Age Better Today 3

Does Protein Restriction and Fasting Slow the Aging Process? Better Aging Part 3

Aging Protein Restriction2In the previous article, we looked at three forms of dietary restriction: caloric restriction, prolonged fasting, and alternate-day fasting. These interventions have helped provide a framework for researchers to unravel the molecular details of how aging happens. But these dietary restrictions are quite extreme, and may not be practical for everyone. In this article, we will look at two less extreme forms of dietary restriction: protein restriction, and the Daniel fast.

 

Protein Restriction

Caloric intake in a typical balanced diet comes from three classes of macronutrients: carbohydrates, proteins, and fats. Studies show that restrictions in carbohydrate and fat intake have no effect on longevity. Protein restriction, however, appears to be a viable option, increasing maximum lifespan by up to 20% in 16 out of 18 reviewed studies in rodents. Given the 40% increase in lifespan found in many studies on calorie restriction, it appears that protein restriction accounts for approximately half of this effect. The most important factor determining the lifespan benefits of protein restriction in multiple species is the ratio of dietary protein to carbohydrate and fat intake. Very few studies on the effects of protein restriction have been conducted in humans, but benefits have been found, including reduced cancer incidence among individuals 65 years and younger.

Proteins are long chains of amino acids strung together, which then form a specific 3-dimensional shape. In humans, there are twenty different types of amino acids coded for by genes. However, other amino acids exist and are often the result of modifications on these twenty. It is not crystal clear whether it is the restriction of proteins as a group or the restriction of specific amino acids that causes the increase in lifespan. The amino acids tryptophan and methionine have both been implicated, but most studies focus on methionine restriction.

A study done by Caro and coworkers investigated the effect of 40% restriction of all dietary amino acids except methionine. It was demonstrated that such a regimen did not reduce mitochondrial reactive oxygen species generation and oxidative damage in mitochondrial DNA. This suggests that methionine is the only amino acid that has any effect on these biomarkers. Furthermore, methionine has been shown to be especially vulnerable to oxidation by reactive oxygen species, compared to other amino acids. Increased methionine intake increases LDL cholesterol oxidation and plasma homocysteine concentrations, which in turn increase the risk of cardiovascular disease and mortality. Methionine-restricted diets in humans are both feasible and tolerable, making these an appealing option for further testing in humans. Here is a list of foods highest in methionine from NutritionData.com. So, it appears that when protein intake is limited, pro-aging pathways are inhibited. What are the mechanisms involved? Two pathways of interest are GCN2 and mTOR.

Slow aging by activating the GCN2 pathway

The GCN2 pathway senses when certain essential amino acids are absent. Once this protein deficiency pathway is triggered, it stabilizes a transcription factor (ATF4) that activates genes implicated in extending lifespan. Additionally, activating GCN2 also reduces mTOR network activity, which I will discuss next.

Slow aging by inhibiting the mTOR pathway

When we eat protein (especially leucine-rich protein sources), it activates the mTOR pathway. This pathway is involved in cell growth, cell proliferation, and protein synthesis. This is why athletes, in fact, aim to stimulate it; it builds muscle and repairs tissue damaged in response to exercise. Athletes better eat their protein, right? However, as we age, this pathway becomes increasingly subject to deregulation and is implicated in various disease states like diabetes, obesity, and cancer. Therefore, it stands to reason that earlier in the lifespan, promoting mTOR activity would be beneficial for age-associated mating behaviors, like maintaining high-levels of muscle to display genetic fitness. But as one ages, suppressing its activity may be wise for long-term health. Of course, we do want to have an adequate level of muscle mass to maintain physical functioning during old age. So there appears to be a tradeoff between physical robustness and longevity.

My hope is that further research will reveal a way to circumvent this tradeoff so that we can aggressively promote the maintenance of lean muscle mass without sacrificing longevity. As you’ll see in my future posts, there are some strategies involving drug therapies that might just allow for us to have the best of both worlds, or at least the better of both worlds.

Here is a quote from Volter Longo of the Longevity Institute at University of Southern California, from an interview with The Low Histamine Chef

“The ideal diet is a plant and fish based diet that is low in protein, about 0.37 grams per kilogram* body weight and that may increase a little bit in proteins after age 65 or 70, depending on the need, and then a diet that is high in nourishment meaning a lot of greens a lot of vegetables, not so much fruit, a little bit but not very much and a diet that is rich in nuts, rich in olive oil, legume-rich also.”

*Important note: while the interview transcript quotes him as saying 0.37 grams per kilogram, we contacted Valter Longo and learned that it should actually be 0.37 grams per pound – a much more realistic protein target.

Please read the rest of that interview to hear the discussion on “ideal diet.”

 

Fasting

Aging research has also investigated societies that elect to utilize different forms of dietary restriction in their culture, usually through adherence to a religious practice. Luckily, many religions do have forms of dietary restriction in their practices, and we have societies that adhere to those practices over long periods of time, sometimes a lifetime. These cultures provide a great resource for us to understand the effects of dietary restriction on health and aging.

Among the different forms of religious fasts that have been examined for their potential life-extending effects, the Daniel fast appears very promising for health and longevity. The modern-day Daniel fast is based on two stories in the Bible, and allows ad libitum intake of fruits, vegetables, whole grains, nuts, seeds, and oil, but forbids meats, preservatives, additives, sweeteners, flavorings, caffeine, and alcohol. This plan might be thought of as a more stringent form of the vegan diet. Studies note excellent mood and satiety (about 7.9 using a 10 point scale) with the Daniel fast, which is likely why compliance has been reported to be very high (>90%).

These compliance rates suggest that the Daniel fast is a practical intervention that people can apply to their life. The question remains as to whether non-religious people would show equal adherence if they don’t infuse the stories of the religion’s text with extramundane meaning.

Still, it has been observed that people who adhere to the Daniel Fast show statistically significant decreases in total cholesterol, LDL cholesterol, and blood pressure. Clinically meaningful decreases in insulin and C-reactive protein, as well as body fat and body weight, were also noted but in degrees that were not of statistical significance. Unfortunately, HDL cholesterol, commonly referred to as good cholesterol, also decreased. In general, the Daniel fast does appear to improve several biomarkers of overall health. It will be interesting to modify the Daniel fast so that HDL cholesterol is increased and see the how the effects of such a regimen compare to others.

 

Conclusions

There are currently no head-to-head trials directly comparing the effects of the different dietary interventions on lifespan itself, which precludes a definitive recommendation as to which dietary pattern is best for this purpose. For people wishing to put these regimens into practice, they should remember that their effects on lifespan have not yet been conclusively demonstrated. Nevertheless, the improvements they induce in surrogate measures of overall health may be enough reason for people to decide to try them out.

The next article in this series will explore how other aspects of lifestyle, like wine and exercise, influence aging.

 

Age Better Today Series

Article 1 – Age Better Today. Is This Really Possible?

Article 2 – Slowing Down Aging with Dietary Restrictions

 

Sources

Longo VD, et al., (2015) Review: Interventions to Slow Aging in Humans: Are We Ready? Aging Cell 14, 497-510

Trepanowski JF, et al., (2011) Review: Impact of caloric and dietary restriction regimens on markers of health and longevity in humans and animals: a summary of available findings. Nutrition Journal 10:107

Johnson JB, et al., (2006) The effect on health of alternate day calorie restriction: eating less and more than needed on alternate days prolongs life. Med Hypotheses 67:209-211.



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  • Travlingypsy

    I have a strong spiritual practice and am aware that the less I eat the more energy, stamina and even strength I have. Ultimately food is a drain on the body. Very advanced spiritual adepts who have arrived, one might say, often don’t eat much at all. Some even run their hands over the food picking up the energy of the food and inhale that. I think as a people we addicted to food. It is one of our major distractions from the higher mind, for lack of a better word.

  • I love Dr Longo and his research, but 0.37 g/kg would not be very much fun to consume for longer than a few days.

    • danpardi

      For me, that equates to only 40 grams per day. Even in the interview he talks about how there is “ideal,” which I gathered is based animal models, would translate to the greatest effect, and there are more practical applications, which won’t be that low. But intermittently? I could easily have no protein days.

      • Yeah I’m with you. I did a no protein dinner last night which was fine, I”m thinking of including more low-protein days mixed in with higher protein days, rather than going moderate each day.

        • danpardi

          And you lived to tell about it!

      • karimus

        So the weight of a blogger like you interested in calorie restriction and so on is 108kg (40/0.37)? Or are you very tall and with muscle?

  • Cody Fyler

    What about getting more protein from glycene rich sources? Collagen/gelatin?

    • danpardi

      Gelatin is a relatively good source of protein for anti-aging purposes.

      The amino acid breakdown of gelatin is as follows (see image):
      glycine 21%,
      proline 12%,
      hydroxyproline 12%,
      glutamic acid 10%,
      alanine 9%,
      arginine 8%,
      aspartic acid 6%,
      lysine 4%,
      serine 4%,
      leucine 3%,
      valine 2%,
      phenylalanine 2%,
      threonine 2%,
      isoleucine1%,
      hydroxylysine 1%,
      methionine and histidine <1%
      tyrosine <0.5%

      Amino acids that SUPPRESS the activity of amino-acid deficiency signaling pathway, GCN2 (an anti-aging pathway) are:
      Lysine [4% of gelatin]
      Histidine [<1% of gelatin]

      Tryptophan [0% of gelatin]
      Methionine [<1% of gelatin]
      Arginine [8% of gelatin]
      Phenylalanine [2% of gelatin]

      Pretty low

      Also, let's look at stimulators of mTOR (a pro-aging pathway):
      leucine [3% of gelatin]
      valine [3% of gelatin]
      isoleucine [1% of gelatin]

      Very low

  • danpardi

    In response to a conversation on Twitter:

    https://twitter.com/_Jamie_Scott/status/674758598539350017

    Hi @DrDeborahMD, @juliannejtaylor, @SkylerTanner @_Jamie_Scott,

    First time trying TwitPlus. Thank you @_Jamie_Scott. I kind of hate twitter for a discussion. How can you respond adequately to good, complex questions?

    Jamie wrote: “I am someone who isn’t caught up in the appeal of living forever, so will take QoL over life extension.”

    Important point. What are the goals of the individual? This series is not about what we should do, but what one might be interested in if longevity is a priority. Still, many of the areas I’m writing about are promising but underresearched in humans. So, it remains to be seen whether the effects of these interventions in non-human models of aging will translate to compelling effects in humans performing similar protocols, and if those protocols are tolerable. The healthspan vs lifespan question is important, but falsely dichotomizing the two is often unnecessary. At extremes, those who may seek to absolutely maximize longevity levels may lead an existence that is unattractive for many. On the other hand, it’s likely possible that someone could strategize a lifestyle oriented towards longevity that would also be suitable, sustainable and desirable for many people. While a variety of interventions have merit, reduced total protein intake, being selective on protein sources, and use of various methods of fasting are things well within our ability.

    Additionally, in animal models, strategies to extend lifespan also seems to increase healthspan in that these same strategies diminish chronic age-related conditions. If you can use anti-aging strategies to reduce incremental cellular damage, the body is able to take of itself better. Long-term calorie restriction in humans does induce metabolic and molecular changes – particularly reduced inflammation and alterations in nutrient sensing pathways, but also increased stress resistance, reduced oxidative stress – such that an older person appears more youthful (by the metabolic, hormonal, molecular). But calorie restriction is hard to do, too hard for many people I think, so it’s worth looking for easier approaches. From the twitter conversation, there are caveats and things to look out for that could put a person in a worse off position, but that is why we need to test. Regarding eggs, specifically, showing increases in QoL, doesn’t mean someone can’t have a satisfactory quality of life without them. Additionally, it’s pretty clear from the research that I’ve been doing that some aging strategies don’t need to be employed for a positive effect until later in life (eg., 70 years old or older). Thanks for your input! Always love hearing from each of you.

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  • Joellen Christiansen

    Hi Dan, love your blog, but now am a bit confused. I am almost 60 (female), & was thinking of doing Simple Food Diet, or even Flash Diet, for a month or two. But perhaps it is better to try some lower protein modified fasting, esp. considering how high my cancer risk is due to family history. Are you & Stephan working on a new diet with aging folks in mind that will be lower protein than the existing IDW plans?

    • danpardi

      Hi @joellenchristiansen:disqus

      Thank you and glad you like the blog! A confusing thing about health is how guidance is
      often context and goal dependent. For example, protein intake can help with the
      better management of calorie intake because of specific hormones that are released in response to its consumption that assist with satiety, but protein also stimulates growth pathways. At certain times of life, inhibiting growth pathways *might* make sense, but read the debate in the discuss below with Jamie Scott for other opinions on this.

      Many things about the Simple Food Diet, however, align with healthy aging strategies. Stephan and I have not discussed modifying the diet for a duel purpose of weight loss – slow aging, but there are other things to consider with aging and diet that could help you decide how to proceed. First, a weight loss phase is temporary. Secondly, you could do a fast one day a week while on the diet where you keep protein low, veggies and fiber high for that day. Those are just some ideas for you, but as I mentioned, at this time we don’t have a fully considered program for the dual purpose of aging and weight loss.

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  • karimus

    ““The ideal diet is a plant and fish based diet that is low in protein, about 0.37 grams per kilogram body”
    It is so low for muscle maintenance that is probably a typo. There is no study mentioning 0.37 in kg but only in lb:
    Tarnopolsky et al. (1988) found that only 0.37g/lb was required to maintain positive nitrogen balance in elite bodybuilders.
    I can hardly imagine that it is a coincidence.
    So 0.37g/lg is 0.81g/kg which is the recommend one to maintain muscle mass. If you have reference to 0.37g/kg for protein, I would like to read it.

    • danpardi

      @disqus_QXiwLuuwzp:disqus, I’m going to quote exactly what I wrote:
      “Here is a quote from Volter Longo of the Longevity Institute at University of Southern California, from an interview with The Low Histamine Chef

      “The ideal diet is a plant and fish based diet that is low in protein, about 0.37 grams per kilogram body weight and that may increase a little bit in proteins after age 65 or 70, depending on the need, and then a diet that is high in nourishment meaning a lot of greens a lot of vegetables, not so much fruit, a little bit but not very much and a diet that is rich in nuts, rich in olive oil, legume-rich also.”

      Please note that protein amount suggested by Dr. Longo is extremely low. Please read the rest of that interview to hear the discussion on “ideal diet.””

      • karimus

        Yep but i am skeptical about that amount because I have read the recommendations and their explanations on protein, written by the Institut of medecine and I have never read that number. I have read elsewhere that he is in favor of limiting protein to maintain muscle mass. Also I am sure he does not invent that number so please if someone has a reference to such number (0.37g/kg), please share it.

        • Virginia Robards

          @karimus:disqus you were right to be skeptical. I contacted Dr. Longo personally and he indicated that it was actually 0.37 grams per POUND. That would translate to roughly 0.8 grams per kilogram, which is a much more realistic figure and is largely consistent with previous literature in this area.

          Dan and I will figure out a way to modify the blog post accordingly to reflect that. Thanks for the feedback!

          • karimus

            Thank you. I would add that 0.8g is the value that would cover

            statistically most need of people but some people my need less (if my
            memories are not rotten, some people will be just fine with just
            0.6g/kg). I suppose it is all trial and error & the important thing
            is to maintain lean mass as the ultimate thermometer of protein need.

            SInce
            you are in touch with Valter Longo, I have a unrelated question: why
            nobody have never try water restriction on animal for lifespan? I have
            read that calorie restriction protein restriction & specific amino
            acid restriction increase lifespan of various species. And how about a
            various water restriction with food ad libitum?Or the difference
            between dry fasting and wa
            ter based fasting on biomarkers and lifespan
            Or could you tell me how to contact him ? Thank you for your help.

          • Virginia Robards

            Well, I don’t know that I would say that I’m in touch with him. I just emailed him via his university email at USC – it isn’t hard to find.

            A couple of studies have suggested that water restriction could prolong lifespan in fruit flies, through reduced stimulation of water-sensing neurons. Not sure if it’s ever been studied in other organisms.

            If you did water restriction + ad lib food intake, I would expect your feeding patterns to shift – both in volume and in food choices – to compensate. We can and do get a significant proportion of our fluid needs met through food.

          • rbrine01

            Hi, Virginia. It has been 8 months since you indicated that someone from the blog will make the correction in the article, but the original error is still there, which could impact people’s health quite significantly if they take it to heart. Please make this change or place an addendum at the bottom of the quote, citing that you contacted Dr. Longo, and he verified the correct amount of protein (0.37g/Lb not 0.37g/kg). Thank you.

          • Virginia Robards

            Thank you for bringing this to my attention, @rbrine01:disqus. I thought I had corrected it before – I have now amended that error.

    • Virginia Robards

      As I understand it, 0.37g/kg is what Longo speculated, in that interview, to be close to an ideal amount of protein for this specific goal (prolonging lifespan).

      That isn’t necessarily a prescriptive statement – and I don’t believe he is saying that adopting such an intake would be free of other potential drawbacks.

  • Yuri J

    It’s strange . . .​
    people make all the fuss of the world to achieve longevity, even in such a considerable hard way, for a mere century or two life span, while take little notice of immortality that is possible here and now.