I was glad to see Valter Longo’s Fasting-Mimicking diet in the news again this week.  I have been enthusiastic about Longo’s work ever since he documented altruistic suicide of yeast cells for his PhD thesis in the 1990s. Programmed death in one-celled protists was considered an affront to evolutionary theory at the time, and he had a devil of a time getting his findings into print.

Longo discovered in 2002-2005 that fasting had a powerful benefit for cancer patients, and that in conjunction with either radiation or chemo, it greatly magnified the benefits while mitigating the side effects.  Intermittent fasting had benefits, too, for the general population, independent of cancer.  It seems to be a way to get the health benefits of caloric restriction and it is easier to stick to for many people than a consistently low calorie diet.

But Longo couldn’t get either doctors or patients interested in the fasting program.  Part of the problem was the toxic mix of capitalism with medicine: the US relies on testing and promotion by profit-making companies to push medical technology forward, and fasting isn’t a product that anyone can make money on.  There was also an emotional truth: cancer patients feel scared, beleaguered, emotionally drained.  So much is dragging them way outside their comfort zone that it takes extraordinary strength not to fall back on food as one of life’s most reliable comforts.

So many medical researchers see their job as finding treatments, and leave the problem of adoption and compliance to someone else.  But Longo set himself single-mindedly to the task of bringing the benefits of fasting to a wider swath of the population.  The question that led to the Fasting-Mimicking Diet (FMD):  What dietary regimen can provide the greater part of the benefits of a water fast while inducing less hunger and minimal disruption to concentration, vitality and the pace of life?

I have done about 9 cycles of the FMD over the past 1½  years, including this week.  In my personal experience, 5 days of the FMD is eminently tolerable once I begin, though I still face resistance when I think in advance about disrupting my comforting food routines.  (Yoga, swimming and meditation have the same barriers for me–difficult in the anticipation, enjoyable once I begin.)  For me, FMD is not a weight loss program.  I gain back all the weight I’ve lost within a week after the 5-day program is finished.  Others may have different experiences.  People have used the 3-meal version of FMD (3 meals at 360 calories) as a medium-term weight-loss program, but the protein content is probably too low for those concerned about maintaining lean mass long term.

In his new study, 100 participants were randomized into two groups.  The first group did three rounds of 5 days on FMD over three months.  The second group did nothing special for three months, but were given an opportunity to try the same three rounds during the following three months.  The average weight loss was 6 pounds for those who completed all three cycles; lean body mass was lost, in the same proportion as fat.  Blood pressure, blood sugar, triglycerides all improved on average, and C-reactive protein (an inflammatory marker) went down as well.  

The study included a range of healthy people as well as people who carried more weight and had higher risk factors.  It was those with the higher inflammation and blood sugar who realized big benefits from the program, and the already-healthy were averaged in.  There is a lot of evidence to indicate that intermittent fasting works, and that the FMD delivers similar benefits.  But if you’re already lean and healthy with low blood sugar, then it’s less clear whether there are substantial additional benefits from intermittent fasting.

Notable was a reduction in the hormone IGF-1, which I don’t necessarily regard as a good thing.  On the one hand, lower IGF-1 is characteristic of all caloric restriction models, in animals and humans, in which life span is increased.  So it is an indication that the FMD was effective.  But low IGF-1 has consistently been found to increase risk for all-cause mortality, and heart disease in particular [ref, ref, ref].  Benefits of higher IGF-1 include maintenance of muscle mass and growth of nerves that diminishes with age.  

An additional benefit documented in the past is a “reset” of the immune system.  The white cell population is pruned during fasting, and the most-needed naive T-cells regrow after eating resumes.

Antidote to Obesity

It’s the (large and increasing) population of unhealthy people that Longo is targeting.  There is every reason to expect substantial benefits, but the big issue remainss: how many people can be motivated to take up the practice and stick to it?  The question was touched on only peripherally in the current study, without discussion; of 48 subjects selected for the first round, 39 stuck it out for three FMD cycles over three months (81% compliance).  That’s encouraging, but what we really want to know is: how many people will actually modify their eating rhythms for years at a time?  Will they feel the benefits and will that motivate them to stick with it month after month, five days each month?

And will this translate into long-term weight loss?  Sustaining weight loss is notoriously difficult for about 95% of the population.  People can stick to a diet for a time, but the Siren song of food is with us everywhere, and sooner or later we succumb.  Fortunately, there’s good reason to hope that the FMD discipline offers benefits even if weight loss is not sustained.

 

How to do it

Longo’s own company, L-Nutra offers a packaged diet, called ProLon, availble through health care professionals.  It’s pricey and may be covered by insurance.  LifeBox offers a non-prescription alternative that is not as much cheaper as it might be.  For my own experimentation, I have preferred to use fresh, whole foods approximating the same macronutrient proportions as the ProLon package.  It requires some time and attention in food prep, but it costs less than you’re currently spending on the same meals, and you can fill yourself with satisfying portions of fresh vegetables for the same 360 calories.  Here is my page of instructions and advice, with recipes designed by Enid Kassner.

For many of us, our relationship to food is central to our psychology.  Shaking up food habits disrupts everything else as well.  It’s the main reason that food habits are so hard to change, but for me, it’s also a good thing.  I enjoy the challenge and the self-awareness that come from a new frame of reference; fasting changes my perspective, my emotional baseline, and my mental state.  For me, the first day is unfocused, low energy, but often a time of creative new ideas; the second day is distracted, obsessive, sometimes headache-y or otherwise uncomfortable, and beginning with the third day there is returning energy, along with a freedom that I didn’t know I missed.

 

Why is life expectancy in America lagging?

Part of the answer is certainly cultural.  Advertising, parties, lunch and dinner meetings often reinforce consumption of food that is designed to be addictive for the sake of corporate profits.  In America, we are surrounded by overweight people, but France and Italy have much lower obesity rates, and you can walk all day around the cities of Japan or China without encountering anyone who is seriously overweight.  Even in America, the problem has grown way out of proportion only in the last 40 years.  This and income disparity are the main reasons that life expectancy in America is at the bottom of the developed world.  Our unaffordable, dysfunctional healthcare system provides many additional reasons.  Meanwhile, life expectancy in Asia is climbing at an exemplary pace.

Longo’s FMD is designed to address this most accessible factor in the diseases of late life for a large swath of people who find they cannot lose weight.  His research is based not just on effectiveness but equally important on tolerability.  How many people will adopt it and reap the benefits?  This will be an important question for public health going forward.  But you are a unique individual, not a statistical median.  I encourage you to experiment with FMD, see what you learn about yourself, and decide if it can be a valuable part of your health program in the long term.

A venerable theory of aging is the Mitochondrial Free Radical Theory (MFRTA).  Mitochondria are the energy factories of the cell, where sugar is burned to create electrochemical energy.  Of necessity, the mitochondria use high-energy chemistry, and this creates toxic waste in the form of ROS–pieces of molecules that are too eager to combine with delicate biomolecules, turning useful compounds to toxic waste.

The MFR theory says that these ROS cause mutations in the DNA of the mitochondria that build up over time and cause the mitochondria to perform less well with age.  Mitochondria are constantly turning over, that is, creating new mitochondria that inherit the mutations and accumulate new ones.

Over the years, this story has come apart.  The key finding goes back to 1980 : mutations (for whatever reason) are not more severe in older people than in younger people.  The mutations that appear in mitochondria with age are at a low level, and inconsistent with the assumed ROS mechanism [2013].

But it remains undeniable that we have fewer mitochondria as we get older, and those we have become less efficient.  Brain and muscle cells are the most energy intensive, and we have less energy for everything from running to thinking.  Mitochondria are not the source of age-related decline; nevertheless maintaining (or restoring) mitochondrial health should be a part of any strategy to resist the ravages of age.

I recently became aware of this Nature paper from Japan:  More important than genetic changes in old mitochondria are the epigenetic changes (changes in gene expression) that render them less efficient.  Is there a way to restore the gene regulation in aging mitochondria to look more like the gene expression in energetic, young mitochondria?

“When glycine was added to culture media containing cells from the 97-year-old, the mitochondria in these cells became like new.” [quote from summary by PD Mangan].  Glycine is the simplest of the 20 amino acids that are building blocks of proteins in all eukaryotes.  It is not classed as an “essential amino acid” because our bodies can manufacture glycine, but maybe we don’t make enough of it to maximize our lifespans.  

 

Glycine

The theory in the Japanese paper is that glycine treats the downstream symptom of epigenetic reprogramming in the mitochondria.  In other words, glycine does not stop the detrimental epigenetic changes in mitochondria that come with age, however one of the most important of these changes results in a glycine shortage in the mitochondria.  Hence, glycine supplementation effectively attacks the problem at an intermediate stage.

Could a molecule as simple (non-specific) as glycine be an anti-aging compound?  Glycine comes to us with a sketchy but promising history.  In one rat study, a hefty dose of glycine increased lifespan by 27% longer than controls.  “Hefty” is the human equivalent of ~3 ounces per day.  I’m tentatively filing this study in the “too good to be true” drawer, because it appeared only as a conference abstract 5 years ago and has never been fleshed out with a peer-reviewed full text.

A shortage of protein has a powerful anti-aging effect across many species.  And a shortage of one critical amino acid–methionine–is sufficient to trigger this response.  This may be because methionine is the “start codon”; every gene begins with a methionine, and a severe shortage of methionine can slow down all protein synthesis.  

Directly engineering a shortage of methionine in the human body is just too difficult to manage, because too many protein foods have methionine, and we’re too fond of protein.  (Animal proteins are consistently loaded with methionine, whereas some vegetable sources have less.)  In studies of lab animals, a methionine shortage is engineered by using fully artificial protein sources, constituted from individual amino acids.  People would never want to live this way on synthetic food, even if we could afford it; but using glycine to create a methionine shortage sounds more palatable.  Glycine plays a role in breaking down methionine in the liver, and if the glycine level is jacked up super-high, it is (theoretically) possible to force this reaction so far as to create a methionine shortage.

For some of us, methionine restriction holds up the tantalizing prospect of gaining benefits of dietary restriction while allowing us to eat to satiety.  But the idea remains untested in humans.  Protein deficiency can lead to loss of strength and endurance and the ability to concentrate–even as it increases life expectancy.  Depression is another risk.  Rats that have tried methionine restriction are not recommending it for humans; in fact, they quickly come to crave methionine; they recognize methionine-deficient foods and shun them.

On the other hand, there are other diverse benefits documented for glycine supplementation, beginning with better sleep, insulin sensitivity and cancer resistance.  A minimum of 3 or 4 grams is required to have any effect.  You can buy it in powder form by the pound.  From Finland, here’s Valdu Heiskanen’s comprehensive page on glycine.

 

Mitochondria have their own DNA

Hundreds (sometimes thousands) of mitochondria dot every cell in our bodies.  They perform the task of burning sugar in a controlled process that captures most of the energy in electrochemical form (ATP) that is convenient for all the cell’s usage.  In the deep evolutionary past, mitochondria were an invading bacteria, which gradually lost their virulence, then became domesticated in a symbiotic relationship, then fell into line doing the bidding of the cell nucleus (like other parts of the cell).  But from that distant era they still retain a snippet of their own DNA–just 37 genes, all essential for the energy metabolism.   

In the old MFR theory, mitochondria were thought to lose genetic integrity through mutations.  In the new view, the genetic information isn’t lost, but the mitochondrial DNA is reprogrammed later in life, with the result that their performance suffers.  Nominally, this is a promising finding; random mutations in a hundred trillion mitochondria would not be a feasible target for anti-aging interventions; but epigenetic reprogramming is presumably something the cell already knows how to do.  The cell knows, but we don’t; our understanding of epigenetic markers and the way that they are programmed is still rudimentary (even in the nucleus, let alone the mitochondria).  Our best hope for the near term would be if we don’t have to understand the process, because the nucleus takes care of the details.  This brings us back to the general strategy of signaling to make each cell think it’s part of a young body.

How does PQQ work?

PGC-1a is a circulating hormone that says to the cell, “make more mitochondria.”  You can’t take PGC-1a orally because it is a large protein molecule, and does not survive digestion.  PQQ is a small molecule, more bioavailable when ingested, that increases circulating PGC-1a.  The two-step process has been documented in rodents; oral PQQ leads to more mitochondria [ref, ref].  

 

Does CoQ10 help?

CoQ10 (or ubiquinone) is essential to the metabolic function of mitochondria.  Supplementation with CoQ10 has been found to enhance athletic stamina in most human studies [ref, ref, ref, exception].  This benefit is not to be sneered at, though it is unrelated to aging.  Heart patients taking statin drugs have an induced deficiency in CoQ10, and need to take supplements.  Other studies of CoQ10 suggest benefits for cardiovascular risk [ref] and for maintaining insulin sensitivity [ref].  On the negative side, CoQ10 cannot stimulate growth of new mitochondria, and rodent studies with CoQ10 have never demonstrated increased life span [ref, ref].

 

Exercise

Exercise is the best thing we know for promoting replication of mitochondria.  This has been substantiated in humans and in rodents.  Exercise is a powerful stimulant for producing PGC-1a, and there are additional channels by which exercise promotes mitochondrial biogenesis, apart from PGC-1a [ref].  There is evidence for endurance exercise and interval training, but maybe not for strength training [another ref].  I was unable to find any direct comparison of the three.

 

Fasting and Ketogenic Diets

Fasting promotes mitochondrial biogenesis by a different pathway: AMPK [ref].  AMPK is expressed in response to a tight energy budget, but the AMPK response also decreases with age [ref].  Ketogenic diets (very low carb) also promote increases in mitochondria [in humans, in mice].

Chronic caloric restriction (as opposed to intermittent fasting) contributes to the health of mitochondria, but not to their number [ref].

 

The Bottom Line

Loss of Mitochondrial energy is connected to many of the deficits of old age; but most of the things you can do to improve mitochondrial function are the same things we do for a generalized anti-aging program.  The new thing here is glycine.  It’s $10 a pound and helps you sleep better.

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I’m grateful to P. D. Mangan at Rogue Health for providing the inspiration and seed references that got me started on this story [link].