Fight Aging!

Today's open access research reports on two specific epigenetic changes observed in old individuals that act to reduce mitochondrial function. This joins an existing list of genes for which expression changes are known to impact mitochondrial function with age. A herd of hundreds of mitochondria are found in every cell, working to provide the cell with a supply of energy store molecules used to power its operations. They are the distant descendants of ancient symbiotic bacteria, now fully integrated into the cell. Loss of mitochondrial function is strongly implicated in the progression of aging and age-related diseases, particularly in energy-hungry tissues such as the brain and muscle.

Proximately, this loss of function is caused by changes in the expression of regulatory or functional proteins. Epigenetic regulation shifts with age in characteristic ways, for reasons that remain debated. While there is a good list of root cause molecular damage that leads to aging, connect those root causes to specific changes in gene expression relevant to downstream problems is quite challenging. It will be the work of decades yet to fill in the grand map of the biochemistry of the detailed progression of aging. This is why it is important for the research community to identify plausible points of intervention now, wherein it is faster to test and observe the outcome than to wait for full understanding.

Epigenetic change may or may not be a plausible point of intervention in the matter of mitochondria and aging. Which of these outcomes is the case should be revealed in the years ahead, via ongoing work on in vivo cellular reprogramming. In the petri dish, the process of reprogramming resets epigenetic markers in old cells and restores mitochondrial function. The hope of groups such as Turn.bio is that this can be made to happen, safely, in vivo as well as in vitro. Comprehensively restoring mitochondrial function throughout the body is a valuable goal, given what is known of the role of mitochondria in aging.

In Aging, Epigenetic Wet Blanket Douses Mitochondria

Researchers have discovered that reining in the expression of two epigenetic regulators could extend the "healthspan" - as opposed to merely the lifespan - of worms and mice. The scientists studied BAZ-2 and SET-6, proteins that read and write epigenetic signals, respectively. They found that levels of both proteins ramp up with age in both species, in turn dampening expression of genes involved in mitochondrial function. The resulting metabolic slowdown put worms off their food and they mated less, and it hastened memory loss in old mice. What about orthologs of these epigenetic proteins in humans? Their levels increased in the brain with age, and correlated with progression of Alzheimer's disease. The study reinforces current thinking that mitochondria are key to aging.

How do BAZ-2 and SET-6 hasten aging? The researchers found that the two proteins together bind to promoter regions of more than 2,000 genes, dampening their expression via histone methylation. Among these target genes were numerous nuclear-encoded mitochondrial genes. Through their repression of these genes, BAZ-2 and SET-6 sapped oxygen consumption and ATP production, and bungled critical stress responses that maintain mitochondrial proteostasis. The researchers extended their nematode findings to mammals, reporting that orthologs of BAZ-2 and SET-6 dampened expression of key mitochondrial genes in cultured mouse and human cells. Knocking out BAZ-2 in mice assuaged age-related decline in brain metabolism, weight gain, and spatial memory loss, but did not extend lifespan.

Next, the researchers accessed a gene-expression dataset of human prefrontal cortex samples from the Harvard Brain Tissue Resource Center, including 376 from people with late-onset Alzheimer's disease and 173 from nondemented elderly. Among the samples from cognitively normal people, levels of human homologs of BAZ-2 and SET-6 increased with age. Among those with Alzheimer's disease, the proteins correlated with Alzheimer's disease progression, and with reduced expression of mitochondrial genes.

Two conserved epigenetic regulators prevent healthy ageing

Here we report a conserved epigenetic mechanism underlying healthy ageing. Through genome-wide RNA-interference-based screening of genes that regulate behavioural deterioration in ageing Caenorhabditis elegans, we identify 59 genes as potential modulators of the rate of age-related behavioural deterioration. Among these modulators, we found that a neuronal epigenetic reader, BAZ-2, and a neuronal histone 3 lysine 9 methyltransferase, SET-6, accelerate behavioural deterioration in C. elegans by reducing mitochondrial function, repressing the expression of nuclear-encoded mitochondrial proteins. This mechanism is conserved in cultured mouse neurons and human cells.

Examination of human databases shows that expression of the human orthologues of these C. elegans regulators, BAZ2B and EHMT1, in the frontal cortex increases with age and correlates positively with the progression of Alzheimer's disease. Furthermore, ablation of Baz2b, the mouse orthologue of BAZ-2, attenuates age-dependent body-weight gain and prevents cognitive decline in ageing mice. Thus our genome-wide RNA-interference screen in C. elegans has unravelled conserved epigenetic negative regulators of ageing, suggesting possible ways to achieve healthy ageing.