These GEITP pages have often discussed multifactorial traits — which reflect the contribution of genetic differences, epigenetic effects, environmental factors, endogenous influences, and each individual’s microbiome. Epigenetic effects are divided into DNA-methylation, RNA-interference, histone modifications, and chromatin remodeling. The attached paper describes epigenetic regulators in the roundworm, Caenorhabditis elegans, that prevent “healthy aging,” which is the (rather vague, in my opinion ☹) multifactorial trait being studied.
It is known that dopamine-signaling declines with age, and that higher dopamine levels in aged humans are associated with improved cognitive functions. In C. elegans, an age-related decline in level of BAS-1 protein (which has L-DOPA decarboxyolase activity encoded by the biogenic amine synthesis-related gene; this is orthologous to the human DDC (which encodes DOPA decarboxylase). Decline in BAS-1 levels results in the loss of these neurotransmitters and a behavioral deterioration —thus providing a genetically traceable marker of aging in the nervous system. Authors [see attached article] therefore performed a genome-wide RNA interference (RNAi) screen for “regulators of aging” by examining changes in the level of the BAS-1 protein in C. elegans. They used transgenic worms that express BAS-1 fused to green fluorescent protein (GFP), and individually fed the worms with bacteria expressing numerous double-stranded RNAs (dsRNAs) that correspond to roughly 80% of the total predicted genes in C. elegans. To enhance neuronal uptake of dsRNAs, authors introduced SID-1 — encoding a channel protein allowing dsRNA diffusion — into the nervous system of the transgenic worms.
After three rounds of testing, they obtained 59 screening hits that prevented an age-related diminution in the BAS-1 protein level; these genes coded for various protein classes — including nucleic-acid-binding proteins, receptors and transporters. Authors then performed gene-network analysis of the 59 screening hits, using GeneMANIA software and constructed a co-expression network that revealed interactions among individual genes and their partners. Authors found ten hits whose human orthologs are involved in age-related neurodegeneration or cell senescence. Next, authors examined whether the genes — corresponding to the screening hits — affected aging-related behavioral decline.
Among these epigenetic modulators, authors found that a neuronal epigenetic reader BAZ-2, and a neuronal histone-3-lysine-9-methyltransferase, SET-6, accelerate behavioral deterioration in C. elegans by lowering mitochondrial function,
repressing the expression of nuclear-encoded mitochondrial proteins; intriguingly, this mechanism is conserved in cultured mouse neurons and human cells. Examination of human databases showed that expression of the human orthologs of these C. elegans regulators, BAZ2B (bromodomain adjacent to zinc finger domain-2B) and EHMT1 (euchromatic histone lysine methyltransferase-1) — in the frontal cortex — increases with age and is correlated with progression of Alzheimer disease. Furthermore, ablation of Baz2b (the mouse ortholog of worm BAZ-2), attenuates age-dependent body-weight gain and prevents cognitive decline in aging mice. These data in the roundworm thus provide interesting evidence of conserved epigenetic negative regulators of aging, which in the distant future might help humans achieve “healthier aging” (the process of developing and maintaining functional abilities that enable ‘well-being’ during older age).
DwN
Nature 5 Mar 2020; 579: 118-122