Calorie restriction is the only dietary intervention to date that can extend both maximal and healthy lifespan in different species. It is important to note that a better term for Calorie restriction is calorie restriction with optimal nutrition (CRON) because a whole variety of nutrients are needed in specific quantities to fulfill biological processes in the body. Think about all the vitamins, minerals and essential amino acids and fatty acids. In practice, CRON is done by restricting calories by up to 65% (depending on the species) and a few humans who dedicated their lives to the calorie restricted diet combine it with a mostly plant-based diet. A plant-based diet is ideal to combine with CRON, and this is because a typical western diet which is rich in protein and refined carbohydrates will spike mammalian target of rapamycin (mTOR), insulin and IGF-1 and will decrease AMP Kinase, to name a few pathways. And this is precisely the opposite of what you want to achieve on CRON for healthy aging benefits.

Mechanisms of action

Reducing oxidative damage
The effects of reduced oxidative damage (which is caused by reactive oxygen/ nitrogen species (ROS/ RNS), and other lesser known oxidants) is very complicated. And is likely influenced by a variety of factors, including sex, species, tissue examined, types of ROS and antioxidant enzymes tested, and duration of CRON. The mitochondria, which are the powerhouses of the cell that produces the energy needed to sustain life, known as ATP play an essential role in this mechanism of action. The process in which ATP is produced when oxygen is available is called aerobic respiration which also releases waste products like ROS. Under caloric restriction your body will produce more mitochondria, this is known as mitochondrial biogenesis and will make them more efficient in producing energy, and the antioxidant enzymes like mitochondrial Sod1 will be up-regulated to decrease oxidative damage.

(Mitochondrial) hormesis
The scientific literature has also pointed towards hormesis. Hormesis is a process in which a low exposure to a toxin or stressor will produce a favorable biological response and will increase the bodies resilience to that toxin or stressor. In this case, the stressor is reduced caloric intake, and this will elicit a defensive response that may protect against aging and age-related diseases. This defense response could be an epigenetic (switching a specific gene on or off, this is oversimplified of course) switch on longevity genes.

Sirtuins
Many CRON studies have shown the importance of sirtuins like Sirt2 and Sirt3. This hypothesis came to stand by researching sirtuin mutants like the Sirt3 KO (knockout) mice. Studies on Sir2 mutant yeasts on a restricted caloric diet did not improve longevity. One of the positive effects of Sirt3 on age-related diseases is by promoting the glutathione-mediated mitochondrial antioxidant defense system. The whole mechanism of action behind sirtuins and longevity is very complicated, and therefore I won’t go into detail.

Down-regulation growth pathways/ hormones
Like I said at the beginning of this article, caloric restriction is known to decrease different pathways that are known to play a role in the growth of various cells like mTOR, insulin, IGF-1,… etc. Those three pathways and hormones are the three most well known to affect aging and age-related diseases. This is because they are also important regulators of cell growth and proliferation that are influenced by CRON. There is broad consensus that reduced mTOR signaling (especially mTORC1) probably contributes to longevity and health benefits. As a result of dietary restriction, mTOR activity is also linked to insulin/ IGF-1 signaling through multiple connections.

Conclusion
Aging is very complicated, and there is still a lot we don’t know. The pathways that have been described in this article are just a few hypotheses that are well known in the scientific field on how caloric restriction can extend maximal and healthy lifespan. I encourage you to read a lot more on Pubmed about CRON and all the mechanism behind it.