Why So Much C. elegans Aging Research is Bunk...

[Michael R]

As I've indicated many times in the past, one should ignore studies on interventions in aging in nematode worms (C. elegans), fruitflies (Drosophila), and all other non-mammalian species: they age and anti-age too differently to be given any credence until at least translated into mice. One of the most remarkable broad categories of such findings is the remarkable number of "hormetic" interventions reported to increase maximum LS in C. elegans, despite the fact that no such interventions with the pseudo-exception of CR have done so in mice. A remarkable new study turned up in a professional-oriented science news outlet by Al Pater finally gets to the bottom of this: it's not just (as I had assumed) an interspecies difference, but a freakin' experimental artifact!
 
Apparently, researchers performing LS studies in C. elegans routinely dose the animals with low levels of 5-fluorodeoxyuridine (FUdR), a drug usually used in chemotherapy as an alternative to  5-fluorouracil, "a thymidylate synthase (TS) inhibitor. Interrupting the action of this enzyme blocks synthesis of the pyrimidine thymidine, which is a nucleoside required for DNA replication." By interfering with cells' ability to replicate their DNA, these drugs drugs work to shut down cancer by preventing them from replicating — and ferocious, unregulated cell replication is the very definition of cancer. Of course, many kinds of normal cells have occasional need to replicate too, which is why you get the awful side-effects of these drugs.
 
Well, apparently (and I assume that my eyeballs must at least have passed over this info on a few occasions, but it never registered — I probably figured "those worm guys know what they're doing"), FUdR is also routinely used at low dose to sterilize the worms and prevent them from laying eggs, both because the new "born" C. elegans mess up their worm counts when they later conduct survival studies, and because reproduction itself reduces the lifespan of C. elegans. This has been thought harmless because FUdR
 

has a negligible impact on C. elegans lifespan under standard conditions (Mitchell et al., 1979). [but] Several laboratories have reported that FUdR has hormetic effects on C.elegans lifespan in specific genetic backgrounds/culture conditions (Aitlhadj and Stürzenbaum, 2010; Angeli et al., 2013; Mitchell et al.,1979; Van Raamsdonk and Hekimi, 2011). Additionally, FUdR treatment increases C. elegans resistance to environmental and cellular stressors, but the site of FUdR action is disputed and the precisemechanism of FUdR action is unclear (Angeli et al., 2013; Feldmanet al., 2014; Mendenhall et al., 2009; Miyata et al., 2008; Rooneyet al., 2014).

We report that hypertonic stress [a classic "hormetic" intervention repeatedly reported to increase LS in C. elegans] in combination with FUdR treatment or inhibition of the FUdR target thymidylate synthase, TYMS-1, extends C. elegans lifespan by up to 30% [as previously reported by many investigators, without specifically mentioning the use of FUdR as an experimental condition -MR]. By contrast, in the absence of FUdR, hypertonic stress decreases lifespan.

Adaptation to hypertonic stress requires diminished Notch signaling and loss of Notch co-ligands leads to lifespan extension only in combination with FUdR.

Either FUdR treatment or TYMS-1 loss induced resistance to acute hypertonic stress, anoxia, and thermal stress. [Mild thermal stress has also been reported to increase LS in these organisms]. FUdR treatment increased expression of DAF-16 FOXO and the osmolyte biosynthesis enzyme GPDH-1. [MR: As many of you will be aware, daf-16 is the target of daf-2, the ortholog of IGF-1 in C. elegans: when daf-2 is present at normal levels, it represses the activity of daf-16. Either inhibiting daf-2 (which in turn "liberates" daf-16 activity) or increasing expression or activity of daf-16 by any number of mechanisms has been repeatedly reported to increase LS in these organisms, with parallel findings in orthologs in other genera (multiple IGF-1 pathway mutants in mice; paralels in CR; parallels in human extreme survivors].

FUdR-induced hypertonic stress resistance was partially dependent on sirtuins and base excision repair (BER) pathways, while FUdR-induced lifespan extension under hypertonic stress conditions requires DAF-16, BER, and sirtuin function.

Combined, these results demonstrate that FUdR, through inhibition of TYMS-1, activates stress response pathways in somatic tissues to confer hormetic resistance to acute and chronic stress. C. elegans lifespan studies using FUdR may need re-interpretation in light of this work.(1)

That may be the biggest understatement to appear in a scientific abstract since Watson and Crick's "It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material" in their landmark paper proposing the double helical structure of DNA as the structural basis of genetic inheritance (Nature 171: 737-738 (1953)).
 
Even studies in mice don't always translate directly to humans -- look at all the failed cancer drugs that cure the disease in mice -- but they're a much better start. Now we know one more massive reason why.
 
Reference
1: Anderson EN, Corkins ME, Li JC, Singh K, Parsons S, Tucey TM, Sorkaç A, Huang H, Dimitriadi M, Sinclair DA, Hart AC. C. elegans lifespan extension by osmotic stress requires FUdR, base excision repair, FOXO, and sirtuins. Mech Ageing Dev. 2016 Mar;154:30-42. doi: 10.1016/j.mad.2016.01.004. Epub 2016 Feb 22. PubMed PMID: 26854551.