The Optimal Anti-Aging Strategy


the optimal anti-aging strategy
Most of us who are into health and fitness also want to know how we can inhibit the aging process, so as to have a healthy old age free of illness, and hopefully live a long time. We’re aware of the usual healthy practices such as clean diet, exercise, a good night’s sleep, limiting the use of alcohol, ensuring we’re well nourished with vitamins, and so on. But we still age. What further measures can we take to slow aging? What’s the optimal anti-aging strategy?

The process I’m going to write about here is not merely an addendum to a healthy diet, exercise, and so on. It is likely as important or more so than those.

The Optimal Anti-Aging Strategy

This strategy is based on the critical knowledge that exceptionally long-lived lab animals, those that have lifespans that are double and more than those of the shorter-lived varieties, have mutations that increase the process of autophagy. Autophagy is the process of cellular “self-eating” that occurs in all animals regularly, and is increased by fasting. In aging, cellular “junk”, such as malfunctioning mitochondria, misfolded proteins, and damaged organelles accumulate, causing the maladies of aging. But this junk accumulates precisely because the organism is unable to initiate and maintain autophagy.

These mutant animals that live twice as long or more than normal animals do eventually die. But the fact that increased autophagy extends their lives shows that it is the most important, the limiting factor in lifespan.

In virtually all organisms tested so far, and there’s no reason to believe that humans are an exception, calorie restriction (CR) extends lifespan, often dramatically. But why does CR do this? In the worm C. elegans, autophagy is required for lifespan extension from CR.

Dietary restriction extends life span in diverse species including Canorhabditis elegans. However, the downstream cellular targets regulated by dietary restriction are largely unknown. Autophagy, an evolutionary conserved lysosomal degradation pathway, is induced under starvation conditions and regulates life span in insulin signaling C. elegans mutants. We now report that two essential autophagy genes (bec-1 and Ce-atg7) are required for the longevity phenotype of the C. elegans dietary restriction mutant (eat-2ad1113) animals. Thus, we propose that autophagy mediates the effect, not only of insulin signaling, but also of dietary restriction on the regulation of C. elegans life span. Since autophagy and longevity control are highly conserved from C. elegans to mammals, a similar role for autophagy in dietary restriction-mediated life span extension may also exist in mammals.

In a review, Autophagy and Aging, the authors state:

Genetic inhibition of autophagy induces degenerative changes in mammalian tissues that resemble those associated with aging, and normal and pathological aging are often associated with a reduced autophagic potential. Pharmacological or genetic manipulations that increase life span in model organisms often stimulate autophagy, and its inhibition compromises the longevity-promoting effects of caloric restriction… Here, we discuss the probable cause and effect relationship between perturbed autophagy and aging, as well as possible molecular mechanisms that may mediate the anti-aging effects of autophagy.

I included excerpts from both of these articles to emphasize how central autophagy is to aging. Many other treatments besides CR that slow aging and extend life, such as lithium and resveratrol, appear to work by enhancing autophagy.

The mitochondrial theory of aging attempts to account for aging by the increased number of damaged, malfunctioning, and free-radical-producing mitochondria. However, under normal, healthy conditions, autophagy removes and recycles these mitochondria, so a more fundamental reason for aging is deranged, that is repressed, autophagy.

Normally, autophagy in humans rises and declines with a strong daily rhythm. Since autophagy is upregulated by fasting (or starvation), it strongly increases at night and in the early morning, since no food is taken during the night. During the day, during the fed state, autophagy proceeds at a low, basal level.

Humans and other organisms exhibit a strong diurnal rhythm of anabolism and catabolism. Both are equally necessary to life and health. With aging, however, that rhythm declines in amplitude. At night, when autophagy should be strongly activated, it is only weakly so or not at all. In the day, when anabolism should be at full speed, aging weakens the process. This is known as anabolic resistance.

Also due to the diurnal or circadian rhythm in autophagy, levels of glutathione, a tripeptide that is the body’s most important antioxidant, rises and falls. The liver, for example, may contain as much as 100% more glutathione during the day as in the early morning.

As a consequence of the age-related decline in autophagy, the amino acids that are necessary for the synthesis of glutathione fall, and not enough glutathione is produced. Since glutathione is an important antioxidant, if cells don’t make enough, free radicals become abundant and a state of oxidative stress ensues, which is a hallmark of aging. Not good. Oxidative stress in turn causes autophagy to decline, so we have a vicious cycle of less autophagy, more oxidative stress, even less autophagy, and so on.

Now, sarcopenia, or muscle wasting, is also characteristic of aging, and anabolic resistance causes it. Maintaining a healthy amount of muscle mass is crucial to healthy aging and longevity. This healthy amount of muscle mass also decreases oxidative stress, since muscle is the main source through which autophagy releases amino acids, and thus synthesizes glutathione.

The key: to avoid aging, one must go through periods of time of a strong breakdown in tissue (autophagy), followed by a rigorous building up again of the same tissue (anabolism). In this way, the body is rejuvenated, since the tissues that are broken down are old, damaged mitochondria, misfolded proteins, and other cellular debris.

By now you’re probably wondering how to do this, and the answer is very simple. Here’s the equation for living a long time: fasting for a time followed by weightlifting + protein = longer life.

The Second Step: Anabolism

I’m dead serious about this. If you fast, you increase autophagy, which rids your cells of junk. But you must follow this by anabolism, and the best way to accomplish this, even if you’re old, is by lifting weights and eating enough protein.

Ideally, one wants to take protein around workouts, and whey protein has been shown to give the best anabolism bang for the buck. It causes amino acid levels to rise rapidly in the blood, which ensures maximum anabolism. Whey also has the additional benefit of being rich in cysteine, which is the rate-limiting factor in glutathione synthesis. Thus whey can increase levels of glutathione, and this is especially beneficial in older people. And you thought it was only good for bodybuilders.

Whey can also be taken with benefit by older people in the morning. The cysteine and other amino acids in whey will help replenish glutathione, and so lower oxidative stress. Alternatively, n-acetylcysteine, a source of cysteine, may be beneficial for this, and should be taken with the first meal of the day to ensure that other amino acids are present.

As for fasting, well, we’ve discussed intermittent fasting a lot around here. Fasting is crucial to maintaining a high level of autophagy as we grow older. A 12-hour fast, between dinner and breakfast, will likely suffice for those not too old. An even healthier practice might be a daily feeding window of 8 to 10 hours, and during the rest of the time not eating at all. (Exercise should of course be done during the feeding phase.) Eating late at night – or in the middle of the night – is to be strongly discouraged, as this is when you want autophagy going full blast.

There are other ways to increase autophagy, such as drinking water at night or in the early morning. And a number of methods exist to overcome anabolic resistance.

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  1. Shawn says:

    “A 12-hour fast, between dinner and breakfast, will likely suffice for those not too old. An even healthier practice might be a daily feeding window of 8 to 10 hours, and during the rest of the time not eating at all. (Exercise should of course be done during the feeding phase.)”

    I’m guessing it would be best to eat 2 meals a day versus grazing throughout those 8-10 hours. What do you think?

    • P. D. Mangan says:

      Shawn, I doubt that would be necessary. Since autophagy only increases after several hours of fasting, I would think it shouldn’t matter if we’re talking an 8 or so hour feeding window. BTW, there’s no clinical test for degree of autophagy; it’s only possible to measure it with relatively complicated procedures in a research lab. What we need is a good clinical test so that people could find out how much their autophagy has increased after x hours. I actually came up with a way that that could work, but I don’t know if there’s demand nor do I have the resources to develop it and get it through testing.

      • Shawn says:

        Thanks for your input.

      • Allan Folz says:

        Hello Dennis,

        That was about to be my question, is autophagy discrete or proportional? If proportional, where lies the minimal effective dose? Seems we might not know?

        My morning routine includes about a 1/4 cup of 1/2-n-1/2 with my coffee. You mentioned previously that cream is likely to be OK, but would that little bit of milk make a difference to kick my system out of its fasted state? Maybe you’ve mentioned this, but is there a way to sense whether one is in autophagy or not? My guess it’s probably a bit like the feeling I get while in ketosis: not hungry, not full, just a bit more “on” than would be expected given how long since my last meal.

        Also, good to know about taking NAC with the first meal of the day. An interesting blog topic might be timing of one’s supplements. Which ones with food, which ones fasted? Which ones in the morning, which ones at night? I tend to think of vitamins in the morning and minerals at night. But there’s things like DHEA and anti-oxidants which I have no idea which category they fall into. Generally, if I don’t notice something interferes with my sleep I go with it in the evening, if it seems to keep my up I go with in the morning. But that’s hardly authoritative.

        Best Regards.

        • P. D. Mangan says:

          Hi Allan, autophagy is proportional, or it rises and falls in amplitude you could say, it isn’t all or nothing. Longer fasts should promote stronger autophagy. As to minimal effective dose, yes I think you’re right, we don’t know. Possibly we know that hardly anyone has practiced intermittent fasting over a long time, like decades, and that regular fasting, say overnight, might not be enough to promote longevity. As for milk, hard to say, I think a little bit might have small effect, or transient effect. Also, no, there’s no way to know if you have increased autophagy, but probably the same signs of fasting, like slight euphoria, hunger, would seem like indicators of autophagy too.

          Supplement timing would be a good topic. One thing is don’t take antioxidants when fasting or exercising.

          • M. says:

            Great topic. I’ve recently purchased nac and trans-resveratol on your recommendation here and in your book. It seems I should take the nac with first meal. Would the same go for the res? Thanks in advance for your help on this.

          • P. D. Mangan says:

            I think you could take resveratrol just about any time. I avoid it around workouts but that’s just a bit of guesswork on my part, might not be necessary.

  2. Shawn says:

    To clarify, I mean eat 2 meals a day during the 8-10 hr. window.

  3. Yash Bonde says:

    Correct me if I’m wrong but it is said that your body heals and repairs itself when you sleep after a workout.
    Considering a fast between dinner and breakfast, wouldn’t your body get put into a catabolic state since you’re fasting and end up not recovering properly.

    • P. D. Mangan says:

      Well, not eating when you’re asleep is the normal state of affairs, right? (Not being sarcastic, just pointing it out.) So unless you want to get up in the middle of the night to eat, you’ll be fasting all night. Tim Ferriss did this, and I have too. But you’re correct that you will enter a catabolic state, that’s the whole point. Autophagy is almost completely turned off during anabolism, i.e. the fed state. Both anabolism and catabolism are equally necessary to health, anyway that’s how I see it. Bodybuilders may try to keep themselves anabolic 24/7, but they then miss the necessary periods of autophagy/catabolism.

      As for recovery, yes, eating is necessary to it, but I would think going overnight without eating isn’t going to hurt recovery much.

      • Random Visitor says:

        How does fasting for Ramadan affect Muslim’s health? They do no food during the day for one month a year. Are there any religious groups that fast regularly on other schedules that have been studied?

        • P. D. Mangan says:

          There have been tons of studies on Ramadan fasting, and I believe it affects Muslims’ health for the better. I recall one study that found that bodybuilders and strength athletes had a very tough time with hypertrophy during that time. Beyond that, I honestly haven’t paid a lot of attention to the Ramadan studies because the fasting isn’t done under controlled conditions, not by everyone, to what degree, etc.

  4. Anon says:

    You mentioned today that “Anti-aging effects of calorie restriction due to protein restriction”. Here you say protein is good for anti-aging. Can you please discuss. Thank you

    • P. D. Mangan says:

      I’m planning to write a post on this, but for now: whey is good to use with exercise, since during your exercise/fed phase you want to build up the muscle that was broken down during fasted phase. But too much protein overall results in high levels of IGF-1, which negatively affects autophagy. If the effects of CR are due to less protein, and CR extends lifespan through increasing autophagy, you can see the problem with too much protein. This isn’t all worked out scientifically by any means.

  5. rowan says:

    Why should exercise be done only during the feeding phase?

    I have done fasting, and worked out in a fasted state with no noticeable ill effects. Obviously this is not scientific, so I’m interested if there’s someone to back your statement up.

    • rowan says:

      Ah, just found your other post answering my question. It fits with my own experience – while I sometimes performed worse during
      a fasted workout, I didn’t have any problems with my numbers overall, or over time.

  6. Josh says:

    Great article and great blog in general.

    If it’s okay with you, I’d love to pick your brain. There’s a supplement called Myo-X – recently recommended by John Doe – which claims to stimulate muscle growth by reducing myostatin by an average of 46%. It’s supposed to be very effective, depending on who you listen to.

    Can you think of any negative side effects to inhibiting the production of myostatin?

    I’m in my mid-twenties. Have been lifting for a few years now. Looking to increase muscle mass, but not at the expense of overall health.

    Would love to hear your thoughts.

    • P. D. Mangan says:

      Josh, from what I know, the reduction in myostatin is one of the main ways that weightlifting induces hypertrophy. So if this supplement reduces it, and doesn’t have any other side effects, it could be effective.

      However – and this is a big one – myostatin is homologous with human GDF-11. You may recall that widely hailed experiment from last year in which old mice were rejuvenated by blood from young mice; the responsible factor there is GDF-11. So I assume that reducing myostatin, at least in the whole body and not just in muscles, and by an average of 46% which seems like a lot, may lead to a promotion of aging, because GDF-11 will also be reduced. I suppose that’s a little speculative, but from the growth-longevity tradeoff that there seems to be no way around, those are my initial thoughts.

      This article might give some insight on that:

      And thanks for the kind remarks.

  7. SJ says:

    Solid post.

    Along with restricting the frequency of meals is there any info regarding caloric restriction too? e.g. a slight surplus vs. a slight deficit?

    • P. D. Mangan says:

      Thanks, SJ. Fasting seems to give much or all of the benefits of calorie restriction without restricting calories, or at least by very much. Animals that are alternate day fasted will usually eat slightly fewer calories overall, even when they can eat ad lib every other day. In other words, with regular fasting it seems hard to make up for the calories missed. That being said, fasting brings benefits even if overall calories remain the same. Anyway that’s my interpretation of the science.

  8. Derek Wolf says:

    Great article and blog!

    I’ve experimented with many eating protocols over the years. Working with intermittent fasting principles have brought the best results; in terms of energy, hormone regulation, cognition, overall well-being.

    Eating every 2-3 hours, all day all night, is a chore and feels terrible. The energy demanded by digestion is strong and in my experience inhibits performance in other pursuits.

    Eating moderate protein + high fat meals, with lots of fresh veggies, in an IF fashion keeps me satiated from dinner until late breakfast/early lunch, when my eating window begins. Most notably, my cognition and performance in the AM is stellar when eating this way.

    It makes sense that biologically, eating this way would carryover beneficially to other matters such as the effects of aging, buildup of oxidative stress, and so on.

    Keep up the great work!

    • P. D. Mangan says:

      Derek, thanks! Grazing, or as you say eating every 2 or 3 hours, is definitely not optimal for health, keeping insulin at relatively high levels constantly and so on. For good health, we need to think of what we are evolutionarily adapted to, which I would say excludes many meals a day plus snacks.

  9. Mike Milam says:

    When fasting for 12 hours, should we avoid water as well, or just food?

    • P. D. Mangan says:

      No, not at all, Mike. Water, coffee, and tea are all fine. The latter two can be taken with small amounts of cream also, just not half and half or milk, because these have protein and carbs, which halt autophagy.

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