Calorie Restriction = Extended Lifespan

What You Need to Know about Caloric Restriction

Caloric Restriction (CR), a significant, sustained reduction of caloric intake from baseline levels, is the most thoroughly and successfully researched method for lifespan and healthspan extension in a broad range of animals and non-human primates.

In many cases, the reduction of caloric intake by 30 to 40 percent in animal models has resulted in longevity increases by 40 percent or more.

Although there is not yet direct human evidence of lifespan extension in humans from CR, results of the NIA-funded CALERIE study have shown significant reductions in risk factors for disease (cardiovascular disease, diabetes, some cancers), from moderate CR.

CR in humans reduces fasting insulin levels and lowers resting body temperature, which are two biomarkers for aging reversal.

Although CR has classically been defined as a long-term 30 to 40 percent reduction in calories, some CR health benefits in humans have been observed at less-restrictive caloric reductions (16 to 25 percent) over short time periods (weeks to months).

CR may work by reducing oxidative damage, increasing cellular repair, lowering production of inflammatory cytokines, or by hormesis, a mild stress that may stimulate cellular protection.

Several compounds may mimic the effects of CR without requiring a reduction in calories; these include resveratrol, metformin, green tea polyphenols, aspirin, pyrroloquinoline quinone (PQQ), and branched-chain amino acids.

Maintaining a dramatically reduced caloric intake over the long-term can be very demanding. Few people are willing to reduce their caloric consumption by the 30 to 40 percent to meet the classic CR definition,111 and even the less restrictive protocols (16-25%) used in human interventions have not been met with full compliance. The search for an alternative or complement to CR has involved the identification or development of compounds that mimic some of the physiological or gene-expression changes associated with CR, without the requirement of lowered caloric intake or loss of body weight. While many compounds can be broadly interpreted as CRMs, a more focused definition of CRM would be a compound or intervention that mimics the metabolic, hormonal, or physiological effects of CR without reducing long-term food intake, while stimulating maintenance and repair processes, and producing CR-like effects on longevity and reduction of age-related disease.

Several compounds have been investigated as CRMs, with encouraging preliminary results in animal models. Tetrahydrocurcumin (a curcumin metabolite) and green tea polyphenols have both demonstrated increases in average and maximum lifespans in mice.  The effects were observed when the mice received treatments by month 13 (if given later in life, the treatments had no effect on lifespan), and in the case of green tea extract, the treatment had no effect on body weight. An investigation of ginkgo biloba on cognitive behavior in male Fischer rats revealed an unexpected, statistically significant increase in average lifespan when compared to controls (26.4 vs. 31.0 months).The NIA Aging Intervention Testing program, a multi-center study on longevity-enhancing compounds, has already identified life-extending or CR mimetic activities in rapamycin and aspirin in rodents, and is currently testing other potential compounds including medium chain triglycerides, caffeic acid esters, and curcumin.

Stress-induced plant compounds can stimulate stress responses in other species, this cross-species hormesis is called xenohormesis. Xenohormesis may have evolved as an early warning in animals about impending changes in the environment (such as scarcities in the food supply), allowing them to adapt accordingly. The most familiar of these stress-inducing compounds is resveratrol, well-known for its presence in grape skin, but present at detectable levels in several plant species. Resveratrol simulates caloric restriction in the absence of actual nutrient deficiency by activating sirtuins (SIRT1 is the human homolog), and has been shown to increase lifespan in fungi, nematodes, flies, fish, and mice SIRT1 also suppresses NF-kB (and the inflammatory cytokines and enzymes NF-kB activates), lending resveratrol anti-inflammatory activity in cell culture and animal models.  High-dose resveratrol reduced IGF-1 levels in healthy human volunteers, a chemopreventive activity that is also associated with CR. Pterostilbene, a methylated analogue of resveratrol from blueberries, similarly attenuates inflammation in a CR-like manner, reducing NF-kB signaling and COX-2 activities in cell culture.

Other plant-derived polyphenolic compounds (such as catechins, curcumin, or flavonoids) may also have xenohormesis activities as well; it has been suggested that the majority of health benefits from plant phytochemical consumption might not be from their antioxidant properties, but rather by a CR-like modulation of stress-response pathways. Fisetin, quercetin, proanthocyanidins, and theaflavins are examples of compounds that have inherent chain-breaking antioxidant chemistries, but appear to exert profound health effects unrelated to their ability to quench free radicals. Fisetin and quercetin have both been shown to stimulate SIRT, a central activity of CR. In vitro, fisetin, like CR, reduced mTOR signaling, Nf-kB activation and COX-2 gene expression, and activated antioxidative and detoxifying gene pathways (Nrf2). Fisetin has also been shown to increase lifespan in Saccharomyces 136 and Drosophila.Quercetin, in addition to proanthocyanidins from grape seed, have also been shown to reduce the production of inflammatory cytokines, and the expression of vascular endothelial growth factor (VEGF), which may prevent tumors from recruiting blood vessels. This same chemoprotective activity has been observed in rats under CR. Theaflavins are flavan-3-ols from black tea that are produced during the oxidation (fermentation) of tea leaves. Aside from their suppression of NF-kB and inflammatory cytokines in vitro and in mice and their induction of apoptosis in cancer cells, theaflavins also stimulate the longevity factor Forkhead box 1 (FOXO1) in invertebrate and mammalian cells.

Nicotinamide riboside is another naturally-occurring compound that may act as a CRM. It is a source of vitamin B3 and a precursor for nicotinamide adenine dinucleotide (NAD+), a molecule involved in a wide array of biological processes. NAD+, one of the important biologically active forms of NAD, is necessary for the activation of proteins called sirtuins, including SIRT1, that regulate cellular metabolism and DNA transcription. NAD+ levels are known to decrease with age, resulting in lower sirtuin activity. This may contribute to dysfunction in cell nuclei and mitochondria, and to a range of age-related disorders. Like calorie restriction and exercise, nicotinamide riboside can increase NAD+ levels and SIRT1 activation, and may be able to prevent or reverse age-related mitochondrial and metabolic dysfunction and disease in yeast cells, nicotinamide riboside supplementation raised NAD+ levels and increased lifespan without calorie restriction. Even in mice on a high-fat diet, nicotinamide riboside supplementation was found to raise NAD+ levels and SIRT1 activity, and was associated with positive metabolic effects, including less weight gain, improved exercise performance, and decreased liver fat.179

The glucoregulatory agent metformin can produce many of the gene expression changes found in mice on long-term caloric restriction, in particular, it can decrease the expression of chaperones; a set of proteins which, in addition to their other functions, can reduce apoptosis (self-destruction of damaged or malignant cells) and promote tumorgenesis. Metformin has increased mean lifespan in the worm C elegans.144 Along with the related anti-diabetic biguanide drugs phenformin and buformin, metformin extended the mean life span of mice by up to 37.9 percent and their maximum life span by up to 26 percent in multiple studies (reviewed in) while significantly decreasing the incidence and size of mammary tumors. These effects on spontaneous tumor incidence, however, were limited to female animals.  Metformin’s CR-like effects are possibly due to influence on insulin or IGF-1 signaling. This mechanism may also explain the lifespan extension properties of the glucoregulatory herb Cinnamomum cassia (cinnamon bark) in the C. elegans.

Numerous studies have found that metformin, which can induce a calorie restriction-like state, activates a critical enzyme called adenosine monophosphate-activated protein kinase (AMPK). This enzyme, which affects glucose metabolism and fat storage, has been called a “metabolic master switch” because it controls numerous pathways related to extracting energy from food and storing and distributing that energy throughout the body.

Gynostemma pentaphyllum (G. pentaphyllum) is used in Asian medicine to promote longevity.163 Its longevity effects appear to be due, in part, to its ability to activate AMPK.161 Studies of G. pentaphyllum supplementation in humans demonstrate effects also found in calorie restriction, such as improved glucose metabolism, and reduced body weight, abdominal fat, and overall fat.  Other studies found that G. pentaphyllum significantly improves insulin sensitivity, a mechanism also observed in studies of caloric restriction.

Trans-tiliroside is an extract obtained from rose hips that has been used for nearly a century to treat a variety of conditions, including cardiovascular disease, diabetes, and inflammatory diseases.  Trans-tiliroside’s effects appear to be due in part to its ability to activate AMPK. Caloric restriction and exercise are both efficient activators of AMPK, as this enzyme pathway is stimulated when energy demand exceeds supply.

In a clinical trial, rose hip extract supplementation in 32 overweight individuals resulted in significantly less total abdominal fat, abdominal visceral fat, body weight, and body mass index by the end of the 12-week trial compared with those who received placebo. Numerous preclinical trials have shown that trans-tiliroside and its derivatives boost AMPK signaling. In a mouse study, administration of a rose hips extract significantly reduced dangerous after-meal glucose spikes and inhibited weight gain, particularly abdominal fat deposition.

Fish oil, while not a CRM, appears to increase the efficacy of CR at preventing free radical damage; fish oil feeding with 40% CR in mice demonstrated synergistic reductions in thiobarbituric acid reactive substances (TBARS, a marker of lipid peroxidation), and was more effective at reducing inflammatory markers (COX-2 and iNOS expression) that CR or fish oil alone. 

The branched-chain amino acids (leucine, isoleucine, and valine) exhibit several CR-like properties, particularly related to mitochondrial biogenesis. Leucine increased mitochondrial mass in cultured human myocytes (muscle cells), and activated genes associated with CR (PGC-1α and SIRT-1).  Elevations in CR gene expression were observed in mouse cardiomyocytes using a mixture of all three BCAAs.151 The BCAAs have also extended lifespan in Saccharomyces as well as in mice, when supplied above normal dietary levels. Similarly, pyrroloquinoline quinone (PQQ), a bacterial electron carrier and cofactor for several bacterial enzymes (and at least one mammalian enzyme increased mitochondrial DNA content and stimulated oxygen respiration (both indicative of biogenesis) in cultured mouse hepatoma cells through the activation of the CR gene PGC.

 

 


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This information (and any accompanying material) is not intended to replace the attention or advice of a physician or other qualified health care professional. Anyone who wishes to embark on any dietary, drug, exercise, or other lifestyle change intended to prevent or treat a specific disease or condition should first consult with and seek clearance from a physician or other qualified health care professional. Pregnant women in particular should seek the advice of a physician before using any protocol listed on this website. The protocols described on this website are for adults only, unless otherwise specified. Product labels may contain important safety information and the most recent product information provided by the product manufacturers should be carefully reviewed prior to use to verify the dose, administration, and contraindications. National, state, and local laws may vary regarding the use and application of many of the treatments discussed. The reader assumes the risk of any injuries. The authors and publishers, their affiliates and assigns are not liable for any injury and/or damage to persons arising from this protocol and expressly disclaim responsibility for any adverse effects resulting from the use of the information contained herein.

The protocols raise many issues that are subject to change as new data emerge. None of our suggested protocol regimens can guarantee health benefits. The publisher has not performed independent verification of the data contained herein, and expressly disclaim responsibility for any error in literature.

Robots And Our Future!

Ray Kurzweil is the Mind Behind the Theory of The Singularity

Futurist and inventor, Ray Kurzweil, is the mind behind the theory of the singularity taking place by 2045, the point when humans multiply our effective intelligence a billionfold by merging with the intelligence we have created. He is attending the festival this year with PHD in order to appear on stage and film elements of a new film the media agency is making around the topic of AI. It is also using the presence of Kurzweil to launch a book on the topic, appropriately named ‘Merge’.

“It’s an optimistic group that welcomes the future as I do,” says Kurzweil when asked what he thinks of the festival. He is sitting quietly on a large deep chair in the middle of the grand lobby of the JW Marriott on Le Croisette having flown in just that morning from the US. He is clearly tired when The Drum greets him but soon warms up while discussing the topic he has spent his professional life leading – the transformational power of technology on people and language.

Asked about his views on the advancement of advertising and communications as a result of technological progress, Kurzweil immediately turns to how useful advertising can be now as it becomes more focused through understanding online user interests.

“Advertising is really blending in with other forms of communication and that is something that people welcome because it is topics that they have an interest in,” he says.

“Brands are very important because we need to trust information. Not everything on the internet can be relied on so we use brands as a way of knowing what is reliable,” he explains, before later adding that AI can help ensure people are treated as individuals rather than a mass audience being served the same message in unison.

“People will resent wasting their time with messages that don’t agree with them, that are in areas they are not interested in, so AI is going to tell people they are going to like a movie or a song and we appreciate that because it’s usually right and brands have to be associated with good quality information. You can’t sell something that people are not going to like,” he says.

He cites advice his aunt, who was a senior vice president of Doyle Dane and Bernbach (DDB) in New York gave, that trying to advertise a brand that people aren’t going to like is the quickest way to kill it: “You have to be selling something that is worthwhile and then people will appreciate the message and it’s more and more important that people can trust in an era that is filled with misinformation.”

He goes on to claim that “language is at the heart of human intelligence” and says that the understanding of human language cannot be faked when asked what technological developments are exciting him currently.

“To really understand language you really have to understand human intelligence and knowledge at human levels. That’s what I work on and that is what I think is most exciting but AI keeps doing things that people thought were only the province of human intelligence. Every time AI does something we say ‘that’s not really AI’ and it has been called ‘the set of problems we haven’t solved yet’ but that is getting smaller and smaller.”

He repeatedly states that the dawn of AI is not “an alien invasion from Mars” but a result of human ingenuity and believes that technology will ultimately “go inside our bodies and brains” to aid health and and that the neo-cortex of the human brain will be linked directly to the cloud, taking man’s evolution a step further as technology assists brains to access more knowledge than ever before.

“We are going to connect our neo-cortex to the cloud and add again to the hierarchy and make ourselves smarter and create capabilities we can’t even imagine today. Try explaining language or music or humor to a primate that doesn’t understand those concepts. We’ll create new types of knowledge that we can’t understand today when we increase our neo-cortex wirelessly to the cloud. That’s my vision of the future that’s a 2030 scenario,” he confides.

“If you read my predictions going back to the 80s and 90s, I am always surprised when things I have talked about come true,” he later admits. “Although I write about them I still find them remarkable. People very quickly get used to them. It’s always been that way,” he says, before using the smartphone as an example of something that was mass adopted five years ago and quickly change society.

And it’s the accuracy of such predictions that have made Kurzweil’s name. For all his writings, he is still best known for his prediction of the Singularity, and despite the continued increase in the speed of technological advancements, he says he still stands by his assertion that the artificial intelligence will be able to pass a Turing test 12 years from now, and that the singularity will still happen in 2045 despite the continued debate of others in the field.

“There are more and more developments that support that view. My view has stayed the same, the consensus view of experts and the general public is moving towards me,” he says.

He continues: “There is a growing group of people who think I’m too conservative but I see no reason to change my view. AI is doing more and more things that people said it would never do… by 2029 they will do anything humans can do…

“We make these machines to be smarter and we are already smarter. The idea that we are going to merge with this technology is not radical. We are doing it right now and the typical dystopian futurist movie is the AI versus the brave band of humans fighting for control of humanity. We don’t have one single AI in the world today, we have, on last count around 3 billion. Phones are AIs. They have really empowered the individual. They are getting more and more capable and they will be in 8 billion hands within a few years and they are getting more and more integrated with us and they are starting to go into our bodies and brains and it starts with extreme cases like Parkinson’s patients but that will be ubiquitous in the 2030s. Whether they are inside our bodies or not, they are already extending our capability.”

Finally, when asked about the most accurate depiction of AI he has seen in film, he says that Spike Jonze‘s Oscar-winning ‘Her’ is his favourite, but that he felt the ending was a ‘cop out’ and admits that despite the Terminator being one of the most famous depictions of AI on screen, he has yet to meet its famous director and writer James Cameron.

“He did express an interest in an interview for a series he’s doing but I haven’t met him yet,” he responds casually.

This century, if Kurzweil is correct, humanity is set to evolve and reach a new level of intelligence and expand its horizons to new heights with the aid of intelligence. How marketers will deal with that challenge when they are already struggling to deal with other technological developments appearing at a rapid rate will be a fascinating leap for the industry to deal with. How do you advertise to robots anyway