Aging Cell (2006) 5, pp97–108 Doi: 10.1111/j.1474-9726.2006.00202.x Blackwell Publishing Ltd REVIEW Calorie restriction mimetics: an emerging research field Donald K. Ingram,1 Min Zhu,1 Jacek Mamczarz,1 fully assess the potential of any CRM. Nonetheless, this Sige Zou,1 Mark A. Lane,1 George S. Roth2 and strategy clearly offers a very promising and expanding Rafael deCabo1 research endeavor. 1Laboratory of Experimental Gerontology, Intramural Research Key words: aging; cancer; glucose; insulin; metabolism; stress Program, National Institute on Aging, 5600 Nathan Shock Drive, 2 Baltimore, MD 21224, USA, and GeroScience, Inc., Pylesville, Introduction MD 21132, USA It is intriguing that one of the oldest paradigms in gerontology is providing the newest synthesis of findings regarding mech- Summary anisms of aging and suggesting directions for intervention that When considering all possible aging interventions evalu- could prove to be highly fruitful. The formal study of calorie ated to date, it is clear that calorie restriction (CR) remains restriction (CR), also known as food restriction or diet restriction, the most robust. Studies in numerous species have is most often traced to the pioneering nutritional research of demonstrated that reduction of calories 30–50% below ad Clive McCay and colleagues at Cornell University beginning in libitum levels of a nutritious diet can increase lifespan, the 1930s (McCay & Crowell, 1934; McCay et al., 1935). As reduce the incidence and delay the onset of age-related reviewed by Kritchesky (1993), however, reports of CR effects diseases, improve stress resistance, and decelerate func- on cancer growth appeared much earlier in the work of More- tional decline. A current major focus of this research area schi in 1909 and Rous in 1914. Results of many subsequent is whether this nutritional intervention is relevant to studies in different laboratories have demonstrated that sub- human aging. Evidence emerging from studies in rhesus stantial reductions of food intake to 30–60% below ad libitum monkeys suggests that their response to CR parallels that (AL) intake levels can increase lifespan (median and maximum) observed in rodents. To assess CR effects in humans, clin- in a wide variety of species (Weindruch & Walford, 1988; Yu, ical trials have been initiated. However, even if results 1994; Weindruch & Sohal, 1997; Masoro, 2000). Moreover, in from these studies could eventually substantiate CR as hundreds of rodent studies ranging over several decades, CR an effective pro-longevity strategy for humans, the utility has been shown to decrease the incidence and age of onset of this intervention would be hampered because of the of many age-related diseases, increase resistance to toxicity and degree and length of restriction required. As an alternative stress, and maintain function at more youthful-like states strategy, new research has focused on the development compared to controls eating at or near AL levels (Weindruch & of ‘CR mimetics’. The objective of this strategy is to iden- Walford, 1988; Yu, 1994). Compared to numerous attempts to tify compounds that mimic CR effects by targeting met- manipulate the rate of aging in animal models, CR remains the abolic and stress response pathways affected by CR, but most robust aging intervention studied to date. without actually restricting caloric intake. For example, Given its robust nature and continued research prominence, drugs that inhibit glycolysis (2-deoxyglucose), enhance the three most compelling questions driving recent CR research insulin action (metformin), or affect stress signaling are: (i) Is this intervention relevant to human aging? (ii) If so, pathways (resveratrol), are being assessed as CR mimetics can mechanisms of CR relevant to human aging be identified? (CRM). Promising results have emerged from initial stud- (iii) If so, can interventions be identified that operate through ies regarding physiological responses which resemble these mechanisms to mimic CR? those observed in CR (e.g. reduced body temperature and plasma insulin) as well as protection against neurotoxicity Relevance of calorie restriction to humans (e.g. enhanced dopamine action and up-regulated neuro- trophic factors). Ultimately, lifespan analyses in addition Arguments have been presented that the marked increases in to expanded toxicity studies must be accomplished to lifespan observed in rodents on CR are not likely to be observed in humans on CR because humans have not evolved such mech- anisms (Harrison & Archer, 1989; de Grey, 2005; Phelan & Rose, Correspondence Donald K. Ingram, Laboratory of Experimental Gerontology, Intramural 2005). CR may be more relevant to short-lived species in which Research Program, National Institute on Aging, 5600 Nathan Shock Drive, a major loss of food supply would be catastrophic, whereas Baltimore, MD 21224, USA. Tel.: 410-558-8180; fax: 410-558-8320; e-mail: humans have evolved cultural mechanisms for dealing with such [email protected] events and might not have to rely on such evolutionary adap- Accepted for publication 16 November 2005 tation. Using a mathematical model relating longevity to relative © 2006 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland No claim to original US government works 97 Journal compilation © 2006 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland 98 Calorie restriction mimetics, D. K. Ingram et al. investment in reproductive effort, Phelan & Rose (2005) have restriction mimetics, that can provide the pro-longevity bene- estimated that CR should have 10 times greater effects on fits of CR without actually having to reduce caloric intake. longevity of rodents than of humans. Of course, many epidemiological studies have reported that Calorie restriction mimetics caloric intake is related to the incidence of several chronic diseases, including cardiovascular disease, cancer, diabetes, as The field of calorie restriction mimetics (CRM) is still in its infancy well as neurodegenerative disorders (Logroscino et al., 1996; but is attracting increasing attention (Lane et al., 2002; Ingram Mayeux et al., 1999; Willet, 2000; Astrup, 2001; Kritchesky, et al., 2004; Everitt et al., 2005; Roth et al., 2005). A recent 2001; Hursting et al., 2003). Studies of Okinawan centenarians search yielded 21 citations, the oldest citation dated 2001. support the view that a low-calorie diet can increase prospects Ironically, one of the citations that does not appear on PubMed for good health and longevity in humans (Suzuki et al., 2001). is the paper by Lane et al. (1998) that first introduced the con- Findings from the small group of volunteers confined to Bio- cept and the first candidate CRM drug. sphere 2 confirmed that CR (∼30%) could be imposed for Unfortunately since that initial report, the concept itself has 2 years and would produce many of the physiological, hormo- evolved to a current context of broad connotation. To many nal, and morphological effects expected (Walford et al., 2002). researchers, CRM applies to any intervention that can evoke A recent study of self-selecting volunteers on CR also noted similar effects on aging, health, and lifespan to those of CR. remarkably low values on risk factors for cardiovascular disease Such interventions can include antioxidants, hormonal replace- (Fontana et al., 2004). These studies are valuable and clearly ment, metabolic enhancers, metal chelators, and even exercise suggestive of the relationship between caloric intake and aging (Hadley et al., 2001; Poehlman et al., 2001). In addition, appetite but are no substitute for experimental evidence. suppressants and even gastric bypass surgery might also qualify Experimental proof that CR can significantly increase lifespan as CRM because they reduce caloric intake. in organisms that live longer than rodents has been limited to We would argue that the concept of CRM should have a one study in dogs (Kealy et al., 2002) and one in cows (Pinney much more focused meaning and application. Specifically, we et al., 1972). Studies in nonhuman primates have indicated that propose the following features for any candidate CRM: (i) it many physiological responses in monkeys parallel those mimics the metabolic, hormonal, and physiological effects of observed in rodents on CR (Mattison et al., 2003; Roth et al., CR; (ii) it does not significantly reduce long-term food intake; 2004). In addition, primate studies relating several of these (iii) it activates stress response pathways observed in CR and responses to markers of disease risk, such as blood lipids and provides protection against a variety of stressors; and (iv) it hormones, also indicate a reduced incidence of chronic diseases, produces CR-like effects on longevity, reduction of age-related such as heart disease and diabetes (Roth et al., 2001). disease and maintenance of function. To assess the feasibility and potential of CR intervention in Taking this approach, the major question is what would humans, recent clinical studies sponsored by the National be the appropriate mechanism/s to target for a CRM? Several Institute on Aging were initiated at three sites – Washington mechanisms underlying the pro-longevity effects of CR have University, Tufts University, and the Pennington Center at Lou- been proposed and include the following: (i) reduced oxidative isiana State University (Heilbronn & Ravussin, 2003). These pilot stress and damage (Sohal & Weindruch, 1996); (ii) reduced studies have now been completed and