This episode is a spectacular round two podcast with Dr. Valter Longo. Dr. Longo is the current director of the longevity institute at the University of Southern California and also director of the Oncology and Longevity Program at the Institute of Molecular Oncology Foundation in Milan, Italy. Dr. Longo’s research focuses understanding the biological mechanisms that regulate the aging process, the role of fasting and diet in longevity and healthspan in humans as well as metabolic fasting therapies for the treatment of human age-related diseases, including those of autoimmune origin and cancer.

In this episode, we discuss…
• 00:01:00 – The problems with using non-specific terms like “intermittent fasting” and a general exploration of what each of the terms that describe types of dietary restriction means, whether we’re talking about intermittent fasting, caloric restriction, time-restricted eating or periodic prolonged fasting. The latter of which is a special focus of Dr. Longo.
• 00:04:11 – What two seminal studies on chronic caloric restriction in primates from the 80s teach us about caloric restriction as a preventer of age-related disease, and how the effects of caloric restriction may actually be stronger when the diet that is being restricted is an unhealthy one – similar, in some ways, to the typical western diet.
• 00:07:34 – How the shift between normal metabolism and what Dr. Longo refers to ketogenic mode is subject to individual variation and the type of restriction practiced. Of particular importance is the protein or essential amino acid consumption.
• 00:08:06 – How the suppression of the IGF-1 pathway, typically a hallmark of prolonged fasting and caloric restriction studies and potentially needed for some of the benefits, may fail to be achieved in human caloric restricters that eat too much protein.
• 00:09:34 – How certain macronutrients influence the insulin/IGF-1/growth hormone axis interact to modulate aging in many cell types.
• 00:10:43 – How mice and humans who have growth hormone receptor deficiencies have low circulating IGF-1 – as little as 10% of normal levels – and have reduced risk of diseases like cancer, diabetes, and age-related cognitive decline, hinting at what future research might reveal about the beneficial effects of prolonged fasting and fasting-mimicking diets through the downstream effects of periodic deprival of growth-related factors.
• 00:11:05 – How the growth hormone / IGF-1 axis got a big boost early on in scientific interest when it was revealed that mice that have either deficiency in growth hormone itself or the growth hormone receptor live up to 40% longer and how this is accomplished through what is essentially a delaying of the decrepitudes of old age.
• 00:13:42 – The clever experiment design where human epithelial cells were incubated either in serum taken from controls or the serum taken from growth hormone receptor-deficient Laron’s patients showed that the reduction in growth factors ultimately lead to the cells manifesting qualities of cancer resistance, like fewer DNA breaks but an increase in cell death, which is also an important protection against cancer known as apoptosis.
• 00:15:02 – The origins of what Dr. Longo calls the fasting-mimicking diet – a 5-day diet focused on recapitulating some of the benefits of prolonged fasting, like dramatic changes in metabolic biomarkers, but without some of the drawbacks like reduced compliance and other risks that can come with multiple days of grueling strict water fasting in large, heterogeneous populations.
• 00:15:42 – How periodic prolonged fasting or the fasting-mimicking diet may be able to render cancer cells more vulnerable while conferring stress resistance to healthy cells, a quality known as differential stress resistance. This can happen because of the way fasting interferes with what is known as oncogenic signaling. Also refer to 00:25:22.
• 00:21:41 – The mixed results associated with the use of the ketogenic diet in treatment of cancer and how some cancers seem to be hurt by the metabolic switch of utilizing ketone bodies, which creates oxidative stress from the use of mitochondria, while other cancers seem to be able to use ketones effectively as an energy source, potentially accelerating their growth.
• 00:22:54 – Some of the early but promising pre-trial clinical anecdata suggesting potential complementary roles for the ketogenic diet and the fasting-mimicking diet (FMD) used in conjunction with conventional treatments like chemotherapy or radiotherapy for certain cancers like gliomas.
• 00:28:05 – How oncologists might approach incorporating the fasting-mimicking diet, which is still seeking further clinical validation and approval, into their patients’ care (if they choose to).
• 00:30:44 – In the context of aging, how the fasting mimicking diet has been shown to “reset” metabolism, driving down biomarkers associated with poor metabolic health, inflammation, and cardiovascular health.
• 00:31:45 – How, in contrast to chronic caloric restriction, the fasting-mimicking diet seems to normalize biomarkers like blood pressure and fasting glucose rather than continuing to drive them down into ranges lower than might be considered healthy.
• 00:34:09 – The prospect of using emerging ways of measuring aging objectively, such as through DNA methylation profiles, to tell whether or not an intervention like fasting is having an effect on aging as a whole.
• 00:35:14 – How long the metabolic effects of the fasting-mimicking diet tend to stick around and how often Dr. Longo thinks the fasting-mimicking diet should be done for most people and what sort of factors influence that.
• 00:38:33 – The fasting-mimicking diet as a boon for the psychology of weight loss where, due to its cyclical nature, adherents can enjoy potential benefits like the reduction of harmful fat known as visceral fat while sparing subcutaneous fat and lean mass, without completely overhauling all other areas of their life the rest of the time.
• 00:40:09 – How the fasting-mimicking diet, due to the shortness of the interval, seems to avoid the deleterious and generally undesirable effect of slowing the metabolism down in the way so-called yo-yo diets seem to.
• 00:44:24 – How fasting, through the shrinking and then re-expansion of whole systems like the liver, kidneys, heart, and immune cells may represent a type of whole-system renewal that originated as a three billion-year-old self-repair mode that was only activated during periods of famine or inconsistent food availability, but might now be dormant in people living in a modern world of regular food intake.
• 00:45:39 – How Dr. Longo’s group has shown that, in animal models of multiple sclerosis and pharmacologically-induced type 1 diabetes, several cycles of the fasting-mimicking diet is able to reverse disease and restore healthful function. This mechanism also may generalize to erasing other diseases of autoimmunity through the destruction of autoimmune immune cells that are essentially reset through fresh differentiation from progenitors untainted by autoimmunity. A very exciting area of continued inquiry!
• 00:46:17 – How shorter fasts may fail to approach some of the effects of periodic fasting and the fasting-mimicking diet by failing to achieve adequate glycogen depletion and ketogenesis.
• 00:53:04 – How clinical trials demonstrated that the effects of IGF-1 are probably context dependent, exhibiting a sort of “Goldilocks principle,” in which too much IGF-1 promotes cancer, but too little (as in the case of chronic, long-term caloric restriction) negatively affects the immune system. But the refeeding that follows fasting mimicking creates an environment that may be just right: it switches on IGF-1, promoting the regeneration of healthy cells, even restoring full organ systems.
• 00:55:05 – The importance of adequate protein during the refeeding phase following prolonged fasting or the fasting-mimicking to promote proper growth signaling to restore systems that have been broken down.
• 00:56:01 – Dr. Longo’s “top picks” for assessing biological age – markers a person can ask their doctor to measure to gauge how well they’re aging.
• 00:59:05 – A sneak peek at what’s covered in Dr. Longo’s new book, The Longevity Diet. https://amzn.to/2zvxz8n