Calorie restriction extends lifespan by lowering iron



Calorie restriction: what it is, what it does

Calorie restriction – cutting back the food of lab animals by 10 to 40%, sometimes more – robustly extends lifespan, in some cases by 50%. It is the most effective anti-aging intervention known. How does it work?

Is it possible that a human could attain most or all of the benefits of calorie restriction without a decreased food intake?

I’m going to make the case here that calorie restriction extends lifespan by lowering iron levels. At least, that’s a major part of its mechanism.

That means that merely by keeping iron accumulation in check, you could counteract aging without any drastic cut in food intake.

How calorie restriction affects physiological pathways to extend lifespan

What does calorie restriction (CR) do that could possibly increase lifespan? Here are a few possibilities.

1. Calorie restriction results in far lower body fat mass. This makes for much better insulin sensitivity and for lower levels of inflammatory cytokines. Since both insulin resistance and inflammation increase with aging, by lessening these, CR decreases aging.

2. CR lowers oxidative stress. Oxygen and molecules like H2O2 can react with macromolecules such as proteins and lipids as well as larger cellular structures, and damage them. When damage exceeds the ability of the body to repair, oxidative stress exists.

3. CR increases autophagy, the cellular self-cleaning process that rids cells of junk, and recycles the components. Autophagy declines with age, and a renewal of it fights aging.

4. CR increases mitochondrial biogenesis. Decline in number and function of mitochondria occurs in aging; increasing mitochondria and improving their function fights aging.

These don’t exhaust all the possibilities, and they aren’t mutually exclusive either.(1)

There’s also another possibility, a main mechanism of action of CR that might account for many of its other effects.

Calorie restriction decreases iron accumulation

CR lowers the accumulation of iron, and iron accumulation is associated with higher rates of disease and with aging overall. Let’s look at the evidence.

Iron accumulation in aging: modulation by dietary restriction.(2)

Male Fischer 344 rats fed ad libitum or dietary restricted (maintained on 60% of ad libitum food intake) were sacrificed at 6, 12 and 24 months of age… Total iron content was measured directly and lipid peroxidation (LPO) was assayed as an index of oxidative stress. Tissue total iron content was shown to increase significantly with age in animals fed ad libitum (AL)… This age-related iron accumulation, however, was found to be markedly suppressed by dietry restriction (DR) in all tissues. Similarly, LPO measurements increased in an age-related, tissue-specific fashion… Again, we found DR to markedly suppress age-related LPO in all tissues. Reported here are our findings on the ability of DR to modulate iron status at the tissue level. Consistent with the proposed anti-oxidative mechanism of DR, these findings further suggest that the modulation of tissue total iron content is an important component of that mechanism.

Both iron accumulation and the oxidative damage which it could be expected to do were markedly decreased by CR.

Restriction of a single amino acid, methionine, extends lifespan just about as much as CR, and given this fact some researchers have suggested that the effects of CR may be due to the fact that it results in methionine restriction.(3,4)

Methionine supplementation results in large increases in iron and oxidative stress in rats.(6) This doesn’t prove that restriction of methionine will lower iron. But if there’s a graded response to methionine, which it appears there is (7), then decreasing methionine both lowers iron accumulation and decreases oxidative damage.

One of the model organisms that scientists use to study aging is the yeast, Saccharomyces cerevisiae, the same yeast used to make beer and wine. They can be calorie restricted by growing them in 0.5% glucose (as opposed to 2.0%).

In Saccharomyces, normally fed organisms accumulate large amounts of iron, along with large amounts of oxidative damage, and this is almost completely abolished by CR.(8) See the following graph. Organisms grown in 2% glucose accumulated more than twice as much iron as the restricted organisms. This almost exactly paralleled the amount of oxidative damage.


calorie restriction extends lifespan by lowering iron

In rats, CR greatly attenuated the accumulation of iron in muscle as well as the accumulation of oxidative damage.(9) “These findings strongly suggest that the age-related iron accumulation in muscle contributes to increased oxidative damage and sarcopenia, and that CR effectively attenuates these negative effects.”

Iron restriction extends lifespan

Sop far, we’ve seen that CR results in lower iron accumulation with age, and that this could be a major part of its mechanism of action. But maybe it’s just a coincidence? Maybe CR just happens to lower iron but its life-extension attributes are caused by something else.

Against the notion that it’s just a coincidence, consider that iron restriction alone can extend lifespan of Drosophila.(10)

Iron restriction also extends lifespan in C. elegans (11), and iron supplementation decreases its lifespan.(12)

To my knowledge, there have been no direct studies of iron restriction and lifespan in mammals.

Calorie-restriction mimetics

CR mimetics are chemical agents that mimic the physiological effects of CR without food restriction.(12) One of their characteristics is that they induce autophagy, just as CR does. Among CR mimetics are: hydroxycitrate, EGCG, spermidine, resveratrol, curcumin, metformin, and others.

Many or most of these also chelate iron.(13)

The fact that they increase autophagy also means that they increase iron homeostasis: autophagy also keeps free iron, the damaging kind, under control.(14) Noteworthy here is that this provides a mechanistic link between the decline of autophagy with aging and increased levels of free iron, causing neurodegeneration and other damage.

Furthermore, lipofuscin, “the toxic waste of aging”, is a complex of which iron plays a crucial role, and it inhibits autophagy.

Summing it up

Plenty of evidence points to lower iron accumulation as well as better iron homeostasis as being a major mechanism of the effects of calorie restriction on the retardation of aging. The evidence, while not conclusive, encompasses a number of areas.

  • CR both extends lifespan and lowers iron accumulation
  • Iron is a reactive metal capable of causing oxidative damage
  • Oxidative damage correlates with lifespan across species and is a major correlate of human aging
  • Iron restriction also extends lifespan
  • Many CR mimetics chelate and remove iron
  • Increasing autophagy increases lifespan and allows for better iron homeostasis

If all this is true – and, while not the whole story, I believe it is – then keeping iron levels in low normal range could mimic many of the lifespan-extending effects of calorie restriction.

Urgently needed are studies of iron restriction and lifespan in mammals, as well as further elucidation of the interactions between CR and iron.

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Leave a Comment:

jer says January 3, 2016

Hi Dennis
How does this tie in with the hypothesis that intermittent fasting (but maintaining calorie number) has the same effect as CR?

Great article as usual.

    P. D. Mangan says January 4, 2016

    Hi jer, I believe that IF should have the same effect as CR in this regard. One of the explanations for lower iron accumulation in CR is not merely the consumption of less iron, but CR apparently has hormonal and other effects that mean less iron is absorbed, and body iron stores are controlled better so less of the iron is in its free form. For instance, fasting (and CR presumably) increases hepcidin, a master iron hormone. Fasting and CR increase Nrf2, which up-regulates production of ferritin and other phase 2 enzymes, so free iron gets locked down.

    In short, I believe that fasting should have similar effects on iron as CR.

      Jer says January 5, 2016

      thanks for replying!

      Yes, I thought it would simply be the case that CR would be better because less iron was consumed as a result of consuming less food. Instead, it looks like lots of wonderful iron neutralisers pop out into the blood as a result of CR or IF. Sometimes you got to say – “I don’t care why it happens, but it works”.

      Joshua says January 7, 2016

      “…and body iron stores are controlled better so less of the iron is in its free form.”
      Hi PD — This comment makes me wonder something. Is it ferritin levels, or free iron (which I guess corresponds with serum iron?) that really matters? At my last check-up, I had managed to lower serum iron considerably (with IP6), but my ferritin is still pretty high. I believe you had stated in other posts that ferritin levels were the one to watch, but if free iron is the more dangerous, wouldn’t that be the major cause of concern?

        P. D. Mangan says January 7, 2016

        Hi Joshua, first of all, I’ve been asked by many as to whether IP6 really does lower iron, and I’ve replied that all reports I’ve read have been anecdotal. While your story would be another anecdote, I’d like to hear how much you lowered your ferritin with IP6, and how long it took, what dose.

        Free iron is indeed more dangerous. If iron is locked down in ferritin it’s not much of a problem. The reasons I emphasize ferritin are 1)it’s the most common measure of iron stores, the one most likely to be ordered by a doctor, and 2)free iron levels are generally correlated with ferritin. The lower the ferritin, the less likely you are to have a lot of free iron bouncing around inside. This doesn’t always hold, apparently, for instance neurodegeneration via iron as in Parkinson’s may be due at least in part to loss of iron homeostasis: the cells just lose control of their ability to sequester iron.

        But, for the average person, ferritin and free iron are related.

          Joshua says January 8, 2016

          Sure, I can share my n=1 experience with IP6. My iron levels have been high for several years now. For quite a while I’ve tried to keep them under control by drinking tea/coffee/milk/wine when I have red meat (or any meat, really). This seemed to help a little, based on my lab results, but was definitely insufficient on its own. Having followed this strategy for a couple of years, in May 2014 my serum iron was tested at 174 ug/dL. Far from ideal.
          This last summer, I started taking IP6 in August. I had made a couple of other changes — I was dieting (via IF) and also had largely cut out red meat (as a diet strategy, rather than to explicitly lower iron). I ended the dieting in September, and also added more red meat back. I kept with the IP6. My usual method is about 3-4 times a week, I take 1 capsule (I believe 500 mg) in the morning on an empty stomach, with a glass of water. I then make sure not to eat for at least an hour. This is the VitaCost brand IP6.
          Anyways, in December (1 month ago), my serum iron was down to 71 ug/dL.
          I can’t rule out that the dieting and the red meat exclusion over the summer made the difference, but I don’t think that could explain all of it. I’ve done summer dieting/red meat reduction in other summers, but even after that my serum iron tested significantly higher. So I’m pretty sure the IP6 had a significant effect in reducing my serum iron. My ferritin was still high, though, at 235 ng/mL. (I had a cold when the blood was drawn….I’ve read that having a viral infection can raise ferritin levels temporarily. Not sure how much this affected it.) This was the first time I had ferritin tested, though, so I can’t say how high it was in the past.
          Anyways, I’m sure that was TL; DR for many, but wanted to include the relevant details for those who are interested.

          Last thing — I think I can partially answer my own question about testing free iron. From a FAQ page by the Iron Disorders Institute: “Free iron is iron that is not bound; it is the most dangerous kind of iron because free iron can cause damage to organs, nourish harmful bacteria, change DNA or help to spread cancer. Unbound iron is determined by measuring UIBC (unbound iron binding capacity).”

          So, next time I get tested, I guess I’d like to get my UIBC measured also.

          P. D. Mangan says January 8, 2016

          Thanks, Joshua.

Shaq says January 4, 2016

You may have covered this topic (my apologies in advance…), but does plant-based iron (e.g., spinach) differ in any way from animal-based iron? Thanks….

    P. D. Mangan says January 4, 2016

    Yes, it does. Plant iron is free iron, animal iron is heme iron (bound in a protein). Heme iron is more readily absorbed than free iron, according to what I’ve read maybe 2 or 3 times more readily.

Shaq says January 4, 2016

Thanks. Great stuff at your site, much appreciated.

Matt N says January 5, 2016

Hi Dennis,

I’ve been taking a desiccated beef liver supplement for years, considering how healthy organ meat is generally regarded as, but beef liver is high in iron. I’ve never given any thought to it before, however now I am since reading all of your posts on the possible harm of elevated iron levels in the body. Do you have an opinion on whether liver supplementation is a net benefit or negative in an otherwise healthy person that eats a generally low-carb paleo type diet?

Thanks Matt

    P. D. Mangan says January 5, 2016

    Matt, I’ll go out on a limb here and say that in your case it may be a net negative, though not a large one. If you eat low-carb paleo (minimal processed foods) I’m not sure what benefit the dessicated liver would add, and as you say, the iron in it is something to be considered.

      Matt N says January 5, 2016

      Awesome, thanks for the quick response and great stuff on your site. I’ve been taking the liver as a fruit and vegetable quasi-replacement since I don’t consistently eat a lot of either on a daily basis (my diet is mostly meat, grass-fed dairy products, and coffee) and I don’t want to take a multivitamin. Thanks again!

Helmut S says January 11, 2016

This site is generally not about performance enhancing drugs, and I don’t personally have any desire to live past say 75, so I do take them.

As is probably known, there are many different performance enhancing drugs, of which anabolic steroids are the primary examples. All, even testosterone, increase red blood cell count, but the effect varies from drug to drug. Part of the reason Primobolan is so popular for long-term usage is that it has only a nominal effect on hematocrit and RBC levels.

Anyway, there isn’t much in the way of “science” on the abuse of these drugs – but I will give a personal anecdote. There are medical journal articles about EPO, which is designed to increase red blood cell production and anecdotes of endurance athletes abusing it and dying. But, no other studies that I am aware of.

Talk to most AAS users, and they will tell you that Trenbolone is by far the best drug. And it is true, if you are interested in quick results. It will transform your body in 6-8 weeks, increase your strength by 20% or more, and make you look like a god. It has terrible side effects, and is really the only steroid that causes “roid rage”.

Anyway, I used to abuse the stuff. I’d run it for two 12-week cycles a year, and did so for 2 years in a row. I ended up flying out to Montana one time, and I felt like I couldn’t breath on the plain. The whole time I was at a mountain ski resort, suffocation and exhaustion is what I felt.

I ended up going to the ER, and my RBC and hematocrit was significantly above the maximum range. Several pints of blood were drawn over 3 days. The doctors thought I had cancer, and told me to follow up when I got back home.

The feeling of relief after that phlebotomy was incredible. I felt like a new man, pulled back from the verge of death. And I probably was.

The higher the RBC and hematocrit you have, the more viscous your blood. At high altitude levels, this severely impacts your ability to deliver oxygen throughout your body despite the theoretically greater oxygen capacity if your blood, primarily because the viscosity is most apparent in the capillaries in your lungs.

There are many theories with respect to age – increased viscosity + plaque buildup leads to strokes, blood clots, etc. Long-term high blood viscosity also puts stress on your heart in a fashion similar to being obese. But, there is just not a lot of science here.

What I can say, as a regular user of performance enhancing drugs, is I have 1) never used trenbolone since that incident 2) used Primobolan in most cases and when I don’t 3) I keep doses low and 4) I take 2ius of HGH daily, which greatly potentiates low-dose anabolic steroid doses and aids in recovery off cycle.

Lastly, I have a doctor friend prescribe a therapeutic phlebotomy of 1 unit per month year round.

For those on TRT, I would say this is still a good policy. The only natural way to deal with high RBC is to engage in near constant physical activity, the way our ancestors did who had much higher natural testosterone levels. For most men, this is simply not an option.


    P. D. Mangan says January 11, 2016

    Helmut, thanks for relaying your experience. I’ve seen up close a case of polycythemia rubra vera, an excess production of red blood cells – in this case, it wasn’t due to steroids but was apparently genetic. Very serious, if untreated can be fatal.

    The thing that strikes me the most about your comment is the frequency of therapeutic phlebotomy. Once a month seems a lot, though if you had hemochromatosis it probably wouldn’t be. I’m wondering if you couldn’t actually become iron deficient on that frequency.

    Where do you have the phlebotomies performed, a blood bank or doctor’s office (or elsewhere)? Does your doctor friend think that prescribing it is no big deal? Reason I ask is for an option for myself and other readers who want to lower iron levels but are ineligible to donate blood. Does it cost much?

B says January 12, 2016

What are your thoughts on 5-aminolevulinic acid?

Also — and maybe you’ve addressed this question — but is the problem iron intake itself, or is high iron merely symptomatic of the deteriorating body’s inability to process iron?

    P. D. Mangan says January 13, 2016

    Interesting study. Some older people have lower hemoglobin levels, and this seems to be due to lower heme synthesis, not lack of iron, so providing 5-ALA and iron to the subjects seems to have increased heme synthesis. In that study, the subjects were older Japanese women, and if any group in the world is unlikely to have iron overload, it would be them.

    Another possibility for what could have been happening is the the 5-ALA chelated free iron. The fact that glucose tolerance improved suggests that.

    In any case, 5-ALA might be of use in older people with mildly decreased hemoglobin, but it wouldn’t appear to have much relevance to a healthy middle-aged, or even older, person.

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