IGF-1 link: Fasting, Laron Syndrome vs. Aging & Diseases

Intermittent fasting, lowered levels of the Insulin-like Growth Factor (IGF-1) hormone and the little people from Ecuador (known as the Laron Syndrome patients) all collide in the research of Dr. Jaime Guevara-Aguirre and Dr. Valter Longo. Until now, true fasting and the fasting mimicking diet (FMD) were seen as they only two ways to attain diminished levels of IGF-1. Can there be another way?

In recent years, intermittent fasting has been linked with an ever-increasing list of significant health benefits; the practice has been shown to mitigate the negative effects of chemotherapy, to guard against Alzheimer’s and Parkinson’s, to reduce the size of cancerous tumours, and to reverse various aging processes. [1]

Dr Valter Longo, Professor of Gerontology and Professor of Biological Sciences at the University of Southern California, has conducted extensive research into the effects of intermittent fasting on human health. Through his research, Dr Longo has uncovered the underlying mechanisms by which fasting effects human health, and has unveiled the vital role of Insulin-like growth factor 1 (IGF-1) in the process.

The IGF-1 Link

IGF-1 is a hormone that has been implicated in various aspects of aging and disease, and much of Dr Longo’s research suggests that the positive health benefits associated with fasting occur as a result of fasting-induced lowering of circulating levels of IGF-1. [2]

Valter Longo; USC Davis School of Gerontology [2014-11-26. Michelson Medical Research Foundation]Valter D. Longo is an American biogerontologist and cell biologist known for his studies on the role of starvation and nutrient response genes on cellular protection aging and diseases and for proposing that longevity is regulated by similar genes and mechanisms in many eukaryotes. (Credit: MMRF)
IGF-1 Link: IGF-1 ProteinInsulin-like growth factor 1 (IGF-1) is a protein that in humans is produced throughout life: it plays an important role in childhood growth and continues to have anabolic effects in adults. The highest rates of IGF-1 production occur during the pubertal growth spurt. The lowest levels occur in infancy and old age.
Valter Longo; USC Davis School of Gerontology [2014-11-26. Michelson Medical Research Foundation]Valter D. Longo is an American biogerontologist and cell biologist known for his studies on the role of starvation and nutrient response genes on cellular protection aging and diseases and for proposing that longevity is regulated by similar genes and mechanisms in many eukaryotes. (Credit: MMRF)
IGF-1 Link: IGF-1 ProteinInsulin-like growth factor 1 (IGF-1) is a protein that in humans is produced throughout life: it plays an important role in childhood growth and continues to have anabolic effects in adults. The highest rates of IGF-1 production occur during the pubertal growth spurt. The lowest levels occur in infancy and old age.
Valter Longo; USC Davis School of Gerontology [2014-11-26. Michelson Medical Research Foundation]

Dr Valter Longo, Professor of Gerontology and Professor of Biological Sciences at the University of Southern California. (Credit: MMRF)

Valter Longo; USC Davis School of Gerontology [2014-11-26. Michelson Medical Research Foundation]

Dr Valter Longo, Professor of Gerontology and Professor of Biological Sciences at the University of Southern California. (Credit: MMRF)

The immunoregenerative effects of fasting, for example, occur as fasting stimulates destruction of old, damaged immune cells, leading to lowered levels of IGF-1 in the bloodstream. Lowered IGF-1 levels are known to stimulate immune cell proliferation and differentiation – and hence promote immune system regeneration. [3]

Similarly, fasting has been shown to slow the progression of Alzheimer’s in mice by reducing circulating IGF-1 levels. [4]

Fasting as a medical intervention is attractive due to it being cost-free, easy to implement, and non-invasive, however the development of drug-based interventions designed to mimic or enhance the effects of fasting would provide an additional, and potentially more effective, therapy.

IGF-1 Link: CONSORT diagram of 102 contacted subjects of which 100 were enrolled into the study two arms. 50 made it to the finish line. (Credit: Science Translational Medicine)
The Difficulty of Fasting:
Control Diet vs. Fasting Mimicking Diet
Fig. 1. Consolidated Standards of Reporting Trials (CONSORT) diagram of 102 contacted subjects of which 100 were enrolled into the study two arms. (Credit: Science Translational Medicine)


Prolonged fasting is difficult to implement in human subjects and may exacerbate preexisting nutritional deficiencies, making it not feasible and/or safe for children, the elderly, frail individuals, and even most of the healthy adults.


The Fasting Mimicking Diet (FMD) is designed to achieve effects similar to those caused by fasting on IGF-1, insulin-like growth factor–binding protein 1 (IGFBP-1), glucose, and ketone bodies. To prevent nutrient deficiency, this FMD provided between 3000 and 4600 kJ per day, as well as high micronutrient nourishment, to each human subject.

  • Arm 1 (n = 48), the “control” group, maintained their normal caloric intake for a 3-month monitoring period. Data were collected at enrollment and again after 3 months.

  • Arm 2 (n = 52) participants started the FMD after randomization. The FMD is provided for 5 days per month for 3 consecutive cycles. Data were collected at enrollment, at the completion of the first FMD cycle but before resuming normal dietary intake, and also on average 5 days after subjects resumed their normal diet after the final FMD cycle.


After the initial 3-month period, subjects in arm 1 also started the FMD. An optional follow-up visit in the clinic for analysis was offered to all participants about 3 months after the completion of the third FMD cycle.

IGF-1 Link: CONSORT diagram of 102 contacted subjects of which 100 were enrolled into the study two arms. 50 made it to the finish line. (Credit: Science Translational Medicine)
The Difficulty of Fasting:
Control Diet vs. Fasting Mimicking Diet
Fig. 1. Consolidated Standards of Reporting Trials (CONSORT) diagram of 102 contacted subjects of which 100 were enrolled into the study two arms. (Credit: Science Translational Medicine)


Prolonged fasting is difficult to implement in human subjects and may exacerbate preexisting nutritional deficiencies, making it not feasible and/or safe for children, the elderly, frail individuals, and even most of the healthy adults.


The Fasting Mimicking Diet (FMD) is designed to achieve effects similar to those caused by fasting on IGF-1, insulin-like growth factor–binding protein 1 (IGFBP-1), glucose, and ketone bodies. To prevent nutrient deficiency, this FMD provided between 3000 and 4600 kJ per day, as well as high micronutrient nourishment, to each human subject.

  • Arm 1 (n = 48), the “control” group, maintained their normal caloric intake for a 3-month monitoring period. Data were collected at enrollment and again after 3 months.

  • Arm 2 (n = 52) participants started the FMD after randomization. The FMD is provided for 5 days per month for 3 consecutive cycles. Data were collected at enrollment, at the completion of the first FMD cycle but before resuming normal dietary intake, and also on average 5 days after subjects resumed their normal diet after the final FMD cycle.


After the initial 3-month period, subjects in arm 1 also started the FMD. An optional follow-up visit in the clinic for analysis was offered to all participants about 3 months after the completion of the third FMD cycle.

IGF-1 Link: IGF-1 ProteinInsulin-like growth factor 1 (IGF-1) is a protein that in humans is produced throughout life: it plays an important role in childhood growth and continues to have anabolic effects in adults. The highest rates of IGF-1 production occur during the pubertal growth spurt. The lowest levels occur in infancy and old age.
IGF-1 Link: IGF-1 ProteinInsulin-like growth factor 1 (IGF-1) is a protein that in humans is produced throughout life: it plays an important role in childhood growth and continues to have anabolic effects in adults. The highest rates of IGF-1 production occur during the pubertal growth spurt. The lowest levels occur in infancy and old age.

By uncovering the molecular mechanisms linking fasting and human health, Dr Longo has shed light on potential targets for such drug-based therapeutic interventions.

Currently, the most promising target for such an intervention appears to be IGF-1, due to both its crucial role in human health, and promising experimental results. Drugs targeting the hormone in mice, for example, have been found to result in a 50% increase in lifespan and a significant reduction in the prevalence of various diseases. [5]

Evidence supporting IGF-1 as a target for drug-based therapeutic interventions has also been observed outside of the laboratory, in a perhaps unexpected location – in the remote, rural villages of Ecuador. Dr. Jaime Guevara-Aguirre, an endocrinologist, has since 1987 been observing a small population of 100 Ecuadorian individuals suffering from Laron Syndrome.

IGF-1 Link: Dr. Jaime Guevara-Aguirre, Dr. Valter Longo, Laron Syndrome Patient Merci Valarezo. (Credit: Jake Whitman)

Dr. Valter Longo (top), Dr. Jaime Guevara-Aguirre with Laron Syndrome patient Merci Valarezo. (Credit: Jake Whitman)

Laron Syndrome is a genetic condition caused by the presence of a defective growth hormone receptor. The receptor is normally responsible for stimulating production of the hormone IGF-1, however in individuals suffering from Laron Syndrome defective growth hormone receptors are unable to stimulate IGF-1 production. This results in low circulating IGF-1 levels, which is turn causes significantly stunted growth.

Whilst observing the population, Dr. Guevara-Aguirre noticed an unusual phenomenon – a remarkably low incidence of cancer and diabetes. Due to this observation, both Dr Longo and Dr. Guevara-Aguirre believe the low circulating IGF-1 levels in the population not only result in stunted growth, but also confer a protection against cancer and diabetes. [5]

The IGF-1 link in healthy individuals

Since joining the project in 2005, Dr Longo has sought to mimic this protection against cancer and diabetes by developing and testing drugs that target IGF-1 in healthy individuals. Dr Longo believes his team are “getting closer” to developing drugs which target IGF-1, and clarified that the ultimate aim of such a therapeutic intervention would be to “extend the human healthspan.” [6]

The observation of protection against cancer and diabetes in Laron Syndrome sufferers, as well as promising experimental results when targeting IGF-1 in mice, suggests that targeting IGF-1 is potentially an effective and viable means to improve both human healthspan and lifespan. This gives hope that Dr Longo’s research will result in the development of impactful drugs with a potentially huge real-world impact.

Little People of Ecuador: Laron Syndrome May Unlock Cancer, Diabetes Cure feat. Dr. Valter Longo, Dr. Jaime Guevara-Aguirre. [2016-02-15. Tracy Connor, Cynthia McFadden and Jake Whitman, NBC News]

References

  1. The 5:2 diet helps beat cancer and Alzheimer’s, study finds [2014-11-24. Tom Brooks-Pollock, The Telegraph]
  2. Fasting-mimicking diet and markers/risk factors for aging, diabetes, cancer, and cardiovascular disease — Min Wei, Sebastian Brandhorst, Mahshid Shelehchi, Hamed Mirzaei, Chia Wei Cheng, Julia Budniak, Susan Groshen, Wendy J. Mack, Esra Guen, Stefano Di Biase, Pinchas Cohen, Todd E. Morgan, Tanya Dorff, Kurt Hong, Andreas Michalsen5, Alessandro Laviano and Valter D. Longo. [2017-02-15. Science Translational Medicine: Vol. 9, Issue 377, eaai8700. DOI: 10.1126/scitranslmed.aai8700]
  3. Fasting Against Cancer [2014-09-26. Christopher Edward Jones, Michelson Medical Research Foundation]
  4. Low-protein diet slows Alzheimer’s in mice [2013-02-19. Robert Perkins, USC News]
  5. Little People of Ecuador: Laron Syndrome May Unlock Cancer, Diabetes Cure [2016-02-15. Tracy Connor, Cynthia McFadden and Jake Whitman, NBC News], Little people of Ecuador: Laron Syndrome may unlock cancer, diabetes cure [2016-02-15. Cynthia McFadden, Jake Whitman and Tracy Connor, NBC Today].
  6. IGF-1 & Intermittent Fasting: Discussion with Valter Longo [2014-12-26. Christopher Edward Jones, Michelson Medical Research Foundation]

Related Fasting / Fasting Mimicking Diet Articles

Christopher Edward Jones is a biochemist and writer currently affiliated with Queen Mary University of London, where he is part of a research group focusing on the restriction factors of HIV. In the past he has worked with multiple biomedical research groups in both industry and academia. He has a research interest in the biochemical mechanisms of virus restriction and a general interest in all areas of science.

Christopher Edward Jones is a biochemist and writer currently affiliated with Queen Mary University of London, where he is part of a research group focusing on the restriction factors of HIV. In the past he has worked with multiple biomedical research groups in both industry and academia. He has a research interest in the biochemical mechanisms of virus restriction and a general interest in all areas of science.

Christopher Edward Jones is a biochemist and writer currently affiliated with Queen Mary University of London, where he is part of a research group focusing on the restriction factors of HIV. In the past he has worked with multiple biomedical research groups in both industry and academia. He has a research interest in the biochemical mechanisms of virus restriction and a general interest in all areas of science.

Christopher Edward Jones is a biochemist and writer currently affiliated with Queen Mary University of London, where he is part of a research group focusing on the restriction factors of HIV. In the past he has worked with multiple biomedical research groups in both industry and academia. He has a research interest in the biochemical mechanisms of virus restriction and a general interest in all areas of science.



The Michelson Medical Research Foundation's Groundwork blog is brought to you thanks to the generous support of Dr. Gary K. Michelson and his wife, Alya Michelson.

The Michelson Medical Research Foundation's Groundwork blog is brought to you thanks to the generous support of Dr. Gary K. Michelson and his wife, Alya Michelson.

The Michelson Medical Research Foundation's Groundwork blog is brought to you thanks to the generous support of Dr. Gary K. Michelson and his wife, Alya Michelson.

The Michelson Medical Research Foundation's Groundwork blog is brought to you thanks to the generous support of Dr. Gary K. Michelson and his wife, Alya Michelson.