The prevailing wisdom in the research community is that a reduced level of the essential amino acid methionine is the primary trigger for the sweeping changes to metabolism that take place due to the practice of calorie restriction. Essential amino acids are not manufactured in the body, and thus must be obtained through the diet. The changes provoked by a reduced calorie intake lead to a slowing of aging and increased healthy life span and overall life span, largely mediated via an increase in the cellular maintenance processes of autophagy. Many other processes are involved as well, however, each adding their own small contribution, and animal studies suggest that reduced levels of other essential amino acids also have their own, lesser triggers that contribute to the whole.
That the response to calorie restriction does change just about everything in cellular metabolism makes it a challenging research topic, though the usual approaches have worked well: disable specific proteins one by one and see what happens. There is a lot of ground to cover and only so many researchers and so much funding to cover it with. The modern phase of the investigation of calorie restriction has been running in earnest for more than 25 years, but a complete understanding of calorie restriction will likely only slightly predate a complete understanding of cellular metabolism - a goal that is in no way near term.
Comparatively recent genomics, transcriptomics, and proteomics tools have added a great deal of data to the study of metabolism, and thus a great deal more work to the existing task list leading to the aforementioned complete understanding. Transcriptomics and other approaches to measuring gene expression patterns show that calorie restriction, intermittent fasting (with and without consequent calorie restriction), methionine restriction, and restriction of other specific nutrients (one by one), are all somewhat different. Yet the experiments showing that disabled autophagy prevents extension of life via calorie restriction suggest that it all converges at the same place.
While mapping the calorie restriction response and searching for calorie restriction mimetic drugs has made up the lion's share of translational gerontology to date, it is a sad truth that this class of intervention, meaning the upregulation of stress responses such as autophagy, works a great deal better in short-lived species such as mice than it does in long-lived species such as humans. Mice live 40% longer when calorie restricted, and humans most certainly don't. So while the long term health benefits of calorie restriction are meaningful, when compared with the little that modern medicine has been able to do to maintain the health of basically healthy people, they are not meaningful enough to merit major research funding, given the far better options on the table, those outlined in the SENS rejuvenation research programs.
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. Although it is clear that each of the three branches of methionine metabolism - the methionine cycle, the transsulfuration pathway, and polyamine biosynthesis - plays a significant role in lifespan extension, how these branches crosstalk during regulation of lifespan is unknown. Moreover, how activity in these different branches of methionine metabolism change with age in different tissues and organs remains to be elucidated.