Menopause linked to grey matter loss in key brain regions

 

New findings from the University of Cambridge suggest that menopause is associated with changes in brain structure, along with higher levels of anxiety, depression, and sleep difficulties. Researchers found reduced grey matter volume in several important brain regions among women who had gone through menopause.

The study, published in Psychological Medicine, also examined the effects of hormone replacement therapy (HRT). While HRT did not appear to prevent these brain or mental health changes, it was associated with a slower decline in reaction speed.

Understanding Menopause and Its Symptoms

Menopause marks the stage of life when a woman's menstrual periods permanently stop due to declining hormone levels. It most commonly occurs between ages 45 and 55 and is often accompanied by symptoms such as hot flushes, low mood, and disrupted sleep. Previous research has also linked menopause to changes in cognitive abilities, including memory, attention, and language.

To help manage menopause related symptoms, particularly depression and sleep problems, many women are prescribed HRT. In England, 15% of women were prescribed HRT in 2023. Despite its widespread use, scientists still have limited insight into how menopause and HRT affect the brain, thinking skills, and mental health.

A Large Study Using UK Biobank Data

To better understand these effects, researchers analyzed data from the UK Biobank involving nearly 125,000 women. Participants were divided into three groups: women who had not yet reached menopause, women who were post-menopause and had never used HRT, and women who were post-menopause and had used HRT.

Participants completed questionnaires about menopause symptoms, mental health, sleep patterns, and overall health. Some also completed cognitive tests measuring memory and reaction time. In addition, around 11,000 women underwent magnetic resonance imaging (MRI) scans, which allowed researchers to examine differences in brain structure.

The average age at menopause among participants was about 49.5 years. Women who were prescribed HRT typically began treatment at around age 49.

Anxiety Depression and Sleep After Menopause

Women who had gone through menopause were more likely than those who had not to seek help from a GP or psychiatrist for anxiety, nervousness, or depression. They also scored higher on depression questionnaires and were more likely to have been prescribed antidepressant medications.

Women in the HRT group showed higher levels of anxiety and depression compared with women who did not use HRT. However, further analysis revealed that these differences were already present before menopause began. According to the researchers, this suggests that some GPs may have prescribed HRT in anticipation that menopause could worsen existing symptoms.

Sleep problems were also more common after menopause. Post-menopausal women were more likely to report insomnia, reduced sleep, and ongoing tiredness. Women using HRT reported feeling the most fatigued of all three groups, even though their total sleep duration did not differ from post-menopausal women who were not taking HRT.

The Importance of Lifestyle and Mental Health Support

Dr. Christelle Langley from the Department of Psychiatry said: "Most women will go through menopause, and it can be a life-changing event, whether they take HRT or not. A healthy lifestyle -- exercising, keeping active and eating a healthy diet, for example -- is particularly important during this period to help mitigate some of its effects.

"We all need to be more sensitive to not only the physical, but also the mental health of women during menopause, however, and recognize when they are struggling. There should be no embarrassment in letting others know what you're going through and asking for help."

Reaction Time Slows While Memory Remains Stable

Menopause was also linked to changes in cognitive performance. Women who were post-menopause and not using HRT showed slower reaction times compared with women who had not yet reached menopause and those who were using HRT. Memory performance did not differ significantly among the three groups.

Dr. Katharina Zühlsdorff from the Department of Psychology at the University of Cambridge, said: "As we age, our reaction times tend to get slower -- it's just a part of the natural ageing process and it happens to both women and men. You can imagine being asked a question at a quiz -- while you might still arrive at the correct answer as your younger self, younger people would no doubt get there much faster. Menopause seems to accelerate this process, but HRT appears to put the brakes on, slowing the ageing process slightly."

 Journal Reference:

1. Katharina Zuhlsdorff, Christelle Langley, Richard Bethlehem, Varun Warrier, Rafael Romero Garcia, Barbara J Sahakian. Emotional and cognitive effects of menopause and hormone replacement therapy. Psychological Medicine, 2026; 56 DOI: 10.1017/S0033291725102845 

Courtesy:

 University of Cambridge. "Menopause linked to grey matter loss in key brain regions." ScienceDaily. ScienceDaily, 7 February 2026. <www.sciencedaily.com/releases/2026/02/260207092904.htm>. 

 

One protein may decide whether brain chemistry heals or harms

Tryptophan is widely known for its connection to sleep, but its importance goes much further. The compounds produced from tryptophan help build proteins, generate cellular energy (NAD+), and create essential brain chemicals such as serotonin and melatonin. Together, these processes support mood, learning, and healthy sleep patterns.

As the brain ages or develops neurological disease, this system begins to break down. Scientists have repeatedly observed disruptions in how tryptophan is processed in aging brains, with even stronger effects seen in neurodegenerative and psychiatric disorders. These changes are linked to worsening mood, impaired learning, and disturbed sleep. Until now, however, researchers did not know what caused the brain to shift how it uses tryptophan in the first place.

SIRT6 Identified as a Key Regulator of Brain Chemistry

Prof. Debra Toiber and her research team at Ben-Gurion University of the Negev have now uncovered a clear biological explanation. Their work points to the loss of a longevity-related protein called Sirtuin 6 (SIRT6) as the driving factor behind this metabolic imbalance.

Using experiments in cells, Drosophila (fly), and mouse models, the researchers showed that SIRT6 plays an active role in controlling gene expression (e.g., TDO2, AANAT). When SIRT6 levels drop, this control is lost. As a result, tryptophan is redirected toward the kynurenic pathway, which produces neurotoxic compounds, while the production of protective neurotransmitters such as serotonin and melatonin declines.

Published Evidence and a Reversible Effect

The findings were recently published in Nature Communications.

Importantly, the researchers also found that the damage caused by this shift is not permanent. In a SIRT6 knockout fly model, blocking the enzyme TDO2 led to a significant improvement in movement problems and reduced the formation of vacuoles, which are signs of brain tissue damage. These results suggest that there may be a meaningful window for therapeutic intervention.

"Our research positions SIRT6 as a critical, upstream drug target for combating neurodegenerative pathology," says Prof. Toiber.

Research Team and Funding Support

Additional researchers include: Shai Kaluski-Kopatch, Daniel Stein, Alfredo Garcia Venzor, Ana Margarida Ferreira Campos, Melanie Planque, Bareket Goldstein, Estefanía De Allende-Becerra, Dmitrii Smirnov, Adam Zaretsky, Dr Ekaterina Eremenko -- Sgibnev, Miguel Portillo, Monica Einav, Alena Bruce Krejci, Uri Abdu, Ekaterina Khrameeva, Daniel Gitler, and Sarah-Maria Fendt.

The study was supported by the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement No 849029), the David and Inez Myers foundation, the Israeli Ministry of Science and Technology (MOST), the High-tech, Bio-tech and Negev fellowships of Kreitman School of Advanced Research of Ben-Gurion University and The Israel Science Foundation (Grant no. 422/23). The RNA-seq data analysis was supported by the Russian Science Foundation (grant number 25-71-20017). 

 

Journal Reference:

1. Shai Kaluski-Kopatch, Daniel Stein, Alfredo Garcia Venzor, Ana Margarida Ferreira Campos, Melanie Planque, Bareket Goldstein, Estefanía De Allende-Becerra, Dmitrii Smirnov, Adam Zaretsky, Ekaterina Eremenko, Miguel Portillo, Monica Einav, Alena Bruce Krejci, Uri Abdu, Ekaterina Khrameeva, Daniel Gitler, Sarah-Maria Fendt, Debra Toiber. Histone deacetylase SIRT6 regulates tryptophan catabolism and prevents metabolite imbalance associated with neurodegeneration. Nature Communications, 2025; 17 (1) DOI: 10.1038/s41467-025-67021-y 

Courtesy:

Ben-Gurion University of the Negev. "One protein may decide whether brain chemistry heals or harms." ScienceDaily. ScienceDaily, 15 January 2026. <www.sciencedaily.com/releases/2026/01/260115022811.htm>.