In a recent study, researchers investigated how restricting dietary methionine and inhibiting the tyrosine degradation pathway affects healthspan in aged mice. While affecting tyrosine didn’t show any benefits, methionine restriction improved many, but not all, measures of healthspan, including frailty, pathological disease burden, and neuromuscular function [1].
Aging of metabolism
Changes in metabolism accompany aging and are associated with many age-related diseases. Reprogramming metabolism to its youthful state could help to alleviate the signs and symptoms of aging or even reverse some aspects of it.
The authors of this study focus on two metabolic pathways that are dysregulated in aging: methionine metabolism and the tyrosine degradation pathway.
Methionine is an important metabolite, as it is the initiating amino acid during protein synthesis. Improving methionine metabolism has shown positive effects on healthspan and lifespan in model organisms, such as fruit flies, rodents, and human cell lines [2-4]. Still, the role of methionine restriction started late in life hasn’t been sufficiently explored.
Similarly, previous research in fruit flies indicated increased levels of enzymes in the tyrosine degradation pathway during aging, but the levels of tyrosine and tyrosine-derived neurotransmitters decrease. Reducing the levels of those enzymes leads to positive effects on healthspan and lifespan in fruit flies and worms [5, 6]. However, there is a lack of similar research in aged mice.
Metabolic interventions
In a population of aged (18-month-old) mice, the researchers either restricted methionine by decreasing the concentration of methionine in the diet from 0.86% (as a proportion of protein) to 0.17% or inhibited the tyrosine degradation pathway using nitisinone, a compound that elevates circulating tyrosine levels. This 6-month intervention was intended to test healthspan.
Unsurprisingly, a control group of young mice gained weight throughout the experiment, while aged mice with restricted methionine lost weight to levels similar to young mice at the start of the experiment, with a stronger effect observed in males. The weight loss of aged mice was caused by a loss of fat mass, but their lean mass was increased. No impact of nitisinone was observed.
After two weeks of treatment, the researchers tested blood plasma to determine whether these treatments were indeed impacting the levels of methionine and tyrosine. Compared to young mice, methionine levels were increased in aged mice, but only in males, which might suggest why males experienced a stronger effect of methionine restriction on weight loss. Dietary methionine restriction led to decreased plasma methionine levels in males and females, compared to aged animals of the same sex. Additionally, dietary methionine restriction improved hormonal markers of metabolic health in male mice.
Tyrosine levels were not significantly different between young and old mice. Inhibiting the tyrosine degradation pathway increased plasma tyrosine levels but didn’t affect hormonal markers.
Improved physical health
While testing molecular markers is important to understand effects, a successful treatment must improve the quality of life in an aged organism. To assess that, the resarchers conducted several tests on these mice at baseline and after 6 months of the treatment.
For a broad look at healthspan, the researchers assessed pathological disease burden scores of organs along with a frailty index that encompasses 26 different assessments and can address “the effect of treatment on different aspects of healthspan and predict life expectancy and the efficacy of lifespan–extending interventions up to a year in advance.”
The researchers reported more frailty and higher pathological disease burden scores in older animals. Frailty was significantly decreased in aged animals whose methionine was restricted, while a methionine-restricted diet reversed disease burden in female mice to that of young (10-month-old) mice.
Compared to old, normally-fed mice, methionine restriction improved neuromuscular function in aged mice, as measured by coordination, balance, grip strength, and time spent on exploratory activity.
Aged animals on a methionine-restricted diet also had improved lung functions compared to their aged, normally fed counterparts. However, clarity of vision, short-term spatial working memory, cardiovascular function, age-related hearing loss, or enlarged prostate were not improved in that group.
There were also no changes in any of those measures in the nitisinone-treated group, even though the researchers confirmed sufficient inhibition of the tyrosine degradation pathway. This is in contrast to previously observed lifespan extension in fruit flies upon inhibition of this pathway. In that study, the effect was even more substantial when tyrosine degradation pathway inhibition was neuron-specific [5]. For future studies, the researchers propose inhibiting the tyrosine degradation pathway in mouse neurons or using different drug concentrations.
Metabolism and cognition
Previous research had linked methionine to age-related changes in cognitive health. Therefore, these researchers aimed to determine whether dietary methionine restriction can reduce amyloid plaque deposition. They used aged genetically engineered mice that exhibit many features of human Alzheimer’s disease.
After measuring multiple biomarkers, the researchers noted improvements in renal and neuromuscular functions in aged mice that underwent methionine restriction for 6 months but didn’t observe a significant effect on plasma amyloid levels. Conversely, it increased the levels of insoluble (intracellular) amyloid brain deposits.
The study’s authors suggest that to obtain beneficial effects, methionine levels might need to be in a specific concentration range, and levels that are too high or too low would not have fully beneficial effects and might even cause more problems.
Still biologically aged
Since the researchers determined that there were improvements in healthspan, they used epigenetic clocks to determine if the animals were biologically younger. However, mice on a restricted methionine diet did not have significant epigenetic changes compared to aged controls.
These surprising results prompted the researchers to also analyze human blood samples from a clinical trial. During that double-blind 8-week study, participants received either low or high sulfur amino acids (methionine and cysteine). The results were similar to those obtained in mice, with no significant effects on biological age.
The researchers suggested a few reasons for this absence of epigenetic changes. First, epigenetic clocks may have higher sensitivity to lifespan extension than healthspan improvements. As this experiment began methionine restriction late in life, it might not lead to a lifespan increase, but lifespan was not measured in this study.
Second, since many epigenetic clocks are built from blood samples, they might not catch beneficial changes in single organs, such as muscle, as observed in this study.
Third, methionine is the essential building block of a metabolite that delivers methyl groups for methyltransferases, which can methylate DNA. It is possible that lower levels of dietary methionine can affect this process, thus disturbing the measurements of epigenetic clocks that rely on DNA methylation patterns.
Overall, this study found that dietary methionine restriction, even when started later in life, can benefit healthspan in mice. Clinical trials are necessary to test whether these benefits will translate to humans.
Literature
[1] Hernández-Arciga, U., Stamenkovic, C., Yadav, S., Nicoletti, C., Albalawy, W. N., Al Hammood, F., Gonzalez, T. F., Naikwadi, M. U., Graham, A., Smarz, C., Little, G. J., Williams, S. G., McMahon, B., Sipula, I. J., Vandevender, A. M., Chuan, B., Cooke, D., Pinto, A. F. M., Flores, L. C., Hartman, H. L., … Parkhitko, A. A. (2025). Dietary methionine restriction started late in life promotes healthy aging in a sex-specific manner. Science advances, 11(16), eads1532.
[2] Parkhitko, A. A., Wang, L., Filine, E., Jouandin, P., Leshchiner, D., Binari, R., Asara, J. M., Rabinowitz, J. D., & Perrimon, N. (2021). A genetic model of methionine restriction extends Drosophila health- and lifespan. Proceedings of the National Academy of Sciences of the United States of America, 118(40), e2110387118.
[3] Kozieł, R., Ruckenstuhl, C., Albertini, E., Neuhaus, M., Netzberger, C., Bust, M., Madeo, F., Wiesner, R. J., & Jansen-Dürr, P. (2014). Methionine restriction slows down senescence in human diploid fibroblasts. Aging cell, 13(6), 1038–1048.
[4] Orentreich, N., Matias, J. R., DeFelice, A., & Zimmerman, J. A. (1993). Low methionine ingestion by rats extends life span. The Journal of nutrition, 123(2), 269–274.
[5] Parkhitko, A. A., Ramesh, D., Wang, L., Leshchiner, D., Filine, E., Binari, R., Olsen, A. L., Asara, J. M., Cracan, V., Rabinowitz, J. D., Brockmann, A., & Perrimon, N. (2020). Downregulation of the tyrosine degradation pathway extends Drosophila lifespan. eLife, 9, e58053.
[6] Ferguson, A. A., Roy, S., Kormanik, K. N., Kim, Y., Dumas, K. J., Ritov, V. B., Matern, D., Hu, P. J., & Fisher, A. L. (2013). TATN-1 mutations reveal a novel role for tyrosine as a metabolic signal that influences developmental decisions and longevity in Caenorhabditis elegans. PLoS genetics, 9(12), e1004020.
