How to Increase Autophagy for Lifespan Extension

how to increase autophagy for lifespan extension

The four pathologies of aging

Aging can be defined as a breakdown of homeostasis; that is, the organism as it gets older finds it increasingly difficult to regulate itself and to maintain all systems in a state of balance and of health.

A more practical way of defining aging is as increasing susceptibility to disease. Aging is the prime factor in disease risk.

There are four main cellular derangements of aging:

  • increased inflammation
  • increased oxidative stress
  • increased mitochondrial dysfunction
  • lower levels of autophagy.

They are all related and linked through cellular sensors and pathways, most notably through the cellular energy sensor AMPK, which regulates aging.

Improving the parameters of any one of these factors also improves the others. Lowering oxidative stress, for example, also entails lower levels of inflammation and better mitochondrial function.


Autophagy, from the Greek for “self-eating”, is the regulated process through which the cell breaks down parts of itself and by sequestering them into vacuoles and digesting them. The parts that are broken down are mainly organelles and proteins that have passed their expiration dates.

In this way, autophagy provides for a continuous process of self-renewal by breaking down older structures, allowing for new ones to be built in their place.

One characteristic of aging is the accumulation of damage, and this is largely due to the failure of autophagy to attain normal functional levels. It can be seen that bringing levels of autophagy to youthful levels can ameliorate aging by clearing out damaged parts of the cell.

In rats, stimulating autophagy by either fasting every other day, or by fasting once a week together with the anti-lipolytic drug Acipimox, fully restored levels of autophagy in older rats to those of 3-moth-old rats. Acipimox is a derivative of niacin (vitamin B3) and works the same way. (Experimental Gerontology). Markers of accumulated damage also decreased to those of young animals.

In old rats (27 months), the rate of autophagy was only 1/6 that of young animals. (Journal of Gerontology.)

That’s a huge difference. Think of the functional decline of an older person: depending on the exact comparison made, it wouldn’t be an exaggeration to say that many older people have only 1/6 the physical function of a young man in his prime. That difference may largely be due to autophagy.

In aging, the importance of maintaining clean cells is paramount. (Autophagy.)

Autophagy is central to life extension

A number of different treatments and protocols, for example resveratrol, calorie restriction, and genetic manipulation of IGF-1 signaling, have been found to extend the lifespans of experimental animals.

These treatments and protocols have something in common: they all cause an increase in autophagy.

Autophagy is central to extending lifespan and to avoiding the diseases of aging.

There is no such thing as healthy aging. Aging means increasing susceptibility to disease and the breakdown of the organism. Being healthy when older requires retarding the aging process.

How central is autophagy to life extension? It is not only necessary, but sufficient: “Essential role for autophagy in life span extension” (Journal of Clinical Investigation). This article by the world-class scientific team led by Guido Kroemer states:

Life and health span can be prolonged by calorie limitation or by pharmacologic agents that mimic the effects of caloric restriction. Both starvation and the genetic inactivation of nutrient signaling converge on the induction of autophagy, a cytoplasmic recycling process that counteracts the age-associated accumulation of damaged organelles and proteins as it improves the metabolic fitness of cells. Here we review experimental findings indicating that inhibition of the major nutrient and growth-related signaling pathways as well as the upregulation of anti-aging pathways mediate life span extension via the induction of autophagy. Furthermore, we discuss mounting evidence suggesting that autophagy is not only necessary but, at least in some cases, also sufficient for increasing longevity. [my emphasis]

Autophagy can be increased easily

The beauty of autophagy as a life-extending process is that, in the right physiological milieu, that is, under conditions over which we have a great deal of control, it can be strongly increased. Kroemer himself explicitly states that autophagy is “a druggable process that is deregulated in aging and human disease” (JCI).

Autophagy (“self-eating”) constitutes one of the most spectacular yet subtly regulated phenomena in cell biology. Similarly to cell division, differentiation, and death, autophagy is perturbed in multiple diseases, in that excessive or deficient autophagy may contribute to pathogenesis. Numerous attempts have been launched to identify specific inducers or inhibitors of autophagy and to use them for the therapeutic correction of its deregulation. At present, several major disease categories (including but not limited to age-related, cardiovascular, infectious, neoplastic, neurodegenerative, and metabolic pathologies) are being investigated for pathogenic aberrations in autophagy and their pharmacologic rectification. Driven by promising preclinical results, several clinical trials are exploring autophagy as a therapeutic target.

Increasing autophagy to youthful levels is, in my view, essential to any anti-aging protocol.

Much of the decrease in autophagy seen in aging is also less related to aging per se than it is to types of behavior associated with aging.

Even in older animals, autophagy can be robustly increased through, for example, fasting and exercise, two interventions that have nothing to do with aging in itself.

Before we get to ways to increase autophagy, how can you completely screw up the process and ensure that your autophagy levels decline and that you get old and unhealthy in a hurry?

  • First of all, eat all the time: graze, eat snacks, never let your body out of the fed state.
  • Second, be sedentary and gain weight. Doing this increases levels of inflammation and oxidative stress and causes a decline in autophagy.
  • Third, make sure all your food is processed and that you never eat a vegetable.

How to increase autophagy

Several reliable interventions increase autophagy, and you can do them on your own.

1. Exercise: Exercise induces autophagy in the body and in the brain (Autophagy). Since it’s been shown that autophagy is required for the beneficial effects of exercise, including performance adaptation, exercise would have to be intense enough to cause these adaptations for autophagy to take place.

The benefits of weightlifting are in part caused an increase in autophagy: “Chronic resistance training activates autophagy and reduces apoptosis of muscle cells” (Experimental Gerontology).

Autophagy Is Required to Maintain Muscle Mass. (Cell Metabolism.) Absence of autophagy causes profound muscle atrophy.

2. Fasting: Autophagy is “potently triggered by fasting” (Kroemer again, Cell). How much fasting? In young animals and humans, overnight fasting is enough to get it started. When older, longer periods of fasting may be necessary, which is why I regularly fast for 16 hours or more.

Even better news is that fasting can strongly protect against cognitive decline, dementia, Alzheimer’s, and Parkinson’s: Short-term fasting induces profound neuronal autophagy (Autophagy). “Our data lead us to speculate that sporadic fasting might represent a simple, safe and inexpensive means to promote this potentially-therapeutic neuronal response.”

If you want to keep your mind as well as your body in youthful condition, fasting should be added to the arsenal.

3. Chemical autophagy boosters: See my article “Intermittent Fasting Boosters / Autophagy Enhancers”. These chemical autophagy boosters include resveratrol, hydroxycitrate, nicotinamide, curcumin, lithium, and EGCG (from green tea). These are all readily available over-the-counter, and are cheap and safe.

Insulin signaling from food could override the autophagy-boosting effects of these supplements, so take them during the fasted state.

4. Ketosis. Ketosis results from relatively prolonged abstention from dietary carbohydrates. It stimulates autophagy (JBC) and promotes autophagy in the brain (Medical Hypotheses), which is likely important to the neuroprotective effects of the ketogenic diet.


Virtually every known method of life extension, as well as methods that protect the organism from disease, are mediated by autophagy. Fortunately for us, we have many methods at our disposal for increasing autophagy to youthful levels.

PS: For more on this, see my book Stop the Clock: The Optimal Anti-Aging Strategy.

PPS: Check out my Supplements Buying Guide for Men.

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  1. JJS says:

    Hey PD!
    I have been fasting and taking both nicotinamide and hydroxycitrate in the middle of my fasting days. Soon after taking these both–maybe 1-2 hours later– I develop bad headaches and have to take ibuprofen for relief. Any thoughts on why this is happening? Any suggestions to prevent this from occurring? (On fasting days when I don’t take these I can go 24-36 hours without an issue)

    • P. D. Mangan says:

      JJS, I can’t say I know why. I take both myself, but I don’t think I’ve ever taken them at the exact same time; I have taken them both on the same day. In any case neither one has ever given me a headache. Maybe if you took one or the other, not both, and see if a headache occurs. My opinion is that if you determine that either one or both is giving you a headache, then it’s probably best not to take them; your body may be trying to tell you something by that reaction.

    • billcor2014 says:

      Hi JJS: magnesium/calcium supplements before a fast causes headaches for me. 🙂

  2. Jim Jones says:

    Hello Mangan, glad to see you are still blogging. Have you seen this study? (I couldn’t find free version, although I have seen one on the interwebz before)

    Very intriguing. Multi-day fasting is brutal, but I have tried the diet in the study above and 5 days, while challenging, is definitely nowhere near as tough.

    • P. D. Mangan says:

      Thanks, Jim, I wrote about that study here: Thanks for adding your experience with the diet. I think it was developed for the exact reason you describe: it’s a lot easier than fasting.

      • Jim Jones says:

        Ah, you’re on top of it already! I saw that on, which as you probably know is a great resource. I recently saw this study as well on longecity. It is the most comprehensive and systematic paper I have ever seen on aging and supplementation.

        I am not sure if I am on board with all of that- it seems to me that supplementing with everything that he does is unlikely to give a massive benefit but could up risk massively- but nonetheless it is a very interesting paper for anyone with knowledge of biology (which excludes me).

        Do you still blog on politics? I used to visit your site weekly but it appeared as though google “disappeared” the site.

        • P. D. Mangan says:

          Thanks, Jim, I’ve read quite a bit from that Giuliano guy, he has an extensive blog on aging. I’m no longer blogging on politics, at least for the present, and that blog has been “privatized” – hidden in other words. Maybe some day I’ll go back to it.

  3. IP says:

    Hi, PD!

    One of the things that has recently been swirling in my head is the speed with which different proteins are absorbed by our digestive system. Let’s take Whey and Casein as an example – as far as i have read Whey is absorbed within 2 hours( 1.5 hours is the usual time given by people) and Casein within up to 7. This to me seems quite important. If one fasts for 16 hours per day ( last meal 8 pm / first meal noon next day), it seems to me, that eating dairy protein (usually 80% casein) is a bad idea for increasing Autophagy as it seems to cut the time without protein and keep you in the fed state longer. Since i do like hard cheese and many other dairy products( they are a staple here), i have moved them mainly to my lunch/breakfast meal. Any thoughts on that?

    • P. D. Mangan says:

      IP, I agree with you. Some studies have shown that taking casein at night before bed leads to greater muscle growth when training. The reason it does this is because casein stays in the system virtually throughout the night, preventing muscle protein breakdown. It will also prevent autophagy, so I won’t be doing that. As far as amounts and timing, that could make for different results; for instance, having a piece of cheese with or after dinner may not have much of an effect – or it might, I don’t think we know.

  4. Tisha says:

    I’ve been intermittent fasting alot over the past 3 years and at 46, my health and immune system is impeccable. I look 26. I birthed 5 children. I don’t have any diseases and I look and feel great. I intermittent fast 12 to 16 hrs a day. No need to eat all the time. The body needs rest and needs to heal. I am a vegan…mostly raw vegan.

  5. Juan Salgado says:

    Im new to autophagy and a question I have is I normally drink warm lemon water or apple cider vinegar with water will that stop autophagy process?

    • P. D. Mangan says:

      Hi Juan – no, that seems doubtful. There can’t be more than a few calories in either of those, so any effect would be very transient. For instance, vinegar has 3 calories in a tablespoon, so that’s negligible.

  6. Rob H says:

    Hi Dennis, I’ve just come across this short article from Dr Michael Eades (of Protein Power fame) that you may be interested to read: In the article he states that eating meat and proteins whilst in ketosis actually promotes autophagy: but surely this cannot be true? My understanding was that ingesting any BCAAs (particularly leucine) quickly stopped auotphagy? If his article is in fact true, then that would mean we don’t need to intermittent fast anymore – just go into ketosis, but keep eating meat, dairy and BCAAs to promote autophagy: but surely he has got this wrong? Even Mark Sisson was echoing this view in his weekly ‘Dear Mark’ post yesterday (despite having stated in the past that protein stops autophagy). Would love to hear your view on this – and also if this is untrue, why on earth someone as respected as Dr Eades would be propagating this misinformation?

    • P. D. Mangan says:

      Hi Rob, at the moment Eades’ site isn’t responding, but I read Sisson’s post. What this comes down to is whether the benefits of fasting are entirely due to carbohydrate restriction or not. One study, which I discussed here, concluded that absence of carbohydrate accounted for 100% of the benefits of fasting. Another, discussed here, found that absence of carbohydrate was responsible for 70% of the benefits of fasting. If the latter is true, which I believe it is, then absence of protein would be responsible for the rest. Bottom line is that ketosis does promote autophagy, but complete absence of food promotes it more so. Anyway, that’s how I interpret the state of the evidence; we would need reliable measures of autophagy in humans and a study comparing fasting to a ketogenic diet to settle the matter completely.

    • sten bjorsell says:

      I agree with Dennis below. Apart from that, mTOR is elevated to “growth state” by too much protein while low mTor stimulates what we want when we get older, better maintenance and no cancer growth. Also, excess protein can be converted to carbohydrates as blood glucose, immediately contradicting the arguments for unrestricted proteins.
      Dr Ron Rosedale would want to keep proteins low for good reasons. I have now read your book “Stop the Clock”, which I like much! Added to me knowledge several adjuncts for autophagy and confirmed the importance of diurnal abstinence from food. That we maintain our youth “while young” through substantially higher levels of autophagy is also a crucial piece of knowledge! Hopefully we will not see many attempts from Big Food and Big Pharma to demonize fasting and autophagy as “dangerous” because the practices are result in healthier people eating less junk food.

  7. amy says:

    I have read the contrary regarding green tea extract. I understand EECG inhibits autophay where as Green tea encourages it. also I have read that both Zoloft and Niacin increases autophagy as it inhibits mTOR activation. can you elaborate

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