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Regarding activation of HSF overexpression |
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HSF is a cellular heat shock factor. The so-called heat shock factor is a protein that can react to self-protection when the cell is hit by high temperature, toxins, and free radicals. It is also called heat shock protein. In the complete cell process, heat shock factors (collectively known as SHPs) have molecular chaperone functions, which can ensure the correct folding, polymerization, transport and signal transmission of proteins and maintain the stable conformation of proteins. (Gong Yan et al. 1) It bears a very important responsibility. As a heat shock factor, HSF1 has a very unique ability, that is, when its overexpression activity increases, it will promote the balance and integrity of the cell protein structure, and extend the lifespan by 22%. One theory is that ubiquilin-1 (ubql-1) is necessary for hsf-1 OE to extend lifespan. It is a multifaceted, conservative shuttle protein that is localized in the cytoplasm and nucleus, where they act as chaperones and are the strongest modifiers of hsf-1 OE lifespan. However, ubiquitin-1 does not promote longevity by altering general protein homeostasis capacity. Instead, it extends lifespan after HSF-1 overexpression by reducing NPL-4.1 levels and promoting mitochondrial network remodeling. Another statement is that HSF-1 is the main determinant of biological lifespan under non-stress physiological conditions. HSF-1 is required for lifespan extension associated with several longevity regulatory mechanisms, such as insulin/IGF-1-like signaling, target of rapamycin (TOR) signaling, and food deprivation (Hsu et al. 2003; Morley and Morimoto 2004; Steinkraus et al. 2008; Seo et al. 2013). Under normal physiological conditions, the transactivation potential of HSF-1 is restricted by several regulatory mechanisms that determine the context-dependent activation state of the HSF-1 protein (Anckar and Sistonen 2011; Gomez-Pastore et al. 2018). One of the negative regulators of HSF-1 is the evolutionarily conserved heat shock factor binding protein 1 (HSB-1) (Morimoto 1998); in C. elegans, HSB-1 physically associates with HSF-1 to form an inhibitory multiprotein complex (Satyal et al. 1998; Jiang et al. 2012). Interestingly, the formation of this HSF-1-inhibitory complex is not affected by heat stress, but is promoted by insulin/IGF-1-like signaling (Chiang et al., 2012), which is an evolutionarily conserved longevity regulatory pathway (Riera et al. 2016). Genetic ablation of hsb-1 leads to the dissociation of HSF-1 from this inhibitory complex and induces a significant extension of the lifespan of animals that are dependent on HSF-1 activity (Chiang et al. 2012). (Surojit Sural et al.) HSB1 is a negative regulator of HSF1. Inhibiting or eliminating HSB1 significantly extends lifespan. When HSF1 is independently activated, it leads to the dissociation from HSB1, the activity of HSF-1 increases, and the level of histone H4 in somatic tissues is increased during development, while H4 overexpression promotes the extension of lifespan. The complete process here is HSF1 (activation) - HSB1 (inhibition) - H4 (extend lifespan). However, we are unable to distinguish the differences between these identifications. We hope to get a unified understanding: activating HSF1 and increasing its activity can prolong life. Fortunately, there is no objection to this conclusion. So, what exogenous substances are used to activate HSF1? Rosolutamide, the Chinese name of which is Rosolutamide, is a curcumin analog that can activate Nrf1, Nrf2 and HSF1. However, it is still a medical experimental agent. Except for research units, individuals cannot obtain it. There is naturally a safety issue here. It must be excluded from use. According to relevant reports on the Internet, curcumin is the most suitable first choice. Because its ability to activate HSF1 is very clear, and it is easy to obtain and cheap. As for its low bioavailability, many manufacturers who sell this supplement have noticed that most curcumin capsules are added with guide enhancers such as piperine, and the utilization has been greatly improved. Of course, you can choose to use other supplements. For example, thioraphanine, pure white veratrum, 6 celastrol, etc., and even some studies have confirmed that some non-steroidal anti-inflammatory drugs (NSAIDs) can activate HSF1. There are so many activation channels, of course, it will give us many unexpected conveniences. But here comes another problem. On the one hand, research institutions have confirmed that HSF1 overexpression can prolong life. On the other hand, there are also many papers on cancer research pointing out that HSF1 is found in many cancer cells of the digestive system. The survival and metastasis of cancer cells seem to be inseparable from HSF1. This is an unavoidable problem. Before we thoroughly understand the relationship between HSF1 and cancer, we only need to know the relationship between HFS1 and life span, and there is no need to activate HSF1. Don't include it in the strategic means of intervening in life span.
https://lifescience.sinh.ac.cn/webadmin/upload/20114369.pdf https://www.nature.com/articles/s41467-024-54136-x https://www.nature.com/articles/nrm2938 https://pubmed.ncbi.nlm.nih.gov/22360389/ https://pmc.ncbi.nlm.nih.gov/articles/PMC6505166/ https://www.cell.com/cell-metabolism/fulltext/S1550-4131(15)00396-4 https://pubmed.ncbi.nlm.nih.gov/38506376/ |