In 1934, researchers at Cornell University discovered that laboratory rats fed a severely restricted diet lived up to twice as long as those fed a regular diet. Subsequent research has confirmed the health and longevity benefits of dietary restriction (DR, also referred to as “calorie restriction”, CR) across a wide range of species, including primates. In addition to increased lifespan, reduced dietary intake typically results in a prolonged youthful appearance, increased physical energy and activity levels, improved cognitive function, and a pronounced reduction in age-related disorders including cognitive decline, heart disease and cancer.
Vince has discussed Calorie restriction previously in this blog. It was first raised in a July 2009 blog entry Calorie Restriction, longevity, and waiting for proof of what works. In December 2009 and January 2010 Vince also published Calorie restriction research roundup – Part I dealing with the effects of CR on cancers and Calorie restriction research roundup – Part IIfocused on the somatotropic axis and the involved gene activation pathways. As CR still remains the best-known and most-studied intervention for life extension, insights on it continue to accumulate. The current blog entry represents a fairly comprehensive review of the topic looking at newer as well as older reports.
Understanding the mechanisms of these remarkable effects holds great potential for the development of anti-aging, health-promoting therapeutics.
How exactly does DR work? It would be convenient if a single pathway were responsible for all of the remarkable health benefits of DR. However, given the complexities of human physiology, this would appear to be wishful thinking. Indeed, evidence indicates that multiple pathways are involved. I will briefly review several likely mechanisms of action. In one or more follow-up pieces, I intend to discuss the epigenetic concomitants of DR and therapeutic strategies targeting DR pathways.
Do the Benefits of DR Result from Decreased Body Fat?
Obesity (or just being “overweight”) is a well-known risk factor for many illnesses, including many which are greatly reduced under DR. Perhaps the improved health and increased longevity of DR simply result from decreased body fat stores? This hypothesis, although superficially plausible, is not supported by the evidence. One recent study (2011) actually found that in 41 genetically distinct strains of mice, those that lost the most fat under DR, consistently had the shortest lifespan.(ref) DR produces the greatest benefits in those who lose the least amount of weight.
Despite the fact that overweight individuals are incessantly urged to lose weight, this recommendation is not supported by human clinical or epidemiological studies. The successful, intentional loss of excess body fat consistently results in worse health outcomes, and increased mortality/morbidity. This phenomenon is known as the “obesity paradox”. Although perceptive readers may find hints for the reason of this paradox, I won’t go into a detailed discussion of it here. I will, however, provide some references for those with further interest in this unorthodox topic. See:
A review and meta-analysis of the effect of weight loss… 
Combined effects of weight loss and physical activity… 
Explaining the obesity paradox 
Association between body mass index and morality… 
Weight, mortality, years of healthy life,… 
Fitness and fatness as mortality predictors… 
Intention to Lose Weight, Weight Changes, and 18-y Mortality… 
Body Composition and Heart Failure Prevalence and Prognosis 
Does DR Decrease Metabolic Rate?
It has been commonly reported that DR decreases metabolism; and that this directly accounts for decreased production of ROS, and many of the observed health benefits. This has theoretical and intuitive appeal, particularly given the negative correlation between metabolic rate and longevity observed across species. Although DR can slightly lower body temperature, some researchers have questioned the empirical evidence for the claim that DR significantly decreases metabolic rate. Some even claim that DR increases metabolism: “CR does not seem to decrease the metabolic rate, as was formerly thought, but it appears to actually increase it , and this increase is responsible for its buffering effects on oxidative stress (Figure 1).” (ref) “Data are presented in this report showing that food restriction can have a marked life-prolonging action in rats without reducing caloric intake per gram of body weight. Moreover, the food-restricted rats consumed a greater number of calories per gram of body weight during their lifetimes than did the rats fed ad lib, yet they lived longer. Thus, the data in this report do not support the concept that food restriction slows the rate of aging by decreasing the metabolic rate.”(ref) An interesting, recent model based on energy repartitioning, in accordance with the Disposable Soma Hypothesis, predicts that “CR’s effects on health maintenance are negatively correlated to the temperature drop observed in endothermic animals, and is positively correlated to animals’ body masses. . .The negative correlation between body temperature and lifespan has only been observed in animals fed ad libitum. No experiments have been done to investigate lifespan of endotherms with different body temperatures under CR conditions. CR extends lifespan and in many cases lowers body temperature, but as far as we are concerned there is no evidence showing lowered body temperature as the mechanism underlying CR’s effect on health maintenance.”(ref)
Does DR increase mitochondrial biogenesis?
DR is believed to improve mitochondrial function through various mechanisms such as uncoupling, which will be discussed later. Many researchers have also claimed that DR increases the number of mitochondria.(ref, ref) Others have recently disputed these claims. “It has been reported that 30% calorie restriction (CR) for 3 mo results in large increases in mitochondrial biogenesis in heart, brain, liver, and adipose tissue, with concomitant increases in respiration and ATP synthesis. We found these results surprising, and performed this study to determine whether 30% CR does induce an increase in mitochondria in heart, brain, liver, adipose tissue, and/or skeletal muscle. To this end, we measured the levels of a range of mitochondrial proteins, and mRNAs. With the exception of long-chain acyl-CoA dehydrogenase protein level, which was increased ∼60% in adipose tissue, none of the mitochondrial proteins or mRNAs that we measured were increased in rats subjected to 30% CR for 14 wk. There was also no increase in citrate synthase activity. Because it is not possible to have an increase in mitochondria without any increase in key mitochondrial proteins, we conclude that 30% CR does not induce an increase in mitochondria in heart, brain, liver, adipose tissue, or skeletal muscle in laboratory rodents.”(ref) (The observed increased levels of acyl-CoA dehydrogenase are likely due to the metabolic shift towards fat oxidation, which is discussed below.)
The Hypothalamus and Neuropeptide-Y
The hypothalamus is a small part of the brain, roughly the size of an almond. Despite its small size, the hypothalamus plays a central role in the regulation of a broad range of biological systems and functions. It regulates the release of pituitary hormones, and controls circadian patterns of sleep and activity. It is the central regulator of energy homeostasis, controlling energy expenditure, energy intake, and energy storage. The hypothalamus responds to peripheral signals including insulin, glucose and adipokines such as leptin. In response to these signals the hypothalamus regulates energy utilization. Neuropeptide Y (NPY) is produced in response to fasting conditions. NPY has many complex effects throughout the body.
Hungry for Life: How the arcuate nucleus and neuropeptide Y may play a critical role in mediating the benefits of calorie restriction
“It is well established that CR raises NPY levels (Bi et al., 2003; Brady et al., 1990; de Rijke et al., 2005; Kim et al., 1988; Mercer et al., 2001; Widdowson et al., 1997). Because the normal response to increased NPY levels is hyperphagia and a return to normal energy balance, animals on CR must be maintained on a strict regimen and fed periodically their restricted meals. . . Whether the increased NPY is a necessary precursor to the functional benefits associated with dietary restriction is not known, but considering NPY’s unique long-term response to CR compared with other neuropeptides (Bi et al., 2003) and its plethora of physiological actions, a causal relationship is certainly plausible.
One way CR may act to extend lifespan through NPY is by prolonging youthful expression levels of NPY. Aging is associated with reduced levels of NPY in the brain in general (Gruenewald et al., 1994; Higuchi et al., 1988; Sohn et al., 2002; Vela et al., 2003) and in response to fasting (Gruenewald et al., 1996). Reduced NPY has been associated with Alzheimer’s disease (Alom et al., 1995; Edvinsson et al., 1993) and the development of a condition termed ‘anorexia of aging’, thought to be responsible for aging-associated under-nutrition and consequent physical deterioration such as osteoporosis, sarcopenia, impaired immunity and parenchymatous organ failure (Matsumoto et al., 2000; Morley, 2001). Evidence from the rat showing NPY loss with age is progressive and independent of testosterone levels has been interpreted to suggest an active role for NPY in the anorexia of aging (Gruenewald et al., 1994).
The increase in NPY under CR conditions can lead to a wide array of physiological modifications. Among these, there exist a number of parallels between the observed effects of CR and NPY that extend beyond their obvious influence on hunger (Fig. 3). For example, CR is well known for lowering core body temperature in mammals (Walford and Spindler, 1997), as does central administration of NPY (Billington et al., 1991; Kotz et al., 2000), both of which may act through an increase in ghrelin emission from the stomach (Gluck et al., 2006). . .Altered metabolism is another hallmark of CR, manifest in part by reduced levels of circulating blood glucose (Harris et al., 1994). Likewise, acute administration of NPY has been shown to lower blood glucose in both rats and humans (Ahlborg and Lundberg, 1994; Bischoff and Michel, 1998; Marks and Waite, 1997). The effects of CR and NPY on blood glucose mirror their effects on corticosterone in rodents, which is to say they both induce increased circulating levels of this glucocorticoid (Harris et al., 1994; Leibowitz et al., 1988; Wahlestedt et al., 1987).”
The arcuate nucleus and neuropeptide Y contribute to the antitumorigenic effect of calorie restriction.
“Calorie restriction (CR) is known to have profound effects on tumor incidence. A typical consequence of CR is hunger, and we hypothesized that the neuroendocrine response to CR might in part mediate CR’s antitumor effects. We tested CR under appetite suppression using two models: neuropeptide Y (NPY) knockout mice and monosodium glutamate-injected mice. While CR was protective in control mice challenged with a two-stage skin carcinogenesis model, papilloma development was neither delayed nor reduced by CR in the monosodium glutamate-treated and NPY knockout mice. Adiponectin levels were also not increased by CR in the appetite-suppressed mice. We propose that some of CR’s beneficial effects cannot be separated from those imposed on appetite, and that NPY neurons in the arcuate nucleus of the hypothalamus are involved in the translation of reduced intake to downstream physiological and functional benefits.”
Will the Hunger Eventually Subside?
This is an interesting question which has practical implications for the viability of DR interventions in humans. All available evidence from animal studies demonstrates that the hunger never subsides. When released from DR, even after the equivalent of many human years of restriction, animals invariably display a hyperphagic response indicating a persistent hunger drive.(ref, ref) An even more important point is that we would not want the hunger to subside, since the sensation of hunger resulting from hypothalamic production of NPY appears to play a necessary role in mediating the beneficial effects of DR.
Decreased Oxidative Stress
“There is evidence that both CR and IF [intermittent fasting] prevent oxidative damage by three major mechanisms: diminished production of mitochondrial reactive oxygen species (ROS), increased antioxidant defenses and increased repair mechanisms for molecules that have been damaged as a result of oxidation . Several studies have shown low levels of mitochondrial ROS generation in various tissues of CR rodents including the brain [35,36]. There is evidence that this is due to a mild enhancement of the mitochondrial respiratory rate, resulting in lower ROS release. Recent studies provided substantial evidence to confirm the link between respiratory rate, ROS release  and aging  by causing mild uncoupling in the passage of protons through the inner mitochondrial membrane from mitochondrial phosphorylation. This uncoupling is partly mediated by the so-called uncoupling proteins (UCP), whose levels are increased by CR in various tissues, including the neuron-specific UCP4 (Figure 1) . There is evidence for the neuroprotective effects of UCP2, UCP4 and UCP5; however, their effects seem to encompass more than just mild uncoupling of the mitochondrial membrane and in some cases they appear to mediate protection through totally different mechanisms [40–43].”(ref) Space does not permit a detailed discussion of uncoupling here, although it may be the topic of a future post.
Another way DR appears to lower mitochondrial ROS production is by inducing a metabolic shift away from glucose to fat utilization. This metabolic shift has other benefits which are discussed in greater detail below. “Unlike carbohydrate catabolism, in which most of the reducing power generated for electron transport is in the form of NADH, β-oxidation of fatty acids produces FADH at a molar equivalence of NADH. FADH must enter the electron transport chain not via complex I but via the electron transfer flavoprotein dehydrogenase (ETF) (coupled to acyl-CoA dehydrogenase) (Figure 2). ETF passes electrons to ubiquinone, which then donates them to complex III and thence onward down the chain. Therefore, use of fat as an energy source increases the frequency with which electrons enter the electron transport chain by bypassing complex I. Given that complex I is one of the primary stations of ROS production, this simple metabolic shift from carbohydrate to fat utilization may reduce ROS production.”(ref)
Increased Fatty Acid Utilization
One remarkable fact about DR is that it increases lipid oxidation far in excess of dietary fat consumption, yet once energy balance is achieved, body fat mass is maintained. Where does the extra fat come from? DR increases both fatty acid synthesis and oxidation. In other words, under conditions of DR, the body is programmed to convert nutrients into fat, which is then used as the primary energy substrate. Normal aging, on the other hand, is associated with a decrease in fat metabolism.(ref) Isotope measurements demonstrate that mice under DR burn four times as much fat per day as controls, even though they actually consume less. DR has also been shown to increase glucose uptake in fat cells despite a 60% decrease in plasma insulin level.(ref) What are the practical consequences of this metabolic shift?
- Decreased oxidative stress. This effect was previously mentioned. Fatty acid beta-oxidation bypasses complex I, generating fewer ROS.
- Improved distribution of fat deposits Under DR, fat is preferentially stored near muscle tissue where it can be readily used for energy, rather than in the liver, or visceral compartments where is known to be more harmful.(ref) DR also increases the production of a healthful type of fat, called “brown adipose tissue.”(ref)
- Improved adipokine secretion profile, including increased production of adiponectin.(ref) Fat tissue is not a dormant storage depot, but rather an endocrine organ, actively secreting many hormones called “adipokines”, with wide-ranging effects on health. Many have inflammatory effects; however, adiponectin is anti-inflammatory, increases insulin sensitivity, has multiple health benefits, and increases longevity.(ref) In fact, centenarians of diverse genetic backgrounds have elevated levels of adiponectin suggesting an important role in human longevity. For more information on the role of adipokines in longevity, see: Adipokines and Aging. It is also interesting to note that certain genetic mutants with increased longevity exhibit elevated levels of adiponectin, as well as decreased glucose/increased fat utilization.(ref)
- Improved insulin sensitivity. This effect has already been alluded to. Increased fat utilization is one of multiple pathways by which DR increases insulin sensitivity. It results, in part, from the improved adipokine secretion profile, as well as decreased plasma insulin and glucose levels. Liver production of glucose (gluconeogenesis) becomes suppressed.(ref) Gluconeogenesis relies more heavily on amino acids and lactate in place of glycerol.(ref) It is very likely that this improved insulin/glucose profile explains the observed decrease in dangerous AGEs (Advanced Glycation End Products) under DR.(ref)
- Decreased inflammation. Again, this results, in part, from improved secretion of adipokines (ref), as well as reduced adipocyte infiltration by macrophages.(ref) Reduced glycemia and AGEs further lessen systemic inflammation.(ref) Although not a direct consequence of fat utilization, glucocorticoids, which are increased by NPY, also have well-known anti-inflammatory effects. PPARs, which are discussed in the next section, have powerful anti-inflammatory effects, as well.
- Increased production of ketones. When carbohydrate availability is restricted, the body derives energy from fats by converting them into ketones. In The neuroprotective properties of calorie restriction, the ketogenic diet, and ketone bodies, researchers propose that “ketone bodies mediate, at least in part, the neuroprotective effects of calorie restriction by showing that ketone bodies are equally neuroprotective and that calorie restriction and ketone bodies act on neural cells by similar mechanisms.” Antioxidant, metabolic, and anti-apoptotic mechanisms of ketone neuroprotection are discussed.
- Decreased tumorigenesis. Cancer cells are well-known to rely on glycolysis rather than lypolysis for their energy needs. This has been called the “Warburg Effect”. The shift to fatty acid beta-oxidation deprives cancer cells of the energy they need to grow and poliferating.
Upregulation of PPAR
Peroxisome proliferator-activated receptors comprise a group of nuclear receptors with three subtypes alpha, gamma, and beta/delta. They regulate many important of physiological functions, including energy metabolism, insulin function, and immune function. The age-related decline in PPAR levels appears to play a key role in the etiopathogenesis of many disorders.(ref) Decreased PPAR activity has a well-established role in cancer formation; however, much research has shown associations with heart disease, kidney disease, rheumatoid arthritis, neurological, and even infectious diseases. DR induces favorable changes in many of the same downstream targets of PPAR activity, suggesting a possible role of PPARs in mediating the effects of DR. In fact, animal models have shown that DR increases PPAR activity, partially offsetting the age-related decline.(ref) Transgenic research has further demonstrated the central role of PPARs in mediating the effects of DR.(ref, ref) It is interesting to note that not only does DR have a direct effect on PPAR activity, but maternal dietary intake can even alter the expression of PPAR in adult offspring.(ref) (The therapeutic value of PPAR agonists will be discussed in a future discussion.)
Increased PGC-1 Expression
“PPAR-Gamma Coactivator-1” refers to a family of proteins which regulate the transcriptional activity of many nuclear receptors including the PPARs. The subtypes are PGC-1alpha, PGC-1beta, and PRC (PGC-1 related coactivator). These regulatory proteins are highly responsive to changes in metabolic signals; hence, they are able to directly regulate the transcription of specific genes in response to cues such as nutrient status, oxidative and inflammatory stress, and energy requirements. They even respond to ambient temperature; in fact, PGC-1alpha was originally discovered to promote uncoupled thermogenesis in BAT in response to cold temperatures. The PGC1 family plays a central role in mitochondrial function and the regulation of energy homeostasis. PGC-1alpha induces expression of Sirt3, a sirtuin known to improve mitochondrial function.(ref) Relationships among PGC-1alpha and Sirt3 are discussed in the blog entry SIRT3 research– tying together knowledge of aging. PGC-1alpha deficiency is associated with metabolic and neurodegenerative disorders such as Parkinson’s and Huntington’s disease.(ref) Like PPAR, PGC-1alpha is known to decline with age, but is increased by DR.(ref) A recent rodent study found that DR increased PGC-1alpha up to 5-fold. “CR mice exhibited a significant increase in PGC-1alpha level in the heart (5.13-fold), kidney (3.57-fold), skeletal muscle (3.02-fold), liver (2.60-fold), small intestine (2.45-fold) and brain (2.05-fold), compared to normal (ad libitum) fed. The elevation in PGC-1alpha level, especially in highly oxidative tissues such as heart, kidney and skeletal muscle of CR mice might synergistically up-regulate genes that require PGC-1alpha co-activation.”(ref) Overexpression of PGC-1alpha, also further contributes to the metabolic shift towards fat oxidation.(ref)
PGC-1beta has many of the same gene targets as PGC-1alpha.(ref) The beta form is especially important for lipid metabolism, and is the target of niacin for improving lipid profile.(ref) PRC plays an important role in cell proliferation (ref), and appears to be involved in inflammatory responses.(ref) Overexpression of PGC-1, specifically in fruit fly progenitor cells was recently shown to increase longevity, suggesting that increased progenitor cell supplies may be a key mechanisms of DR.(ref) See, also the ScienceDaily article: Fruit Fly Intestine May Hold Secret to Fountain of Youth.
Peroxiredoxin (Prx) is a member of the thioredoxin superfamily of endogenous antioxidants. For more information on thioredoxin enzymes, see: Redox Regulation of Cell Survival by the Thioredoxin Superfamily (As an interesting side note, peroxiredoxins play a central role in the oldest form of circadian regulation, which does not rely on genetic transcription. For a very interesting discussion, see: Circadian Clock without DNA – History and the Power of Metaphor.)
Prx is responsible for breaking down harmful hydrogen peroxide. Prx also prevents the aggregation of damaged proteins associated with cancer and various degenerative diseases. The activity of Prx is dependent on a partner enzyme, known as sulfiredoxin (Srx), which is able to regenerate oxidized Prx, returning it to its functional form. Recent research has shown that
- Prx is necessary for DR to increase lifespan,
- Prx becomes damaged with age and deactivated,
- DR increases expression of Srx restoring Prx activity,
- An extra copy of the Srx gene slows yeast aging, even in the presence of high levels of glucose.
Life Span Extension and H2O2 Resistance Elicited by Caloric Restriction Require the Peroxiredoxin
Translating a Low-Sugar Diet into a Longer Life by Maintaining Thioredoxin Peroxidase Activity of a Peroxiredoxin
Live Longer With Fewer Calories? Key Enzyme Involved in Aging Process Found
Increased Protein Turnover
Proteins can be damaged by oxidation, glycation and other insults. Such altered proteins accumulate with age, leading to cellular dysfunction by interfering with normal physiologic processes. The body has developed mechanisms for the disposal of such altered proteins, primarily by either the lysosome or proteasome pathway. However, these pathways appear to become compromised with age. DR has been shown in rodent models to reduce the accumulation of altered proteins, very quickly, even when begun in late life. In fact, in just two months, DR reduced the levels of altered proteins in liver and brain tissue of old mice to that of young adults. Additional studies have shown that protein turnover rates are extended in older mice, but are quickly reduced to that of young mice within two months of DR. This indicates that the normal protein degradation pathways become compromised in older animals, and that the reduction of altered proteins under DR may be due to improved protein turnover. These effects were negated by a proteasome inhibitor, but unaffected by a lysosome inhibitor, demonstrating that the proteasome pathway is the one rejuvenated by DR. See: Beneficial Biochemical Outcomes of Late-Onset Dietary Restriction
The human body has no effective means for eliminating excess iron. Aging is associated with increased iron accumulation(IA), and dysregulation of iron metabolism. Iron is a powerful pro-oxidant, which through Fenton reactions generates ROS increasing oxidative damage and inflammatory stress. Iron has also been called a “double-edged sword”, because it not only causes oxidative genomic damage, but also interferes with normal DNA repair mechanisms.(ref)
Iron and Mechanisms of Neurotoxicity
“Iron itself has been related to neurotoxicity, and its accumulation, mainly in the hippocampus and cortex, has been observed to occur before AD lesions are detectable. Moreover, it has been also demonstrated to accumulate both in AD senile plaques  and in amyloid deposits in AβPP2576 transgenic mouse model of AD . Interestingly, Aβ insoluble aggregates have been shown to be dissolved by metal chelators . Oxidative stress is considered to be the earliest change in the pathogenesis of AD, and high levels of oxidative stress have been demonstrated to occur in the clinical precursor of AD, known as mild cognitive impairment (MCI) [51, 52]. Coincidently, increased iron levels were found both in the cortex and cerebellum from the preclinical AD/MCI cases. Moreover, iron concentrations have been found to be increased in the bilateral hippocampus, parietal cortex, frontal white matter, putamen, caudate nucleus, thalamus, red nucleus, substantia nigra, and dentate nucleus subregions of patients with diagnosed AD and in normal elderly patients [53, 54]. It is important to note that these brain iron concentrations, particularly those in the parietal cortex at the early stages of AD, have been found to positively correlate with the severity of patients’ cognitive impairment . Alterations in iron metabolism with age have been described, and they may involve iron uptake and release, storage, and intracellular metabolism [56–59]. Although some issues remain unclear, it is well known that the dyshomeostasis of brain iron metabolism is one of the initial events that trigger neuronal death in some neurodegenerative disorders [60–63]. Existing evidence shows that these mechanisms may well be altered by the ageing process with increased (IA) in the brain as the final outcome [64–66]. Age-induced IA has shown to be a consequence of the accumulation of different iron-containing molecules in different brain regions known to be particularly affected in disorders such as AD and PD [18, 56].”
Iron Accumulation and Muscle Atrophy
IA is also associated with age-related muscle atrophy (“sarcopenia”). Sarcopenia is rapidly becoming a major public health crisis. Approximately 10% of the population will suffer from sarcopenia between the ages of 60 and 70. However, this number rapidly increases to nearly fifty percent for those over age 80.(ref) Iron accumulation in muscle tissue causes atrophy by promoting apoptosis (cell death) likely through the NF-kB pathway. Excess non-heme iron (not bound to hemoglobin) also interferes with the activation of satellite cells (a type of muscle progenitor cell that when activated fuses with existing myotubes contributing their nuclear content). IA is also associated with a deterioration in the organizational efficiency of muscle fibers, and with a shift from fast-twitch to slow-twitch type fibers. This switch in muscle type further reduces strength. IA also prevents recovery from muscle atrophy resulting from injury or immobilization.(ref)
DR Prevents the Harmful Effects of Iron Accumulation
In animal models, DR has been shown to effectively counteract the deleterious age-related effects of IA. A calorie-restricted diet decreases brain iron accumulation and preserves motor performance in old rhesus monkeys:
“We used two common indicators of aging, motor performance speed and brain iron deposition measured in vivo using MRI, to determine the potential effect of CR on elderly rhesus macaques eating restricted (n = 24, 13 males, 11 females) and standard diets (n= 17, 8 males, 9 females). Both the CR and control monkeys showed age-related increases in iron concentrations in globus pallidus (GP) and substantia nigra (SN), although the CR group had significantly less iron deposition in the GP, SN, red nucleus and temporal cortex. A Diet x Age interaction revealed that CR modified age-related brain changes, evidenced as attenuation in the rate of iron accumulation in basal ganglia and parietal, temporal, and perirhinal cortex. Additionally, control monkeys had significantly slower fine motor performance on the Movement Assessment Panel, which was negatively correlated with iron accumulation in left SN and parietal lobe, although CR animals did not show this relationship. Our observations suggest that the CR induced benefit of reduced iron deposition and preserved motor function may indicate neural protection similar to effects described previously in aging rodent and primate species. . . The influence of age on iron accumulation was positively modulated by CR in caudate, SN, red nucleus, hippocampus, parietal and temporal cortices. This iron homeostasis suggests that CR slowed the aging process in these regions. A flattening of the aging slope concurs with previous findings suggesting a protective effect of CR, including grey matter volume preservation in CR monkeys (Colman et al., 2009). Improved motor performance and manual dexterity in the CR animals further underscores the functional significance of these findings. Fine motor deficits in the q-mark task were evident in the split-level correlations with iron accumulation. Increased iron was associated with slower food retrieval time in left SN and left parietal cortex for control but not CR monkeys. . . . Monkeys on a CR diet show reduced iron accumulation in the GP, SN and temporal cortex compared to controls in addition to showing less correlation between iron concentration and Age in GP and SN. Consumption of a CR diet from middle age slows the rate of iron accumulation in parietal and temporal cortices, GP, SN and RN. CR monkeys showed preservation of motor performance, appearing similar to published reports of monkeys 10 years younger, which were associated with the iron determination in brain areas associated motor function. Our observations suggest that the CR benefit of reduced iron deposition and preserved motor function may indicate neural protection similar to effects described previously in aging rodent and primate species.”
Iron Accumulation with Age, Oxidative Stress and Functional Decline
“In conclusion, our findings complement and extend previous observations in several ways. First, we have rats that are considerably older (37 months), and we find that gastrocnemius muscle non-heme iron levels change dramatically in these rats (i.e., 600% higher than 8-month-old controls). Secondly, we studied rats of four ages (8, 18, 29, and 37 months), which allows us to document the progression of changes over time and to make correlations, such as that with RNA oxidation. Thirdly, our study is unique because it includes indices of sarcopenia and shows strong correlations with iron level changes. Importantly, our study is the first to show that caloric restriction attenuates this age-related iron accumulation in muscle, and mitigates oxidative stress and sarcopenia. Whether iron accumulation is a causative factor or merely a consequence of aging is still unclear. However, the strong association of iron levels with oxidized nucleic acid damage and the connection of oxidative damage with markers of sarcopenia warrant potential targeted interventions in an attempt to reduce iron levels and mitigate sarcopenia. Our study provides valuable insights into the mechanisms of the beneficial factors of CR on sarcopenia. Additional studies need to determine if and how specific iron-related proteins change, and if interventions such as metal chelation can attenuate the levels of oxidative stress, apoptosis and/or mitochondrial dysfunction with age.”
Space does not permit a detailed discussion of epigenetic mechanisms of DR here though these are very important. A future blog entry may discuss, in greater detail, what is currently known about the epigenetic modifications induced by DR. Epigenetic changes appear to play a key role in many of the pathways previously discussed. Vince has written extensively about epigenetic changes associated with aging. See Aging as a genomic-epigenomic dance which also lists a number of Vince’s other blog posts and treatise material relating epigenetics to aging.
DR has been shown to reverse many age-associated epigenetic changes in both DNA methylation, and in chromatin structure, thereby restoring youthful gene expression patterns.(ref, ref) Although the complexities involved in epigenetic mechanisms of aging and DR are greater than can be covered in this brief summary, clearly epigenetic modifications are important mechanisms in the dramatic effects of DR. The possibility to directly alter these modifications opens the door to potential therapeutic interventions, and I may also treat this subject in a subsequent blog entry.
What is your feeling about CR mimetics? It seems that due to the generally uncomfortable feeling regarding hunger, that this might be, if not now, then in the future, a more viable approach to life extension. Do you think mimetics will be capable of such a result?
I am very optimistic about the therapeutic potential of compounds targeting these pathways. In fact, many such compounds are already being effectively used to treat a variety of metabolic conditions, and could potentially be used to increase longevity, as well. Other approaches, which I have not yet discussed in detail, that show great promise are intermittent fasting, and the dietary restriction of specific nutrients, such as methionine, without reducing total caloric intake. I hope to be able to address some of these related topics in future blog entries.
Thanks Victor. I was going to ask about intermittent CR. For example, if you implemented a CR diet every other month. would it have any effect? Or would it need to be sustained for any effect?
No need to answer now. I will wait for your future blog entry.
Pingback: Benefits of Chod | School of Tibetan Healing Chö
Pingback: Alternate-day Fasting – a better alternative | AGING SCIENCES – Anti-Aging Firewalls
Pingback: Circadian Regulation, NMN, Preventing Diabetes, and Longevity | AGING SCIENCES – Anti-Aging Firewalls
Pingback: The pivotal role of Nrf2. Part 1 – a new view on the control of oxidative damage and generation of hormetic effects | AGING SCIENCES – Anti-Aging Firewalls
Pingback: Focus on phytosubstances – amazing properties of epimedium and icariin | AGING SCIENCES – Anti-Aging Firewalls
Pingback: Multifactorial hormesis – the theory and practice of maintaining health and longevity | AGING SCIENCES – Anti-Aging Firewalls
Pingback: Response to Jim Watson’s wager challenge | AGING SCIENCES – Anti-Aging Firewalls
Pingback: PART 1: Slaying Two Dragons with One Stone – How to Prevent Cancer and Aging with the Same Strategy | AGING SCIENCES – Anti-Aging Firewalls
Pingback: PART 3: Slaying Two Dragons with the Sound of Silence: – How to Keep Your Repetitive DNA Turned Off with “3 Songs”: Sirtuins, Polycomb Proteins, and DNMT3. And a Master List of Drugs and Natural Compounds for Cancer Chemoprevention | AGING SCIEN
Pingback: THE HORMESIS BARS | AGING SCIENCES – Anti-Aging Firewalls
Pingback: Glucosamine for longevity | AGING SCIENCES – Anti-Aging Firewalls