The Holt Report: Calorie Restriction and Calorie Restriction Mimetics
Stephen Holt, MD, PhD, DSc, LLD, DNM, Distinguished Professor of Medicine (Emerite), Scientific Advisor, Natural Clinician LLC and

The only intervention that has been shown to extend average and maximal lifespan in a wide variety of living organisms is the restriction of calorie intake. As experimental studies over the past two decades started to define the beneficial biochemical and physiological effects of calorie restriction, scientists started to propose that there were a variety of substances (drugs and natural compounds) that could mimic these desirable effects on body structures and functions. In the late 1990s scientists started to propose the notion that there were calorie restriction mimetics that have anti-aging properties as a consequence of their ability to induce biological changes that occurred as a consequence of direct reductions of overall calorie intake.9 Many experiments involving reduction of total calorie intake (up to a level of 70% less than ad libitum dietary intake in (free-feeding) animals) show that calorie restriction improves a number of biomarkers of aging, with overt evidence of improved general health.
The use of calorie restriction mimetics, in isolation of significant dietary calorie reduction, has the naïve appeal to some of providing an “easy option” for longevity promotion, but it seems quite reasonable to conclude that the combined use of calorie restriction mimetics with tolerable reductions of overall calorie intake would act in a highly synergistic manner. This approach seems to be deeply rooted in good scientific agreement, derived from almost eight decades of research.
While one may acknowledge the call for more research on the use of calorie restriction as a longevity promoter in humans, the benefits of this intervention appear to be well documented and highly credible. A key health initiative that has been repeatedly promoted for the U.S. nation is an overall restriction of calorie intake, in what have been somewhat futile attempts to reverse the obesity epidemic.

Biological Effects of Calorie Restriction
A simple understanding of the biochemical and physiological effects of calorie restriction explains why this intervention can extend average lifespan (defined as the average number of years that an organism is expected to live). There is a major and added bonus to the intervention. Calorie restriction induces the prolongation of maximum lifespan (defined as the greatest number of years that a living organism can survive).
It is efficient to classify several areas of the biological outcome of calorie restriction. These areas include, but may not be limited to, the following: alteration of the expression and actions of many key enzyme systems that control body metabolism and protein synthesis, reduction of the accumulation and removal of damaged protein, modulation of normal processes of cell death (apoptosis), modification of the actions of chaperone molecules, secondary reduction in protein/sugar cross-linking (glycosylation), variable reversal of dysglycemia, reduction of chronic inflammation and inflammatory markers, hormetic effects, inhibition of glycolysis with insulin sensitizing actions and specific influences on genes that alter cell repair or death (e.g. Sir2 gene or the human homologous SIRT1 gene)

– Favorable effects on cardiovascular structure and function, with reductions in heart rate, blood pressure, LDL cholesterol and triglycerides.
– Improvements in insulin sensitivity and overall normalization of blood glucose levels.
– Increase in protein synthesis and the elimination of abnormal proteins from the body. Enhanced action of chaperone molecules which contribute to the synthesis and maintenance of essential proteins, with the benefit of enhanced elimination of damaged proteins.
– Modulation of the process of “orderly cell death” (apoptosis) with improvement in the repair and maintenance of integrity of DNA. Secondary benefits on transcription.
– Reduction of oxidative stress to tissues by diminution of free radical generation in a quantitative and qualitative manner.
– Reduction in body temperature.
– Reduction in body fat mass, including visceral adiposity, with concomitant increase in muscle mass.
– Beneficial effects on hormonal secretions that tend to fall with age, e.g. DHEA and growth hormone.
– Improvements in brain function, including memory, cognition and perhaps mood.
– Spontaneous enhancement of an ability to engage in physical activity.
– Stimulation of growth factors, e.g. BDNF, a nerve growth factor.
– Weight loss.
Table 1. The bio-physiological and clinical outcomes that have been described in many experiments that have utilized calorie restriction or in some cases, calorie restriction mimetics.

Individuals who interpret the data in Table 1 with some degree of skepticism should recognize that essentially all species of animals, that have had their responses to calorie restriction studied, have shown overall parallel biochemical or physiological outcomes. In addition, scientists and physicians who are focused on anti-aging medicine have developed a consensus opinion that the effects noted in animals are often present in non-human primates and humans.
Calorie Restriction Mimetics
A calorie restriction mimetic can be defined as a pharmaceutical or chemical compound or natural agent which has the ability to reproduce one or more principal biological effects of calorie restriction. There are many putative calorie restriction mimetic compounds which have variable effects on body structures and functions (Table 2). It appears that these agents can be administered to humans or animals to induce substantially similar biochemical or physiological changes that have been documented to occur when significant dietary restriction of calories has been undertaken. One may assume that there may be great inter-individual and intra-individual variation in the human response to a calorie restriction mimetic. For example, some of these mimetics may have primary effects on genetic controls of aging, whereas others may have more specific effects on glucose metabolism. In other words, the biochemical versatility of calorie restriction mimetics is quite variable.
It seems obvious that there is a highly complex cascade of biological events that occurs with calorie restriction, which matches, in part, the even more complicated cascade of events that determines aging. I have repeatedly reminded myself and other practitioners of Integrative Medicine that the power of synergy is a pivotal component of natural therapeutics. While many practitioners of bio-integrative medicine have rejected, in part, the flawed concept of the single drug receptor actions in therapeutics, it continues to surprise me that many physicians or healthcare givers are using single supplement or natural product interventions. For example, resveratrol has been heralded as a key anti-aging supplement and its effects are likely to be significantly enhanced by the synergistic action of other calorie restriction mimetics.
Against this background, I have undertaken a review of putative calorie restriction mimetics which have good scientific agreement for their use in longevity promotion. Of course, efficacy is important in attempts to mimic the biological actions of calorie restriction, but safety is a key issue. Table 2 provides an incomplete list of calorie restriction mimetics, but it focuses upon those that appear to be evidence-based with credible scientific support for their biological effects in animals or humans. Analysis of these putative calorie restriction mimetics, permits the rational and logical synergistic formulation of a dietary supplement that can be expected to provide nutritional support for the modification of body structures and functions that change favorably with calorie restriction.

Synergistic Calorie Restriction Mimetics: A Novel Anti-Aging Strategy
Longevity in unquestionably the legacy of positive and healthy lifestyle and anti-aging medicine must be defined within the context of advanced preventive medicine. Elegant arguments have prevailed where the prevention or reduction in prevalence of premature causes of death and disability may not have as significant an impact on average and maximum lifespan than has been hitherto supposed. However, there is no doubt that the prevention of fatal illness and the promotion of wellbeing are key initiatives for all practicing physicians.
It is with optimism that I propose the combined use of several dietary supplements that can have additive calorie restriction mimetic effects, to be used with appropriate lifestyle guidance. I am not optimistic that the active restriction of calorie intake in the diet is an achievable intervention for industrialized society, but I believe that the use of natural substances that can reproduce the documented benefits of calorie restriction is a major advance in the anti-aging field.
In summary, my recommendations would include the synergistic use of formulations of dietary supplements that would include key ingredients such as carnosine, resveratrol, gymnema alkaloids, alpha lipoic acid, cinnamon and avocado, with the added benefits of grape seed extracts, ellagic acid and pine bark polyphenols. It would be highly advisable to have longitudinal studies that can assess the benefits of calorie restriction mimetics, but it may take many years before, what now seems obvious, becomes apparent in “hard-nosed,” scientific language. It appears to be increasingly clear that calorie restriction mimetic compounds have intrinsic health giving benefits in addition to any potential benefits that they may have as a consequence of their ability to mimic the biochemical and physiological effects of the dietary restriction of calories

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