The TFEB orthologue HLH-30 regulates autophagy and modulates longevity in Caenorhabditis elegans

Abstract

Autophagy is a cellular recycling process that has an important anti-aging role, but the underlying molecular mechanism is not well understood. The mammalian TFEB was recently shown to regulate multiple genes in the autophagy process. Here we show that the predicted TFEB orthologue HLH-30 regulates autophagy in Caenorhabditis elegans and, in addition, has a key role in lifespan determination. We demonstrate that hlh-30 is essential for the extended lifespan of Caenorhabditis elegans in six mechanistically distinct longevity models, and overexpression of HLH-30 extends lifespan. Nuclear localization of HLH-30 is increased in all six Caenorhabditis elegans models and, notably, nuclear TFEB levels are augmented in the livers of mice subjected to dietary restriction, a known longevity-extending regimen. Collectively, our results demonstrate a conserved role for HLH-30 and TFEB in autophagy, and possibly longevity, and identify HLH-30 as a uniquely important transcription factor for lifespan modulation in Caenorhabditis elegans.

A salicylic acid derivative extends the lifespan of Caenorhabditis elegans by activating autophagy and the mitochondrial unfolded protein response

“…To further confirm these results, we next treated mutants that were either lacking or overexpressing the transcription factor hlh‐30 . These worms are known to be impaired for autophagy or to display constitutively increased autophagy levels, respectively (Lapierre et al, 2013). In the two cases, C8‐SA lost its capacity to increase lifespan (Figure 5g,h).…”

The role of protein clearance mechanisms in organismal ageing and age-related diseases

“…TFEB/HLH-30 induces many autophagy and lysosomal-related genes 150 . However, the longevity phenotype induced by TFEB/HLH-30 is caused by increased lysosomal lipolysis and might be independent of proteostasis 149,151 .…”

“…Furthermore, an increase in the levels of LAMP-2A prevents ageing-associated dysfunctions in the liver of old mice 148 . In C. elegans, enhanced autophagy via overexpression of the basic helix-loop-helix (HLH) transcription factor EB (TFEB) extends lifespan 149 . TFEB/HLH-30 induces many autophagy and lysosomal-related genes 150 .…”

Nuclear hormone receptors as mediators of metabolic adaptability following reproductive perturbations

“…7,[20][21][22] Multiple lines of evidence have indicated that these factors link lipid metabolism to reproductive stimuli and aging. DAF-16/FOXO3A, TCER-1/ TCERG1, SKN-1/NRF2 and DAF-12/FXR targets include lipid-metabolic genes, 15,19,20,[23][24][25] PHA-4/ FOXA-and HLH-30/TFEB-mediated enhancement of autophagy contributes to increased lipase activity 17,18 and NHR-80/HNF4 promotes fatty-acid desaturation in long-lived, GSC-less adults. 21 However, the generegulatory network (GRN) in which these factors operate is poorly defined and it remains unclear how their activities allow an animal to not only survive the physiological disruption created by loss of GSCs but to convert it into a beneficial enhancement of health and lifespan.…”

“…These conserved proteins are essential for the longevity of GSC-less animals and include DAF-16/FOXO3A, TCER-1/TCERG1, PHA-4/FOXA, HLH-30/TFEB, HSF-1/HSF1, SKN-1/ NRF2. 7,[15][16][17][18][19] Additionally, three members of the nuclear hormone receptor (NHR) family of transcription regulators, DAF-12/FXR, NHR-80/HNF4 and NHR-49/PPARa are important for GSC-less longevity. 7,[20][21][22] Multiple lines of evidence have indicated that these factors link lipid metabolism to reproductive stimuli and aging.…”