the worm Caenorhabditis elegans. DAF-1 is one of the type I receptor of TGF-beta pathway. DAF-1 acts as a receptor protein serine/threonine kinase, is activated by type II receptor Daf-4 phosphorylation after the ligand Daf-7 binds to the receptor heterotetramer, and then phosphorylates Daf-8 or Daf-14, the SMAD proteins in C. elegans.

The Dod-13 gene in the worm Caenorhabditis elegans encoding a cytochrome p450 enzyme, which have steroid hydroxylase activity, with the CYP Symbol CYP35B1. Dod-13 is downstream gene of Daf-16 influenced the lifespan of C. elegans.

<span class="mw-page-title-main">Collin Y. Ewald</span> Swiss molecular biologist

Collin Yvès Ewald is a Swiss scientist investigating the molecular mechanisms of healthy aging. He is a molecular biologist and a professor at ETH Zurich, where he leads the Laboratory of Extracellular Matrix Regeneration. His research focuses on the remodeling of the extracellular matrix during aging and upon longevity interventions.

<span class="mw-page-title-main">Age-1</span> Gene

The age-1 gene is located on chromosome 2 in C.elegans. It gained attention in 1983 for its ability to induce long-lived C. elegans mutants. The age-1 mutant, first identified by Michael Klass, was reported to extend mean lifespan by over 50% at 25 °C when compared to the wild type worm (N2) in 1987 by Johnson et al. Development, metabolism, lifespan, among other processes have been associated with age-1 expression. The age-1 gene is known to share a genetic pathway with daf-2 gene that regulates lifespan in worms. Additionally, both age-1 and daf-2 mutants are dependent on daf-16 and daf-18 genes to promote lifespan extension.

References

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  11. 1 2 Pierce SB, Costa M, Wisotzkey R, Devadhar S, Homburger SA, Buchman AR, et al. (March 2001). "Regulation of DAF-2 receptor signaling by human insulin and ins-1, a member of the unusually large and diverse C. elegans insulin gene family". Genes & Development. 15 (6): 672–86. doi:10.1101/gad.867301. PMC   312654 . PMID   11274053.
  12. Lee SJ, Murphy CT, Kenyon C (November 2009). "Glucose shortens the life span of C. elegans by downregulating DAF-16/FOXO activity and aquaporin gene expression". Cell Metabolism. 10 (5): 379–91. doi:10.1016/j.cmet.2009.10.003. PMC   2887095 . PMID   19883616.