Unraveling the molecular mechanisms behind age-related memory loss

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

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

A recent study conducted by Professor Anne Massey and her team at the Vrije Universiteit Brussel, published in Molecular psychiatry, may reveal clues about how to prevent age-related memory loss. Massey and her team found that, surprisingly, the loss of a membrane transport protein — the antiporter system xc- — prevented memory loss during aging in mice.

In an interview with technological networks, Massey tells us about his research and explains why this finding was unexpected.

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

Anne Massey (AM): Our life spans are skyrocketing; we can’t avoid getting older, but we can try to avoid spending the extra years in poor health. Understanding the process of physiological aging will give us clues to understanding the process of pathological aging.

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

in the morning: The xc – system, with xCT as a specific subunit, is an antiporter that exports cystine in exchange for glutamate. The ingested 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, cause toxicity. Improving the xc – system may have a dual effect: increasing its activity may lead to a better defense system against oxidative stress, but may also contribute to toxicity caused by excess glutamate in the brain. We and others failed to detect signs of increased oxidative stress in the brains of mice with a genetic deletion of the antiporter. However, we have previously identified this antiporter as an important source of extracellular glutamate in several brain regions.1,2 Several lines of evidence have also highlighted the function of the xc – system in promoting neuroinflammation.3,4,5 Finally, we previously reported that genetic loss of the xc – system results in protective effects in mouse models for epileptic seizures, epilepsy, some Parkinson’s disease models, etc.1,6,2,7

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

in the morning: Given the very broad scope of this study, ample technology was used. To better understand how mice age in the presence and absence of the xc – system, we analyzed lifespan and performed extensive in vivo analyzes of our mice. This includes measuring grip strength, blood tests, glucose tolerance tests, clinical analyzes of weakness and even cognitive function using a specific maze called the Barnes maze. With the latter, we can observe that the cognitive function of mice that age in the absence of system xc – is preserved, in contrast to “normal” mice. Given that the xc – system is mainly expressed in the central nervous system and on cells of the immune system, we investigated differences in immune cell populations using flow cytometry and measured various markers of inflammation in the blood and in the hippocampus. We investigated the morphology and functionality of 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 the xc- system, a metabolomic analysis was performed that generated a detailed metabolic profile of the hippocampus of the different groups of mice.

KB: How does xc system function differ between healthy and diseased brains? Does function change with age?

in the morning: Although there is no indication that the function, expression, or activity of the xc – system changes with age, the needs of the aging body/brain do. For example, deletion of the xc − system may reduce extracellular glutamate levels in the aged brain, which may be beneficial because glutamate removal may become less efficient with age, leading to toxic accumulation. Also, reduced “priming” of the innate immune system as well as metabolic changes in the hippocampus of adult xCT genetic deletion mice may contribute to the positive effects we observe in adult xCT-/- mice.

KB: The finding that the lack of system xc – improved brain function and memory in aging mice has been described as “unexpected”. Why is that?

in the morning: The fact that their lifespan was increased was the most unexpected finding, since the oxidative change in the plasma cystine/cysteine ​​ratio observed in 2005 by H. Sato and colleagues in aged antiporter-deficient mice suggested that the process of aging of these mice may be accelerated. 8 This hypothesis is based on the observation that in humans a similar oxidative shift occurs with age. 9 However, the preservation of memory in the old mice lacking system xc was the most exciting finding.

KB: Do you think the xc system could provide an anesthetic target in the future?

in the morning: We believe that the xc – system is an anesthetizable target. However, at the time of writing, there are no specific inhibitors without adverse effects of the xc system – that can be used in vivo.

KB: What are your next steps for moving this research forward?

in the morning: We are currently investigating several pathways that are disrupted by the aging process and that may be affected by system xc – deficiency. This will help us understand the mechanism or mechanisms underlying our observations and what molecular pathways may be critical to maintaining our cognitive functions as we age.

Professor Ann Massey spoke to Katie Brighton, Science Copywriter at Technology Networks.


1. De Bundel D, Schallier A, Loyens E, et al. Loss of system xc− does not induce oxidative stress but reduces hippocampal extracellular glutamate and affects 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 attenuates LPS-induced disease and depression-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. Deletion of the cystine-glutamate antiporter accelerates motor recovery and improves histological outcomes after 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. The xC− system is a mediator of microglial function and its deletion delays symptoms in mice with amyotrophic lateral sclerosis. 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 xc− system inactivation in models of chronic epilepsy. epilepsy. 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 to lactacystin-, but not 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-, induced degeneration of the nigrostriatal pathway. Anterior cell neurons. 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 the prooxidant events of aging from the decline in antioxidant defenses. Free Radical Biol Med. 2002; 33 (9): 1290-1300. doi: 10.1016 / S0891-5849 (02) 01040-7

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