Unpicking the Molecular Mechanisms Behind Age-Related Memory Loss

Original from: Technology Network

Forgetfulness and memory loss can be a normal part of aging, but can also signify the onset of dementia, one of the major causes of disability and dependency in old age.

With a rapidly aging global population where 1.4 billion people are predicted to be over 60 by 2030, understanding age-related memory decline could not be more critical. By unpicking the molecular mechanisms behind how we age, the hope is to prevent age-related memory loss and improve the quality of our lives in the later years.

A recent study conducted by Professor Ann Massie and her team from Vrije Universiteit Brussel, published in Molecular Psychiatry, may reveal clues into how to prevent age-related memory loss. Massie and her team identified that, surprisingly, the loss of a membrane transport protein – the antiporter system xc- – prevents memory loss during aging in mice.

Katie Brighton (KB): Can you highlight the importance of studying the physiological aging process?

Ann Massie (AM): Our life expectancy is rising steeply; we cannot avoid getting older, but we can try to avoid spending the additional years in poor health. Understanding the physiological aging process will give us clues for understanding the pathological aging process.

KB: Can you explain the function of system xc -, and what we know about this system so far?

AM: System xc -, with xCT as a specific subunit, is an antiporter that exports cystine in exchange for glutamate. The imported cystine will be reduced to cysteine, which can be used as a building block in the synthesis of glutathione, an important antioxidant.

In the brain, exported glutamate can modulate glutamatergic neurotransmission or, when present in excess, induce toxicity. Enhancement of system xc - could thus have a dual effect: increasing its activity might lead to a better defense system against oxidative stress but could also contribute to toxicity caused by glutamate excess in the brain. We and others have been unable to detect signs of increased oxidative stress in the brains of mice with a genetic deletion of the antiporter. However, we did previously identify this antiporter as an important source of extracellular glutamate in several brain regions.1,2 Several lines of evidence also highlighted a function of system xc - in driving neuroinflammation.3,4,5 Finally, we previously reported that genetic loss of system xc - results in protective effects in mouse models for epileptic seizures, epilepsy, some models for Parkinson’s disease etc.1,6,2,7

KB: What key technologies and methodologies did you adopt in this research study, and why?

KB: How does the function of system xc - differ between healthy and diseased brains? Does the function change as we age?

KB: The finding that an absence of system xc - improved brain function and memory in aging mice was described as “unexpected”. Why is this the case?

KB: Do you think that system xc - could provide a druggable target in future?

AM: We do believe that system xc - is a druggable target. However, at the time of writing, there are no specific inhibitors without off-target effects of system xc - that can be used in vivo.

KB: What are your next steps for progressing this research?

AM: We are currently exploring several pathways that are impaired by the aging process and that could be affected by system xc - deficiency. This will help us understand the mechanism or mechanisms underlying our observations and what molecular pathways might be crucial to maintaining our cognitive functions as we age.

Source: Unpicking the Molecular Mechanisms Behind Age-Related Memory Loss