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In each of our cells there are hundreds of mitochondria, each containing copies of the mitochondrial genome. A mixture of mutant and healthy mitochondrial genomes is frequently observed both in rare mitochondrial diseases and also in many age-related diseases. This phenomenon is called heteroplasmy. Mutant genomes lead to faulty proteins that compromise the mitochondrial OXPHOS energy system.

We have identified small molecules that can reduce the number of mutant copies and increase the number of healthy, wild type copies, thus restoring the performance of the energy system. This rejuvenation process is triggered by the activation of biological pathways that already exist inside cells.

This effect can be observed in cells taken from patients with completely different diseases where the only common denominator is increased mutation in the mitochondrial genome. When mutant mtDNA genes are shifted to healthy (wild type) genes, we have been able to show a simultaneous increase in energy utilisation in the cell.

MITOCHONDRIAL DYSFUNCTION DRIVES TRANSCRIPTIONAL CHANGES

It’s been known for some time that cells adapt their transcriptional state and morphological shape in response to stressors. Examples of stressors include DNA damage, mitochondrial dysfunction, toxins, infections and vitamin or mineral deficits.

Picard & Wallace demonstrated in 2014 that increasing the level of pathogenic mitochondrial DNA mutations in a cell triggers an abrupt transcriptional reprogramming. They characterised four discrete states of cells, each with a distinctive morphology and transcriptional profile. Shifts between these states were triggered first at a level of 20%, then at 50% and finally at a 90% level of mutant mtDNA.

Fibroblasts also show a distinct morphology change in response to aging, with a substantial loss of dendrites and surface area.

MITOCHONDRIAL DYSFUNCTION DRIVES EPIGENETIC CHANGES

The discovery of the first highly-accurate aging biomarkers – epigenetic aging clocks – was a major breakthrough in anti-aging science, enabling scientists to interrogate ageing mechanisms and candidate interventions with unprecedented precision and speed.

In 2011, Bocklandt & Horvath at UCLA provided the first evidence that DNA methylation levels could generate an accurate biomarker of the human aging process. Two years later, Steve Horvath described a novel multi-tissue epigenetic clock for human ageing based on a set of 353 CpG markers. Wolf Reik went on to describe the first multi-tissue epigenetic clock for mouse ageing (2017). In 2021, a ‘Mammalian Methylation Consortium’ led by Steve Horvath described the first multi-tissue epigenetic clock for ageing processes conserved across all mammalian species.

This Mammalian Clock implicates multiple genes related to mitochondrial function, supporting the long-argued importance of this organelle in the aging process. We have demonstrated that acute mitochondrial dysfunction (an intracellular internal stressor) causes an acceleration of the epigenetic aging clock.

The background of Shift Bioscience’s founders in mitochondrial biology is leading us to new insights into the biological mechanisms that may underpin epigenetic aging clocks.

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