What everyone wants is to live a long life. However, whilst already living longer, we have realized that longevity is of little value when associated with diseases and disability. As a result, we intensely search for interventions that can extend life and improve its quality.
In my former blog entry, I wrote about epigenetic diets that are proposed to supply the organism with nutrients that influence the epigenome and, supposedly, delay epigenetic drift. Today I will briefly discuss what is known about the epigenetic effect of a calorie restriction diet, without malnutrition and/or a micronutrient deficiency.
Limitation of calorie intake by 20-30% compared to usual intake was found to significantly extend the life of rodents, yeast, C. elegans, D. melanogaster, and potentially primates . In mammals, such a diet was also found to lower the risk of obesity, cardiovascular disease, cancer, inflammation, and neurodegenerative diseases (shown in 1 and 2).
The mechanisms by which caloric restriction (CR) exerts its health-promoting effect are multiple and include modifications of the epigenome. For example:
- A reduction in calories attenuates age-associated changes in the expression of DNMTs, increases the activity of HDAC and affects the expression of various miRNAs.
- It also changes the gene methylation profile, e.g. HRAS and reduces the MYC hypomethylation observed in aging mice. RNA-seq data from the rat cerebral cortex showed that miR-98-3p (overexpressed during CR) alters HDAC and HAT activities .
The best established link between CR and epigenetic modifications is represented by sirtuins. Amongst the seven mammalian sirtuins, the most studied within the context of aging are SIRT1, SIRT3 and SIRT 6. The expression of sirtuins increases during CR and is associated with prolonged lifespan in model organisms. This effect is confirmed by the lack of CR-associated lifespan extension in the absence of these proteins.
The newest data has suggested that a restriction of only 10% might be enough to delay/prevent a number of age-related diseases.
The role of sirtuins in CR seems to be crucial due to their interaction with a variety of proteins such as PGC-1α, p53, LXR, FOXO family and NF-κB. The deacetylation of FOXO increases downstream gene expression. Whilst, the deacetylation of NF-κB results in the inhibition of its pro-inflammatory action.
In summary, CR is, so far, the only intervention with well proven beneficial effect on healthspan and lifespan. Fortunately for us, the newest data has suggested that a restriction of only 10% might be enough to delay/prevent a number of age-related diseases or to alleviate their course. However, a 20-30% restriction might be necessary to extend the length of life.