Nutrition and aging

A human diet is composed of macronutrients and micronutrients. Macronutrients, including protein, carbohydrate, and lipids, provide our calorie needs. Micronutrients, including vitamins and essential minerals, support biochemical and metabolic activities required for optimal health. A link between malnutrition and accelerated aging or age-related degenerations has long been postulated. Recent years have witnessed major progress on the mechanisms by which nutritional deficiency or excess contribute to the aging process. Dietary restriction is known as the most effective longevity intervention ranging from yeast to primates (Masoro, 2005; Piper and Bartke, 2008; Cox and Mattison, 2009; Barzilai and Bartke, 2009), and obesity is now reaching epidemic status in developed countries. Ample evidence generated over the past decade has suggested novel roles of key micronutrients in the protection against aging and age-related disorders. There seems to be a worldwide increasing interest in the importance of nutrition as a means to prevent disease and to achieve a healthy aging.

This special issue of Nutrition and Aging contains reviews discussing how aging and age-related degenerations can be mitigated by nutrients including folate, selenium, vitamin B3, vitamin E, vitamin D, and phosphate, by dietary components such as resveratrol and coenzyme Q from grapes, and by dietary restriction that limits energy intake from macronutrients. The reviews discuss the impact of nutritional control on events that are associated with aging and age-related pathologies. Many of the age-related disorders, including metabolic diseases and neurodegeneration, are attributed to excessive production of reactive oxygen species during DNA metabolism in the mitochondria and the nucleus.

Ample evidence demonstrates the impact of dietary restriction on lifespan extension and on metabolic diseases (Masoro, 2005; Piper and Bartke, 2008; Cox and Mattison, 2009; Barzilai and Bartke, 2009), but it is important to ask whether we should suffer through the kind of hunger and discomfort associated with caloric restriction in order to obtain a long and healthier life. Maybe a calorie restriction mimetic could be attractive. A typical calorie restricted diet contains 25–50% less calories than normal, but maintains essential vitamins and minerals at a nutritionally adequate level. Vitamin B3 and its important metabolites, NAD and NADP, are key factors underlying the molecular basis of calorie restriction. Dr. Anthony Sauve and Ping Xu discuss how NAD⁺ metabolism regulates diverse aspects of the aging process, including redox status, calcium signaling pathways, DNA damage and stress responses, DNA repair, and energy metabolism. Dr. Joseph Baur presents evidence supporting the potential of resveratrol as a means to mimic the beneficial effects of dietary restriction. He focuses on sirtuins, a target of both resveratrol and dietary restriction with NAD-dependent deacetylase and ADP-ribosyltransferase activities. These two excellent reviews provide novel insight into the molecular basis of dietary restriction, and the potential of targeting vitamin B3-mediated metabolic pathways and of employing resveratrol for healthy aging and lifespan extension.

Age-related neurodegeneration is associated with increased oxidative stress and genome instability, which in principle can be counteracted by nutrients that slow down the toxic processes. Dr. Michael Fenech and Dr. Wen-Hsing Cheng discuss the important roles of folate and selenium in protecting the brain during the aging process. Folate is a critical methyl donor for the synthesis of nucleotides and for the epigenetic control of gene expression via cytosine methylation. Dr. Fenech reviews the impact of folate deficiency on genomic instability such as increased incorporation of uracil and DNA base oxidation in the genome. Selenium is an essential mineral and is required for the expression of 25 human selenoproteins, which contain selenocysteine, the “21st amino acid” (Kryukov et al., 2003). More than one-third of selenoproteins exhibit antioxidative activities, and selenium content and selenoprotein expression are refractory to dietary selenium deficiency in the brain (Burk, 1991; Cheng, 2009). Dr. Cheng and colleagues summarize recent advances in the role of selenoproteins in protecting against neurodisorders. Interestingly, folate and selenium interactions appear to exist via redox control, genome maintenance, and common metabolites such as homocysteine (Fenech et al., 1998; Fenech, 2001; Handy et al., 2005; Cheng, 2009; Wu et al., 2010).

Although the free radical theory of aging was proposed more than 50 years ago, it has yet to be proven or disproven. Whatever the answer, mitochondria is the major organelle that mediates redox metabolism in the process of mammalian aging and age-related pathologies. Dr. Jeffrey Stuart and colleagues provide an insightful overview detailing the sources and consequences of endogenous reactive oxygen species generated in the mitochondria. Furthermore, they discuss the efficacy of dietary manipulations on mitochondrial redox metabolism for a healthy aging process via calorie restriction, methionine restriction, folate deficiency and resveratrol supplementation. Similarly, Dr. Placido Navas and colleagues focus on the role of coenzyme Q in the regulation of energy metabolism and redox maintenance in mitochondria, and possibly in the protection against aging and age-related diseases. As the prevalence of type 2 diabetes reaches an endemic status, it is urgent to elucidate the molecular basis of this age-related metabolic syndrome. Dr. John Burgess and Robert Pazdro discuss the danger of elevated blood glucose and the associated oxidative stress in damaging DNA, protein and lipid. Furthermore, they address the efficacy of vitamin E, a lipid-soluble antioxidant, in alleviating diabetic complications including neurodegeneration.

Perhaps the most intriguing link between nutrient and aging is how phosphate homeostasis, together with a bone–kidney endocrine axis, can mediate lifespan and age-related pathologies. Dr. Makoto Kuro-o addresses this issue by providing evidence generated mainly from mice deficient in klotho, a membrane co-receptor that binds and activates fibroblast growth factor receptors. Fibroblast growth factor-23 is a hormone that negatively regulates body phosphate levels by promoting phosphate excretion from the kidney and by reducing phosphate absorption from the intestine via a reduction of serum vitamin D levels. Increased body phosphate concentrations by klotho or fibroblast growth factor-23 deficiency result in the premature onset of aging phenotypes and compromised glucose metabolism.

It is an unequivocal statement that aging is a complicated biological process and a target of dietary intervention. Nutrients and their metabolites control energy balance, enzymatic activities, and genome stability throughout the lifecycle. Nutrition was once a leading field in science, and a few Nobel laureates have been awarded on the basis of seminal contributions that characterize key nutrients in the early 20th century. However, the nutrition studies in the post-Watson–Crick era have somehow suffered by lack of mechanistic investigations, including the studies in the aging field until recently. It is time to resume the glorious days of nutritional studies by elucidating the molecular targets and pathways which dietary components act on as they counteract the aging process.