Reduced folate intake enhances metabolic plasticity in aged mice

By Dr. Liji Thomas, MDReviewed by Lily Ramsey, LLMAug 6 2024

Folate fortification of staple foods has long been practiced in many countries, including the USA. However, little is known about its requirement for health at later phases of life. A recent study in Life Science Alliance explored this question in elderly mice.

Study: Late-life dietary folate restriction reduces biosynthesis without compromising healthspan in mice. Image Credit: Benoit Daoust/Shutterstock.com

What is folate?

Folate is a vitamin cofactor required as a one-carbon (1C) donor in multiple metabolic pathways. Its role is within the folate-mediated one-carbon metabolism (FOCM).

This network of reactions participates in metabolizing amino acids like serine, glycine, and methionine and building nucleic acids and phospholipids. It is also essential for methylation.  

Folate is required to divide cells actively during fetal life. Folate antagonists are, therefore, useful in suppressing abnormal cell proliferation in cancer chemotherapy, rheumatoid arthritis, and psoriasis.

Folate-fortified foods promote normal development in early human life, especially preventing neural tube defects such as spina bifida. Some researchers suggest a negative impact on older humans, such as possibly increased rates of colorectal cancer.

While this hypothesis has not been confirmed, this does not mean that health in late life is not affected by a high folate intake.

There is little solid evidence in favor of or against the opposing postulate that moderately reduced folate supplementation in older adults may increase the healthspan. Previous research suggests such an effect following the suppression of one-carbon (1C) metabolism.

Longevity is associated with lower methylation levels and by restricting methionine levels. This pattern has been observed at the transcriptional level as well. The current study examined changes in healthspan in aged mice with altered dietary folate intake.

About the study

Genetic changes that reduce 1C metabolism cause increased lifespan in yeast. Treatment with methotrexate (MTX), a well-known and clinically useful folate antagonist, caused an increase in yeast replicative lifespan without any effect on cell proliferation but with a dose-dependent increase in cell size due to cell cycle arrest.

With wild-type Caenorhabditis elegans, this effect was not seen with high-dose MTX in adults. However, with exposure beginning in embryonic life until death, low doses increased the lifespan by 15%, but not with high doses, confirming the results seen with yeast.

Another folate antagonist, an ATIC (AICAR Transformylase/Inosine Monophosphate Cyclohydrolase) inhibitor, increased lifespan in worms at low doses. This compound is a metabolic activator in mice, and at equivalent doses, it mitigates the effects of the metabolic syndrome.

This is the first direct evidence in favor of using drugs that limit 1C metabolism to increase the lifespan in invertebrates.

The safety of MTX at low doses over long periods in mice, rats and dogs has been established.

Using historical data, the researchers showed increased lifespan in mice on low-dose MTX in five of eight experiments without adverse effects on health. This led to the present study where folate limitation in late life was tested in mice for its impact on healthspan.

What did the study show?

The results reveal that lower folate intake in aged mice does not negatively impact their health. The folate-restricted mice kept their weight steady (females) or increased it (males). They did not develop anemia or show megaloblastosis, indicating no impact on red cell DNA replication.

Since the mice were sacrificed at 120 weeks, longevity was not measured. However, the healthspan showed significant differences between mice on the standard diet and those with a diet limited in folate and choline (F/C-). Survival was unaffected in either group.

No signs of increased frailty or ambulatory issues appeared in mice on the F/C- diet. Cardiac function appeared unaffected by diet.

Males in the F/C- group greyed less than in the other group, possibly indicating an improved healthspan.

This diet may improve metabolic adaptation in females. These mice shifted more easily between glycolytic or oxidative phosphorylation pathways during normal diurnal transitions between inactive and active states.

For males, the metabolic benefit of the F/C- diet came from increased carbohydrate use and, therefore, higher respiratory exchange ratios (RER) at night when they became active. However, male mice on this diet showed a significant increase in kidney lesions, which were also found in autoimmune conditions.

Mice on the F/C- diet may obtain metabolites from their gut microbiome that would otherwise come from 1C metabolism. These include methionine and the purine precursor inosine monophosphate (IMP). No evidence of epigenetic changes associated with genomic instability was found.

The folate restriction resulted in a lower anabolic rate, with reduced anabolic metabolites and limited transcripts expressing protein-encoding genes.

Increased glutamine and reduced insulin growth factor 1 (IGF-1) activity were observed and associated with improved longevity in humans and mice.

Conclusions

The effect of interventions that increase or decrease folate intake may change with the individual's age. This could be explained by the “antagonistic pleiotropy” theory, which suggests that individuals with abundant health and reproductive fitness in youth do not typically live as long as others.

This is exemplified by the rapamycin (TOR) pathway targeting growth, aging, and metabolism across all organisms from yeasts onwards.

“These results are consistent with a view of 1C metabolism as a tunable platform that allocates cellular resources for biosynthesis.”

1C pathways may act in the same way and fulfil functions as the TOR pathway, with its pleiotropic metabolic effects inhibiting cell proliferation but enhancing longevity.

This could make it possible to adjust the folate intake with age to optimize the benefits.

Long-lived individuals in a French population have higher than expected levels of gene alleles that lower a critical 1C pathway enzyme to half. In mice, animals with a heterozygous mutation leading to a 50% reduction in folate levels live as long as the wild-type mice.

Keeping in mind that mice do not respond as readily to folate restriction as humans because of their unique metabolism, further studies are essential to establish these findings and extend them to humans.