7/7 In sum, hlh-30 mutation causes misalignment of nutrient cues and growth signaling, resulting in DNA damage & cellular senescence, which abrogates stem cell and organismal longevity. Cellular senescence is an evolutionarily ancient response to damage conserved even in C. elegans.

6/7 Together with Manuel Serrano’s group, we found that TFEB loss reduces survivorship in both embryonic and cancer diapause, and that TFEB and TGFβ signaling are regulated during diapause. Hence, targeting TFEB might undermine cancer dormancy and prevent relapse in vivo.

5/7 HLH-30 downregulates TGFβ signaling from neurons to germline stem cells, promoting stem cell quiescence upon ARD to safeguard against cellular senescence. Mutations in TGFβ signaling prevent senescence upon hlh-30/TFEB loss, restoring resilience and reproductive competence.

4/7 Genetic suppressor screens reveal mutations that disrupt TGFβ, cGMP and insulin/IGF signaling potently reverse hlh-30/TFEB collapse.

3/7 hlh-30/TFEB is a master regulator of ARD, whose loss leads to complete collapse during ARD and recovery. Mutants arrest in a novel senescent-like state never described before in worms, and germline stem cells show features strikingly similar to mammalian cellular senescence.

2/7 Worms fasted in late larval development progress to a sleep-like quiescent state called the adult reproductive diapause (ARD) and can survive for months without food. Upon refeeding they undergo restoration, regenerating germline, soma and reproduce.

3/7 hlh-30/TFEB is a master regulator of ARD, whose loss leads to complete collapse during ARD and recovery. Mutants arrest in a novel senescent-like state never described before in worms, and germline stem cells show features strikingly similar to mammalian cellular senescence.

2/7 Worms fasted in late larval development progress to a sleep-like quiescent state called the adult reproductive diapause (ARD) and can survive for months without food. Upon refeeding they undergo restoration, regenerating germline, soma and reproduce.

To sum up, hil-1/H1-0 is a critical mediator that reprograms epigenetic state in response to metabolic inputs. We believe studying refeeding after a prolonged fast can help elucidate adult organismal rejuvenation in a natural context.

Looking at the flip side of the coin, hil-1 is an equally important regulator of the refeeding response. Further enhancing the natural downregulation of hil-1 during refeeding by RNAi improved restoration, as measured by body size regrowth and functional muscle regrowth.

Loss of HIL-1/H1.0 reduced survival during prolonged fasting in C. elegans worms and in a human in-vitro model for nutrient restriction, suggesting that this epigenetic factor has a key role in promoting adaptation to quiescent and low nutrient states.

What regulates the fasting-refeeding switch? Unexpectedly, we found a linker histone regulated by nutrients and mTOR signaling, that promotes resilience during fasting and restoration upon refeeding. Its regulation is evolutionarily conserved, including in fasted human patients.

Rejuvenation of gene expression patterns also occurred in refed killifish, suggesting refeeding as a time window for age restoration from simple worms to vertebrates!

Can organisms reverse their biological age? In the worm C. elegans we found striking biological age restoration during refeeding after a prolonged fast, based on aging clocks! Fasting is usually linked to anti-aging, but our study points to the age-restorative role of refeeding.