Calorie restriction slows the progression of aging, and remains a benchmark yet to be beaten by pharmaceutical approaches to the manipulation of metabolism aimed at slowing down aging. Much of the beneficial response to calorie restriction is downstream of nutrient sensing, the complex package of cellular mechanisms that react to, for example, levels of essential amino acids that are only obtain via the diet. The most studied of these sensory systems of metabolic regulation is that targeting the essential amino acid methionine. Studies in rodents suggest that a sizable fraction of the calorie restriction response derives from methionine sensing, and promising results have been observed studies using low methionine diets without overall restriction of calories.
Low methionine diets are challenging to manage in day to day life, arguably harder than simply eating less, which might go some way towards explaining why they are not a popular option. A low methionine diet is a jigsaw puzzle lacking most of the pieces; near every lynchpin ingredient in a reasonable, balanced diet of any type is high in methionine. Low methionine medical diets do exist, however, and those who manufacture them for a few specialized uses would no doubt welcome evidence for their broader application to age-related conditions. Today’s paper is an example of researchers gathering more supporting evidence for methionine restriction to be particularly applicable to a specific condition of interest, Alzheimer’s disease in this case.
Systems genetics identifies methionine as a high risk factor for Alzheimer’s disease
Recently researchers have found that amino acid homeostasis is disrupted in the serum and brain of patients with Alzheimer’s disease (AD). Moreover, alterations in the levels of different amino acids in the physiological range have been linked to various pathological conditions, including neurological disorders. Longitudinal studies using mouse models of AD have also demonstrated abnormal essential amino acid levels. These findings suggest that dietary intervention may affect the progression of AD by regulating amino acids metabolism.
Methionine is a widely-used sulfur-containing amino acid that serves as a precursor for substances such as spermine, spermidine, and ethylene. It plays a pivotal role in various aspects of growth and development, including cell division, differentiation, apoptosis, homeostasis, and gene expression. Studies have shown that the methionine cycle is involved in the pathogenesis of AD. Methionine serves as a crucial methyl donor in certain methyltransferase reactions, providing methyl groups to various compounds. High methionine diet has been proven to induce AD-like symptoms. As a dietary intervention, methionine restriction has been reported to alleviate AD, but the molecular mechanisms remain unclear. Therefore, it is of great significance to explore the specific mechanisms, by which methionine is involved in the pathogenesis of AD.
This study utilized the data from BXD recombinant inbred (RI) mice to establish a correlation between the AD phenotype in mice and methionine level. Gene enrichment analysis indicated that the genes associated with the concentration of methionine in the midbrain are involved in the dopaminergic synaptic signaling pathway. Protein interaction network analysis revealed that glycogen synthase kinase 3 beta (GSK-3β) was a key regulator of the dopaminergic synaptic pathway and its expression level was significantly correlated with the AD phenotype. Finally, in vitro experiments demonstrated that methionine deprivation could reduce the expression of amyloid-β and phosphorylated tau, suggesting that lowering methionine levels in humans may be a preventive or therapeutic strategy for AD. In conclusion, our findings support that methionine is a high risk factor for AD. These findings predict potential regulatory network, theoretically supporting methionine restriction to prevent AD.
