Longevity Briefs: Ageing May ‘Spread Like An Infection’ From Cell-To-Cell

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Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

Why is this research important: Before anyone panics, being around older people will not make you age faster. However, there are ways in which a cell that has suffered age-related damage might promote similar damage in nearby cells. One outcome of damage thought to be fundamental to the ageing process is mitochondrial dysfunction.

As you’ve probably heard many times, the mitochondria are the power plants of the cell, responsible for converting nutrients from food into usable fuel. Mitochondria contain their own mitochondrial DNA that is kept separate from the rest of the human genome. Unfortunately, this mitochondrial DNA is not well protected and accumulates damage during ageing. As a result, an increasing proportion of mitochondria stop functioning correctly and produce inflammation-triggering free radicals.

Since the brain is an energy-hungry organ and vulnerable to inflammation, mitochondrial dysfunction in the brain may be particularly harmful and is thought to play an important role in neurodegenerative diseases like Parkinson’s disease.

What did the researchers do: In this study, researchers took brain samples from patients with sporadic Parkinson’s disease with dementia (sPDD) and analysed gene expression and molecular pathways in diseased neurons. They then generated mouse models of sPDD by deleting the gene for IFNβ (a protein that is deficient in sPDD patients), or by deleting the gene for its receptor.

Next, researchers extracted mitochondrial DNA from the neurons of sPDD mice and injected it into the brains of healthy mice. Some mice received injections of mitochondrial DNA from healthy mice as a control treatment.

Key takeaway(s) from this research:

Mouse neurons with mitochondrial dysfunction release damaged mitochondrial DNA
Injecting damaged mitochondrial DNA into the brains of healthy mice results in motor and cognitive deficits compared to controls
Toll-like receptors appear to be at least partly responsible for this link and targeting them is beneficial for diseased mice

As expected, post-mortem analysis of brain samples from sPDD patients revealed damage to mitochondrial DNA and defective IFNβ signalling. By deleting the gene encoding IFNβ or its receptor, researchers were able to create mouse models with a disease resembling sPDD. They found that neurons from such mice not only carried damaged mitochondrial DNA, but also released damaged mitochondrial DNA into their surroundings.

To investigate whether this released DNA might have a negative effect on other cells, researchers took damaged mitochondrial DNA from diseased mouse cells and injected it into the brains of healthy mice. They found that when compared to an injection of normal mitochondrial DNA, damaged mitochondrial DNA resulted in significantly worse cognitive function one month post-injection as well as other typical features of Parkinson’s disease. Damaged mitochondrial DNA also resulted in the death of neurons in cell culture.

Performance in various motor and cognitive tests for mice injected with saline (PBS), normal (mitochondrial) DNA (WT (mt)DNA) or mitochondrial DNA from diseased mice (KOmtDNA). E shows how long mice were able to maintain balance on a rotating rod before falling off. F shows how long it took for mice to climb to the top of a cylinder (so higher values are worse). G shows what percentage of mice succeeded in finding an object in a maze over time.
Mitochondrial DNA damage triggers spread of Parkinson’s disease-like pathology

Researchers also identified a potential mechanism for this effect, which hinges on a class of receptors called toll-like receptors (TLRs). TLRs are receptors that have evolved to detect various pathogens and trigger an inflammatory immune response. However, it appears from this study that some TLRs (specifically TLR9 and TLR4) are activated by damaged mitochondrial DNA, leading to a detrimental inflammatory response in the brain. The researchers also showed that inhibiting or genetically removing these receptors improved mitochondrial health in the diseased mouse model.

How can we apply this knowledge today: This research raises the possibility that we might one day treat Parkinson’s disease by targeting TLRs or mitochondrial dysfunction. However, we have to be cautious about drawing conclusions from mouse studies, especially when it comes to neurodegenerative diseases. Mice do not normally get Parkinson’s disease, so any mouse model of Parkinson’s must be somehow genetically or chemically induced, making it even further removed from the human disease than most animal models. The researchers did find evidence that TLR signalling was enhanced in human sPDD patients, but whether targeting these signals would prove beneficial remains to be tested.