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Some people say that a calorie restriction (CR) diet is difficult to follow. It used to be. But things have changed: Thanks to great work by leading scientists, current approaches to calorie restriction are just as much about cell signaling as about limiting calories.

It is known, for example, that serious long-term CR dramatically lowers insulin levels.1 Another hormone, with a similar molecular structure, insulin-like growth factor one (IGF-I), shares the same pathway with insulin and is downregulated by CR in animal studies and by calorie restricted humans who do not follow high protein diets.2

And there’s the rub. For if you hope to benefit from calorie restriction and do not pay attention to the special properties of macronutrient intake, individual foods, and food preparation, you may get an unpleasant surprise: excessive stimulation of the insulin/IGF-I pathway. For example, in a study using healthy volunteers, just 50 grams of white potato starch sends glucose and insulin soaring3 to levels associated with increased risk of cancer, heart disease and diabetes.4

Back in the 1930s, when the term calorie restriction was first applied to Dr. Clive McCay’s rat and mouse experiments,5 it was entirely appropriate because the focus was on calories since he was looking at growth retardation. Of course, little was known about the signals involved in the life-extending effects of the diet. All that changed as scientists discovered important cell-signaling patterns that produce the phenomenal life-transforming effects.6

In 2008, The CR Way took the latest CR science and crafted it into a holistic lifestyle that makes following a CR diet easier by transforming it into a happy, positive lifestyle that focuses on living better now and quite possibly living longer. Recipes, food choices, and lifestyle are deliciously and strategically planned to reduce the insulin / IGF-I pathway activity – making disease risk plummet, while increasing the probability of a longer life.
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1. Fontana L, Meyer T.E., Klein S, Holloszy J.O. Long-Term Calorie Restriction Is Highly Effective In Reducing The Risk For Atherosclerosis In Humans. Proceedings of the National Academy of Science USA 2004;101(17):6659–6663.
2. Fontana L, Klein S, Holloszy J.O. Long-term low-protein low-calorie diet and endurance exercise modulate metabolic factors associated with cancer risk. American Journal of Clinical Nutrition. 2006;84:1456–62.
3.Brand-Miller JC, et al. Mean changes in plasma glucose and insulin responses in 10 young adults after consumption of 50g carbohydrates from potato (high-glycemic index; GI) or barley (low-GI) meal. American Journal of Clinical Nutrition. 2005 Aug;82(2):350–4
4. Guideline for Management of Post-meal Glucose, International Diabetes Federation, 2007 ISBN 2−930229−48−9
5. McCay CM, Crowell MF, Maynard LA. Journal of Nutrition. l0:63–79, 1935
6. McGlothin PS, Averill MS. Advances in Calorie restriction. Antiaging Medicine. 2009 Aug;4(4):440–441

As leaders of calorie restriction research and practice, Meredith Averill and I often participate in media events. A recent news conference covered rapidly evolving aspects of calorie restriction research that anyone could benefit from, whether they choose to follow a low-calorie lifestyle or not. Therefore, we thought it appropriate to share the details of the event with the Lifeboat Foundation audience.

The conference was hosted by the American Federation of Aging Research (AFAR). AFAR is a forward-looking organization that provides financial support for early- and mid-career scientists who are developing careers in the study of aging.

This conference, entitled “You are What you Don’t Eat!” presented two world-famous CR scientists, Drs. Luigi Fontana and Donald Ingram. After an introduction from AFAR’s board member, Dr. Jack Watters, both scientists shared many profound insights that could extend healthy lifespan for millions of people.

Dr. Fontana first reminded us how important calorie restriction research is for the health and financial viability of the health care system: “Cardiovascular disease (CVD), cancer, stroke and diabetes account for nearly 70% of the deaths in the United States and Europe. About 80% of adults over 65 years of age have at least one chronic disease, and 50% have two or more of these chronic diseases that accelerate the aging process1 .” The point he makes is that health care systems, especially with our rapidly aging population cannot sustain this large number of people with disease.

Meanwhile, his CR studies – many done in conjunction with the CR Society Intl. – show that those following a serious CR diet exhibit less risk of cardiovascular disease, cancer, stroke, and diabetes – all chronic diseases that people in Western societies are so prone to. Drawing parallels with animal studies, Fontana points out that CR mice are found to live much longer and in better health. When they die, autopsies show no sign of a chronic condition. Dr. Fontana says the same is possible for people. He hailed the healthiest old people as “escapers:” people who live to 100 and contract no chronic disease.

Against that backdrop, Dr. Fontana explained that his human CR studies have looked carefully at various markers in human calorie restrictors – T3, IGF-I, insulin, glucose, correlating them to successful CR, established in animal studies. This has given him a battery of indicators that can used by anyone to judge the effectiveness of a CR regimen. These are the core of the CR Way biomarkers that we recommend for testing and tracking by anyone following a CR diet. Fontana’s presentation underlines the reality that living free of chronic disease is attainable for humans.

Dr. Ingram presented valuable research results. He discussed many aspects of his productive CR research career, including his search for a CR mimetic. He has looked at some well known candidates such at Metformin (producing no difference in life span extension in his studies), 2 d-oxyglucose, (proving to be unusable because of dangerous side effects in the heart). And a promising possibility: avocado-derived mannoheptulose. Highly recommended by The CR Way, avocados have a profound glucose/insulin-lowering effect, according to Dr. Ingram. He attributes this to mannoheptulose, a sugar that’s rare in the human diet and that reduces glycolysis via hexokinase inhibition.

Bioavailability of avocado-derived mannoheptulose in dogs

Gary Davenport1, Stefan Massimino1, Michael Hayek1, Michael Ceddia1, John Burr1, Chyon-Hwa Yeh1, Lijuan Li1, George Roth2 and Donald Ingram3

1 Procter & Gamble, Lewisburg, OH
2 Geroscience, Pylesville, MD
3 Pennington Biomedical Research Center, Baton Rouge, LA

The FASEB Journal: The Journal of the Federation of the Societies for Experimental Biology, now on their Web site:, accessed April 1, 2011

Mannoheptulose (MH) is a 7-carbon sugar found in avocados and other natural sources that acts to reduce glycolysis via hexokinase inhibition. It has been proposed as a calorie restriction (CR) mimetic that delivers anti-aging and health-promoting benefits of CR without reducing food intake. Three studies were conducted to evaluate MH bioavailability when fed to dogs as an avocado extract (AvX) based on MH levels in urine (Study 1) and plasma (Study 2 & 3). In Study 1, Labrador Retrievers (LR; n=15) and Fox Terriers (n=15) were fed AvX-containing diets formulated to deliver 0, 2 or 5 mg MH/kg BW. All dogs were subjected to 24-hour quantitative urine collections. A dose-dependent increase (p<0.05) in urinary MH occurred with increasing dietary MH. In Study 2, LR (n=6) were fed AvX-containing diets once daily to deliver 0, 1 or 2 mg MH/kg BW. Sequential blood samples were collected before and after feeding through 12 hr and at 24-hr post-feeding. Plasma MH increased (P<0.05) with both MH diets compared to control. Peak MH occurred 6–8 hr post-feeding and returned to non-detectable levels by 24 hr. In Study 3, similar MH results were observed for LR (n=10) fed AvX-containing diets twice daily to provide 0 or 2 mg MH/kg BW. Peak MH occurred within 2–4 hr of MH consumption and returned to non-detectable levels by 24 hr.

Mannoheptulose, fed as an avocado extract, is biologically available in dogs based on its appearance in plasma and urine.

Dr. Ingram shared some additional successful research2 on the neuroprotective effects of blueberries. He and his colleagues found that mice that were injected with a blueberry extract were protected against neurodegeneration induced by a toxic substance.

The growing interest in phytonutrients for health and longevity was reinforced by Dr. Fontana, who reported a current experiment gauging the effects of a cocktail of polyphenol extracts.


On behalf of everyone interested in longevity, we asked the scientists to tell us where they think the next important areas of their research should be. Dr. Fontana wants to turn his attention to CR and cancer, noting that many unknowns continue to make preventing cancer’s occurrence – even predicting its likelihood – difficult. He reminded us that “cancer is the second leading cause of death in many developed countries,” accounting for approximately one-fourth of all deaths. Among women, aged 40 to 79, and among men aged, 60 to 79, cancer is the leading cause of death in the U.S. The lifetime probability of developing cancer is 46% for men and 38% for women2 . Furthermore, many of the processes of cancer mirror processes of aging, so this research will do double duty.

Dr. Fontana believes that by looking at CR, which has been shown to reduce cancer incidence and rate of metastasis in animal and human studies3, better ways will be found to predict the likelihood of cancer as well as to prevent it.

This line of study will also help determine potential aging markers, a recurring theme for both presenters. Dr. Ingram declared in his answer to our question: Rate-of- aging markers need to be established and validated. Future projects need to focus on this work. Further, he called on the gerontological community to work hard on building consensus on these biomarkers, so that they can be used by researchers, healthcare professionals, and longevists.

We are heartened to know that forward-thinking organizations like AFAR are facilitating the work of talented scientists who will likely make it possible ultimately for all to live in good health longer.

The hope of the CR Society Intl. and The CR Way is that the work of these scientists will be fully appreciated and that government and other funders will respond with the support that is needed to pursue research that helps us all live longer, disease-free lives and ultimately makes a big difference in the financial viability of health care.

Thanks to the Lifeboat Foundation for inviting me to share this information.

Paul McGlothin,

Vice President Research, The CR Society International

Co-author, The CR Way

Executive Director, The CR Way Longevity Center

[email protected]


1 Modulating Human Aging and Age-Associated Diseases

Luigi Fontana, M.D., Ph.D.

Biochimica Biophysica Acta. 2009 Oct;1790(10):1133–8. Epub 2009 Feb 10.

Population aging is progressing rapidly in many industrialized countries. The United States population aged 65 and over is expected to double in size within the next 25 years. In sedentary people eating Western diets aging is associated with the development of serious chronic diseases, including type 2 diabetes mellitus, cancer and cardiovascular diseases. About 80 percent of adults over 65 years of age have at least one chronic disease, and 50 percent have at least two chronic diseases. These chronic diseases are the most important cause of illness and mortality burden, and they have become the leading driver of health care costs, constituting an important burden for our society.

Data from epidemiological studies and clinical trials indicate that many age-associated chronic diseases can be prevented, and even reversed, with the implementation of healthy lifestyle interventions. Several recent studies suggest that more drastic interventions (i.e. calorie restriction without malnutrition and moderate protein restriction with adequate nutrition) may have additional beneficial effects on several metabolic and hormonal factors that are implicated in the biology of aging itself. Additional studies are needed to understand the complex interactions of factors that regulate aging and age-associated chronic disease.

PMID: 19364477

2A blueberry-enriched diet provides cellular protection against oxidative stress and reduces a kainate-induced learning impairment in rats.

Duffy KB, Spangler EL, Devan BD, Guo Z, Bowker JL, Janas AM, Hagepanos A, Minor RK, DeCabo R, Mouton PR, Shukitt-Hale B, Joseph JA, Ingram DK.

Laboratory of Experimental Gerontology, Intramural Research Program, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA.

Neurobiology of Aging. 2008 Nov;29(11):1680–9. Epub 2007 May 23.

Young male Fischer-344 rats were fed a diet containing 2% blueberry (BB) extract or control diet for at least 8 weeks and then received bilateral hippocampal injections of kainic acid (KA 200 ng/0.5 microl) or phosphate buffered saline (PBS). One week later rats were trained in one-way active footshock avoidance in a straight runway followed the next day by training in a footshock motivated 14-unit T-maze with documented sensitivity to hippocampal glutamatergic manipulations. Based on analyses of several performance variables, KA-treated rats exhibited clearly impaired learning performance; however, the BB diet significantly reduced this impairment. Supporting the behavioral findings, stereological assessment of CA1 pyramidal neurons documented greater neuronal loss in KA-treated controls compared to KA-treated rats on the BB diet.

In an in vitro experiment, FaO cells grown in medium supplemented with serum from BB-fed rats had enhanced viability after exposure to hydrogen peroxide. These findings suggest that BB supplementation may protect against neurodegeneration and cognitive impairment mediated by excitotoxicity and oxidative stress.

3 Calories and carcinogenesis: lessons learned from 30 years of calorie restriction research.
Hursting SD, Smith SM, Lashinger LM, Harvey AE, Perkins SN.
Carcinogenesis. 2010 Jan;31(1):83–9. Epub 2009 Dec 7.

Calorie restriction (CR) is arguably the most potent, broadly acting dietary regimen for suppressing the carcinogenesis process, and many of the key studies in this field have been published in Carcinogenesis. Translation of the knowledge gained from CR research in animal models to cancer prevention strategies in humans is urgently needed given the worldwide obesity epidemic and the established link between obesity and increased risk of many cancers.

PMID: 19969554

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The field of life extension is broad and ranges from regenerative medicine to disease prevention by nutritional supplements and phytomedicine. Although the relevance of longevity and disease prevention to existential risks is less apparent than the prevention of large-scale catastrophic scenarios, it does have a high relevance to the future of our society. The development of healthy longevity and the efficiency of modern medicine in treating age-related diseases and the question of how well we can handle upcoming issues related to public health will have a major impact on our short-term future in the next few decades. Therefore, the prospect of healthy life extension plays important roles at both a personal and a societal level.
From a personal perspective, a longevity-compatible lifestyle, nutrition and supplementary regimen may not only help us to be active and to live longer, but optimizing our health and fitness also increase our energy, mental performance and capacities for social interaction. This aids our ability to work on the increasingly complex tasks of a 21st-century world that can make a positive impact in society, such as work on existential risk awareness and problem-solving. Recently, I wrote a basic personal orientation on the dietary supplement aspect of basic life extension with an audience of transhumanists, technology advocates with a high future shock level and open-minded scientists in mind, which is available here.
On a societal level, however, aging population and public health issues are serious. A rapid increase of some diseases of civilization, whose prevalence also climbs rapidly with advanced age, is on the march. For example, Type-II-Diabetes is rapidly on its way to becoming an insurmountable problem for China and the WHO projects COPD, the chronic lung disease caused by smoking and pollution, as the third leading cause of death in 2030.
While the currently accelerating increase of diseases of civilization may not collapse society itself, the costs associated with an overaging population could significantly damage societal order, collapse health systems and impact economies given the presently insufficient state of medicine and prevention. The magnitude, urgency and broad spectrum of consequences of age-related diseases of civilization currently being on the march is captured very well in this 5-minute fact-filled presentation on serious upcoming issues of aging in our society today by the LifeStar Foundation. Viewing is highly recommended. In short, a full-blown health crisis appears to be looming over many western countries, including the US, due to the high prevalence of diseases of aging in a growing population. This may require more resources than available if disease prevention efforts are not stepped up as early as possible. In that case, the required urgent action to deal with such a crisis may deprive other technological sectors of time and resources, affecting organizations and governments, including their capacity to manage vital infrastructure, existential risks and planning for a safe and sufficient progress of technology. Hence, not caring about the major upcoming health issue by stepping up disease prevention efforts according to latest biomedical knowledge may indirectly pose challenges affecting our capabilities to handle existential risks.
It should be pointed out that not all measures aimed at improving public health and medicine need to be complex or expensive to attain, as even existing biomedical knowledge is not sufficiently applied. A major example for this is the epidemic Vitamin D deficiency of the western population which was uncovered several years ago. In the last few years, the range of diseases that Vitamin D deficiency and –therapy can influence has grown to include most cancers, diabetes, cardiovascular diseases, brain aging including Alzheimer’s disease and many infectious diseases. Ironically, Vitamin D is one of the cheapest supplements available. Moreover, correcting an existing Vitamin D deficiency, which may affect as much as 80% of western population, may cut mortality risk in half. The related mortality decrease would likely coincide with a reduced morbidity and illness of elderly people, resulting in large savings of public healthcare and hospital funds, since Vitamin D effectively prevents and treats some of the most costly age-related diseases. The Life Extension Foundation, for example, has already offered a free initial supply to the U.S. population and shown that massive healthcare costs (and many lives) could be saved if every hospitalized patient was tested for Vitamin D and/or given the supplement, however this offer was ignored by the US government. This is detailed in an article on the effects of widespread Vitamin D deficiency from the Life Extension Foundation, along with many references for the above health effects of Vitamin D at the end of that article.
To recapitulate, there are plenty of important reasons why the focus on disease prevention and regenerative medicine, by applying existing state-of-the-art biomedical knowledge, as well as advancing key areas such as stem-cell research, rejuvenation technologies and nanomedicine should be an urgent priority for advocates of existential risk management today and during the next few decades.

It would be helpful to discuss these theoretical concepts because there could be significant practical and existential implications.

The Global Brain (GB) is an emergent world-wide entity of distributed intelligence, facilitated by communication and the meaningful interconnections between millions of humans via technology (such as the internet).

For my purposes I take it to mean the expressive integration of all (or the majority) of human brains through technology and communication, a Metasystem Transition from the human brain to a global (Earth) brain. The GB is truly global not only in geographical terms but also in function.

It has been suggested that the GB has clear analogies with the human brain. For example, the basic unit of the human brain (HB) is the neuron, whereas the basic unit of the GB is the human brain. Whilst the HB is space-restricted within our cranium, the GB is constrained within this planet. The HB contains several regions that have specific functions themselves, but are also connected to the whole (e.g. occipital cortex for vision, temporal cortex for auditory function, thalamus etc.). The GB contains several regions that have specific functions themselves, but are connected to the whole (e.g. search engines, governments, etc.).

Some specific analogies are:

1. The Broca’s area in the inferior frontal gyrus, associated with speech. This could be the equivalent of, say, Rubert Murdoch’s communication empire.
2. The motor cortex is the equivalent of the world-wide railway system.
3. The sensory system in the brain is the equivalent of all digital sensors, CCTV network, internet uploading facilities etc.

If we accept that the GB will eventually become fully operational (and this may happen within the next 40–50 years), then there could be severe repercussions on human evolution. Apart from the fact that we could be able to change our genetic make-up using technology (through synthetic biology or nanotechnology for example) there could be new evolutionary pressures that can help extend human lifespan to an indefinite degree.

Empirically, we find that there is a basic underlying law that allows neurons the same lifespan as their human host. If natural laws are universal, then I would expect the same law to operate in similar metasystems, i.e. in my analogy with humans being the basic operating units of the GB. In that case, I ask:

If, there is an axiom positing that individual units (neurons) within a brain must live as long as the brain itself, i.e. 100–120 years, then, the individual units (human brains and, therefore, whole humans) within a GB must live as long as the GB itself, i.e. indefinitely.

Humans will become so embedded and integrated into the GB’s virtual and real structures, that it may make more sense from the allocation of resources point of view, to maintain existing humans indefinitely, rather than eliminate them through ageing and create new ones, who would then need extra resources in order to re-integrate themselves into the GB.

The net result will be that humans will start experiencing an unprecedented prolongation of their lifespan, in an attempt by the GB to evolve to higher levels of complexity at a low thermodynamical cost.

Marios Kyriazis