DAF-16 is the sole

ortholog Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a speci ...

of the FOXO family of transcription factors in the

nematode The nematodes ( or ; ; ), roundworms or eelworms constitute the phylum Nematoda. Species in the phylum inhabit a broad range of environments. Most species are free-living, feeding on microorganisms, but many are parasitic. Parasitic worms (h ...

Caenorhabditis elegans ''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 Hybrid word, blend of the Greek ''caeno-'' (recent), ''r ...

''. It is responsible for activating genes involved in

longevity Longevity may refer to especially long-lived members of a population, whereas ''life expectancy'' is defined Statistics, statistically as the average number of years remaining at a given age. For example, a population's life expectancy at birth ...

lipogenesis In biochemistry, lipogenesis is the conversion of fatty acids and glycerol into Adipose tissue, fats, or a metabolic process through which acetyl-CoA is converted to triglyceride for storage in adipose, fat. Lipogenesis encompasses both fatty aci ...

heat shock The heat shock response (HSR) is a cell stress response that increases the number of molecular chaperones to combat the negative effects on proteins caused by stressors such as increased temperatures, oxidative stress, and heavy metals. In a norm ...

survival and

oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal ...

responses. It also protects ''C.elegans'' during food deprivation, causing it to transform into a

hibernation Hibernation is a state of minimal activity and metabolic reduction entered by some animal species. Hibernation is a seasonal heterothermy characterized by low body-temperature, slow breathing and heart-rate, and low metabolic rate. It is mos ...

- 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 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. DAF-2 is also known to regulate reproducti ...

''. 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.

Genetics

DAF-16 is a gene conserved across species, with

homologs Homologous chromosomes or homologs are a set of one maternal and one paternal chromosome that pair up with each other inside a cell during meiosis. Homologs have the same genes in the same loci, where they provide points along each chromosome th ...

being found in ''C. elegans'',

humans Humans (''Homo sapiens'') or modern humans are the most common and widespread species of primate, and the last surviving species of the genus ''Homo''. They are Hominidae, great apes characterized by their Prehistory of nakedness and clothing ...

mice A mouse (: mice) is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse (''Mus musculus' ...

, and ''

Drosophila ''Drosophila'' (), from Ancient Greek δρόσος (''drósos''), meaning "dew", and φίλος (''phílos''), meaning "loving", is a genus of fly, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or p ...

'' (fruit flies). In ''C. elegans'', DAF-16 is located on

Chromosome 1 Chromosome 1 is the designation for the largest human chromosome. Humans have two copies of chromosome 1, as they do with all of the autosomes, which are the non-sex chromosomes. Chromosome 1 spans about 249 million nucleotide base pairs, which a ...

, at position 175-268. It is made up of 15

exons An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence i ...

. DAF-16 is also located downstream of

, which signals in the IIS pathway.

Mutants In biology, and especially in genetics, a mutant is an organism or a new genetic character arising or resulting from an instance of mutation, which is generally an alteration of the DNA sequence of the genome or chromosome of an organism. It i ...

in this pathway age slower and have a lifespan up to twice as long as normal. Further studies have demonstrated that the lifespan extension is dependent on DAF-16. Other consequences of mutations in the DAF-16 gene is the inability to form dauers.

FOXO (Forkhead box protein O)

DAF-16 encodes FOXO (Forkhead box protein O), which binds to gene promoters that contain the sequence TTGTTTAC in their regulatory region – this is the DAF-16 binding element (DBE). FOXO is involved in the Insulin / IGF1 signalling pathway (IIS) which affects

, dauer formation,

and

responses, by activating proteins such as

MnSOD Superoxide dismutase (SOD, ) is an enzyme that alternately catalyzes the dismutation (or partitioning) of the superoxide () anion radical into normal molecular oxygen (O2) and hydrogen peroxide (). Superoxide is produced as a by-product of oxyg ...

and

Catalase Catalase is a common enzyme found in nearly all living organisms exposed to oxygen (such as bacteria, plants, and animals) which catalyzes the decomposition of hydrogen peroxide to water and oxygen. It is a very important enzyme in protecting ...

. Expression of FOXO in the intestine normally leads to longevity signalling. FOXO has been shown to have a protective role against

cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...

, as it regulates and suppresses genes involved in

tumour A neoplasm () is a type of abnormal and excessive growth of tissue (biology), tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tiss ...

formation. It also has a protective role against

muscular dystrophy Muscular dystrophies (MD) are a genetically and clinically heterogeneous group of rare neuromuscular diseases that cause progressive weakness and breakdown of skeletal muscles over time. The disorders differ as to which muscles are primarily affe ...

. FOXO is also important in

embryonic development In developmental biology, animal embryonic development, also known as animal embryogenesis, is the developmental stage of an animal embryo. Embryonic development starts with the fertilization of an egg cell (ovum) by a sperm, sperm cell (spermat ...

, as it promotes

apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...

. Insulin Signalling Insulin and IGF1 are peptide

hormones A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs or tissues by complex biological processes to regulate physiology and behavior. Hormones a ...

dictating energy functions such as glucose and lipid

metabolism Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...

. The signalling pathway is evolutionary conserved and found across

species A species () is often defined as the largest group of organisms in which any two individuals of the appropriate sexes or mating types can produce fertile offspring, typically by sexual reproduction. It is the basic unit of Taxonomy (biology), ...

. Signalling occurs through kinases such as

PI3K Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...

to produce phospholipid products such as

AKT Protein kinase B (PKB), also known as Akt, is the collective name of a set of three serine/threonine-specific protein kinases that play key roles in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, tra ...

. This causes downstream

phosphorylation In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writ ...

of targets such as DAF-16 by a

phosphorylation cascade A phosphorylation cascade is a sequence of signaling pathway events where one enzyme phosphorylates another, causing a chain reaction leading to the phosphorylation of thousands of proteins. This can be seen in signal transduction of hormone mess ...

, blocking nuclear entry. Therefore, a reduction in insulin signalling generally leads to an increase in FOXO expression, as DAF-16 is no longer inhibited by AKT. When not phosphorylated, DAF-16 is active and present in the nucleus, so FOXO can be transcribed and can up-regulate production of about 100 beneficial proteins that increase longevity.

Species, tissue, subcellular distribution

''C. elegans'' is the only known species to contain the DAF-16 gene, although

orthologs Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a spec ...

are conserved across species. DAF-16 may localise to the

nucleus Nucleus (: nuclei) is a Latin word for the seed inside a fruit. It most often refers to: *Atomic nucleus, the very dense central region of an atom *Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA Nucleu ...

cytoplasm The cytoplasm describes all the material within a eukaryotic or prokaryotic cell, enclosed by the cell membrane, including the organelles and excluding the nucleus in eukaryotic cells. The material inside the nucleus of a eukaryotic cell a ...

, depending on resources. In nutrient rich conditions,

and AKT-1/AKT-2 in the insulin pathway inhibits entry of DAF-16 to the nucleus as it is

phosphorylated In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writt ...

. However starvation, heat and oxidative stress inhibit phosphorylation by AKT and allow the localisation of DAF-16 to the nucleus. DAF-16 is sequestered in the cytoplasm when associated with ''ftt-2''. Translocation to the nucleus and translation of longevity genes occurs after DAF-16 associates with ''prmpt-1'' Translocation to the nucleus is also promoted by ''jnk-1'' in heat stress and ''sek-1'' in oxidative stress. Expression Isoform b and Isoform c are expressed in

muscle Muscle is a soft tissue, one of the four basic types of animal tissue. There are three types of muscle tissue in vertebrates: skeletal muscle, cardiac muscle, and smooth muscle. Muscle tissue gives skeletal muscles the ability to muscle contra ...

ectoderm The ectoderm is one of the three primary germ layers formed in early embryonic development. It is the outermost layer, and is superficial to the mesoderm (the middle layer) and endoderm (the innermost layer). It emerges and originates from the o ...

, the

intestine The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The tract is the largest of the body's systems, after the cardiovascular system. T ...

and

neurons A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...

. Isoform b is additionally expressed in the

pharynx The pharynx (: pharynges) is the part of the throat behind the human mouth, mouth and nasal cavity, and above the esophagus and trachea (the tubes going down to the stomach and the lungs respectively). It is found in vertebrates and invertebrates ...

. Expression can be induced by

quinic acid Quinic acid is an organic compound with the formula . The compound is classified as a cyclitol, a cyclic polyol, and a cyclohexanecarboxylic acid. It is a colorless solid that can be extracted from plant sources. Quinic acid is implicated in the p ...

Clinical significance

Implication in Aging DAF-16 is necessary for dauer formation and the protection of ''C. elegans'' during periods of starvation, as DAF-16, DAF-18 and DAF-12 loss - of - function mutants lose the ability to form dauers. A 2003 study by Murphy et al. showed the significance of DAF-16 for longevity, as it up-regulates genes involved in lifespan extension such as stress response genes and down regulates specific life-shortening genes. It has been proven that

telomeres A telomere (; ) is a region of repetitive nucleotide sequences associated with specialized proteins at the ends of linear chromosomes (see Sequences). Telomeres are a widespread genetic feature most commonly found in eukaryotes. In most, if not ...

have an implication in the

aging Ageing (or aging in American English) is the process of becoming Old age, older until death. The term refers mainly to humans, many other animals, and fungi; whereas for example, bacteria, perennial plants and some simple animals are potentiall ...

process, and in ''C. elegans'' the lifespan - extending effect of long telomeres is dependent on DAF-16. DAF-2 mutations more than double the lifespan of ''C. elegans'', and this effect is dependent on the activity of DAF-16 as it encodes a member of the

hepatocyte A hepatocyte is a cell of the main parenchymal tissue of the liver. Hepatocytes make up 80% of the liver's mass. These cells are involved in: * Protein synthesis * Protein storage * Transformation of carbohydrates * Synthesis of cholesterol, bi ...

nuclear family 3 (HNF3)/ Forkhead family of

transcription factors In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fun ...

. ''C. elegans'' has long been used in aging research. Although DAF-16 increases longevity, treating ''C.elegans'' with

resveratrol Resveratrol (3,5,4′-trihydroxy-''trans''-stilbene) is a stilbenoid, a type of natural phenol or polyphenol and a phytoalexin produced by several plants in response to injury or when the plant is under attack by pathogens, such as bacterium, ba ...

extends lifespan in a method independent of DAF-16 and fully dependent on SIR2.1.

Interactions

DAF-16 is known to interact with: * RLE-1 * PRMT-1 * UNC-43 * TAX-6 * JNK-1 * FTT-2

History

In 1963

Sydney Brenner Sydney Brenner (13 January 1927 – 5 April 2019) was a South African biologist. In 2002, he shared the Nobel Prize in Physiology or Medicine with H. Robert Horvitz and Sir John E. Sulston. Brenner made significant contributions to wo ...

realised the success of biology was due to model organisms, and ''C. elegans'' has been widely used in research laboratories since. In 1998 the genome of ''C. elegans'' was completely sequenced and found to be a 97 megabase genomic sequence consisting of 19,000 genes, with 40% protein products having significant matches in other organisms. The DAF genes

and DAF-16 were discovered in the Thomas and Ruvkun labs, after isolating dauer-constitutive ''(DAF-c)'' mutants and dauer - defective mutants ''(DAF-d)''. Mutations in

and DAF-23 caused the dauer - constitutive phenotype, through activation of the dauer - defective genes DAF-16 and DAF-18. This showed that

and DAF-23 prevent dauer arrest by antagonising DAF-16 and DAF-18 Notable scientists involved in the initial and continued characterization of DAF-16-associated aging pathways: *

Cynthia Kenyon Cynthia Jane Kenyon (born February 21, 1954) 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 ...

Gary Ruvkun Gary Bruce Ruvkun (born March 26, 1952) 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 microRN ...

References

{{Dauer larva Caenorhabditis elegans genes Aging-related proteins