New extraordinary longevity lessons from the nematode

Genetic lifespan regulation has been studied extensively in the nematode roundworm Caenorhabditis elegans (C-elegans) since the 1980s.  Hundreds of research papers have been written on this topic.  And I have generated a number of blog entries on longevity pathways known through nematode-based research, including calorie restriction, FOXO/DAF-16, IGF-1, SIRT1, and mTOR.  And important new studies adding to the knowledge in this area are continuing to appear in the literature.  One showed up only two days ago.  As a result of this collective research, genetic interventions are now known that can extend the lifespans of nematodes by a factor of about seven.  If this were true for people, we could live to the age of 570. 

This blog entry reports on recent findings not discussed in this blog  before related to the ETS and PDEF transcription factors, the AGE protein, TUBBY, WWP-1, and GATA activation factors.  A follow-up blog entry will deal with why nematode life extension has gotten so far during the last 20 years while, during the same period, there has been virtually no progress in creating significant life extension in humans. 

Before I get into the newer findings, I need to review what has been discovered over the years about nematode longevity as related to well-studied pathways.  In the process I will note a few benchmark points relating to life extension in C-elegans.   


Back in 1988 it was noticed that there is a gene called AGE-1 that, when mutated, extends the life of C-elegans by around 50% and longer in hermaphrodite worms.   As described in the publication A Mutation in the age-1 Gene in Caenorhabditis elegans Lengthens Life and Reduces Hermaphrodite Fertility,  “age-1(hx546) is a recessive mutant allele in Caenorhabditis elegans that results in an increase in mean life span averaging 40% and in maximal life span averaging 60% at 20{deg}; at 25{deg} age-1(hx546) averages a 65% increase in mean life span (25.3 days vs. 15.0 days) and a 110% increase in maximum life span (46.2 days vs. 22.0 days for wild-type hermaphrodites).” 

FOXO/DAF-16/IGF-1 pathway, insulin-like signaling  

A subsequent benchmark for radical life extension in C-elegans was telegraphed in a 1993 publication A C. elegans mutant that lives twice as long as wild type.  This time the FOXO/DAF-16/IGF-1 pathway was involved.  The FOXO transcription-factor protein DAF-16 is an important regulator of longevity that I have discussed in a number of previous blog postings and specifically in the April 2010 post Another piece of DAF-16 research.  According to the 1993 publication, “We have found that mutations in the gene daf-2 can cause fertile, active, adult Caenorhabditis elegans hermaphrodites to live more than twice as long as wild type. This lifespan extension, the largest yet reported in any organism, requires the activity of a second gene, daf-16. Both genes also regulate formation of the dauer larva, a developmentally arrested larval form that is induced by crowding and starvation and is very long-lived. Our findings raise the possibility that the longevity of the dauer is not simply a consequence of its arrested growth, but instead results from a regulated lifespan extension mechanism that can be uncoupled from other aspects of dauer formation.  Daf-2 and daf-16 provide entry points into understanding how lifespan can be extended.” 

It did not take researchers very long to figure out how to go from doubling nematode lifespans to nearly quadrupling it based on Daf mutations and associated modifications in insulin-like signaling.  The 1995 publication Genes that regulate both development and longevity in Caenorhabditis elegans reported: “The increased life spans are suppressed completely by a daf-16 mutation and partially in a daf-2; daf-18 double mutant. A genetic pathway for determination of adult life span is presented based on the same strains and growth conditions used to characterize Daf phenotypes. Both dauer larva formation and adult life span are affected in daf-2; daf-12 double mutants in an allele-specific manner. Mutations in daf-12 do not extend adult life span, but certain combinations of daf-2 and daf-12 mutant alleles nearly quadruple it. This synergistic effect, which does not equivalently extend the fertile period, is the largest genetic extension of life span yet observed in a metazoan.” 

As further outlined in the 2006 publication Worming pathways to and from DAF-16/FOXO “In Caenorhabditis elegans, the insulin/IGF-1 signaling pathway controls many biological processes such as life span, fat storage, dauer diapause, reproduction and stress response.  This pathway is comprised of many genes including the insulin/IGF-1 receptor (DAF-2) that signals through a conserved PI 3-kinase/AKT pathway and ultimately down-regulates DAF-16, a forkhead transcription factor (FOXO).”   See the publications An insulin-like signaling pathway affects both longevity and reproduction in Caenorhabditis elegans (1998),  Regulation of C. elegans life-span by insulinlike signaling in the nervous system(2000), and Insulin-like signaling, metabolism, stress resistance and aging in Caenorhabditis elegans(2001).   

MicroRNAs and EGF signaling 

The list of microRNAs and pathways implicated in C-elegans lifespans appears to be ever increasing(ref)(ref).  The August 2010 paper Novel EGF pathway regulators modulate C. elegans healthspan and lifespan via EGF receptor, PLC-gamma, and IP3R activation  reports “Further analysis revealed a potent role of EGF signaling, acting via downstream phospholipase C-gammaplc-3 and inositol-3-phosphate receptor itr-1, to promote healthy aging associated with low lipofuscin levels, enhanced physical performance, and extended lifespan. This study identifies HPA-1 and HPA-2 as novel negative regulators of EGF signaling and constitutes the first report of EGF signaling as a major pathway for healthy aging. Our data raise the possibility that EGF family members should be investigated for similar activities in higher organisms.” 


The TUBBY gene tub-1 is another that seems to play a critical role in nematode aging as described in the 2005 paper C. elegans tubby regulates life span and fat storage by two independent mechanisms.  “Here, we show that mutation in tub-1 also leads to life span extension dependent on daf-16/FOXO. Interestingly, function of tub-1 in fat storage is independent of daf-16. –. Taken together, we define a role for tub-1 in regulation of life span and show that tub-1 regulates life span and fat storage by two independent mechanisms.”  


The 2008 publication An elt-3/elt-5/elt-6 GATA Transcription Circuit Guides Aging in C. elegans identifies another piece of transcriptional circuitry and begins to clarify some of the major issues involved in nematode aging. “To define the C. elegans aging process at the molecular level, we used DNA microarray experiments to identify a set of 1294 age-regulated genes and found that the GATA transcription factors ELT-3, ELT-5, and ELT-6 are responsible for age regulation of a large fraction of these genes. Expression of elt-5 and elt-6 increases during normal aging, and both of these GATA factors repress expression of elt-3, which shows a corresponding decrease in expression in old worms. elt-3 regulates a large number of downstream genes that change expression in old age, including ugt-9, col-144, and sod-3. elt-5(RNAi) and elt-6(RNAi) worms have extended longevity, indicating that elt-3, elt-5, and elt-6 play an important functional role in the aging process. These results identify a transcriptional circuit that guides the rapid aging process in C. elegans and indicate that this circuit is driven by drift of developmental pathways rather than accumulation of damage.”  


There appears to be no end to discovery of critical new genes in nematodes that play a role in aging.  The 2010 publication WWP-1 is a novel modulator of the DAF-2 insulin-like signaling network involved in pore-forming toxin cellular defenses in Caenorhabditis elegans relates “Here we reveal that reduction of the DAF-2 insulin-like pathway confers the resistance of Caenorhabditis elegans to cytolitic crystal (Cry) PFTs produced by Bacillus thuringiensis. In contrast to the canonical DAF-2 insulin-like signaling pathway previously defined for aging and pathogenesis, the PFT response pathway diverges at 3-phosphoinositide-dependent kinase 1 (PDK-1) and appears to feed into a novel insulin-like pathway signal arm defined by the WW domain Protein 1 (WWP-1). In addition, we also find that WWP-1 not only plays an important role in the intrinsic cellular defense (INCED) against PFTs but also is involved in innate immunity against pathogenic bacteria Pseudomonas aeruginosa and in lifespan regulation. Taken together, our data suggest that WWP-1 and DAF-16 function in parallel within the fundamental DAF-2 insulin/IGF-1 signaling network to regulate fundamental cellular responses in C. elegans.”  Here we see an example of an important point:  the same pathway that confers longevity confers bacterial resistance and health. 


A very new publication, Sept 23 2010, ETS-4 is a Transcriptional Regulator of Life Span in Caenorhabditis elegans, points to yet another important set of transcription factors affecting nematode longevity. “Animal life span is regulated in response to developmental and environmental inputs through coordinate changes in gene expression. Thus, longevity determinants include DNA-binding proteins that regulate gene expression by controlling transcription. Here, we explored the physiological role of the transcriptional regulator, ETS-4, in the roundworm Caenorhabditis elegans. Our data showed that worms that lack ETS-4 lived significantly longer, revealing ETS-4s role in the transcription network that regulates life span. We identified 70 genes whose expression was modulated by ETS-4 that function in lipid transport, lipid metabolism and innate immunity. Some of the ETS-4-regulated genes were also controlled by two other regulators of aging, the FOXO and GATA factors. We concluded that a common set of transcriptional targets orchestrate the network of physiological factors that affect aging. ETS-4 is closely related to the human ETS protein SPDEF that exhibits aberrant expression in breast and prostate tumors. Because the genetic pathways that regulate aging are well conserved in other organisms, including humans, our findings could lead to a better understanding of SPDEF function and longevity regulation in mammals.”

The human ortholog of ETS-4 is SPDEF, quite possibly also a longevity determinant in us humans.  Interestingly, SPDEF may play an important role in preventing/treating cancers.  See PDEF is a negative regulator of colon cancer cell growth and migration, Prostate-derived Ets transcription factor (PDEF) downregulates survivin expression and inhibits breast cancer cell growth in vitro and xenograft tumor formation in vivo, Prostate-derived Ets transcription factor as a favorable prognostic marker in ovarian cancer patients and the 2010 paper PDEF and PDEF-induced proteins as candidate tumor antigens for T cell and antibody-mediated immunotherapy of breast cancer.   

I cannot begin here to cover the hundreds of additional papers on factors affecting C-elegans longevity.  Some researchers have been responsible for multiple discoveries related to nematode longevity over the years.  In particular, Cynthia Kenyon of the University of California, a lead author of the 1993 paper describing a doubling of nematode lifespans, has authored or co-authored some 80 relevant papers including these most-recent ones:

·         The somatic reproductive tissues of c. elegans promote longevity through steroid hormone signaling.

·         A pathway that links reproductive status to lifespan in Caenorhabditis elegans.

·         Widespread protein aggregation as an inherent part of aging in C. elegans. 

·         Insulin/IGF-1 signaling mutants reprogram ER stress response regulators to promote longevity.

·         Glucose shortens the life span of C. elegans by downregulating DAF-16/FOXO activity and aquaporin gene expression.

·         A transcription elongation factor that links signals from the reproductive system to lifespan extension in Caenorhabditis elegans.

·         Stimulation of movement in a quiescent, hibernation-like form of Caenorhabditis elegans by dopamine signaling

·         Regulation of the longevity response to temperature by thermosensory neurons in Caenorhabditis elegans.

·         A regulated response to impaired respiration slows behavioral rates and increases lifespan in Caenorhabditis elegans.

·         A role for autophagy in the extension of lifespan by dietary restriction in C. elegans.

·         Distinct activities of the germline and somatic reproductive tissues in the regulation of Caenorhabditis elegans’ longevity.

·         Tissue entrainment by feedback regulation of insulin gene expression in the endoderm of Caenorhabditis elegans.

·         DAF-16/FOXO targets genes that regulate tumor growth in Caenorhabditis elegans.

·         On why decreasing protein synthesis can increase lifespan.

·         Lifespan extension by conditions that inhibit translation in Caenorhabditis elegans.

·         A steroid hormone that extends the lifespan of Caenorhabditis elegans.

·         My adventures with genes from the fountain of youth.

·         Mutations that increase the life span of C. elegans inhibit tumor growth.

·         Worming pathways to and from DAF-16/FOXO.

·         Enrichment of regulatory motifs upstream of predicted DAF-16 targets. 

A list of many additional nematode-related publications coming from the Kenyon lab can be found here.  And oh yes, some of the nematodes living in Dr. Kenyon’s lab are now capable of living seven times as long as their normal wild-type counterparts.   From the Kenyon lab website  Quicktime movie of two active 144 day old worms. [normal life span 21 days]. 

Some lessons from the nematode

·        Very significant lifespan extension is possible in genetically complex organisms that share many common gene activation pathways with humans.

·        Well over a thousand genes affect aging or are age-regulated in nematodes and probably a larger number in humans.

·        Nematode studies strongly supports the hypothesis that aging is an extremely complex process involving the interactions of multiple pathways  and an immense number of genes and is not the result of accumulated damage, oxidative damage or other damage.  [My own theory is that the two smoking guns implicated in aging are accumulated epigenetic changes (e.g. in DNA methylation and histone acetylation) and exhaustion of the stem cell supply chain.  See my presentation Towards a Systems Theory of Aging offered at the 2009 American Aging Society meeting.]

·        C-elegans provides an excellent working model for examining how a limited number of transcriptional regulators can mediate to influence downstream aging  lifespan effector genes.

·        After twenty years of research, the job of studying longevity in nematodes is hardly complete.  Important new transcription factors, pathways and genes are still being identified.  In this blog entry I have been able to cover only highly-selected topics in the nematode research domain.

·        Metabolic regulation is essential for life extension.  The 2010 publication Regulation of metabolism in Caenorhabditis elegans longevity, reports “The nematode Caenorhabditis elegans is a favorite model for the study of aging. A wealth of genetic and genomic studies show that metabolic regulation is a hallmark of life-span modulation. A recent study in BMC Biology identifying metabolic signatures for longevity suggests that amino-acid pools may be important in longevity.”

·        There appear to be certain proteins that both extend longevity in nematodes and combat cancers in humans, ETS-3 and its human homolog SPDEF being a good example.  In general, factors that increase longevity do so by increasing healthspan.

·        In terms of regulation of aging-related genes, some genes act upstream of others, and downstream genes can be regulated by several different upstream pathways.  For example, the FOXO, GATA and Ets-4 transcription factors all regulate common genes.  In fact, it appears that Ets-4 functions in parallel to the insulin/IGF-1 receptor, daf-2 and akt-1/2 kinases. Many pathways impact on many genes to slow down/accelerate aging.  This explains why a similar pattern of age postponement (or acceleration) can be generated by quite different upstream interventions such as calorie restriction, feeding rapamycin, and knocking out of various gene combinations.

There is incredibly good life extension news, if you are happen to be a nematode. The following blog entry will examine why we have not been able to make similar progress with human life extension.

About Vince Giuliano

Being a follower, connoisseur, and interpreter of longevity research is my latest career. I have been at this part-time for well over a decade, and in 2007 this became my mainline activity. In earlier reincarnations of my career. I was founding dean of a graduate school and a university professor at the State University of New York, a senior consultant working in a variety of fields at Arthur D. Little, Inc., Chief Scientist and C00 of Mirror Systems, a software company, and an international Internet consultant. I got off the ground with one of the earliest PhD's from Harvard in a field later to become known as computer science. Because there was no academic field of computer science at the time, to get through I had to qualify myself in hard sciences, so my studies focused heavily on quantum physics. In various ways I contributed to the Computer Revolution starting in the 1950s and the Internet Revolution starting in the late 1980s. I am now engaged in doing the same for The Longevity Revolution. I have published something like 200 books and papers as well as over 430 substantive.entries in this blog, and have enjoyed various periods of notoriety. If you do a Google search on Vincent E. Giuliano, most if not all of the entries on the first few pages that come up will be ones relating to me. I have a general writings site at and an extensive site of my art at Please note that I have recently changed my mailbox to
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7 Responses to New extraordinary longevity lessons from the nematode

  1. admin says:


    Re the Russian guy with a super antioxidant, this is the third comment you hit me with recently regarding oxidative damage and longevity, the other two having to do with vitamin D and the long-lived petrel. I am reeling!

    My first reaction to the news item is skeptecism that a new powerful antioxidant could significantly increase human longevity because: 1. the body already has several powerful antioxidant defenses and we can supplement them with powerful antioxidant supplements like alpha-lipoic acid, co Q-10,curcumin, vit D, Resveratrol, etc. 2. while external antioxidant supplementation can provide many health benefits, numerous studies do not indicate that this strategy particularly increases lifespans, 3. The fact that significant lifespan extension can be realized through genetic manipilations (factor of 7 in nematodes) argues that maximum lifespan is programmed and not due to accumulated damage, oxidative or other.

    In other words, I have come to think that excessive oxidative damage can certainly shorten human lifespansn but no antioxidant defense can make them longer. So antioxidants are good and important to help us reach our genetically and epigenetically determined max. To raise the max, we need something else.

    As usual, I could be wrong about this. We will see.

    Incidentally, during the last couple of months I have been getting 3-10 new blog registrations a day from Russia,


  2. Res says:

    Hi Vince
    No. I dont think I am promoting the anti-oxidant thesis. I have something different in my mind.

    I think Vitamin D is the culprit. Let me clarify. First is the case of the Naked Mole rats who do not depend on the vitamin d to fix the calcium. The grow the teeth so fast and they have to constantly dig to reduce the size of their teeth. But they have no vitamin d in their body and they live 9 times more than similarly sized rodents. It is hypothesized that there might be someother vitamin d analogue that is produced by its own body with out the need of the sun to create the vitamin d.

    Second is the case of vitamin d overdose that is produced by the klotho gene and the symptoms are very similar to progeria.

    But there are many nocturnal animals and birds that do not come in the sun and have the same exact life span of the other animals. These nocturnal animals/birds have no rickets or vitamin d deficiency. If so, they would not have evolved at all.

    So here is my hypothesis. Vitamin D is a necessary part of the evil of aging. without the Vitamin D, humans cannot survive. But the very fact of the vitamin d in the metabolism produces the factors that should be implicated in the aging.

    There are animals that have developed the nocturnal behaviour fall in two categories. One that eat other animals to get their vitamin d. another set that are Naked mole rat and storm petrels that are having a vitamin d independent metabolism with a specific analog (let us say that is yet to be discovered)

    So the sunlight is the culprit. That is what is making us age. But the answer is the find the analog that is helping the storm petrels and nmrats to survive without the vitamin D.

    (So it may be true that the vampires are afraid of sunlight! 🙂 Now we know why 🙂

  3. Res says:

    Hi Vince,
    I think few more clarifications are in order.

    //second is the case of vitamin d overdose that is produced by the klotho gene and the symptoms are very similar to progeria.//

    it should read as
    //Second is the case of vitamin d overdose that is produced by the klotho gene absence and the symptoms are very similar to progeria.//


    //But there are many nocturnal animals and birds that do not come in the sun and have the same exact life span of the other animals.//

    the above live should read as
    //But there are many nocturnal animals and birds that do not come in the sun and have the same exact life span of the other animals of the same size.//

    But that is not true. The nocturnal animal, mammal, bat has 35 years life span. A small rodent of the same size would die in 4 years. Whereas the bat of the same size lives to 35 years.. almost 10 times the lifespan. It is probable the nocturnal bats have developed the similar sun light independent vitamin d metabolism.

  4. admin says:


    As to your two comments, thanks, the second makes answering the first a lot easier.

    I remember you commenting on my old blog entry What every vampire already knows – and something he doesn’t know. Now you are providing a second line of pro-vampire longevity science. Perhaps we are onto something!

    How interesting and impertinent to suggest that our hero Vitamin D may have a dark side as a shortivity substance! Another Dr. Jekyll and Mr. Hyde substance. I will look over the imminst blog for further information. I am interested in knowing:
    1. how we know they these creatures of the dark don’t make vitamin D? Clearly the naked mole rat does not get it from sunlight and does not frequent tanning bed salons.
    2. As you suggest, if they don’t use vitamin D, what do they use in its place or what alternative channels are activated?
    3. Do storm petrels only fly in the dark? If not, don’t they get plenty of sunlight and therefore possibly make vitamin D?

    It is interesting that storm petrels as well as naked mole rats breed in places with few or no predators for longegivity and freedom from predation seem to go together. And does the petrels’ monogomy free them from putting a lot of energy into dating and breeding and therefore help them live longer? I do understand that naked mole rat colonies are very hierarchical and, although they have few predators, colonies can go to war against each other. — Just random questions and thoughts that come up.


  5. admin says:


    This is the same response I have just given to another user. I have removed your comment entry because this is a non-commercial science blog. I cannot condone comments which advertise or promote products or services. If I wanted to I could probably realize a significant revenue stream from advertising. However, I have decided to keep the blog non-commercial and that includes comments. If you had anything significant to say about the science of your product Purity 12, that would possibly be a different matter. But simple personal testimonial is insufficient. This is not about the value of your product or service. It is about the integrity of the blog. If you would like to communicate with me further, please do it via my private e-mail


  6. New extraordinary longevity lessons from the nematode.. Corking 🙂

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