Methionine metabolism and methyltransferases in the regulation of aging and lifespan extension across species

Abstract

Methionine restriction (MetR) extends lifespan across different species and exerts beneficial effects on metabolic health and inflammatory responses. In contrast, certain cancer cells exhibit methionine auxotrophy that can be exploited for therapeutic treatment, as decreasing dietary methionine selectively suppresses tumor growth. Thus, MetR represents an intervention that can extend lifespan with a complementary effect of delaying tumor growth. Beyond its function in protein synthesis, methionine feeds into complex metabolic pathways including the methionine cycle, the transsulfuration pathway, and polyamine biosynthesis. Manipulation of each of these branches extends lifespan; however, the interplay between MetR and these branches during regulation of lifespan is not well understood. In addition, a potential mechanism linking the activity of methionine metabolism and lifespan is regulation of production of the methyl donor S‐adenosylmethionine, which, after transferring its methyl group, is converted to S‐adenosylhomocysteine. Methylation regulates a wide range of processes, including those thought to be responsible for lifespan extension by MetR. Although the exact mechanisms of lifespan extension by MetR or methionine metabolism reprogramming are unknown, it may act via reducing the rate of translation, modifying gene expression, inducing a hormetic response, modulating autophagy, or inducing mitochondrial function, antioxidant defense, or other metabolic processes. Here, we review the mechanisms of lifespan extension by MetR and different branches of methionine metabolism in different species and the potential for exploiting the regulation of methyltransferases to delay aging.

Methionine Dependence of Cancer

“…Whether similar effects are induced in tissue specific stem cells has not been evaluated, but diet induced differentiation of tissue stem cells could lead to stem cell exhaustion and loss of tissue homeostasis. Exhaustion of tissue-specific stem cells in response to a low methionine diet is, however, inconsistent with the extensive literature showing that methionine restriction expands animal lifespan [85][86][87][88][89][90][91].…”

Methionine Restriction and Cancer Biology

“…In general, aging is associated with global DNA hypomethylation despite some regions of specific genes becoming hypermethylated. It has been proposed that methionine metabolism is sensed by DNA methyltransferases that could alter methylation and lifespan [68]. Interestingly, in rodents, dietary methionine restriction has varying effects on global DNA methylation depending on the age of the animal.…”

Emerging Insights into the Metabolic Alterations in Aging Using Metabolomics

“…Methionine metabolism was also reported to be significantly altered with age, as demonstrated by a high-throughput targeted metabolomics study in flies revealing that S-adenosyl-homocysteine (SAH) metabolite accumulates with age, and that suppressing the age-dependent SAH accumulation in turn suppresses the H3K4 trimethylation (H3K4me3), thus mimicking methionine restriction and leading to the health span and lifespan extension in flies [86,87]. The effects of dietary restriction (DR) and age were also investigated in different tissues from flies, demonstrating that DR significantly alters the metabolome and impedes the age-related changes in the metabolome [88].…”