Sestrin 1 is Required for Calorie Restriction to Extend Life in Nematode Worms – Fight Aging!

A common approach taken by researchers when investigating how a specific aspect of cellular biochemistry functions is to disable genes one by one to observe whether they are necessary or not. This isn’t exactly straightforward, as cells typically have several ways of achieving a given goal, and removing one of those ways may or may not appear to do anything, depending on how exactly the researcher chooses to measure the outcome. This is the curse of engaging with complex systems. Nonetheless, sometimes one does find that one gene is critical, and that usually helps to advance the understanding of how the biochemistry of interest functions.

Today’s open access paper is an example of this sort of research applied to calorie restriction, an incremental advance in the understanding of how beneficial effects result from a lowered calorie intake. Calorie restriction induces the activation of cell maintenance processes to produce improved resilience, health, and longevity. This response to starvation evolved very early in the history of life on earth, and is thus remarkably similar in organisms ranging from yeast to worms to mice to humans. In all of these species, it produces sweeping changes to the operation of cellular biochemistry, making it a challenge to pick out the controlling mechanisms and important outcomes. Over the years, researchers have established that autophagy is required for calorie restriction to extend life, and have identified some important regulatory genes, such as mTOR.

There is much left to discover. But it seems plausible that this sizable focus of research, and the development of calorie restriction mimetic drugs that follows, will be only a footnote to the future extension of the healthy human life span. Calorie restriction has nowhere near the same effect on longevity in long-lived species as it does in short-lived species. Calorie restricted mice can live as much as 40% longer, but humans probably gain only a few years in the same circumstances. Why this is the case remains an open question, but it may be that long-lived species are long-lived because they already possess most of the metabolic improvements induced by the practice of calorie restriction in short-lived species.

Sesn-1 is required for lifespan extension during caloric deprivation in C. elegans through inhibition of mTORC1 and activation of autophagy

Sestrins were identified two decades ago as stress-responsive proteins that play an important role in regulating cellular homeostasis. Vertebrate genomes showcase three Sestrin genes (SESN1-3), while invertebrates feature just one. Numerous stressors, ranging from hypoxia and oxidative stress to DNA damage and nutrient deprivation, induce Sestrin expression in mammalian cells. The orchestration behind this expression involves several transcription factors, notably p53, FOXO, ATF4, and NRF2. Highlighting evolutionary conservation, the same signalling pathways trigger the activation of dSesn in D. melanogaster. Consequently, Sestrins play pivotal roles in the regulation of cellular viability under various stress conditions, such as hypoxia, oxidative stress, DNA damage, and glucose deprivation.

Earlier research from our team established Sestrins as antioxidant proteins that play a critical role in inhibiting the mechanistic target of rapamycin complex 1 (mTORC1) kinase. mTORC1 is an intricate environmental sensor that integrates signals from nutrients, growth factors, and stresses to regulate cell fate decisions. Remarkably, mTORC1 plays a key role in lifespan and aging regulation across various species. Application of specific mTORC1 inhibitors, like rapamycin, has been shown to enhance lifespan in different organisms from yeast to mice. Similarly, caloric restriction (CR), a well-documented longevity enhancer across many species, also represses mTORC1 activity, further cementing the role of this kinase in aging control.

This study aimed to elucidate the influence of the sesn-1 gene on lifespan modulation during caloric restriction (CR) in the nematode model organism C. elegans. Our findings reveal that sesn-1 mediates lifespan extension under CR, primarily through the repression of mTORC1 kinase and activation of autophagy. Moreover, we identified an essential role for sesn-1 in enhancing stress resilience in nematodes, particularly in the context of nutrient sensing. Further investigations demonstrated sesn-1’s interaction with the GATOR2 protein complex, its role in maintaining muscle integrity and a potential synergy between sesn-1 and the FOXO pathway. Overall, our research underscores the profound implications of Sestrins in aging and stress resistance, shedding light on possible therapeutic avenues for prevention and treatment of age-associated disorders.