A recent Chinese study has identified two novel anti-aging targets that accelerate aging by suppressing the expression of genes involved in mitochondrial function maintenance: promoting metabolic slowdown.
For several years Longevity was believed to be associated with health, yet, despite the overall increase in human life expectancy in recent decades, it is often accompanied by health deterioration. Over the past decades, the role of genetics in lifespan and healthspan has become evident [1, 2]. However, little is known about the role of epigenetics in aging.
A recent study conducted at the Chinese Academy of Sciences in Shanghai has identified two epigenetic regulators of aging. The study involved experiments in the nematode Caenorhabditis elegans, a model organism that has been widely used in aging genetics research. The scientists identified BAZ-2 and SET-6 (BAZ2B and EHMT1 in humans) as critical regulators of healthy aging. This study was led by Dr Shi-Qing Cai and Dr Lubin Jiang and was published in February 2020 in the journal Nature .
… screening led to the identification of 59 genes, most of which encoded for proteins involved in epigenetic modifications …
The study involved a genome-wide RNA-interference screening of genes involved in health deterioration during aging in C. elegans. This screening led to the identification of 59 genes, most of which encoded for proteins involved in epigenetic modifications, which regulate gene expression without introducing any changes in the sequence of the genome.
Among these modulators, the neuronal epigenetic reader BAZ-2 and the neuronal histone SET-6 accelerated health deterioration in C. elegans by impairing the function of mitochondria. The researchers also found that the levels of these two proteins increase during aging in C. elegans and mice, resulting in a lower expression of genes that maintain mitochondrial function.
BAZ-2 and SET-6 regulate gene expression via different epigenetic mechanisms. SET-6 mediates the addition of epigenetic modifications (epigenetic writer), while BAZ-2 acts as “epigenetic reader” recognizing modified histones and recruiting proteins that regulate transcription.
The researchers found that BAZ-2 and SET-6 can regulate the expression of more than 2,000 genes, many of which are involved in mitochondrial function. By suppressing the expression of these genes, BAZ-2 and SET-6 reduce oxygen consumption and ATP production, impairing the health and behaviour of the worms. Importantly, ablation of Baz2b, the mouse orthologue of BAZ-2, prevented cognitive decline in aging mice.
This study provided strong evidence supporting the importance of epigenetic regulation of aging and suggested that BAZ-2 and SET-6 are novel anti-aging targets.
This study provided strong evidence supporting the importance of epigenetic regulation of aging and suggested that BAZ-2 and SET-6 are novel anti-aging targets. Although the expression of these epigenetic proteins increases with age in humans and is associated with cognitive decline in patients with Alzheimer’s disease , further studies are required to uncover the relevance of epigenetic modulations in aging in humans and how to translate this into interventions that promote healthy aging.