Associations of Plasma Homocysteine Reflecting Vitamin B12 and Folate Status with Fatigue-Related Outcomes in Healthy Adults, 2026, Kanouchi

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https://www.mdpi.com/2072-6643/18/6/941

Open Access Article

Associations of Plasma Homocysteine Reflecting Vitamin B12 and Folate Status with Fatigue-Related Outcomes in Healthy Adults​

by
Hiroaki Kanouchi
1,*<i></i>,
Ayaka Yamamoto
1,
Akiko Kuwabara
1,
Shigeo Takenaka
1,
Eiji Nishikubo
2,
Yukihiro Nomura
2,
Takehiro Naruto
2,
Kyosuke Watanabe
3,4,
Kei Mizuno
3,4 and
Yasuyoshi Watanabe
3,4


1
Department of Nutrition, Graduate School of Human Life and Ecology, Osaka Metropolitan University, Osaka 536-8525, Japan
2
Alinamin Pharmaceutical Co., Ltd., Tokyo 100-0005, Japan
3
Kobe University Graduate School of Science, Technology and Innovation, Osaka 530-0011, Japan
4
Center for Health Science Innovation, Osaka Metropolitan University, Osaka 558-8585, Japan
*
Author to whom correspondence should be addressed.
Nutrients 2026, 18(6), 941; https://doi.org/10.3390/nu18060941
Submission received: 24 February 2026 / Revised: 11 March 2026 / Accepted: 12 March 2026 / Published: 17 March 2026
(This article belongs to the Section Nutritional Epidemiology)

Abstract​

Background/Objectives:

Fatigue and reduced motivation impair daily functioning and quality of life. Homocysteine (Hcy) has been implicated in oxidative stress and one–carbon metabolism, but its relationship with fatigue–related outcomes remains unclear. We explored associations between plasma Hcy and fatigue-related measures in healthy adults.

Methods:

We analyzed cross–sectional data from 602 community–dwelling adults. Plasma Hcy concentrations were categorized into sex−specific tertiles. Fatigue and motivation were assessed using the Chalder Fatigue Scale and a visual analog scale (VAS). Sex−stratified multivariable linear models adjusted for lifestyle and biochemical covariates were used to examine associations. Sensitivity analyses additionally modeled Hcy as a continuous variable.

Results:

Higher Hcy tertiles were associated with lower serum folate and vitamin B12 concentrations in both sexes (p < 0.001). In men, the lowest Hcy tertile was associated with lower Chalder physical fatigue scores, whereas in women the highest Hcy tertile was associated with lower VAS motivation scores in multivariable analyses. Pairwise contrasts indicated higher physical fatigue in men in the highest tertile compared with the lowest (T3–T1: 1.55; 95% CI 0.24–2.86; p = 0.022) and lower motivation in women (T3–T1: −5.62; 95% CI −10.65 to −0.59; p = 0.029). However, no significant associations were observed when Hcy was modeled as a continuous variable.

Conclusions:

In this exploratory cross−sectional analysis, plasma Hcy showed associations with fatigue−related outcomes in sex−stratified analyses. These findings should be interpreted cautiously and considered hypothesis–generating. Longitudinal and mechanistic studies are needed to clarify potential causal relationships.
Keywords:
homocysteine; fatigue; motivation; vitamin B12; folate; oxidative stress; cross−sectional study

 

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Nutrition’s role in chronic fatigue

An Osaka Metropolitan University-led research team found that deficiencies in vitamin B12 and folate lead to elevated homocysteine levels, which may be linked to fatigue and decreased motivation.

www.eurekalert.org

News Release 28-May-2026

Nutrition’s role in chronic fatigue​

Diet and homocysteine may influence fatigue and motivation

Peer-Reviewed Publication
Osaka Metropolitan University


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image:

Dietary imbalance, low B12, and folate may correlate with high homocysteine levels and indicate fatigue and low motivation in participants.

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Credit: Osaka Metropolitan University

With less time and more work, chronic fatigue has become a moniker of modern society. However, this not only reduces the quality of life but also constitutes as a social issue that affects work efficiency and leads to accidents. On the surface, the cause of fatigue is often attributed to not getting enough rest, but there may be another underlying issue—the lack of proper nutrition.

Taking this into account, a research group led by Professor Hiroaki Kanouchi at Osaka Metropolitan University’s Graduate School of Human Life and Ecology focused on nutritional status and water-soluble vitamin deficiencies found in unbalanced diets. The team hypothesized that a lack of folate (B9) and vitamin B12 may be related to fatigue, and centered their research around homocysteine (Hcy), a biomarker known to increase when these deficiencies are present. Blood concentrations of Hcy, folate, and vitamin B12 in approximately 600 healthy Japanese participants were measured. Participants’ fatigue and motivation were assessed using the Chalder Fatigue Scale questionnaire and Visual Analog Scale. The initial results showed that individuals with higher blood Hcy levels had lower levels of vitamin B12 and folate, regardless of sex.

The researchers then examined the relationship between homocysteine levels and fatigue separately for men and women. In their analysis, factors that may influence fatigue, such as age, sleep duration, workload, and dietary habits, were simultaneously accounted for. The results revealed higher Hcy levels were associated with greater physical fatigue in men and higher levels were associated with decreased motivation in women.

“This suggested relationship between vitamin B12, folate, and fatigue in healthy individuals may represent the first report of its kind,” said Professor Kanouchi. “Blood homocysteine levels have traditionally raised concerns in relation to cardiovascular disease, dementia, and fractures. However, our findings suggest that attention should also be paid to fatigue and motivation in the future. To prevent an increase in homocysteine levels, it is important to avoid deficiencies in vitamin B12 and folate. Maintaining a well-balanced diet on a daily basis is essential.”

The findings were published in Nutrients.

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About OMU

Established in Osaka as one of the largest public universities in Japan, Osaka Metropolitan University is committed to shaping the future of society through the “Convergence of Knowledge” and the promotion of world-class research. For more research news, visit https://www.omu.ac.jp/en/ and follow us on social media: X, Instagram, LinkedIn.

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Journal​

Nutrients

DOI​

10.3390/nu18060941

Method of Research​

Observational study

Subject of Research​

People

Article Title​

Associations of Plasma Homocysteine Reflecting Vitamin B12 and Folate Status with Fatigue-Related Outcomes in Healthy Adults

Article Publication Date​

17-Mar-2026

COI Statement​

E.N., Y.N. and T.N are employees of Alinamin Pharmaceutical Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.