How Fasting, Calorie Restriction, and a Fasting-Mimicking Diet Can Encourage Longevity

The Genius LifeHi folks, today’s post comes from my friend Max Lugavere, New York Times best-selling author of Genius Foods and The Genius Life, which will be available for purchase on March 17, 2020. Max is a young guy, but he’s accomplished a lot so far, including an impressive bit of research and writing about longevity and how to age optimally with grace. I know you’ll enjoy Max diving into the weeds a bit about the nutrient sensors, proteins, and catalysts that may help us live long, healthy, thriving lives. This post comes from an excerpt from Max’s newest book The Genius Life.

From now until March 11, 2020 at 11:59 p.m. PST, enter for your chance to win a FREE copy of The Genius Life as well as Primal Kitchen salad dressings and Primal Sun. All you have to do is head over to Instagram, follow @marksdailyapple and @maxlugavere, and tag some friends in the comments of the giveaway post. Three winners will be selected and notified via DM. Good luck, and enjoy the excerpt.

When it comes to slowing down the clock, life extension is indeed possible. The catch? There are two: it involves calorie restriction, and it has only been successfully demonstrated in lab animals. Studying longevity in humans is a bit more challenging. We don’t sleep in labs, we live a lot longer, and we like to eat. (Correction: we love to eat.) So while most of us would happily opt for a 40 percent increase on our life spans like food-deprived lab rats seem to achieve, we need a better route to get there.1

Thankfully, longevity researchers have begun to look for calorie restriction mimetics—compounds or strategies that can mimic the beneficial effects of prolonged calorie restriction but without the misery that goes along with it. Some emerging food-based candidates include resveratrol, the antioxidant found in red wine; fisetin, found in strawberries and cucumbers; and curcumin, found in turmeric. The most promising of all, however, may derive from a practice as old as humanity itself: fasting.

How do the cells of the body know when we’ve decided to fast? Answering that question has been mission critical for longevity researchers. Why? Because if we’re able to find the signal that tells our cells “food is scarce,” we may be able to activate those signals on demand and reap the myriad cellular benefits that ensue. Plus, we’d be able to do it without committing to a lifetime of starving ourselves. The chief nutrient sensor that our bodies use to assess whether or not we are in a calorie-deprived state is—and it’s a mouthful—adenosine monophosphate-activated protein kinase or, simply, AMPK.

AMPK senses overall energy (i.e., calorie) availability. You may have heard of adenosine triphosphate, or ATP, the basic energy currency of cells. Under normal circumstances, ATP is able to be generated to meet the demands of our activity. But when ATP can’t get replenished fast enough, such as during calorie restriction or high-intensity exercise, AMP builds up in the cell. AMP is an energy-depleted version of ATP, and too much AMP leads to the activation of AMPK.

AMPK sits at the helm of coordinating the body’s response to the sudden lack of energy. It promotes increased fat burning, better glucose handling, improved insulin sensitivity, and reduced inflammation. It also decreases the liver’s synthesis of fats like cholesterol and triglycerides.2 And, since AMPK’s duties include making sure your cells are better prepared for next time, it spurs the creation of healthy, new energy-generating mitochondria (dysfunction of these little power plants is associated with aging and numerous age-related diseases). This is all why activating AMPK is considered a powerful lever for the life-extending properties of calorie restriction.

Other Potential AMPK Activators:

  • Astaxanthin (in krill oil and wild salmon)
  • Berberine
  • Coffee
  • Cold exposure
  • Curcumin (in turmeric)
  • Extra-virgin olive oil
  • Green tea
  • Heat (e.g., saunas)
  • Metformin (a type 2 diabetes drug)
  • Quercetin (in capers and onions)
  • Reishi mushroom
  • Resveratrol
  • Sulforaphane (in cruciferous veggies)
  • Vinegar

What might you do to support the activation of AMPK? Calorie restriction, of course. Other than that, high-intensity interval training, which I describe in more detail on page 122 in my book The Genius Life, is a potent AMPK activator, precisely because it creates a temporary state of energy deprivation. And new research suggests that a few hours of daily fasting can also activate this pathway. By simply eating less frequently, we allow AMPK to become active, whereas eating around the clock keeps AMPK perpetually subdued. Avoid food for the first hour or two (or three) after waking up and avoid food for two to three hours before bed.

Slowing the Clock

One pathway that AMPK stimulates is the FOXO family of proteins. One of them, FOXO3, has been proposed as a longevity protein. It boosts stress resilience (important if you want to live a long time) and may help prevent age-related diseases including cardiovascular disease, type 2 diabetes, cancer, and neurodegenerative diseases. Some lucky people have genes that make their FOXO3 more active, and those people have markedly higher odds of living to one hundred.

Genes or not, you can activate FOXO3 just as easily.

For FOXO3 to activate, it needs a signal, and AMPK is just that. While eating around the clock keeps AMPK chronically deactivated, constraining your feeding window to eight to twelve hours every day encourages AMPK—and subsequently FOXO3—to ramp up. (FOXO3 is also sensitive to insulin, which acts like a nutrient sensor for glucose availability and is discussed on pages 12–13. By keeping insulin within a normal healthy range with a lower carbohydrate diet among other things, we allow FOXO3 to come out of its hole.)

Finally, there’s mTOR, which may be the most potent antiaging protein of all. mTOR was discovered decades ago while scientists were investigating how a strange bacterial compound discovered on Easter Island seemed to exhibit powerful anticancer effects. It appeared to work by inhibiting a protein in the body involved in cell proliferation, which is increased in cancer. The compound was named rapamycin for Rapa Nui, the Polynesian name for the island on which it was discovered, and its target, the anticancer protein, came to be known as mTOR, or mammalian target of rapamycin.3

mTOR promotes storage and growth. As with insulin, this can be highly beneficial when that growth occurs in your muscle tissue, which mTOR helps to achieve. It is also an important player in the formation of synapses—the connections between brain cells—and neuroplasticity, which is your brain’s ability to change over time. These processes all require mTOR-regulated growth.

But mTOR also has a dark side. Too much mTOR activity has been linked with autism, seizures, and certain cancers.4 It can even accelerate aging. When activated, it’s the central gatekeeper to the house-cleaning process known as autophagy. Autophagy clears away old and damaged cell components, such as old mitochondria—the energy generators of your cells—making way for new powerhouses to be created. But by being stuck in an always-on state, this rejuvenation process is blocked. We can see this play out in old mice, whose lives can be extended by up to 60 percent by inhibiting mTOR with rapamycin.5 Rapamycin is not a free lunch, however, and its chronic use is associated with numerous potential side effects such as insulin resistance, the hallmark of type 2 diabetes. This begs the question: is there a healthier way of inhibiting mTOR?

mTOR is sensitive to two things: dietary protein and energy availability. When protein is abundant and energy is flowing, mTOR is revved up. When energy is lacking or protein is restricted, mTOR is inhibited. By limiting our food consumption to eight hours a day—effectively half the feeding time of your average person—we can easily achieve both and spend more time in an mTOR-inhibited state.

And while the story on fasting and longevity is still being written, one proposed method has emerged, with clinical research to back it up.

The Fasting-Mimicking Diet

The raw power of activating AMPK and simultaneously inhibiting mTOR was on display with the results of a fasting protocol devised by scientists at the University of Southern California, led by gerontologist Valter Longo. The research suggests that a periodic very low-calorie diet can not only potentially extend life and health span, but even treat conditions like multiple sclerosis and type 1 diabetes.

It’s known as the fasting-mimicking diet. When it was first tested in mice, Dr. Longo and company witnessed essentially a “resetting” of the immune system. The energy-restricted diet destroyed old and dysfunctional autoimmune cells, which were then re-created in a non-autoimmune state during the refeeding process.6 The rejuvenation of the immune system mimicked what Dr. Longo calls “an embryonic-like program,” causing an increase in healthy new stem cells similar to those seen in development.

We don’t often get to restart with a clean slate, but that’s what fasting seemed to do for these rodents’ immune systems. Moving on to higher-level organisms, the human version of the fasting mimicking diet involved five consecutive days of very low-calorie eating. How low? About half of participants’ normal calorie intake. And the calories were specifically intended to come predominantly from veggies and healthy Mediterranean fats like extra-virgin olive oil. It was then repeated monthly, for a total of three months.

By the end, the subjects had decreased risk factors and biomarkers for aging, diabetes, and neurodegenerative and cardiovascular disease, without any major adverse effects and with just a few days of calorie restriction per month. The diet was also deliberately low in protein, but it’s hard to know whether the benefits seen were due to protein restriction, or calorie restriction in general. Independent of calorie restriction, protein restriction hasn’t yet proved beneficial in humans—quite the opposite, actually—and is likely a recipe for weight gain and muscle loss, especially over the long term.

The takeaway here is that aside from minding your meal timing, occasional low-calorie dieting may be useful for a long and healthy life. It makes sense from an evolutionary standpoint that our bodies would know what to do once food became scarce, since it’s unlikely our ancestors had successful hunts all year round.

Pick up a copy of Max’s book, The Genius Life, on or after March 17, 2020, or pre-order your copy today and get a number of generous freebies, including “The 10 Supplements for Better Brain Function.”


1. Les Dethlefsen et al., “The Pervasive Effects of an Antibiotic on the Human Gut Microbiota, as Revealed by Deep 16S rRNA Sequencing,” PLOS Biology 6, no. 11 (2008): e280, doi:10.1371/journal.pbio.0060280.

2. Tsepo Ramatla et al., “Evaluation of Antibiotic Residues in Raw Meat Using Different Analytical Methods,” Antibiotics 6.4 (2017): 34, doi:10.3390/antibiotics6040034; Khurram Muaz et al., “Antibiotic Residues in Chicken Meat: Global Prevalence, Threats, and Decontamination Strategies: A Review,” Journal of Food Protection 81, no. 4 (2018):619–27.

3. Marcin Bara?ski et al., “Higher Antioxidant and Lower Cadmium Concentrations and Lower Incidence of Pesticide Residues in Organically Grown Crops: A Systematic Literature Review and Meta-Analyses,” British Journal of Nutrition 112, no. 5 (2014):794–811.

4. Jotham Suez et al., “Post-antibiotic Gut Mucosal Microbiome Reconstitution Is Impaired by Probiotics and Improved by Autologous FMT,” Cell 174, no. 6 (2018): 1406–23.

5. Ruth E. Brown et al., “Secular Differences in the Association Between Caloric Intake, Macronutrient Intake, and Physical Activity with Obesity,” Obesity Research & Clinical Practice 10, no. 3 (2016): 243–55.

6. Tetsuhide Ito and Robert T. Jensen, “Association of Long-Term Proton Pump Inhibitor Therapy with Bone Fractures and Effects on Absorption of Calcium, Vitamin B12, Iron, and Magnesium,” Current Gastroenterology Reports 12, no. 6 (2010): 448–57, doi:10.1007/s11894-010-0141–0.

About the Author

Max Lugavere

Max Lugavere is an author, researcher, writer, and leading voice on real-food nutrition. As a researcher, he has co-authored peer-reviewed literature, including a clinicians textbook on the science of dementia prevention. His first book Genius Foods became an instant New York Times best-seller, and is now published in eight languages around the globe; his second book The Genius Life is a comprehensive guide to how to detox, rejuvenate, gain health, and improve longevity.

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