Some of the popular media touted new April 2010 research as heralding the discovery of a new gene(e.g., AOL news(ref)), but what the new piece of research does is only add another perspective to a long-developing story on how the DAF-16 gene contributes to longevity in nematode worms, and possibly – only possibly – in higher organisms like us.
I have mentioned the DAF-16 gene in previous blog entries. See FOXO genes and protecting stem cells — What does resveratrol do?, Calorie restriction research roundup – Part II, and my comment MicroRNAs in cancers and aging, and back-to-the-nematode. It is an evolutionary-conserved gene belonging to what is called the forkhead family involved in the insulin/IGF-1 pathway and the response to calorie restriction and possibly to taking resveratrol. Most of the research on DAF-16 the gene has been on members of the Caenorhabditis family of nematodes, but since the related pathways seem to be evolutionary-conserved, have been thought possibly to apply to us as well.
For over 22 years it has been known that mutations in certain genes can drastically extend the lives of nematodes. For example, the 1988 publication A mutation in the age-1 gene in Caenorhabditis elegans lengthens life and reduces hermaphrodite fertility reports “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 degrees; at 25 degrees 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).” It was known back then that the IGF1 insulin-like signaling pathway was involved and that two other key genes involved on both longevity and reproduction of caenorhabditis elegans were DAF-2 and DAF-16(ref). So, forget the idea that DAF-16 is “a newly discovered gene.”
Identification of the potential life-expanding role of DAF-16 in C. elegans is evidenced in the 1993 paper A C. elegans mutant that lives twice as long as wild type: “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. — daf-2 and daf-16 provide entry points into understanding how lifespan can be extended.” Also, DAF-16 is discussed in the 1997 paper The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. The 2006 review article Worming pathways to and from DAF-16/FOXO summarizes the knowledge as of that time: “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). DAF-16 also receives input from several other pathways that regulate life span such as the germline and the JNK pathway –. JNK regulates lifespan in by modulating nuclear translocation of forkhead transcription factor/DAF-16. Therefore, DAF-16 integrates signals from multiple pathways and regulates its downstream target genes to control diverse processes. Here, we discuss the signals to and from DAF-16, with a focus on life span regulation.” So, DAF-16 has long been known to be involved in lifespan regulation in caenorhabditis elegans.
The new research
The this-week publication of interest is Phenotypic Covariance of Longevity, Immunity and Stress Resistance in the Caenorhabditis Nematodes. Basically, the research looked at four different members of the Caenorhabditis family of nematodes that have widely different levels of expression of DAF-16 and widely different disease resistance and longevities. Higher levels of expression of DAF-16 were found to be correlated with increased disease resistance and longevity. “It is known that lifespan varies significantly among the Caenorhabditis species but, although DAF-16 signaling is highly conserved, it is unclear whether this phenotypic linkage occurs in other species. Here we investigate this phenotypic covariance by comparing longevity, stress resistance and immunity in four Caenorhabditis species. — We show using phenotypic analysis of DAF-16 influenced phenotypes that among four closely related Caenorhabditis nematodes, the gonochoristic species (Caenorhabditis remanei and Caenorhabditis brenneri) have diverged significantly with a longer lifespan, improved stress resistance and higher immunity than the hermaphroditic species (C. elegans and Caenorhabditis briggsae). Interestingly, we also observe significant differences in expression levels between the daf-16 homologues in these species using Real-Time PCR, which positively correlate with the observed phenotypes. Finally, we provide additional evidence in support of a role for DAF-16 in regulating phenotypic coupling by using a combination of wildtype isolates, constitutively active daf-16 mutants and bioinformatic analysis.”
Going on, “The gonochoristic species display a significantly longer lifespan (p<0.0001) and more robust immune and stress response (p<0.0001, thermal stress; p<0.01, heavy metal stress; p<0.0001, pathogenic stress) than the hermaphroditic species. Our data suggests that divergence in DAF-16 mediated phenotypes may underlie many of the differences observed between these four species of Caenorhabditis nematodes. These findings are further supported by the correlative higher daf-16 expression levels among the gonochoristic species and significantly higher lifespan, immunity and stress tolerance in the constitutively active daf-16 hermaphroditic mutants(ref).”
So, an interspecies comparison among closely related nematodes establishes a correlation between expression level of DAF-16 and disease resistance/lifespan. It was already known that “In the nematode Caenorhabditis elegans, these phenotypes are molecularly linked such that activation of the forkhead transcription factor DAF-16 both extends lifespan and simultaneously increases immunity and stress resistance(ref).” The new research is interesting but, given what was already known, hardly earth shaking or even surprising.
Implications for humans of the new research are not completely clear. It appears that “sir-2.1 and daf-16 have both overlapping and distinct functions in regulation of C. elegans life span(ref).” But I have had difficulty finding any research directly related to DAF-16 in mice or rats, let alone in humans. Will resveratrol activate DAF-16 in humans? Probably not. A 2008 publication reports “Treatment of C. elegans with the small molecule resveratrol, however, extends life span in a manner fully dependent upon sir-2.1, but independent of daf–16.” So, it looks like it is going to be a while before implications in humans are known. First, we will have to hear about implications in mice.