Fight Aging!

Methionine is one of the essential amino acids for mammals, a molecule necessary for synthesis of proteins but which our biochemistry cannot manufacture from scratch. Thus we have to obtain methionine from our diets, and without it we will die. But eating less than we might choose to has the opposite effect: the evidence to date strongly suggests that a large fraction of the beneficial effects on health and longevity produced by calorie restriction actually stem from methionine restriction: eat less food overall and you eat less methionine, since comparatively few foodstuffs have low methionine content. The operation of inroads are being made. It is also a great deal more difficult to organize as a lifestyle in comparison to calorie restriction, intermittent fasting, and the like, as the data on methionine levels is comparatively poor and there are few options when it comes to assembling meal plans. Most dietary staples are rich in methionine. If you want to obtain the benefits of an optimal metabolism, the old fashioned way is still best supported by evidence: regular moderate exercise and calorie restriction.

Beyond less food and less methionine there are many ways to manipulate the operation of metabolism in order to modestly slow aging and extend life in laboratory animals such as mice and flies. The most effective at present involve gene therapy to disable growth hormone or its receptor: the longest lived growth hormone receptor knockout (GHRKO) mice are dwarfs with life spans as much as 60-70% longer than their unmodified peers. Unfortunately that isn't likely to translate into extension of human life spans. The small population of mutants with Laron Syndrome have a similarly impacted growth hormone metabolism, and while it is possible that they are more resistant to some common age-related diseases, they don't live markedly longer than the rest of us.

There has been some interest in mixing and matching various means of slowing aging as a way to better identify which of them are just different ways of altering the same root mechanisms. It is probably the case that while there exist dozens of genetic alterations that extend life in laboratory animals, only a few underlying important changes in metabolism actually determine variations in longevity. Cells are machine shops in which everything connects to everything else: evolution produces promiscuous reuse of parts, and any given protein usually has multiple roles to play in quite diverse processes. It is impossible to change anything in isolation in the biochemistry of the cell.

Hence here is an open access paper in which researchers try methionine restriction for long-lived growth hormone mutant mice, and find that the mutants don't benefit from it at all. This strongly implies that whatever is turned on by methionine restriction is already turned on in the growth hormone mutants, and thus these are just different windows onto the same room. Growth hormone disruption is just another way to trigger something that looks like the calorie restriction response. That in turn reinforces the present consensus that both calorie restriction and disruption of growth hormone metabolism are not going to perform miracles for human longevity: we have too many examples in which that is not the case. The evolutionary explanation for calorie restriction is that it is an adaptation to seasonal famine, and thus short-lived animals evolve a much more plastic life span in response to that circumstance. A season is a large fraction of a mouse life span, but not so for humans.

Growth hormone signaling is necessary for lifespan extension by dietary methionine

Growth hormone significantly impacts lifespan in mammals. Mouse longevity is extended when growth hormone (GH) signaling is interrupted but markedly shortened with high-plasma hormone levels. Methionine metabolism is enhanced in growth hormone deficiency, for example, in the Ames dwarf, but suppressed in GH transgenic mice. Methionine intake affects also lifespan, and thus, GH mutant mice and respective wild-type littermates were fed 0.16%, 0.43%, or 1.3% methionine to evaluate the interaction between hormone status and methionine. All wild-type and GH transgenic mice lived longer when fed 0.16% methionine but not when fed higher levels. In contrast, animals without growth hormone signaling due to hormone deficiency or resistance did not respond to altered levels of methionine in terms of lifespan, body weight, or food consumption. Taken together, our results suggest that the presence of growth hormone is necessary to sense dietary methionine changes, thus strongly linking growth and lifespan to amino acid availability.

Ames dwarf and GHRKO mice lived a similar length of time as their wild-type controls when fed the 0.16% MET. Importantly, this finding reflects both a lack of response to low MET by the GH signaling-deficient mice and a significant extension of lifespan by their respective wild-type mice. On higher levels of MET, both the GHRKO and Ames mice outlived (median) their wild-type counterparts by 7-8 and 11-12 months, respectively. Maximal longevity did not differ between GHRKO or Ames mice, regardless of diet.

Here, we show that active GH signaling is necessary for mice to respond to changes in dietary methionine in terms of lifespan, body weight, and food consumption. The survival curves of mice with normal or excess plasma GH levels appeared similar. In contrast, the lifespans of Ames dwarf and GHRKO mice indicate that without GH signaling, the system is unable to detect or sense changes in dietary methionine. Thus, the underlying genotype effects that result in a lack of GH signaling are not apparent when animals consume low MET diets. In cases of either GH or MET deficiency, metabolic reprogramming occurs possibly shifting resources away from growth toward more protective mechanisms, resulting in lifespan extension.