The longevity advantage of genetic deficiencies in growth hormone/IGF-1 signaling | Valter Longo
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A growing body of scientific evidence suggests that there is a correlation between decreased activation of the IGF-1 pathway and increased lifespan. Studies in worms and mice indicate that when the IGF-1 receptor is knocked out, the organisms remain disease-free and live longer. In humans, a naturally occurring IGF-1 deficient population exists in a region of Ecuador. These individuals live slightly longer and do not succumb to the diseases of aging compared to their relatives with typical IGF-1 receptors, regardless of diet and lifestyle practices. In this clip, Dr. Valter Longo discusses the longevity-conferring effects of diminishing the pro-aging IGF-1 pathway.
Valter: So, we prefer, for example, we always prefer to go with where we have human evidence, then there are no consequences and there's a growth hormone receptor, right?
Rhonda: Mm-hmm.
Valter: So, we're now developing drugs against growth hormone receptor, why? Because we have the Ecuadorean that we've been following for 10 years, and Guevara, our colleagues, has been following them for 30 years. And they're fine, they make it to very old age.
Rhonda: In years by now, so people like, you know, the IGF-1, and growth hormone pathway...
Valter: Right. So, essentially, proteins and amino acids control two major pathways, right? One is the growth hormone IGF-1, which is called an axis, it's not really a pathway, but an axis. And then, the other one is TOR–S6 kinase, right? So, if you have a lot of amino acids, those two are activated, and both are now widely recognized, it's very powerful pro-aging pathways. And so, yeah, of course, you could do it by food, or you could do it by mutations.
So, if you take a mouse and you knock out the growth hormone receptor, this mouse will live 40 percent, 50 percent longer. It's also, and in spite, and this is work by John Kopchick and Andre Barkey, and in spite of living longer, it has much less diseases. So, almost half of these mice will get to the end of life with no diseases that are visible, right? So, it's really remarkable. And as remarkable, I think, is our work with humans that have the same mutation in the growth hormone receptor, and these people will live, maybe, a little bit longer. Not 40 perfect longer, for sure, but they have a terrible diet, they smoke, they drink, they really don't watch anything they do. And in spite of all this, they almost never get cancer, they almost never get diabetes, we really haven't seen any chronic disease in these people, in the same household like a normal diseases, right? So, it's nothing to do with Ecuador, it has to do with mutation.
Rhonda: Mm-hmm.
Valter: Which matches very well with the mouse data. So, yeah, I think that that is a much better target. I mean, I'm biased, but I think having all of it available to us for a long time, and we picked the target that was the least likely to cause any side effects also based on, you know, very long-term human data.
Rhonda: There's also human data showing that there's polymorphisms in, for example, the IGF-1 receptor, or that whole pathway, you know, that are also consistent with longevity as well.
Valter: Yeah, yeah. FOXO that are in communication and polymorphism. And FOXO in the IGF-1 receptor, in the growth hormone receptor, yeah.
Rhonda: Right. It's all consistent, where, I mean...
Valter: I think so, yeah.
Rhonda: I remember, in fact, one of my first experiments in biology was doing, you know, manipulating the IGF-1 signaling pathway in worms, in Andrew Dillin's lab at the Salk Institute. And I remember when I saw, you know, when you get rid of that pathway in these worms, they live 100 percent longer. I mean, it was like amazing to me that you could change one genetic pathway and cause a worm to live like 100 percent longer. I mean, that, to me, was mind-blowing. Like how is that...and these are genes that are conserved in humans, nonetheless, so it really makes you think, "Well, if this can happen to a worm, you know, what's the potential for humans?"
And we know, centenarians have like, you said, FOXOs. So IGF-1 just for people, so that IGF-1 is a growth signaling pathway that...I don't, and maybe you can answer this question for me. When I think about it, for human aging, I always think about too much IGF-1 playing an important role in cancer, promoting cancer growth. When I was studying it in worms, it was more about not inhibiting this very important stress response pathway, the FOXO3 pathway, and how that's important for turning on all these genes that are involved in stem cell, making stem cells, and autophagy, and degrading proteins. And it's just like a master regulator of all these, like, amazing genes that can help you if you smoke, or just help you deal with the stresses of aging in general. For humans, do you think that lowering IGF-1 is going to have a more profound effect on human lifespan via, like, not getting cancer, or do you think not inhibiting that FOXO3 pathway is just as important?
Valter: Probably it's very much connected, meaning that the aging process is the driver for the cancer, about to the level of a cancer cells and accumulation of mutation, but also the level the tissues getting more inflammation, be more permissive to the metastasis, and also the level of the immunosenescence, and the immune system getting weaker. And we know that if you have an immune deficient mouse, the cancer grows a lot faster. So, yeah, so then, the aging process is really anything most of us agree, the primary driver of the age-related disease, which is cancer, and, of course, all the other age-related diseases. So, yeah, so we're always looking in terms of, you know, treat aging, and then the rest comes. Now, of course, yeah, there are all the things that might not be necessarily related to aging. For example, if you have a high IGF-1 in the moment where the cancer cell is generated, that cancer cell might still love to have a lot of IGF-1 because it helps prevent apoptosis. And so, yeah, there could be a dual role of some of these growth factors in making sure that the cancer becomes a metastatic cancer, that some of it maybe an independent of the aging process.
Rhonda: Mm-hmm, yeah.
Programmed cell death. Apoptosis is a type of cellular self-destruct mechanism that rids the body of damaged or aged cells. Unlike necrosis, a process in which cells that die as a result of acute injury swell and burst, spilling their contents over their neighbors and causing a potentially damaging inflammatory response, a cell that undergoes apoptosis dies in a neat and orderly fashion – shrinking and condensing, without damaging its neighbors. The process of apoptosis is often blocked or impaired in cancer cells. (May be pronounced “AY-pop-TOE-sis” OR “AP-oh-TOE-sis”.)
An intracellular degradation system involved in the disassembly and recycling of unnecessary or dysfunctional cellular components. Autophagy participates in cell death, a process known as autophagic dell death. Prolonged fasting is a robust initiator of autophagy and may help protect against cancer and even aging by reducing the burden of abnormal cells.
The relationship between autophagy and cancer is complex, however. Autophagy may prevent the survival of pre-malignant cells, but can also be hijacked as a malignant adaptation by cancer, providing a useful means to scavenge resources needed for further growth.
A bidirectional cell signaling pathway that may regulate cell function, metabolism, or other aspects of physiology. Most signaling pathways are unidirectional. However, an axis may involve two or more signaling proteins and their secreting organs or cells in a type of feedback loop. For example, the growth hormone/IGF axis, also known as the Hypothalamic–pituitary–somatotropic axis, is a highly regulated pathway involving IGF-1 (produced by the liver), growth hormone (produced by the pituitary), and growth hormone-releasing hormone (produced by the hypothalamus).
A person who is 100 or more years old.
A protein that provides the instructions for genes responsible for the regulation of cellular replication, resistance to oxidative stress, metabolism, and DNA repair. FOXO3 may play an integral part in both longevity and tumor suppression. Variants of FOXO3 are associated with longevity in humans. Humans with a more active version of this gene have a 2.7-fold increased chance of living to be a centenarian.
A naturally occurring substance capable of stimulating cellular growth, proliferation, healing, and differentiation. Growth factors typically act as signaling molecules between cells. Examples include cytokines and hormones that bind to specific receptors on the surface of their target cells.
The gradual deterioration of the immune system brought on by natural age advancement. Immunosenescence is considered the most important reason for the increased rate of infections (and cancers) in older adults and is believed to be the diminished or exhausted function of the immune system that naturally occurs with aging.
A critical element of the body’s immune response. Inflammation occurs when the body is exposed to harmful stimuli, such as pathogens, damaged cells, or irritants. It is a protective response that involves immune cells, cell-signaling proteins, and pro-inflammatory factors. Acute inflammation occurs after minor injuries or infections and is characterized by local redness, swelling, or fever. Chronic inflammation occurs on the cellular level in response to toxins or other stressors and is often “invisible.” It plays a key role in the development of many chronic diseases, including cancer, cardiovascular disease, and diabetes.
Cancer that has spread from the part of the body where it started to other parts of the body. When cancer cells break away from a tumor, they can travel to other areas of the body through the bloodstream or the lymph system.
Senescence is a response to stress in which damaged cells suspend normal growth and metabolism. While senescence is vital for embryonic development, wound healing, and cancer immunity, accumulation of senescent cells causes increases inflammation and participates in the phenotype of aging.
A cell that has the potential to develop into different types of cells in the body. Stem cells are undifferentiated, so they cannot do specific functions in the body. Instead, they have the potential to become specialized cells, such as muscle cells, blood cells, and brain cells. As such, they serve as a repair system for the body. Stem cells can divide and renew themselves over a long time. In 2006, scientists reverted somatic cells into stem cells by introducing Oct4, Sox2, Klf4, and cMyc (OSKM), known as Yamanaka factors.[1]
- ^ Takahashi, Kazutoshi; Yamanaka, Shinya (2006). Induction Of Pluripotent Stem Cells From Mouse Embryonic And Adult Fibroblast Cultures By Defined Factors Cell 126, 4.
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