Loss of FLCN increases longevity in C. elegans

Several signalling pathways – namely the mTOR, HIF and insulin signalling pathways – are known to slow ageing and increase longevity under certain conditions. This is a topic of much research, and was discussed at the recent “Talks about TORCs” meeting mentioned in last week’s blog. A recent study by Gharbi et al. has now shown that FLCN also regulates longevity in the nematode worm, C. elegans.

As shown in our signalling diagram, VHL functions in similar pathways to FLCN and its loss has previously been shown to increase longevity in C. elegans (Mehta et al., 2009; Müller et al., 2009). With this in mind, Gharbi et al. decided to investigate whether the C. elegans homologue of FLCN, which they identified as F22D3.2, also regulates longevity. In two separate experiments, the authors used a deletion mutant and RNAi knock-down to ablate FLCN function in C. elegans. Both types of FLCN mutant lived for 25 days – an increase of 19% compared to wild type nematodes, which usually live for 21 days, demonstrating that the loss of FLCN increases longevity significantly.

Increased HIF signalling and reduced insulin signalling both increase longevity in C. elegans, Drosophila and mice (Leiser and Kaeberlein, 2010; Parrella and Longo, 2010). Thus, Gharbi et al. wanted to determine whether perturbation of either of these pathways was responsible for the increased lifespan observed in FLCN-null worms. RNAi inhibition of hif-1 ablated the increased longevity of FLCN-null worms, whilst RNAi inhibition of daf-2 and daf-16, components of the insulin signalling pathway, increased longevity by up to an additional 15 days. The authors hypothesised that the increased longevity seen was due to increased stress resistance and tested this by exposing worms to high temperatures (35oC) for up to ten hours. FLCN-depleted worms showed increased survival compared to wildtype worms under these conditions and, as in the longevity assays, the observed thermo-resistance required HIF signalling and not insulin signalling. Together, these data indicate that FLCN regulates longevity via HIF signalling and independently of insulin signalling.

FLCN-null worms in this study also displayed a mild developmental delay. FLCN can control cell cycling, as discussed here, suggesting it may be a dysregulation of this process causing the developmental delay observed in these worms. Indeed, as the lifespan of C. elegans is precisely 21 days under normal conditions, the delayed development and increased lifespan of FLCN-null animals could represent a generalised “slowing down” of cell division, growth and metabolism. Alternatively, as discussed in a previous blog, FLCN- null cells are known to escape apoptosis and thus the extended lifespan observed in these animals may be analogous to FLCN-depleted cells in BHD patients evading cell death and forming cysts and tumours. Additionally, autophagy, which is induced by HIF signalling, also regulates lifespan in C. elegans and has been shown to become dysregulated in polycystic kidney disease in mice and – as previously discussed – to require FLCN interacting protein 1 (FNIP1) in human embryonic kidney cells (Belibi et al., 2011; Schiavi et al., 2013; Zhang et al., 2008). Therefore, increased autophagy could also be responsible for the extended lifespan of FLCN-null nematodes.

Determining the exact mechanism through which FLCN deletion increases longevity in C. elegans is likely to shed light on mechanisms that contribute to tumour formation in BHD patients. Furthermore, lifespan may prove a useful readout to interrogate FLCN’s interactions with other genes, pathways or molecules in C. elegans, making it an informative model in which to investigate BHD.


  • Belibi F, Zafar I, Ravichandran K, Segvic AB, Jani A, Ljubanovic DG, Edelstein CL (2011). Hypoxia-inducible factor-1α (HIF-1α) and autophagy in polycystic kidney disease (PKD). American Journal of Physiology – Renal Physiology, 300 (5), 1235-43 PMID: 21270095
  • Gharbi H, Fabretti F, Bharill P, Rinschen M, Brinkkötter S, Frommolt P, Burst V, Schermer B, Benzing T, & Müller RU (2013). Loss of the Birt-Hogg-Dubé gene product Folliculin induces longevity in a hypoxia-inducible factor dependent manner. Aging cell PMID: 23566034
  • Leiser SF, Kaeberlein M (2010). The hypoxia-inducible factor HIF-1 functions as both a positive and negative modulator of aging. Biological Chemistry, 391 (10), 1131-7 PMID: 20707608
  • Mehta R, Steinkraus KA, Sutphin GL, Ramos FJ, Shamieh LS, Huh A, Davis C, Chandler-Brown D, Kaeberlein M (2009). Proteasomal regulation of the hypoxic response modulates aging in C. elegans. Science, 324 (5931), 1196-8 PMID: 19372390
  • Müller RU, Fabretti F, Zank S, Burst V, Benzing T, Schermer B (2009). The von Hippel Lindau tumor suppressor limits longevity. Journal of the American Society of Nephrology, 20 (12), 2513-7 PMID: 19797165
  • Parrella E, Longo VD (2010). Insulin/IGF-I and related signaling pathways regulate aging in nondividing cells: from yeast to the mammalian brain. The Scientific World Journal, 10, 161-77 PMID: 20098959
  • Schiavi A, Torgovnick A, Kell A, Megalou E, Castelein N, Guccini I, Marzocchella L, Gelino S, Hansen M, Malisan F, Condò I, Bei R, Rea SL, Braeckman BP, Tavernarakis N, Testi R, Ventura N (2013). Experimental Gerontology, 48 (2), 191-201 PMID: 23247094
  • Zhang H, Bosch-Marce M, Shimoda LA, Tan YS, Baek JH, Wesley JB, Gonzalez FJ, Semenza GL. Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. Journal of Biological Chemistry, 283 (16), 10892-903 PMID: 18281291

www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.

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