While manipulating DNA methylation has taken up most of our lifespans, the manipulation of methyl donors critical to this process may just be the key to making up for the lost time.
During one-carbon metabolism, the essential amino acid methionine is metabolized into S-adenosylmethionine (SAM), a methyl donor responsible for DNA and histone methylation. Donation of the methyl group by SAM produces S-adenosylhomocysteine (SAH), which also acts as a feedback inhibitor for DNA methylation.
SAMTOR Senses SAM Levels for the mTOR Pathway
If the quest for longevity has your senses tingling, you are not alone, since Gu et al. from the lab of David Sabatini at MIT have just demonstrated how a crucial longevity pathway senses SAM levels.
The mTOR complex 1 (mTORC1) is an environmentally responsive regulator of cellular metabolism and growth that responds to nutrients. The amino acids leucine and arginine activate this pathway; however, a role for other amino acids has yet to be fully appreciated.
By making use of human embryonic kidney (HEK-293T) cells, the talented team characterized a previously unstudied protein that putatively interacts with key players of the pathway, which they termed SAMTOR (S-adenosylmethionine sensor upstream of mTORC1). Here’s what the team discovered:
- True to its name, SAMTOR binds SAM and interacts with members of the mTORC1 pathway
- SAMTOR inhibits the mTORC1 pathway upon methionine starvation
- Methionine activation of mTORC1 signaling requires the SAM binding ability of SAMTOR, thus demonstrating that SAMTOR lets a cell know when there’s enough methionine via the mTORC1 pathway
Co-first author Jose Orozco shares, “People have been trying to figure out how methionine was sensed in cells for a really long time. I think that this is the first time in mammalian cells a mechanism has been found to describe the way methionine can regulate a major signaling pathway like mTOR.” Senior author David Sabatini adds, “There are a lot of similarities between the phenotypes of methionine restriction and mTOR inhibition. The existence of this protein SAMTOR provides some tantalizing data suggesting that those phenotypes may be mechanistically connected.”
Co-first author Xin Gu concludes, “It is very interesting to consider mechanistically how methionine restriction might be associated in multiple organisms with beneficial effects, and identification of this protein provides us a potential molecular handle to further investigate this question. The nutrient-sensing pathway upstream of mTOR is a very elegant system in terms of responding to the availability of certain nutrients with specific mechanisms to regulate cell growth. The currently known sensors raise some interesting questions about why cells evolved sensing mechanisms to these specific nutrients and how cells treat these nutrients differently.”
Interestingly, since low methionine diets increase lifespan in rodents, the authors speculate that SAMTOR might play a role in these benefits and believe that it may be possible to control SAMTOR function by pharmacologically targeting its SAM binding pocket.
Metformin Manipulates Mitochondrial One-Carbon Metabolism to Increase DNA Methylation
On the subject of pharmacological targeting, metformin is a drug commonly employed to treat type 2 diabetes, which also comes with an unexpected side effect: it promotes longevity in healthy individuals too. This unexpected beneficial effect appears to be due, in part, to the targeting of a number of important metabolic pathways, including mTOR. However, a new epigenetic mechanism has emerged thanks to Cuyàs et al. from the lab Javier Menéndez at the Catalan Institute of Oncology (Catalonia, Spain).
Here’s what the team uncovered when examining non-cancerous, cancer-prone, and metastatic cancer cells:
- Metformin promotes global DNA hypermethylation, which includes LINE-1 retrotransposons, by decreasing SAH levels and increasing SAM levels
- This hypermethylation may help counter the hypomethylation typically observed in cancerous cells
- Making use of a mitochondria/complex I (mCI)-targeted analog of metformin (norMitoMet), the team established a critical connection between one-carbon metabolism in the mitochondria and the increase in nuclear DNA methylation
- CRISPR/Cas9 knockout of a crucial component of mitochondrial complex I (part of the respiratory chain) blunted this effect, thus demonstrating a functional role for mitochondrial metabolism
The team concludes, “The induction of an energy crisis in the cell by inhibiting the respiratory chain of the mitochondria produces a decrease in the levels of SAH, the natural inhibitor of epigenetic writers. Simultaneously, metformin and its derivatives are also able to break the flow of methyl groups through mitochondria, which leads to the accumulation of SAM, the ink used by epigenetic writers.”
Longer Living Through Pharmacology
Overall, these two studies offer up new mechanistic insight into how one-carbon metabolism shapes our lifespans. Furthermore, this new research also suggests that pharmacological targeting of key players in pathways that connect epigenetics and metabolism may one day lead us to the fountain of youth.