Last week, an article about the cell biology of fasting made headlines in the science news press. Valter Longo cites evidence that a 3-day fast can rejuvenate our immune systems, with broad anti-aging benefits. 4 or 5 days may be better yet.
Socially, I was a late bloomer, clinging too tightly to love, driving away partners until I was in my 20’s. I took a full year to allow Marsha into my heart. Four years later, she broke up with me, and it launched a full-scale spiritual crisis, beginning with three days in which I had no interest in eating.
Those of you who have probed my Aging Advice page know that I fast a day a week, water only from Wednesday evening to Friday morning. I have grown quite comfortable with this routine. I ease off other disciplines on Thursdays, take a day off from aerobic exercise, allow myself to sleep more and be less productive. I still do yoga, and like to take long walks on Thursdays.
But not since I was 28 have I fasted three days. Monday morning, I awoke with the thought that this is as good a time as any to begin a three-day fast. If I wait longer, I will have time for fear and worry. My mind will play tricks on me, making it harder than it has to be.
I first became acquainted with Valter Longo’s work when, in 2004, he published a remarkable paper in Journal of Cell Biology based on work he did on yeast cells for his dissertation almost a decade earlier. The results were considered so unlikely that it had taken him that long to convince a journal editor to take a chance and publish them. What Longo had discovered was that when he starved a colony of yeast cells, about 95% of the cells would commit suicide, using the controlled death mechanism of apoptosis. They would disassemble their proteins, dissolve the cell membranes, and turn themselves into food for the remaining 5%.
Impossible! replied the reviewers, schooled in traditional evolutionary theory. How could such an adaptation evolve? The colony must be closely related genetically, and how could the 5% be genetically different from the other 95%? And whatever that difference was, the 5% would pass on their genes, the genes of the 95% would perish, and the next generation would no longer have the suicide adaptation. We know this from basic theory, said the reviewers. Longo must have made a mistake in his biochemistry. These cells are not committing suicide – they are starving to death.
“Extraordinary claims require extraordinary evidence.*” The paper was returned to him over and over, demanding more and more validation that what he saw was really apoptosis. It took ten years before the paper was finally accepted for publication.
Today the fact that Longo discovered is widely accepted, though the message for evolutionary theory has yet to filter through. But Valter saw the full implication of his work: If yeast cells had failed to read the basic textbooks in population genetics, what other animals and plants might have been similarly negligent? Yeast cells are just one example of programmed death in the biosphere. I was honored and excited the following year when Valter invited me to join him and Vladimir Skulachev in a paper for Nature Genetics on Programmed and Altruistic Aging.
In the intervening decade, Valter has been a ubiquitous presence in the biology of aging and of caloric restriction. Of many creative innovations he has introduced, the one he is best know for is fasting as a cancer treatment. He has documented that a three-day fast before chemotherapy has a powerful and extraordinary effect on the metabolism: The body’s normal cells are in a heightened state of protection, and are much more resistant to chemical toxins. Hence the discomfort, headaches and nausea that generally accompany chemotherapy are attenuated – not to mention the long-term damage. At the same time, the cancer cells are sensitized by the fast, so that more of them are knocked out by the chemo treatment. This is a win-win for the patient, but Valter has undertaken a long and arduous campaign to convince oncologists that such a simple protocol could be so effective. Worst of all, no one can make a dollar from fasting.
And what of the rest of us, who don’t have cancer? This is the subject of Valter’s most recent work, that made science news headlines last week. He puts together evidence from mice and humans that the three-day fast is a boon for us as well. (Here is the full text, and here is an editorial in the same issue of Cell Stem Cell putting the article in context.)
Evidence in this week’s Longo Article
The experiment around which the paper is written involves depriving mice of food, then looking at the stem cell environment in their bone marrow. Fasting actually increases the number of active stem cells in the bone marrow, even as the circulating white blood count is down sharply. Two chemical signals are identified that mediate the process: Both IGF-1 and PKA are down-regulated with fasting.
IGF-1 (insulin-like growth factor) is an old friend, first discovered in worms in the 1990s, and later identified as a pro-aging hormone generally. PKA (protein kinase A) is less well known, and has many independent functions, de-activating several different signals by tacking on a phosphate group. The cell’s energy cycle uses ATP, which yields energy and is recycled in its low-energy form, AMP. Accumulation of AMP occurs when energy stores are low, and this signals a reduction in PKA.
The article makes a point that, though the benefits of long-term caloric restriction have been studied extensively, this kind of rejuvenation of the immune system has never been observed with CR alone.
Much of the article is theoretical, connecting decline of the immune system to many of the medical issues associated with aging. Arthritis and even Alzheimer’s disease are rooted in auto-immune reactions. The steep rise in cancer with age is believed to be related to the immune system’s failure to detect cancer in its early stages and to eliminate pre-cancerous cells. It is to be hoped that rejuvenating the immune system might have broad anti-aging effects.
Why does it work?
Evidence for programmed aging
In write-ups of this material, the failure of stem cells with age is described as “dysregulation”, and the reason the strategy works is attributed to a clearing out of damaged and ineffective immune cells from the blood, as they are converted by the body to food. Perhaps you have noticed that this makes little sense. Certainly Valter knows this better than anyone, given his history, but he has chosen not to fight the abstract battle about evolutionary theory, because he knows it would likely interfere with the credibility of his other, practical and life-saving work.
The point is that if the fasting body is able to rejuvenate and multiply the bone marrow cells that are responsible for blood and immunity (hematopoietic stem cells), then it is obvious that the body could do this as well or better when it has plenty to eat. If it wanted to. The fact that hardship and deprivation can induce the body to rejuvenate implies that aging is a programmed choice. Even when it looks as though the cells are suffering damage over time, that damage is entirely avoidable (indeed, repairable), and it is only with chemical switches that the repair mechanisms are turned off as we age. In PKA and IGF-1, Longo has identified two of the signals that keep the repair mechanisms dialed down, and make our health deteriorate with age.
Why is the body intent on killing itself? It is an adaptation for population regulation, a response to natural cycles of boom and bust in population size. When times are good, the population expands too fast. Aging is a way of slowing down the population boom. This is why we age more rapidly when there’s plenty to eat. In times of famine, there is already plenty of death, and the danger is the opposite – that the population might plunge to extinction. This is why aging backs off in the face of hunger. (Ideas in this paragraph are not yet standard evolutionary theory, but this is a theme that I have developed in computer simulation, and it is the core of my contribution to publications in the field.)
Fasting in Ancient Religious Traditions
Though they are not controlled and not founded in a knowledge of biological mechanisms, traditional writings nevertheless embody experience of large numbers of people over a long period of time, and I look to them for ideas, for cautions and confirmations. Before writing this piece, I had the impression that fasting was recommended in many religious traditions, and I eagerly googled associations with the 3000-year-old Ayurvedic (longevity) tradition of India. I was surprised to learn that fasting for more than a day is regarded as an extreme practice, and that Ayurvedic texts don’t provide prescriptions or recommendations for long-term fasts, but rather cautions against fasting, suggesting that fasting practice has been prevalent for a long, long time, and the ancient Ayurveda was already reacting against it.
Frequent 12-24 hour fasts, however are recommended, even prescribed in the Ayurveda. Eating the main meal early in the day is a practice that ancient traditions and modern medicine agree on. Avoiding food for several hours before bedtime is part of yogic practice. For Buddhist monks in the Theravada tradition, all eating is confined to the morning hours, implying a daily fast of 16 hours.
Implications for the clinician, for you and me
I find it remarkable, if no longer quite surprising, that in write-ups of the therapeutic effects of fasting, medical professionals and researchers focus on what we can learn that will help us produce a drug that mimics the benefits of fasting. Fasting is providing all the benefits with little or no downside (except temporary hunger, need for warmer clothing); but medical science is busy search for drugs that will probably target just some of the signals that fasting sends, and will probably have more serious side-effects than fasting. Longo says that the constellation of benefits from fasting “would be difficult to achieve with any pharmacological or other dietary intervention.”
It is deep in the culture of today’s medicine that the patient is passive and it is the doctor who is the agent of healing. Medical professionals de-emphasize all that the patient can do with diet, exercise and life-style modifications to improve his own health, despite the proven power of these regimes. Part of the problem is in the conection to capitalism, which creates a focus on what can be healed profitably, ignoring remedies that cannot be sold.
Fasting and weight loss
It is my experience that I don’t lose weight from fasting, presumably because I eat more before and after a fast. Other people I know have reported similar experiences, and both ancient texts and modern medical advice agree that fasting is not an effective way to lose weight for most people. That doesn’t mean it won’t work for you, if you have experience to the contrary.
I’m now in Day 3, and it seems long only psychologically. In my weekly Thursday fasts, I sometimes experience headaches (one week in 5 or 6), and that hasn’t happened. I have the luxury of no busy schedule, no deadlines. That’s a good thing, because productivity on fast days is not reliable. During fasts, I don’t have the focus to be able to write computer code, and writing is often slow. But often deep and creative thoughts are given to me during fasts.
I can sit contentedly for long periods of time without feeling a need to accomplish anything, or even to get up. I tend to a shorter night’s sleep, but enjoy naps during the day. Once in my life I tried public speaking on a day I was fasting, and I won’t do that again. Words come out more slowly, trying the patience of the audience. (My one experience was speaking to the Caloric Restriction Society, and my audience understood and were patient.)
How long is optimal?
I wrote to Valter yesterday, asking this question. Does he have evidence from people suggesting how long it takes for the immune reset? Is it different for people who start with a lot of fat on their bodies compared to people who have nothing in reserve? His answer was short and to the point:
“3 days is optimal for mice. For humans 4-5 minimum, depending on what you are trying to achieve”
You can already tell I have a lot of faith in Valter as a scientist, and it is easy for me to believe that, from his experience, he knows more than he is able to publish. So I’m deep into Day 4 as I finish writing this. I’m a little spacey and my rhythms are disrupted, but I’m not suffering or food-obsessed. I plan to start fruit or juice soon.