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Unpicking the Molecular Mechanisms Behind Age-Related Memory Loss

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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.

In an interview with Technology Networks, Massie talks us through her research and explained why this finding was unexpected.


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?

AM: Given the very broad scope of this study, ample technologies have been used. To better understand how mice age in the presence and absence of system xc -, we analyzed the lifespan and performed extensive in vivo analyses on our mice. This includes grip strength measurements, blood analyses, glucose tolerance tests, clinical frailty analyses and even cognitive function using a specific maze, called the Barnes maze. With the latter we could observe that the cognitive function of mice that age in the absence of system xc - is preserved, contrary to “normal” mice. Given that system xc - is mainly expressed in the central nervous system and on cells of the immune system, we studied the differences in immune cell populations using flow cytometry and measured different markers of inflammation in the blood and in the hippocampus. We studied the morphology and functionality of the neurons in the hippocampus, using microscopy and slice electrophysiology, respectively. To try to understand the mechanism behind the observed differences in the hippocampus of adult and aged mice in the presence and absence of system xc -, a metabolomics analysis was performed that generated a detailed metabolic profile of the hippocampus of the different groups of mice.

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

AM: Even though there are no indications that the function, expression or activity of system xc - changes with age, the needs of the aging body/brain do change. For example, the deletion of system xc - can reduce extracellular glutamate levels in the aged brain, which could be beneficial as the glutamate removal might become less efficient with age, leading to a toxic build-up. Also, the reduced “priming” of the innate immune system as well as the metabolic changes in the hippocampus of aged mice with a genetic deletion of xCT, could contribute to the positive effects we have observed in the aged xCT-/- mice.

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?

AM: The fact that their lifespan is increased was the most unexpected finding, as the oxidative shift in the plasma cystine/cysteine ratio that was observed in 2005 by H. Sato and colleagues in the adult mice lacking the antiporter suggested that the aging process of these mice might be accelerated. 8 This hypothesis was based on the observation that in humans, a similar oxidative shift appears with age. 9 The memory preservation in the aged mice lacking system xc - was, however, the most exciting finding.

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.

Professor Ann Massie was speaking to Katie Brighton, Scientific Copywriter at Technology Networks.


1. De Bundel D, Schallier A, Loyens E, et al. Loss of system xc− does not induce oxidative stress but decreases extracellular glutamate in hippocampus and influences spatial working memory and limbic seizure susceptibility. J Neurosci. 2011;31(15):5792-5803. doi: 10.1523/JNEUROSCI.5465-10.2011

2. Massie A, Schallier A, Kim SW, et al. Dopaminergic neurons of system xc–-deficient mice are highly protected against 6-hydroxydopamine-induced toxicity. FASEB J. 2011;25(4):1359-1369. doi: 10.1096/fj.10-177212

3. Albertini G, Deneyer L, Ottestad-Hansen S, et al. Genetic deletion of xCT attenuates peripheral and central inflammation and mitigates LPS-induced sickness and depressive-like behavior in mice. Glia. 2018;66(9):1845-1861. doi: 10.1002/glia.23343

4. Sprimont L, Janssen P, De Swert K, et al. Cystine–glutamate antiporter deletion accelerates motor recovery and improves histological outcomes following spinal cord injury in mice. Sci Rep. 2021;11(1):12227. doi: 10.1038/s41598-021-91698-y

5. Mesci P, Zaïdi S, Lobsiger CS, et al. System xC− is a mediator of microglial function and its deletion slows symptoms in amyotrophic lateral sclerosis mice. Brain. 2015;138(1):53-68. doi: 10.1093/brain/awu312

6. Leclercq K, Liefferinge JV, Albertini G, et al. Anticonvulsant and antiepileptogenic effects of system xc− inactivation in chronic epilepsy models. Epilepsia. 2019;60(7):1412-1423. doi: 10.1111/epi.16055

7. Bentea E, De Pauw L, Verbruggen L, et al. Aged xCT-deficient mice are less susceptible for lactacystin-, but not 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine-, induced degeneration of the nigrostriatal pathway. Front Cell Neurosci. 2021;15:796635. doi: 10.3389/fncel.2021.796635

8. Sato H, Shiiya A, Kimata M, et al. Redox imbalance in cystine/glutamate transporter-deficient mice. J Biol Chem. 2005;280(45):37423-37429. doi: 10.1074/jbc.M506439200

9. Jones DP, Mody VC, Carlson JL, Lynn MJ, Sternberg P. Redox analysis of human plasma allows separation of pro-oxidant events of aging from decline in antioxidant defenses. Free Radic Biol Med. 2002;33(9):1290-1300. doi: 10.1016/S0891-5849(02)01040-7