Fasting and the Mechanism of Longevity

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Self-cleansing and aging

Arguably, the most important driver of aging is the decline in autophagy, the cellular self-cleansing process that rids cells of junk.

Aging just is damage, yet at younger ages, both humans and animals are capable of clearing up the damage and renewing their tissues. They do this through autophagy, which regularly turns over — that is, breaks down — proteins, organelles, and other damaged cellular constituents. 1

The process of ageing denotes a post-maturational deterioration of cells and organisms with the passage of time, an increased vulnerability to challenges and prevalence of age-associated diseases, and a decreased ability to survive. Causes may be found in an enhanced production of reactive oxygen species (ROS) and oxidative damage and not completed housekeeping, with an accumulation of altered ROS-hypergenerating organelles in older cells. It has been shown that autophagy is the only tier of defence against the accumulation of effete mitochondria and peroxisomes; that functioning of autophagy declines with increasing age and determines cell and individual lifespan; that autophagy can be intensified by drugs; and that the pharmacological intensification of autophagy may be a big step towards retardation of ageing and prevention and therapy of age-associated diseases including neurodegeneration.

Calorie restriction, the most robust life-extension intervention known, requires autophagy to work. 2

Life-extending interventions require autophagy

So at least one thing that calorie restriction does to extend lifespan is increase autophagy. When animals lack food, autophagy ramps up to increase the supply of nutrients, especially amino acids, which it gets from breaking down cellular waste.

Other interventions that increase lifespan also appear to depend on increased autophagy. For example, FIRKO — fat insulin receptor knockout — mice have extended lifespan. These mice lack an insulin receptor in adipose tissue. 3

Among the consequences of lacking an insulin receptor in fat tissue is a 60% reduction in that tissue, leading to 20% lower body weight, while calories ingested were more than 50% greater than controls. 4

Wait a minute. These animals ate a lot more than controls but also lived longer. What about calorie restriction?

These animals have lower insulin levels, and that leads to higher levels of autophagy. 5

Increased autophagy allows these animals to clear damage more effectively and thus to live longer.

One of the main themes of my book Stop the Clock is that living longer and in good health requires that you counteract the decline in autophagy that happens to everyone as they age.

How to increase autophagy to youthful levels

How do you increase autophagy?

  • Intermittent fasting. This is probably the best way to increase autophagy. While in young humans and animals, an overnight fast may be sufficient to ramp up autophagy, the decline in the process with age means that a fast longer than overnight is required. Fasting for 16 to 24 hours should do the job, and even longer may be better.
  • Drink water at night. This unusual way of increasing autophagy works by diluting the bloodstream. Leucine is the amino acid regulator of autophagy, and when it rises sufficiently due to the breakdown of tissues, autophagy stops. By drinking water at night (during fasting), the leucine concentration in blood drops, thus restarting autophagy.
  • Calorie restriction. Just mentioned in passing. Not many people want to do this, including me. But your BMI will be down around 19 or 20. Probably requires eating under 2,000 calories each and every day. fasting is easier.
  • Autophagy boosters. Certain substances, calorie restriction mimetics, boost the process of autophagy. These substances include hydroxycitrate, resveratrol, nicotinamide (vitamin B3), and green tea extract. Taking them during a fast will boost autophagy even more than fasting alone.

Another interesting way to stimulate autophagy and extend lifespan uses the drug Acipimox, a derivative of niacin. 6

Once a week fasting with Acipimox or niacin

Acipimox does the same thing as niacin, only with less of a flushing effect, which puts many niacin users off. Unfortunately, it appears that Acipimox is not available in the U.S., so niacin must be used if you live here.

In rats, fasting once weekly and receiving Acipimox on the day of the fast was as effective in increasing autophagy to youthful levels as fasting every other day without the drug. 7

Huge, if you ask me. Every other day fasting is a strenuous burden unlikely to be embraced by most people (like me). But fasting once a week and taking Acipimox is just as effective and much more doable.

Furthermore, niacin ought to be equally effective.

I tried this yesterday. About 16 hours into what proved to be an 18-hour fast, I took a 500 mg tab of extended-release niacin. I has quite a bit of flushing and itching, and while not disastrous or painful, it’s kind of unpleasant.

Supposedly, the flushing goes away with continued use.

Intermittent fasting may be the strongest, most effective anti-aging intervention we currently have. The logic behind this reasoning is that it does the same thing that calorie restriction does in terms of physiology, and calorie restriction is the most effective anti-aging intervention in lab animals.

Boosting the physiological effects of intermittent fasting with the substances noted above should make it even more effective.

Intermittent fasting directly counteracts the mechanism of aging.

PS: Check out my book, Stop the Clock, for much more on how to fight aging.

PPS: Check out my Supplements Buying Guide for Men, where you’ll find some of these autophagy boosters.

  1.  Bergamini, Ettore. “Autophagy: a cell repair mechanism that retards ageing and age-associated diseases and can be intensified pharmacologically.”Molecular aspects of medicine 27.5 (2006): 403-410.
  2. Hansen, Malene, et al. “A role for autophagy in the extension of lifespan by dietary restriction in C. elegans.” PLoS Genet 4.2 (2008): e24, Jia, Kailiang, and Beth Levine. “Autophagy is required for dietary restriction-mediated life span extension in C. elegans.” Autophagy 3.6 (2007): 597-599.
  3.  Blüher, Matthias, Barbara B. Kahn, and C. Ronald Kahn. “Extended longevity in mice lacking the insulin receptor in adipose tissue.” Science299.5606 (2003): 572-574.
  4.  Blüher, Matthias, et al. “Adipose tissue selective insulin receptor knockout protects against obesity and obesity-related glucose intolerance.”Developmental cell 3.1 (2002): 25-38.
  5.  Bergamini, Ettore, et al. “Insulin, food restriction and the extension of lifespan: the mechanism of longevity.” European journal of endocrinology150.1 (2004): 95.
  6.  Tornvall, P., and G. Walldius. “A comparison between nicotinic acid and acipimox in hypertriglyceridaemia—effects on serum lipids, lipoproteins, glucose tolerance and tolerability.” Journal of internal medicine 230.5 (1991): 415-421.
  7.  Cavallini, Gabriella, Alessio Donati, and Ettore Bergamini. “Antiaging therapy: a novel target for antilipolytic drugs.” Mini reviews in medicinal chemistry 14.7 (2014): 551-556.

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  1. Stuart Mather says:

    Did the study include another group of rats who intermittent fasted every day AND got the acipimox?

  2. Stuart Mather says:

    Also, what’s your take on whether a 36 hr fast three times a week (presumably with the niacin/acipimox) or every day for 22.5. I personally find just earing once a day every day entirely doable. I’ve just stopped being hungry outside that one mealtime. It also seems to make evoltionary sense.
    Eextending the fast to 36 hrs is a bit of a stretch But if so doing fewer times per week conferred some special benefit, I’m sure I could get used to it. I think you said somewhere that autophagy trails off after 24 hrs?. Ketosis increases, but not autophagy.

    • P. D. Mangan says:

      Stuart, autophagy doesn’t trail off, but the rate reaches a maximum. But it will keep going the longer you fast.

  3. garymar says:

    Just came off a 60-hour fast (2-1/2 days). Nothing but black coffee, green tea, and water. This morning broke it with some miso soup (tofu and seaweed). For lunch, more soup, kefir, and fruit. Will eat resistant-starch filled potatoes for dinnerr.

    I can fast 24 hours without a hitch, but longer fasting does make me feel pretty weak towards the end. I don’t notice any special “mental clarity” while fasting, but then I don’t have any major health problems and the brain is usually clear anyway.

    It was just that after overeating for a week or two, the body started telling me, “it’s time to fast!”

  4. Arren Brandt says:

    I’m reading a lot about fasting on a Russian forum and on Longecity.
    There is a concept called “Crisis” that happens twice when you undergo fasting regimens. There are two, sometimes three stages. Chinese forums refer to them as First wind, Second wind, Third wind.
    1. Crisis nr 1 Occurs after 24-36 hours when the liver runs out of glycogen. Worst for newbs since it fills one with doubt.
    2. Occurs after more than a week. It was explained by Longecity forum-member Xeva in this quote:

    “Now I am awaiting for what Russians call with the French word crise. It happens around 7th-10th day and marks the moment when the brain switches to getting 30% of its energy from ketones. The dynamics of the process are the following:

    The liver continues to produce ketones at a constant rate throughout the fast. In the meantime, peripheral muscles begin to feed exclusively on FFAs, ignoring both glucose and ketones. This allows the level of ketones in plasma to rise steadily. When it reaches ~3 mmol/L, they easily penetrate into the brain. While this is happening, the plasma pH keeps on dropping, making the fasters miserable in reverse proportion to their body’s buffering capacity. Besides the carbonate ion, O2 in erythrocytes happens to be the best buffer for falling pH, making one even hungrier for oxygen.

    As the days pass, this drop in the plasma pH crescendos making the faster feel more and more miserable, until, finally, the switch happens. Within half an hour it is as if the sky clears and fine weather ensues. Passage through this metabolic hump is called the crise.

    The healthy, metabolically fit people hardly feel the crise but still can judge that they are past this hurdle by monitoring their daily weight loss. It suddenly drops in half, which reflect the fact that less protein is needed to be catabolized to make glucose for the brain.

    Subjectively, at this point, most people feel very well. They are not hungry and are full of energy, both mental and physical, and feel fully rested after only 4-5h of sleep. Most very much enjoy this week and the freedom it brings from the need to eat and associated hustles. ..until the next crise.. “

  5. Garrett says:

    It occurred to me that intermittent fasting and something like “bulletproof coffee” is done for decades in a subgroup of the population: A lot of (heavy) smokers tend to eat very little, and I have witnessed them at work to only smoke and drink coffee in the morning, and going at least until lunchtime with nothing more that that.

    I wonder if that is the reason that slim (smoking reduces appetite in most people, is even used as a slimming technique for that end) smokers tend to live much longer than the fat smokers.

    The effect of smoking itself should be quite cleanly be statistically separable from the effect of intermittent fasting, therefore yielding yet more proof of the health-improving effects of intermittent fasting and autophagy.
    Maybe it would be as simple as subtracting lung cancer from the smoker’s data and see what happens as a function of intermittent fasting lifestyle, resulting from the almost absent appetite of many smokers.

    • P. D. Mangan says:

      Garrett, it seems to me unfortunately that since smoking causes so many health problems, the slimming effects couldn’t be separated from the ill effects. In fact, the studies that have shown higher BMI to be healthier than lower ones are confounded by smokers, who have lower BMIs but worse health.

  6. Ole says:

    Has anyone tried trehalose for kickstarting autophagy during IF?:

    • Stuart Mather says:

      I’ve noticed mention of trehalose as an autophagy booster to. But I’m a bit confused. It’s a sugar, so it has calories. So presumably taking it while fasting would be counterproductive, because it would break the fast, and also the autopnagic benefits of fasting. But if you take it in your eating window, it promotes autopnagy precisely when you don’t want it , but want your body to be anaboilic.
      So when is the best time to consume trehalose, fasted or unfasted? Maybe at the end of a fast, just before you start eating? Or maybe right at the end of your eating window. Just as you’re about to start eating again.
      Ideas anyone?

      • Stuart Mather says:

        Oops , typos.Should be : … ‘mention of trehalose ‘TOO’.
        … ‘autop’H’agic benefits
        ..anabolic not anaboilic
        …’ just before you start ‘FASTING’ (not ‘eating’)

    • Stuart Mather says:

      Also, what’s an ideal trehalose dose?

  7. Vikram says:

    Examine’s write up on Trehaolose:

    Poorly digested by the gut and turned into glucose – but not much glucose. Fasting benefits still occur when you eat a modest amount of calories. So if it’s absorbed then I think it could be of benefit.

    See here for an example of a fasting protocol that improves symptoms of multiple sclerosis due to a 3 day fast where calories will still consumed:

    Keto diet & FMD (Fasting Metabolic Diet) both improved MS and resulted in cellular regeneration. Fasting more powerful than keto. Done in mice and humans.

    • P. D. Mangan says:

      Thanks for those, Vikram. Somewhere on this site I posted a study that showed that the benefits of fasting were approximately 70% due to absence of carbohydrates, so a VLCKD (no carbohydrates) should in theory give about 70% of the benefits of fasting.

      • Stuart Mather says:

        Really interesting Vikram,
        Good O. Trehalose eyedrops it is . It sounds like you don’t need much trehalose to get the cellular benefits as long as you can get it past the body;s trehalase barriers. I wonder why the studies Ole linked to where the 1% trehalose in the drinking water of the experimental rodents showed such a powerful effect (particularly with polyglutamine expansion degenerative conditions like Huntington’s) though? Maybe rodent guts don’t produce trehalase ?

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