Mikhail Blagosklonny might be, to my eyes, a little too focused on mTOR as the be-all and end-all of aging, but he certainly writes a good paper when he puts his mind to it. This one is a thought-provoking look at similarities and differences in mechanisms that come into play at the opposite ends of the calorie intake spectrum. Differences in dietary habits lead, on average, to a longer, healthier life when eating less and a shorter, more unhealthy life when eating more. Naturally, the mechanisms underlying these changes are of interest to researchers who work on calorie restriction mimetic drugs, seeking to understand and then recreate the health benefits through medical technology:
Calorie restriction (CR), which deactivates the nutrient-sensing mTOR pathway, slows down aging and prevents age-related diseases such as type II diabetes. Compared with CR, rapamycin more efficiently inhibits mTOR. Noteworthy, severe CR and starvation cause a reversible condition known as "starvation diabetes." [and] chronic administration of rapamycin can cause a similar condition in some animal models. ... Here I introduce the notion of benevolent diabetes and discuss whether starvation-like effects of chronic high dose treatment with rapamycin are an obstacle for its use as an anti-aging drug.
[You] might wonder whether rapamycin extends lifespan despite or because of "starvation-like diabetes". ... Rapamycin, which inhibits mTOR, is a "starvation-mimetic", making the organism "think" that food is in a short supply. The most starvation-sensitive organ is the brain. The brain consumes only glucose and ketones. Therefore, to feed the brain during starvation, the liver produces glucose from amino acids (gluconeogenesis) and ketones from fatty acids (ketogenesis). Since insulin blocks both processes, the liver needs to become resistant to insulin. Also secretion of insulin by beta-cells is decreased. And adipocytes release fatty acids (lipolysis) to fuel ketogenesis by the liver. Thus, there are five noticeable metabolic alterations of starvation: gluconeogenesis, ketogenesis, insulin resistance, low insulin levels and increased lipolysis. This metabolic switch is known as starvation diabetes, a reversible condition, described 160 years ago.
Starvation-diabetes is not a true type II diabetes. Type II diabetes is a consequence of insulin-resistance in part due to excessive nutrients and obesity. ... Type II diabetes and starvation diabetes seem to be the two opposite conditions: the first is associated with activation of nutrient-sensing pathways, whereas the second is associated with deactivation of nutrient sensing pathways such as mTOR. Type II diabetes is dangerous by its complications such as retinopathy, neuropathy and accelerated atherosclerosis and cancer. Long-term effects of prolonged "starvation diabetes" is not known of course: it could not last for a long time, otherwise an animal (or human) would die from starvation. Or would not? ... Among individuals who had been practicing severe CR for an average of 7 years, 40% of CR individuals exhibited "diabetic-like" glucose intolerance, despite low levels of fasting glucose, insulin and inflammatory cytokines as well as excellent other metabolic profiles. In comparison with the rest CR individuals, they had lower BMI, leptin, circulating IGF-I, testosterone, and high levels of adiponectin, which are key adoptations to CR in rodents, suggesting severe CR.
The authors speculated that the "insulin resistance" in this severe CR group might have the effect of slowing aging, also based on the finding that a number of insulin-resistant strains of mice are long-lived. The same conclusion could be reached from the mTOR perspective
Metabolism is a complex thing, is it not? The benefits of calorie restriction in humans are legion, per the research to date, and it's well worth your time to look into it and give it a try. Heart health vastly improved, near every measure of aging slowed, greater resistance to age-related diseases, and much more - far more than any medical technology can yet accomplish for a basically healthy individual, in fact.