On Methionine Restriction
Methionine is an essential amino acid, one that we do not manufacture ourselves but must obtain from what we eat. It seems that a large fraction of the benefits of calorie restriction derive from alterations in metabolism that are based on sensing levels of methionine. Here is a review:
Comparative studies indicate that long-lived mammals have low rates of mitochondrial reactive oxygen species production (mtROSp) and oxidative damage in their mitochondrial DNA (mtDNA). Dietary restriction (DR), around 40%, extends the mean and maximum life span of a wide range of species and lowers mtROSp and oxidative damage to mtDNA, which supports the mitochondrial free radical theory of aging (MFRTA).Regarding the dietary factor responsible for the life extension effect of DR, neither carbohydrate nor lipid restriction seem to modify maximum longevity. However protein restriction (PR) and methionine restriction (at least 80% MetR) increase maximum lifespan in rats and mice. Interestingly, only 7 weeks of 40% PR (at least in liver) or 40% MetR (in all the studied organs, heart, brain, liver or kidney) are enough to decrease mtROSp and oxidative damage to mtDNA in rats, whereas neither carbohydrate nor lipid restriction change these parameters. In addition, old rats also conserve the capacity to respond to 7 weeks of 40% MetR with these beneficial changes. Most importantly, 40% MetR, differing from what happens during both 40% DR and 80% MetR, does not decrease growth rate and body size of rats.
All the available studies suggest that the decrease in methionine ingestion that occurs during DR is responsible for part of the aging-delaying effect of this intervention likely through the decrease of mtROSp and ensuing DNA damage that it exerts. We conclude that lowering mtROS generation is a conserved mechanism, shared by long-lived species and dietary, protein, and methionine restricted animals, that decreases damage to macromolecules situated near the complex I mtROS generator, especially mtDNA. This would decrease the accumulation rate of somatic mutations in mtDNA and maybe finally also in nuclear DNA.
Thanks for all your investigations into methods of extending human lifespan. Regarding caloric/dietary restriction: If a 40% reduction in ingested calories (e.g. 800 incoming calories eliminated from a 2000 calorie diet) yields efficacious results, would any combination of reducing incoming calories plus increasing outgoing calories (i.e. exercise) yield similar benefits?
Calorie restriction works in a completely different way to exercise, while both are beneficial.
There's plenty of evidence from animal studies to suggest that calorie restriction benefits scale by how much you restrict up to around 40% or thereabouts, and thus mild calorie restriction is mildly beneficial.
On the exercise front, human studies support moderate regular exercise as being far better than no exercise, but it's hard to find good evidence to suggest that more is better from the standpoint of health and longevity, or results showing scaling of effects by amount of exercise in humans. That's a causality issue in the association studies. For example, athletes live longer than the rest of the population, but is that because of all the exercise, or is it that they are more robust to start with and thus more likely to be athletes? Could be either of those options.
If complex-I plays an active role in aging, there are several agents that reduce its activity, such as metformin and minocycline. I believe they are non-selective, though. The ROS generated may play important signaling roles also.
Good work!
Dr Ullis