Our body is constantly being stressed. There’s nothing new about it and everybody seems to understand what it means. But I’d like to clarify what stress is from the biological point of view. The term stress stands for the negative effects including oxidation of macromolecules with free radicals, inflammation and infections, lack of nutrients, increase or decrease in temperature, light regime disturbance, impact of ionizing radiation. It all leads to damage on molecular and tissue levels. Our body has got the mechsnisms that protect us from this damage. It’s the mechanisms of stress resistance: DNA repair (the glossary is below), autophagy, proteasome activity, xenobiotic detox systems and anti-oxidant systems, heat shock factors, LON mitochondrial protease, methionine sulfoxide reductase, neuroendocrinological regulation of homeostasis.
A paper of extreme importance for fighting aging came out in the Nature journal on Thursday. A research group from Buck Institute lead by Professor Gordon Lithgow was able to prolong life of nematodes by 78% by adding one compound to the worms’ diet – a dye Thioflavin T. The authors showed that the effect of the dye was due to activation of stress resistance mechanisms, which lead to significant increase in median (60%) and maximum lifespan (43-78%). Thioflavin T is used to mark the amyloid protein aggregates in Alzheimer’s disease. Dr. Lithgow’s group showed that this compound regulates protein homeostasis, which leads to life extension in nematodes and improvement of their health later in life. The effect of Thioflavin T depends on autophagy, proteasomal functions, heat shock factor-1 (HSF-1) and transcription factor SNK-1. Both of these proteins play a role in response to stress in nemamtodes: HSF-1 triggers the production of heat shock proteins and SNK-1 takes part in neutralizing oxidative stress. So, Thioflavin T intensificates cellular stress response by activating signaling pathways dependant on HSF-1 and SNK-1, which lealds to misfolded protein stabilization and increased longevity.
This article proves the possibility to prolong life by activating stress resistance using chemical compounds simply added to the diet. There’s also some research where the positive effect on longevity was achieved by mutations in genes governing stress resistance. For example, the work of Dr. Alexey Moskalev, where they activated the DNA repair gene GADD45 and extended maximum lifespan of drosophilas by 77%. Right now it is necessary to identify the chemicals that would activate GADD45 genes in humans and develop drugs based on these compounds.
I’d like to highlight the need of creation of a new class of drugs – geroprotectors. Their distinctive feature is that not so much they will cure the already manifested diseases, as they will prevent them. And the most important part is that geroprotectors will extend our lives. In order for these drugs to be created it is necessary to fund research on activation of stress resistance genes and clinical trials of chosen chemical activators. Again, I’d like to stress that it is time to start clinical trial of geroprotectors.
Glossary:
DNA repair – restoration of damaged DNA structures
Autophagy – process of digestion of cellular components, including damaged proteins and organelles, in lysosomes
Proteasome – protein complex that degrades proteins in the end of their life cycle
Xenobiotics – foreign chemical compaound for an organism, like antibiotics
Heat shock proteins – class of protection proteins, which expression is increased upon high temperature or other stresses
LON Mitochondrial protease – enzyme that cleaves oxidized proteins in the mitochondrial matrix
Methionine sulfoxide reductase – enzyme that restores the oxidized proteins structure by turning methionine sulfoxide into methinine
Neuroendocrinal regulation of homeostasis – maintaining the equilibrium of the internal environment of the organism via the vegetative nervous and endocrine systems
HSF-1 – heat shock factor-1, triggers synthesis of heat shock proteins as a response to ovarious types of stress
Transcription factors – regulatory proteins that control the transfer of the information from the DNA to the mRNA molecules that recognize their target genes by binding to specific fragments of DNA
SNK-1 – transcription factor in nematodes that participates in protection from the oxidative stress
