#035 Gordon Lithgow, Ph.D. on Protein Aggregation, Iron Overload & the Search for Longevity Compounds
Dr. Gordon Lithgow, Professor at the Buck Institute for Aging, explores C. elegans in aging research, discussing protein homeostasis, heat shock, iron, and vitamin D. He also highlights the Caenorhabditis Intervention Testing Program for longevity compound screening.
Deep Dive Analysis
8 Topic Outline
Introduction to C. Elegans as an Aging Model
The Role of Proteostasis in Aging
Heat Shock, Hormesis, and Lifespan Extension
Impact of Excess Iron on Protein Aggregation and Disease
Vitamin D Deficiency and Accelerated Aging
Caenorhabditis Intervention Testing Program (CITP) Overview
Challenges and Learnings from Compound Screening in Worms
Future Directions and Compound Suggestions for CITP
5 Key Concepts
Gene Homology
Gene homology refers to the similarity between genes of different species. C. Elegans, for example, shares about 35% of its genes with humans, meaning a version of these genes is also found in humans, making it a relevant model for studying human biology.
Proteostasis (Protein Homeostasis)
Proteostasis is the process of maintaining the proper three-dimensional shape and function of proteins within a cell. During aging, proteins can lose their shape, become insoluble, and aggregate, a process linked to neurological diseases like Alzheimer's and Parkinson's, and also to the general aging process.
Hormesis
Hormesis is a biological phenomenon where a low dose of an otherwise harmful stressor (such as heat, fasting, or certain compounds) can induce a beneficial adaptive response. This activates cellular stress response pathways, increasing the organism's resilience against larger stresses, including those associated with aging.
Heat Shock Proteins (HSPs)
Heat shock proteins are a class of molecular chaperones produced by cells in response to various stressors, particularly heat. Their primary role is to help other proteins maintain their correct three-dimensional structure, refold misfolded proteins, and prevent harmful protein aggregation.
Caenorhabditis Intervention Testing Program (CITP)
The CITP is a multi-institution initiative, sponsored by the National Institute on Aging, designed to screen bioactive compounds for their potential to extend lifespan and enhance health. It uses nematodes (C. elegans) as a model system to rapidly and economically identify promising compounds that could later be tested in mammals.
10 Questions Answered
C. elegans are tiny, transparent, have a short lifespan of 15-20 days, and share about 35% of their genes with humans, making them a quick and economical model to study longevity interventions compared to more expensive and time-consuming mammalian models like mice.
During aging, proteins can lose their correct three-dimensional shape, become insoluble, and aggregate. This process is observed in neurological diseases like Alzheimer's and Parkinson's, but also occurs during normal aging, potentially disrupting tissue and cellular functions.
Yes, in lower organisms like C. elegans and flies, controlled heat stress (like a 'heat shock') has been shown to increase lifespan. This occurs by activating cellular defense systems against misfolded proteins, including the production of heat shock proteins and the process of autophagy.
Sitting in a 163°F sauna for 30 minutes can increase human heat shock proteins (like HSP70) by 50% for up to 48 hours. Regular sauna use (4-7 times a week) has been associated with significantly lower all-cause mortality and a reduced risk of Alzheimer's disease in men.
Excess dietary iron can accelerate aging and the accumulation of insoluble proteins, which is a molecular pathology of aging. Elevated iron levels are linked to an increased risk of neurological diseases such as Parkinson's and Alzheimer's disease.
Vitamin D deficiency is associated with an elevated risk for many adult cancers and neurological diseases. Research suggests that vitamin D may play a role in preventing protein insolubility and regulating the aging process, with deficiency potentially leading to accelerated aging phenotypes.
While C. elegans are known to move away from light, they possess the precursor (7-dehydrocholesterol) and the necessary enzymes to convert vitamin D3 into its active form, 1,25-dihydroxyvitamin D, suggesting a conserved metabolism similar to mammals and potential for natural production.
A large meta-analysis found that human blood levels of 25-hydroxyvitamin D between 40 and 60 nanograms per milliliter are associated with the lowest all-cause mortality.
The CITP aims to screen a wide range of bioactive compounds for their ability to extend lifespan and enhance health using various species of C. elegans. The goal is to identify robust and reproducible candidates that can then be advanced to more expensive and time-consuming mammalian studies.
Standardizing experimental protocols across different laboratories is a significant challenge, as subtle variations in factors like plate preparation, bacterial food, and worm handling can lead to inconsistent results, even for basic aging measurements.
7 Actionable Insights
1. Sauna Use for Longevity
Engage in sauna use 2-3 times per week for a 20-24% lower all-cause mortality and 20% lower Alzheimer’s risk, or 4-7 times per week for a 40% lower all-cause mortality and 60% lower Alzheimer’s risk, as this activates heat shock proteins crucial for protein homeostasis and stress response.
2. Monitor Dietary Iron Levels
Get your iron levels measured and avoid blindly taking iron supplements, as excess dietary iron can accelerate aging and the accumulation of insoluble proteins, potentially increasing the risk of neurological diseases.
3. Optimize Vitamin D Levels
Get your 25-hydroxyvitamin D blood levels measured before and after supplementation, aiming for levels between 40-60 ng/mL, as deficiency is linked to elevated risk for adult cancers and neurological diseases, and optimal levels are associated with lower all-cause mortality and improved cognition; always discuss supplementation with your doctor.
4. Incorporate Sulforaphane into Diet
Consider incorporating sulforaphane, found in cruciferous plants like broccoli, into your diet; it’s a potent activator of the NRF2 pathway, which lowers inflammation and oxidative stress, and has shown lifespan extension in animal studies.
5. Check Iron Metabolism Genes
If you’ve done 23andMe genetic testing, use the tool at foundmyfitness.com/genetics to check for gene polymorphisms in the hemochromatosis and transferrin genes, which can indicate an increased risk for iron overload and associated neurological diseases.
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5 Key Quotes
People fall in love with them, right? I mean, they actually come in and they're a little worm. But before long, they're just devoted to, you know, all the biology and all the interesting things that happen.
Dr. Gordon Lithgow
And it's really dramatic when you have a mutation or a chemical compound that stops that from happening or slows it down. And people are just kind of amazed to see down the microscope a worm that's crawling around and behaving normally when it shouldn't be, when it should be dead.
Dr. Gordon Lithgow
But if the same process is happening in the course of normal aging, it shows a connection between normal aging and disease.
Dr. Gordon Lithgow
I spent most of my career just interested in worms. I mean, I thought if we can solve worm aging, that's fantastic. But over the years, this creeping realization that actually what we're doing could be important for people as well, making all these connections to disease and all the model organism people coming to this conclusion, working on flies and mice and yeast even, that these are basic mechanisms of aging. They're likely to be playing out in humans as well. And therefore, we should do something with this knowledge we've accumulated over the last 25 years. It's really time to try and translate that and do something that might be beneficial.
Dr. Gordon Lithgow
It's beginning to join up into a sensible story. Now, that said, we should be cautious. And I'm not an MD, and I'm not prescribing vitamin D for anyone, although it's likely that if you're deficient, you really would benefit from coming up into a sensible range.
Dr. Gordon Lithgow