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Mitochondrial sirtuins sir-2.2 and sir-2.3 regulate lifespan in C. elegans
Sarah M Chang1, Latisha P Franklin1, Sampurna Sattar1
1Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA 16802, United States.
Abstract:
Mitochondrial sirtuins regulate metabolism and are emerging drug targets for metabolic and age-related diseases such as cancer, diabetes, and neurodegeneration. Yet, the extent of their functions remains unclear. Here, we uncover a physiological role for the Caenorhabditis elegans mitochondrial sirtuins, sir-2.2 and sir-2.3, in lifespan regulation. Using genetic alleles with deletions that destroy catalytic activity, we demonstrate that sir-2.2 and sir-2.3 mutants live an average of 25% longer than controls when fed the normal lab diet of live E. coli OP50. While decreased consumption of food is a known mechanism for lifespan extension, we did not find evidence of reduced pharyngeal pumping. Interestingly, lifespan extension effected by loss of sir-2.2 or sir-2.3 is sensitive to the diet. The lifespan extension of the sir-2.2 mutants is eliminated and that of sir-2.3 mutants is attenuated when the animals are fed the E. coli strain HT115, which is typically used for RNAi experiments. We used growth ability of the food source and a virulent pathogenic strain to ask if differences in pathogenicity are related to the mechanisms for lifespan extension. sir-2.3 deletion results in lifespan extension in all conditions. However, removing the ability of the food source to grow eliminated the sir-2-mediated effect. We also examine the response of the mutants to oxidative stress, and our results suggest that a hormetic response contributes to lifespan extension in both mutants. Our data suggest that sir-2.2 and sir-2.3 use overlapping yet distinct mechanisms for regulating lifespan.
Insights
Mitochondrial sirtuins, sir-2.2 and sir-2.3, regulate lifespan in C. elegans. Loss of these proteins extends lifespan, with mechanisms influenced by diet and oxidative stress.
Area of Science:
- Cellular Biology
- Genetics
- Aging Research
Background:
- Mitochondrial sirtuins are key regulators of cellular metabolism.
- These enzymes are implicated in age-related diseases and are potential drug targets.
- The precise functions of mitochondrial sirtuins, particularly in lifespan regulation, require further elucidation.
Purpose of the Study:
- To investigate the physiological role of C. elegans mitochondrial sirtuins, specifically sir-2.2 and sir-2.3, in lifespan regulation.
- To determine the impact of genetic mutations affecting the catalytic activity of sir-2.2 and sir-2.3 on lifespan.
- To explore the influence of dietary conditions and oxidative stress on the lifespan-extending effects of sir-2.2 and sir-2.3.
Main Methods:
- Utilized genetic alleles with deletions in sir-2.2 and sir-2.3 to assess catalytic activity.
- Compared lifespan of mutant and control C. elegans fed different strains of E. coli (OP50 and HT115).
- Assessed pharyngeal pumping rates to rule out reduced food consumption as a lifespan mechanism.
- Investigated the role of food source growth ability and pathogenicity.
- Examined mutant responses to oxidative stress to understand hormetic effects.
Main Results:
- Mutants lacking functional sir-2.2 or sir-2.3 exhibited a significant lifespan extension (average 25%) on the standard OP50 diet.
- Lifespan extension was diet-dependent; it was abolished in sir-2.2 mutants and attenuated in sir-2.3 mutants fed HT115.
- Loss of sir-2.3 extended lifespan across conditions, but this effect was negated when the food source could not grow.
- A hormetic response to oxidative stress contributed to lifespan extension in both sir-2.2 and sir-2.3 mutants.
- sir-2.2 and sir-2.3 appear to regulate lifespan through both overlapping and distinct mechanisms.
Conclusions:
- C. elegans mitochondrial sirtuins sir-2.2 and sir-2.3 play a crucial role in lifespan regulation.
- The lifespan-extending effects of these sirtuins are modulated by diet composition and microbial growth.
- Hormesis, a response to oxidative stress, is a contributing factor to the observed lifespan extension.
- These findings highlight the complex interplay between mitochondrial sirtuins, metabolism, diet, and aging.
