Fatigue is something that everyone experiences from time to time, but for some people, it is not a transient symptom, but a chronic condition that affects their daily functioning.
Chronic fatigue, the Centers for Disease Control and Prevention (CDC) report, may affect around 3.3 million Americans, interfering with work, school and social life, as well as day-to-day tasks.
Experts believe that chronic fatigue may sometimes follow a viral infection, or could occur after extreme physical stress, such as major surgery. It is 2–4 times more likely to occur in women than men.
A new study from Japan suggests that diet may influence energy levels and motivation. The research, published in Nutrients, found that people who had raised levels of a biomarker, homocysteine, indicating deficiency in vitamins B9 (folate) and B12, were more likely to experience fatigue or lack of motivation than those who had adequate levels.
Although the cross-sectional analysis cannot prove causation, researchers suggest that further studies into links between diet and fatigue should be carried out to verify their findings.
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Eamon Laird, PhD, Lecturer in Nutrition ATU Sligo and Adjunct Professor TCD Dublin, Ireland, who was not involved in this research, told Medical News Today that the study raised an interesting hypothesis, and that there seemed to be an association between these B-vitamins and measures of fatigue, but emphasized that the findings should be interpreted with caution.
And Thomas M. Holland, MD, MS, Physician-Scientist and Assistant Professor, Division of Digestive Diseases and Nutrition, Rush Institute for Healthy Aging, Chicago, likewise not involved in the study, commented that:
“One of the most important takeaways from this paper is that homocysteine may serve as a broader biomarker reflecting metabolic stress, vascular health, inflammation, or micronutrient status rather than simply indicating isolated B12 or folate deficiency alone.”
“The findings fit within a larger body of research linking elevated homocysteine with cardiovascular and cognitive outcomes, suggesting that these metabolic pathways may influence multiple aspects of health simultaneously,” Holland added.
The researchers carried out functional measurements, blood sampling and questionnaires on 2,618 adults who visited the Center for Health Science Innovation at Osaka University between April 2018 and March 2020.
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Of these, 602 were included in the final analysis, after those with missing data or samples (particularly of homocysteine), or who used supplements, were excluded.
Laird expressed some concern about the number of exclusions, telling MNT it “raises questions regarding selection bias and representativeness”.
Homocysteine is an amino acid formed during the breakdown of methionine, an amino acid found in foods such as nuts, beef, lamb, cheese, turkey, pork, fish, shellfish, soy, eggs, dairy, and beans.
Folate and B12 are essential for the breakdown of homocysteine, so the researchers used blood concentration of homocysteine to indicate levels of the vitamins.
“The authors are very explicit that these findings should be interpreted cautiously and viewed primarily as hypothesis-generating rather than definitive evidence of causality. Because the study is cross-sectional, it can identify associations, but it cannot determine whether elevated homocysteine causes fatigue or reduced motivation, or whether other physiological or lifestyle factors contribute to both simultaneously.”
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– Thomas M. Holland, MD, MS
The researchers found that in both men and women, higher homocysteine levels were associated with lower serum folate and B12 levels.
The researchers assessed fatigue and motivation using the 14-point Chalder Fatigue Scale, which is commonly used to assess chronic fatigue, and a visual analog scale.
In men, high homocysteine was associated with higher physical fatigue scores and, in women, with lower motivation scores.
Holland explained possible reasons for the connections:
“Vitamin B12 and folate are heavily involved in cellular energy production, DNA synthesis, red blood cell formation, and neurological function. When levels are inadequate, homocysteine levels can rise because the body cannot efficiently convert it into other important compounds involved in normal metabolism. Elevated homocysteine has been linked with oxidative stress, impaired blood vessel function, inflammation, and altered neurotransmitter pathways, all of which may influence both physical energy and mental motivation.”
“In simpler terms, if cells are not efficiently producing energy or the brain is not optimally regulating signaling chemicals involved in mood and drive, people may experience symptoms such as exhaustion, mental fog, reduced stamina, or decreased motivation,” he continued.
“However,” he added, “it is important to emphasize that this study did not show that low folate or B12 directly caused fatigue; rather, homocysteine appeared to serve as a broader marker connected to these metabolic processes.”
Both Holland and Laird cautioned that the sex differences, while interesting, should be interpreted with caution, with Laird telling us that “the formal sex-by-homocysteine interaction analyses were not statistically significant, suggesting there is no clear evidence that the associations truly differ between men and women.“
“If genuine, the findings may be [due to] biological differences in homocysteine metabolism, hormonal influences (particularly oestrogen), or sex-specific effects on fatigue and motivation pathways,” Laird hypothesized.
Holland advised that “maintaining a dietary pattern rich in fruits, vegetables, legumes, whole grains, lean proteins, omega-3-rich fish, olive oil, and minimally processed foods likely supports healthier homocysteine metabolism and overall physiological resilience.”
Laird added that sufficient of both B12 and folate can be obtained through either diet or supplements:
“Vitamin B12 is mainly found in animal-based foods such as meat, fish, eggs, and dairy products, while folate is abundant in green leafy vegetables, legumes and fortified cereals. For individuals with low dietary intake or increased requirements, supplements containing vitamin B12, folic acid, or both may help improve status and support normal metabolic function.”
“Fortified food products are ideal,” he emphasized, “as they often contain both vitamins and in smaller amounts which can be eaten little and often as vitamin B12 absorption is inversely related to dose with the higher the dose consumed at one time, the lower the percentage being absorbed.”
