Calorie restriction has been rigorously demonstrated to slow aging in mammals for eighty years, but only in the past thirty years has research on this topic picked up. Since calorie restriction has a sizable and very reliable effect in comparison to most other interventions that can modestly slow aging, and requires no advanced technology or expensive treatments, the fact that it does extend life has been the starting point for many researchers interested in the mechanisms of aging. One of the most important tools in the sciences is the comparison of two similar things in order to pinpoint differences that are important, in this case animals of the same species and lineage with varied dietary calorie intake.
The primary goal of the scientific community is to map the changing molecular biochemistry of aging, with doing something about aging a distant second where it is considered at all. The calorie restriction response is at once useful and frustrating because it changes near everything in the operation of metabolism and slows near every measure of aging. Since all aspects of cellular biology are intertwined, this makes it enormously difficult to figure out chains of cause and effect. Understanding calorie restriction is more or less equivalent to fully understanding and mapping a large swathe of cellular biochemistry. This is a task that is expected to run for decades yet at the present pace. There are a lot of details and blank spots left to be filled in, and the closer researchers look, the more there is to find.
It is useful to understand that complex descriptions of what goes on in a calorie restricted individual are still really only sketches. There are lines drawn, and the high level picture is mostly in place in outline at least, but the full details are yet to be cataloged, and there may yet be surprises. If researchers waded through all the work required, and were to develop drugs that accurately mimicked the calorie restriction response - a tall order - the benefits would still be modest. This is not rejuvenation, repair of damage, but only a slowing of the progression of damage in aging. It is something worth doing when it is free, since every healthy year counts in a time of rapid progress, but the price tag for the scientific community to produce drugs that achieve that end seems excessive to me, at least when considering the marginal outcome. At least a billion dollars has been spent on this so far, and there is nothing much to show for it aside from new knowledge of narrow slices of our biology: see the much hyped work on sirtuins for example. We'd be better off supporting SENS-like rejuvenation research, such as senescent cell clearance, as that has already produced more impressive results in the first studies in mice than calorie restriction mimetics ever have.
None of that means that calorie restriction research is uninteresting. Far from it. Take this open access review, for example. Just bear in mind the costs and the benefits of various approaches when reading the literature:
Ageing is not a disease and therefore, disease-oriented research and treatment approaches are not adequate. It has thus been proposed that the use of health-oriented and preventive strategies is more beneficial than disease-oriented treatments. Calorie restriction (CR) is, to date, the most successful intervention to delay ageing progression or the development of age-related chronic diseases. CR has been defined as the reduction of energy intake without malnutrition. During the last few years it has been demonstrated that CR extends lifespan, extending the healthspan by delaying the onset of age-related diseases in many of the animal models studied. This effect of CR on longevity was explained in a unified theory of ageing as not a simple and passive effect but an active, highly conserved stress response that increases the organism's chance of surviving adversity. Thus, CR produces a response that modifies key process in cell protection, reparation mechanisms and modulation of metabolism that permits a higher survival against adversity. This has been supported by the 'Hormesis hypothesis of CR' that suggests that the induction of a moderate stress causes adaptive responses of cells and organs, preventing further damage due to a stronger stress
There are no detailed reports about the effect of CR on longevity in humans. The longer life expectancy of humans in comparison with other animals and the low number of persons tested makes it difficult to reach conclusions about the effect of CR on human longevity. It is not yet clear if the reported effects on longevity and healthspan found in humans are due to the decrease in the calorie intake or are the result of a high quality diet. However, it seems clear that a reduction in calorie intake in humans improves healthspan, and delays cardiac ageing, improving cardiovascular function, one of the main causes of death in humans.
Mitochondrial activity and ROS production are modulated by CR
In spite of the enormous number of articles published about the mechanism involved in the effect of CR on longevity, these mechanisms have not been clarified to date, although an important role of the maintenance of a balanced activity in mitochondria is supported by a large body of evidence. Ageing is associated with the impairment of mitochondria, with a significant increase in reactive oxygen species (ROS) generation and a decrease in antioxidant defences, causing accumulation of mitochondrial DNA and oxidative damage. An important factor involved in the accumulation of damaged mitochondria during ageing is the decline of the mitochondrial turnover by inhibition of mitophagy; the specific autophagy process that removes damaged mitochondria. It is clear that the renovation of mitochondrial network plays a key role in healthspan increase after CR.
Importance of membrane lipid composition on the CR effect
The decrease in the oxidative damage in organic structures is one of the main factors contributing to lifespan extension induced by CR. The fatty acid composition of cell membranes is another important factor involved in ageing progression because it influences the lipid peroxidation rate during ageing. Thus, several findings indicate that the increase in lipid peroxidation during ageing. It is still unclear whether lifespan extension induced by CR can also be explained by changes in membrane fatty acid composition conferring higher resistance to peroxidation. We have recently found that lipid composition in the diet can modulate the effect of CR on longevity, for example.
Antioxidant activities in ageing and CR
Oxidative damage is prevented by endogenous antioxidant activities in cells and organs. Although one of the most popular theories to explain the prolongevity effect of CR on different organisms is based on higher protection against the increase in oxidative stress and subsequent cell damage, the role of antioxidants in CR effect is not clear. Many lines of evidence indicate that CR reduces age-associated accumulation of oxidized molecules. However, the lack of lifespan extension in antioxidant enzyme overexpression experiments casts doubt on the importance of antioxidants in the CR effect. Higher levels of antioxidants do not necessarily indicate a higher antioxidant protection and imbalances produced by the overexpression or higher activity of one antioxidant enzyme must be taken into consideration.
Among the hypotheses to explain ageing, several findings indicate that changes in the insulin-IGF-I receptor signalling system are involved in the modulation of ageing. CR reduces plasma levels of IGF-I, insulin and glucose in rodents and also in humans.
Target of Rapamycin (TOR)
TOR protein members are a conserved family of kinases that respond to stress, nutrient and growth factors. TOR stimulates cell growth when food is available. TOR inhibits autophagy and stimulates protein synthesis and cell proliferation. The importance of TOR in longevity induced by CR was also demonstrated in invertebrates. In these organisms, down-regulation of TOR produces an increase in lifespan.
AMP-dependent protein kinase (AMPK)
AMPK is a very sensitive energy sensor in cells and organisms. AMPK is activated in response to an increase in the AMP/ATP ratio, for example, when cells are deprived of glucose, whereas its activity decreases when cells are full of energy, indicated by a lower AMP/ATP ratio. As in the case of other regulators such as sirtuins, its effect on longevity has been observed in several organisms from yeast to mammals. It has been clearly demonstrated that an increase in AMPK activity is associated with a longer lifespan while its inhibition shortens it. However, in mammals, the importance of this kinase is under debate since it has been reported that its activity is not affected by CR or is even reduced. However, other studies indicate an increase in AMPK activity in heart and skeletal muscle. These discrepancies could be due to differences in the amount of time under CR or the degree of CR which can play an important role in nutrient balance.
Some time ago it was demonstrated that the orthologue of mammalian SIRT-1, Sir2, was able to increase lifespan in invertebrates. In mammals, it is clear that CR induces the expression and the activity of sirtuins in many organs and their activities are associated with many of the metabolic effects found in these organisms after CR. Interestingly, sirtuins seem to play a central role in the response to CR. Sirtuins act as nutrient and metabolic sensors by detecting fluctuations in the NAD+/NADH ratio. When nutrients, especially glucose, decrease, NAD+ accumulates and sirtuins are activated. Thus sirtuins have an opposite effect to TOR activation after glucose input. The complexity of sirtuins in mammals has promoted the idea that they can show both pro- and anti-ageing capacities in mice.
Mitochondrial modifications induced by CR
Several studies found that mitochondrial biogenesis is impaired during ageing, especially in high-energy-demanding tissues such as muscle, brain or heart. CR and other interventions such as exercise or nutraceuticals such as resveratrol induce mitochondrial biogenesis in heart and skeletal muscle in humans and other organisms, indicating their role in the maintenance of the mitochondrial activity in these organs during ageing.
During the past few years, a group of molecularly unrelated compounds have emerged as CR mimetics, able to produce, at least partially, similar effects in different organisms. In general, all these compounds have a common denominator, the activation of the above-described molecular pathways involved in the response to CR such as AMPK and sirtuins. All these compounds have shown, at least in part, similar effects to CR on cells, tissues and organs and all of them have produced mitochondrial regulation by increasing turnover and activating oxidative metabolism through activation of the AMPK/SIRT1 axis and inhibition of TOR. It seems clear then that the regulation of mitochondrial metabolism by these nutrient sensors is at the centre of the effect of CR and its mimetics on healthspan and longevity.
CR and inflammation
Inflammation is also an important factor in ageing. Proinflammatory factors such as TNF-α increase systemically during ageing. It has been shown that the increase in oxidative stress during ageing can be involved in the incidence of age-related diseases and the induction of a chronic inflammatory process. It is likely that the maintenance of mitochondria biogenesis by CR can increase the resistance of muscle against inflammation.
Effect of CR on age-associated diseases in humans
Two of the main age-associated diseases in humans are type 2 diabetes and cardiovascular disease (CVD). In both cases, models of CR, dietary interventions or exercise have shown important improvements in the onset and development of these diseases.
The broad effect of CR on healthspan and longevity occurs through multiple mechanisms that involve most of the metabolic pathways in tissues and organs. The major effectors are sirtuin deacetylases, AMPK and PGC-1α. CR improves aerobic metabolism by increasing efficient mitochondrial metabolism, lowering endogenous ROS production at the same time as it increases the amount and activity of endogenous antioxidant enzymes. These molecular and physiological effects have also been found with some nutraceuticals and compounds that act as CR mimetics such as resveratrol, rapamycin or metformin. CR also affects the lipid composition of membranes by lowering oxidative damage. Further, the study of the mechanisms involved in the prevention of chronic inflammation induced by CR, probably through similar mechanisms to those found in mitochondrial regulation, is increasing and offers new opportunities to understand how CR prevents endogenous damage in the organism.