IGF-1 & Intermittent Fasting: Discussion with Dr. Valter Longo
2014/12/26
Christopher Edward Jones
http://michelsonmedical.org/2014/12/26/ ... ter-longo/Groundwork
Valter Longo is Professor of Gerontology and Professor of Biological Science at the University of Southern California. He also serves as director of the USC Longevity Institute.
¦Dr Longo has established himself as an eminent and prolific researcher in the field of gerontology, recently being awarded the “Rising Star” Award in Aging Research from the American Federation for Aging Research (AFAR) in recognition of his work.
¦His research has so far revolved around the biology of aging, with a particular focus on the effects of fasting on the process of aging and the onset/progression of age-related disorders.
We were fortunate enough to have the opportunity to interview Dr Longo regarding his past research, upcoming publications and long-term plans.
A lot of your work has been into the effects of calorie restriction on age-related disorders, is this a deliberate area of focus for you?
Calorie restriction is a very wide-ranging word. We focus more on periodic fasting – we’re not really big believers in having people be on special diets or restrictions all the time. We just believe in interventions that are short and lasting, that can last a long time and protect from aging and age-related diseases. But also the use of these in improving disease treatment.
Are you surprised at how effective your research has shown periodic fasting to be?
It has been very effective. Originally we did this in simple organisms to understand the molecular basis for it, and then moved to mice, and now we’re finishing a number of clinical trials. The effects have been very, very promising. Most of it is not published in humans yet but a lot of it is already finished. So in the next year or so we’re going to have at least 3 papers and clinical trials showing normal subjects, cancer subjects and also other diseases, showing the efficacy of these techniques, but also the high compliance that we get in doing this. So it’s really something that we’ve found that most people can do.
So are you hopeful that down the line we will get treatments out of this research?
Not so much down the line but actually now. As soon as the clinical trial is over basically that’s it – people can start doing it. Now for the cancer one people could do it, but not to treat the cancer, only to reduce the side effects of chemotherapy. The cancer itself is regulated by the FDA so we’ll have to continue our trials until these are FDA approved if we want to have the treatment included in therapy for delaying cancer progression. But of course people will do it anyway, because if you can use it with chemo obviously you’re already using it to treat cancer but you just can’t say.
So would you advise someone undergoing chemotherapy to try cyclical fasting?
We can advise them to do it with their oncologist. You couldn’t advise them to do it for the sake of the cancer, jut for the sake of protecting their normal organs and cells from the effects of chemotherapy.
How about in healthy individuals? What would you expect to observe in disease-free individuals undergoing cyclical fasting?
We have finished all that, in both mouse and humans. So I can tell you we expect a lot. I can’t really talk about the results because they’re not published yet, but I will say yes, there’s a remarkable range of effects which is hardly matched by anything else I’ve ever seen.
2 to 5 Days Fasting
(A) In both mice and humans, fasting for 2 or 5 days, respectively, causes an over 50% decrease in IGF-I, a 30% or more decrease in glucose, and a 5–10-fold increase in the IGF-1 binding protein and inhibitor IGFBP1 (Cahill, 2006; Lee et al., 2012; Raffaghello et al., 2008; Thissen et al., 1994a, 1994b).
Endocrinological
(A) In both mice and humans, fasting for 2 or 5 days, respectively, causes an over 50% decrease in IGF-I, a 30% or more decrease in glucose, and a 5–10-fold increase in the IGF-1 binding protein and inhibitor IGFBP1 (Cahill, 2006; Lee et al., 2012; Raffaghello et al., 2008; Thissen et al., 1994a, 1994b).
Tumor Prevention
(A) In both mice and humans, fasting for 2 or 5 days, respectively, causes an over 50% decrease in IGF-I, a 30% or more decrease in glucose, and a 5–10-fold increase in the IGF-1 binding protein and inhibitor IGFBP1 (Cahill, 2006; Lee et al., 2012; Raffaghello et al., 2008; Thissen et al., 1994a, 1994b).
These and other endocrinological alterations affect the expression of hundreds of genes in many cell types and the consequent reduction or halting of growth and elevation in stress resistance, which may be dependent in part on FOXO and other stress resistance transcription factors. These periodically extreme conditions can promote changes, which are long lasting and delay aging and disease independently of calorie restriction, although the cellular mechanisms responsible for these effects remain poorly understood. In the presence of chemotherapy drugs, fasting can promote the protection of normal, but not cancer, cells (differential stress resistance [DSR]), since oncogenic pathways play central roles in inhibiting stress resistance, and therefore, cancer cells are unable to switch to the stress response mode.
(B) The extreme changes caused by fasting, and particularly the very low IGF-1 and glucose levels and high IGFBP1, also generate a tumor prevention environment that promotes cancer cell death, since transformed cells have acquired a number of mutations that progressively decrease their ability to adapt to extreme environments (differential stress sensitization [DSS]) (Guevara-Aguirre et al., 2011; Lee et al., 2010, 2012).
These and other endocrinological alterations affect the expression of hundreds of genes in many cell types and the consequent reduction or halting of growth and elevation in stress resistance, which may be dependent in part on FOXO and other stress resistance transcription factors. These periodically extreme conditions can promote changes, which are long lasting and delay aging and disease independently of calorie restriction, although the cellular mechanisms responsible for these effects remain poorly understood. In the presence of chemotherapy drugs, fasting can promote the protection of normal, but not cancer, cells (differential stress resistance [DSR]), since oncogenic pathways play central roles in inhibiting stress resistance, and therefore, cancer cells are unable to switch to the stress response mode.
These and other endocrinological alterations affect the expression of hundreds of genes in many cell types and the consequent reduction or halting of growth and elevation in stress resistance, which may be dependent in part on FOXO and other stress resistance transcription factors. These periodically extreme conditions can promote changes, which are long lasting and delay aging and disease independently of calorie restriction, although the cellular mechanisms responsible for these effects remain poorly understood. In the presence of chemotherapy drugs, fasting can promote the protection of normal, but not cancer, cells (differential stress resistance [DSR]), since oncogenic pathways play central roles in inhibiting stress resistance, and therefore, cancer cells are unable to switch to the stress response mode.
(B) The extreme changes caused by fasting, and particularly the very low IGF-1 and glucose levels and high IGFBP1, also generate a tumor prevention environment that promotes cancer cell death, since transformed cells have acquired a number of mutations that progressively decrease their ability to adapt to extreme environments (differential stress sensitization [DSS]) (Guevara-Aguirre et al., 2011; Lee et al., 2010, 2012).
The hormone IGF-1 comes up a lot in your research; it seems to be a big factor in mediating the effects of calorie restriction and fasting. How big of a role do you think IGF-1 is playing overall in aging?
I think it’s a pretty big role, though it’s not the only thing that’s important. The reduction of IGF-1 is really key in the anti-aging effects of some of the interventions. Both the dietary ones and the genetic ones. We’ve been putting a lot of work into mutations of the growth hormone receptor that are well established now to release IGF-1 and also cause a record life span extension in mice. So we know for example with chemotherapy resistance if you fast mice and inject IGF-1 you reverse a lot of the protective effects of fasting. So it’s important; it’s not the only factor, but it’s certainly one of the key ones.
So could we expect drugs targeting IGF-1 to work in humans?
We’re working on that both with the diet but also with drugs. So we’ve been working on that for a while and we’re getting closer to it. Of course the pharmacological part is much more complicated and expensive and so eventually we need to have big pharma partnered to do it – and that may occur very soon. But yes the growth hormone receptor/IGF-1 pathway is going to be our first target. And in fact we just organised a conference about a year ago on this, on an intervention to extend the human health span in targeting the growth hormone/IGF-1 pathway. We brought 30 of the leading experts in the world on this to Sicily and at the end everybody voted and the growth hormone IGF-1 came out most likely to be active in extending human lifespan.
So is that the direction your research will be heading in over the next few years?
Yes. And of course we are even more interested in regeneration and rejuvenation now. We just published a paper on that, showing how fasting and IGF-1 can cause stem cell based regeneration and rejuvenation of the immune system. So half of my lab has now switched to understanding how this can regenerate systems – and not just regenerate in an unsophisticated way, but regenerate in a very sophisticated way which is reminiscent of what you see during early development.
IGF-1: Insulin-like growth factor 1
IGF-1
Protein
Insulin-like growth factor 1 (IGF-1) is a protein that in humans is encoded by the IGF1 gene. IGF-1 has also been referred to as a “sulfation factor” and its effects were termed “nonsuppressible insulin-like activity” (NSILA) in the 1970s. IGF-1 is a hormone similar in molecular structure to insulin and consists of 70 amino acids in a single chain with three intramolecular disulfide bridges.
Hormone
IGF-1 is produced primarily by the liver as an endocrine hormone as well as in target tissues in a paracrine/autocrine fashion. Production is stimulated by growth hormone (GH) and can be retarded by undernutrition, growth hormone insensitivity, lack of growth hormone receptors, or failures of the downstream signalling pathway post GH receptor including SHP2 and STAT5B.
Lifetime
IGF-1 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.
Influence
Protein intake increases IGF-1 levels in humans, independent of total calorie consumption. Factors that are known to cause variation in the levels of growth hormone (GH) and IGF-1 in the circulation include: genetic make-up, the time of day, age, sex, exercise status, stress levels, nutrition level and body mass index (BMI), disease state, race, estrogen status and xenobiotic intake.
Reduction
Fasting, including intermittent fasting, can reduce IGF-1 levels rapidly and dramatically
Insulin-like growth factor 1 (IGF-1) is a protein that in humans is encoded by the IGF1 gene. IGF-1 has also been referred to as a “sulfation factor” and its effects were termed “nonsuppressible insulin-like activity” (NSILA) in the 1970s. IGF-1 is a hormone similar in molecular structure to insulin and consists of 70 amino acids in a single chain with three intramolecular disulfide bridges.
IGF-1 is produced primarily by the liver as an endocrine hormone as well as in target tissues in a paracrine/autocrine fashion. Production is stimulated by growth hormone (GH) and can be retarded by undernutrition, growth hormone insensitivity, lack of growth hormone receptors, or failures of the downstream signalling pathway post GH receptor including SHP2 and STAT5B.
IGF-1 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.
Protein intake increases IGF-1 levels in humans, independent of total calorie consumption. Factors that are known to cause variation in the levels of growth hormone (GH) and IGF-1 in the circulation include: genetic make-up, the time of day, age, sex, exercise status, stress levels, nutrition level and body mass index (BMI), disease state, race, estrogen status and xenobiotic intake.
Fasting, including intermittent fasting, can reduce IGF-1 levels rapidly and dramatically
Do you have any predictions for where you’ll be in 10 years’ time?
In 10 years’ time we hope that a lot of what we’ve been doing is actually out there. I don’t think it is going to be used by everybody, but judging by the success of Michael Mosley’s 5:2 diet, which is in part taken from our work and the work of Michelle Harvie and others, and is now one of the best-selling books – in fact the best-selling book – in England for the past two or three years, and also one of the best-selling books in the US. So these diets are now making it into the, not mainstream, but certainly are getting exposure. So we hope that we get to a point where maybe 10-20% of the population are using these on a regular basis so that they in some ways, stay away from medicine and drugs and doctors.
I suppose that may be especially beneficial in the UK where we have the NHS; there will be less pressure placed on the service. Maybe these non-pharmacological approaches are the way forward.
Yes I think so. I was surprised at England and the people there – just how supportive it was. Maybe more than any place else in the world. It was interesting how that happened. So I don’t know if there’s something special about England in that sense, but it’s interesting. I was very surprised that that would be two years in a row the best-selling book out of all books – you would think there would be fiction books or something that people would be more interested in than a book on fasting.
It’s good that it’s having an impact. It’s good that people are listening.
Yes. It’s important for us. I can see in my lab – and I have a lab both here and in Europe – that when they can see people – when they feel that people are doing it and the media is interested – they are much more excited about what we’re going to do next and what problem we are going to solve next. I think that’s absolutely important.
Valter Longo’s fields of study include the understanding of the fundamental mechanisms of aging in yeast, mice and humans by using genetics and biochemistry techniques, identifying the molecular pathways conserved from simple organisms to humans that can be modulated to protect against multiple stresses and treat or prevent cancer, Alzheimer’s Disease and other age-related diseases. The focus is on the signal transduction pathways that regulate resistance to oxidative damage in yeast and mice. Photo Credit: Michelson Medical Research Foundation [MMRF].