Elevated methylmalonic acid (MMA) levels are associated with depressive symptoms and increased mortality risk, but depressive symptoms do not mediate the relationship between MMA and mortality.
Highlights:
- Each standard deviation increase in MMA is associated with a small but significant increase in depressive symptoms.
- The association between MMA and depressive symptoms is more pronounced in men and individuals aged 60 and older.
- Higher levels of MMA and greater depressive symptoms are both linked to an increased risk of mortality.
- Depressive symptoms account for approximately 2% of the association between MMA and mortality, indicating they do not significantly mediate this relationship.
- MMA-associated mechanisms contribute to the complex etiology of depression, beyond the effects of vitamin B12 and folate levels.
Source: Translational Psychiatry (2024)
Major Findings: Methylmalonic Acid (MMA) vs. Depression & Mortality (2024)
Bing Cao et al. conducted a population-based study evaluating the link between MMA (methylmalonic acid) levels, depressive symptoms, and mortality risk.
1. MMA & Depressive Symptoms
Each standard deviation increase in methylmalonic acid (MMA) levels corresponds to a small but significant rise in depressive symptoms.
The study found that for every 0.49 µmol/L increase in MMA, depressive symptoms, measured by the Patient Health Questionnaire-9 (PHQ-9), increased by approximately 0.15 points.
This indicates that higher MMA levels might contribute to depressive feelings.
This association remained significant even after adjusting for various factors like age, sex, race, education, income, and other health indicators, suggesting that MMA’s impact on depression is robust and independent of these variables.
2. Sex & Age Differences
The link between MMA and depressive symptoms is stronger in men and individuals aged 60 and above.
When broken down by sex, the data showed that men with higher MMA levels experienced a more noticeable increase in depressive symptoms compared to women.
Specifically, in men, each standard deviation increase in MMA was associated with a 0.17-point rise in depressive symptoms, while no significant association was found in women.
Additionally, the association was more pronounced in participants aged 60 and older, where each standard deviation increase in MMA led to a 0.18-point increase in depressive symptoms.
This suggests that older adults and men may be more vulnerable to the depressive effects of elevated MMA.
3. MMA & Mortality
Elevated MMA levels and higher depressive symptoms are both linked to an increased risk of mortality.
The study followed participants over a median period of 80 months and found that for each 0.49 µmol/L increase in MMA, the risk of death increased by 25.1%.
Similarly, each standard deviation increase in depressive symptoms raised the mortality risk by 15.4%.
These findings suggest that both higher MMA levels and more severe depressive symptoms are significant predictors of mortality, highlighting the importance of monitoring and potentially addressing elevated MMA and depression to improve health outcomes.
4. Lack of Mediation by Depressive Symptoms
Depressive symptoms do not significantly mediate the relationship between MMA and mortality.
While both elevated MMA levels and depressive symptoms are associated with higher mortality, the study found that depressive symptoms only account for about 2% of the increased mortality risk associated with MMA.
This minimal mediation effect indicates that the direct impact of MMA on mortality is much stronger than any indirect effect through depressive symptoms.
This suggests that MMA’s role in increasing mortality is likely due to its direct physiological effects rather than being driven primarily by its impact on mental health.
5. Independent Effects Beyond Vitamin B12 & Folate
The association between MMA and depressive symptoms is independent of vitamin B12 and folate levels.
MMA is often elevated in cases of vitamin B12 deficiency, which can contribute to depressive symptoms.
However, the study’s findings remained significant even after adjusting for vitamin B12 and folate levels.
This indicates that the relationship between MMA and depression goes beyond just vitamin deficiencies.
Elevated MMA may contribute to depression through mechanisms like mitochondrial dysfunction and oxidative stress, which are not solely related to B12 and folate deficiencies.
Study Overview: MMA Levels, Depression, Mortality in General Population (2024)
The study aimed to investigate the extent to which methylmalonic acid (MMA) is associated with depressive symptoms and mortality in the general population and to assess whether depressive symptoms mediate the relationship between MMA and mortality.
Sample
- The analysis included cross-sectional data from 8,343 participants from the US National Health and Nutrition Examination Survey (NHANES).
- Participants were adults aged 18 and above, with complete data on MMA, depressive symptoms, mortality, and relevant covariates.
Methods
- Measurement of MMA: MMA levels were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS).
- Depressive Symptoms Assessment: Depressive symptoms were assessed using the Patient Health Questionnaire-9 (PHQ-9).
- Mortality Data: Mortality data were obtained through linkage with National Death Index records.
- Statistical Analysis: Linear regression models were used to assess the association between MMA and depressive symptoms. Cox proportional hazard regression models were utilized to evaluate the association of MMA and depressive symptoms with mortality. Mediation analysis was conducted within the counterfactual framework to determine if depressive symptoms mediated the relationship between MMA and mortality.
Limitations
- Cross-Sectional Design: The study’s cross-sectional nature limits the ability to draw causal conclusions.
- Self-Reported Data: Depressive symptoms were self-reported, which may introduce measurement errors.
- Lack of Control for Homocysteine: The study did not control for homocysteine, an important factor in the association between depression and vitamin B12 and folate deficiency.
- Missing Biomarkers: The absence of direct measurements for additional specific biomarkers of mitochondrial dysfunction or oxidative stress, such as lactate or fibroblast growth factor 21 (FGF21), limits the understanding of the underlying biological mechanisms.
- Generalizability: The findings may not be generalizable to populations outside the US or to institutionalized individuals.
Likely Reasons for Correlation Between MMA Levels, Depressive Symptoms, Mortality
1. Mitochondrial Dysfunction
Mechanism: MMA is a mitochondrial toxin that disrupts mitochondrial energy metabolism by interfering with succinate dehydrogenase and triggering the generation of reactive oxygen species (ROS).
Impact on Depression: Disrupted mitochondrial function can impair energy production in brain cells, leading to neuronal damage and contributing to depressive symptoms.
Impact on Mortality: Mitochondrial dysfunction can lead to a range of chronic diseases, increasing the risk of mortality.
2. Oxidative Stress
Mechanism: Elevated MMA levels contribute to oxidative stress by increasing the production of ROS, which can damage cellular structures, including lipids, proteins, and DNA.
Impact on Depression: Oxidative stress has been linked to alterations in brain structure and function, which are associated with depression.
Impact on Mortality: Persistent oxidative stress can lead to systemic inflammation and the development of various chronic conditions, increasing mortality risk.
3. Inhibition of Neurotransmission
Mechanism: High MMA levels can inhibit glutamatergic neurotransmission by disrupting neuronal mitochondria.
Impact on Depression: Glutamate is a crucial neurotransmitter for brain function, and its inhibition can lead to mood disorders and depressive symptoms.
Impact on Mortality: Disrupted neurotransmission can affect overall brain health and contribute to conditions that increase the risk of death.
4. Vitamin B12 & Folate Deficiency
Mechanism: MMA is a biomarker of vitamin B12 deficiency since vitamin B12 is required to convert MMA to succinyl-CoA.
Impact on Depression: Deficiency in vitamin B12 and folate can impair one-carbon metabolism, essential for brain function and mood regulation, leading to depression.
Impact on Mortality: Long-term vitamin B12 deficiency can lead to severe neurological and hematological disorders, increasing mortality risk.
5. Age-Related Susceptibility
Mechanism: MMA levels tend to increase with age, reflecting a decline in mitochondrial function and vitamin B12 absorption.
Impact on Depression: Older adults are more susceptible to the effects of elevated MMA on brain function, contributing to higher rates of depression in this population.
Impact on Mortality: The age-related increase in MMA and associated mitochondrial dysfunction can exacerbate age-related diseases, leading to higher mortality rates.
6. Sex Differences
Mechanism: The study found that the association between MMA and depressive symptoms was more pronounced in men, potentially due to sex-specific differences in metabolism and hormone regulation.
Impact on Depression: Men may be more vulnerable to the depressive effects of elevated MMA due to differences in mitochondrial function and stress responses.
Impact on Mortality: These sex-specific differences can also influence overall health outcomes and mortality risk.
Possible Ways to Reduce High MMA Levels
1. Vitamin B12 Supplementation
Since MMA is a biomarker of vitamin B12 deficiency, supplementing with vitamin B12 can help convert MMA to succinyl-CoA, reducing its levels.
Oral or intramuscular vitamin B12 supplements can be used, especially in individuals with a known deficiency or those at risk, such as older adults or vegetarians.
2. Dietary Changes
Consuming foods rich in vitamin B12 can help maintain adequate levels of this essential nutrient, thereby lowering MMA levels.
Including animal-based products like meat, fish, dairy, and eggs in the diet can increase vitamin B12 intake.
Fortified foods and vitamin B12-enriched plant-based options are also beneficial for vegetarians and vegans.
3. Monitoring & Treating Underlying Conditions
Conditions like pernicious anemia and gastrointestinal disorders (e.g., Crohn’s disease, celiac disease) can impair vitamin B12 absorption, leading to elevated MMA levels.
Regular monitoring of vitamin B12 status and managing these underlying conditions with appropriate medical treatments can help reduce MMA levels.
4. Improving Gut Health
A healthy gut can improve the absorption of vitamin B12 from the diet.
Consuming probiotics, prebiotics, and maintaining a balanced diet rich in fiber can promote gut health and enhance vitamin B12 absorption.
5. Regular Screening & Early Intervention
Early detection of elevated MMA levels can prompt timely interventions to address vitamin B12 deficiency before it leads to severe health issues.
Routine screening for vitamin B12 and MMA levels, especially in high-risk populations such as older adults, can ensure early intervention with supplementation or dietary changes.
6. Folate Supplementation
Folate works in conjunction with vitamin B12 in one-carbon metabolism, and adequate levels can support overall metabolic processes that help lower MMA.
Taking folic acid supplements or consuming folate-rich foods like leafy greens, legumes, and fortified cereals can help maintain balanced levels.
7. Avoiding Excessive Alcohol Consumption
Excessive alcohol intake can impair vitamin B12 absorption and utilization, leading to elevated MMA levels.
Reducing or avoiding alcohol consumption can support better vitamin B12 metabolism and lower MMA levels.
8. Regular Medical Check-Ups
Regular health check-ups can help identify and manage factors that may contribute to elevated MMA levels.
Periodic blood tests to monitor vitamin B12 and MMA levels, especially for individuals with symptoms of deficiency or those at risk, can help manage and reduce elevated MMA levels effectively.
Conclusion: Methylmalonic Acid (MMA), Depression, Mortality
This study highlights the significant association between elevated methylmalonic acid (MMA) levels and increased depressive symptoms, particularly in men and individuals aged 60 and above.
The findings also establish a link between higher MMA levels and an elevated risk of mortality.
However, depressive symptoms do not significantly mediate the relationship between MMA and mortality, indicating that MMA’s impact on mortality is primarily due to its direct physiological effects.
These results suggest that mitochondrial dysfunction, as indicated by elevated MMA, plays a crucial role in the etiology of depression and overall health outcomes.
Addressing elevated MMA levels through medical or dietary interventions may therefore be essential in mitigating depressive symptoms and reducing mortality risk in the general population.
References
- Study: Associations of methylmalonic acid and depressive symptoms with mortality: a population-based study (2024)
- Authors: Bing Cao et al.
