The Evolutionarily Conserved Longevity Determinants HCF-1 and SIR-2.1/SIRT1 Collaborate to Regulate DAF-16/FOXO

Abstract

The conserved DAF-16/FOXO transcription factors and SIR-2.1/SIRT1 deacetylases are critical for diverse biological processes, particularly longevity and stress response; and complex regulation of DAF-16/FOXO by SIR-2.1/SIRT1 is central to appropriate biological outcomes. Caenorhabditis elegans Host Cell Factor 1 (HCF-1) is a longevity determinant previously shown to act as a co-repressor of DAF-16. We report here that HCF-1 represents an integral player in the regulatory loop linking SIR-2.1/SIRT1 and DAF-16/FOXO in both worms and mammals. Genetic analyses showed that hcf-1 acts downstream of sir-2.1 to influence lifespan and oxidative stress response in C. elegans. Gene expression profiling revealed a striking 80% overlap between the DAF-16 target genes responsive to hcf-1 mutation and sir-2.1 overexpression. Subsequent GO-term analyses of HCF-1 and SIR-2.1-coregulated DAF-16 targets suggested that HCF-1 and SIR-2.1 together regulate specific aspects of DAF-16-mediated transcription particularly important for aging and stress responses. Analogous to its role in regulating DAF-16/SIR-2.1 target genes in C. elegans, the mammalian HCF-1 also repressed the expression of several FOXO/SIRT1 target genes. Protein–protein association studies demonstrated that SIR-2.1/SIRT1 and HCF-1 form protein complexes in worms and mammalian cells, highlighting the conservation of their regulatory relationship. Our findings uncover a conserved interaction between the key longevity determinants SIR-2.1/SIRT1 and HCF-1, and they provide new insights into the complex regulation of FOXO proteins.

CCAR‐1 is a negative regulator of the heat‐shock response in Caenorhabditis elegans

“…SIRT1‐regulated processes are also conserved in the worm and are mediated by SIR‐2.1. Worms expressing extra copies of sir‐2.1 exhibit increased longevity (Burnett et al, 2011; Rizki et al, 2011; Tissenbaum & Guarente, 2001; Viswanathan & Guarente, 2011). Also, enhancing sir‐2.1 activity through caloric restriction enhances the transcription of hsp‐70 (Raynes, Leckey, Nguyen, & Westerheide, 2012).…”

FOXOs and Sirtuins in Vascular Growth, Maintenance, and Aging

“…Among these are the Forkhead box "O" (FOXO) family of forkhead transcription factors as well as nicotinamide adenine dinucleotide (NAD ϩ )-dependent protein deacetylases termed sirtuins that have been described to prolong lifespan in worms and flies. 9,[11][12][13] Whereas the lifespan-extending effects of sirtuins have been challenged in recent studies, 14 it remains undisputed that FOXOs and sirtuins coordinate a wide range of cellular responses that are frequently deregulated during aging including metabolism, stress resistance, cell cycle progression, and programmed cell death. [15][16][17] Studies in the vascular system point to the vascular endothelium as a pivotal target tissue for the physiological functions of FOXO and sirtuin family members, where they control multiple facets of vessel development and function.…”

Folic acid supplementation at lower doses increases oxidative stress resistance and longevity in Caenorhabditis elegans

“…Life span extension in C. elegans through DR requires sir-2.1, and its increased dosage extends life span and stress resistance (Narasimhan et al 2009;Kenyon 2010;Rizki et al 2011;Viswanathan and Guarente 2011). We administered FA to sir-2.1(ok434) mutants, and did not notice any life span extension; also in real-time quantification experiments, 4.7-fold (Fig.…”