The Search For Longevity Compounds With Dr. Gordon Lithgow

The podcast I share with you today features Dr. Gordon Lithgow, a professor of gerontology at the Buck Institute for Research on Aging. Gordon studies mechanisms of aging by identifying compounds that extend lifespan or prevent age-related disease. He has discovered a range of factors that can lengthen life in the microscopic worm Caenorhabditis elegans or C. elegans as they are known, and he applies these findings to studies in human cell cultures. The Search for Longevity

The Search for Longevity Compounds With Dr. Gordon Lithgow Now, you may ask yourself, what do I have in common with something like a tiny nematode worm? And the answer to that is… gene homology! In fact, about 35% of the genes possessed by C. elegans have human homologs, which means that a version is also found in humans. The beauty of a model like C. elegans in aging research, as you will learn in this conversation with Dr. Gordon Lithgow, is that these animals have a very short lifespan. That means that, in comparison to more long-lived higher order organisms like rodents, it’s a bit more straightforward to change up the conditions and see what happens to their lifespans! You can do this more quickly and more cheaply.

By way of example, you might try adding in something like even a small amount of environmental stress, which, if we’re talking about heat stress, actually was shown to increase lifespan in worms when used in the right dose… a discovery that, as we’ll also discuss, Dr. Gordon Lithgow, today’s guest, actually made in the course of his research back in 1995.

But, it’s also practically useful for determining if certain compounds, including vitamins and minerals, may be candidates for increasing lifespan as well. This is where the Caenorhabditis Intervention Testing Program comes in. The Caenorhabditis Intervention Testing Program, which Dr. Gordon Lithgow is the director of, is a multi-institution effort, sponsored by the National Institute on Aging, a division of the NIH, designed to screen bioactive compounds for their ability to extend lifespan and enhance health using nematodes as a model system for potential effects. The Caenorhabditis Intervention Testing Program is actually a spin-off of another program called more simply the Intervention Testing Program, which began in the early 2000’s to look at the potential for various interventions, including vitamins and pharmaceuticals and otherwise, to extend the lifespan of mice. While mice are much more genetically close to us, sharing 92% of their genome in common with us, and discoveries are thus far more likely to have eventual clinical applicability, the cost and time involved in screening are also geometrically more expensive. Herein lies the value of doing broad screening with lower organisms like C. elegans which can then potentially make its way up to mammal research and maybe, if we’re very very lucky, clinical research in humans.

The Role of Proteostasis In Aging

Gordon talks about the role of proteostasis in the aging process. Proteostasis refers to homeostasis of all the proteins inside and outside of cells. New proteins are constantly being made inside cells and secreted outside of cells in order to perform the various functions of each cell whether it is a neuron or a heart cell. At the same time, older proteins are degraded so they can be replaced by new proteins. This relationship between the production of new proteins and the clearance of old proteins is known as proteostasis. When proteostasis becomes disrupted with age and this can lead to age-related aggregation of proteins which can then accelerate the aging process. Gordon’s data, as discussed in this podcast, suggests there is a correlation between compounds that affect protein aggregation also affect lifespan.

Heat Shock Increases Lifespan of C. elegans

In a paper that Gordon published a little more than 2 decades ago, he showed that heat shocking worms could extend their lifespan by 15% and that this was dependent on heat shock proteins. He also found that repeated heat stress treatments had an even more robust effect. Heat shock is a prime example of hormetic stress…which is a type of stress that in the right dose is slightly stressful to cells, elicits a biological stress response that has a cumulative effect that is otherwise a net gain in resilience that creates a benefit to the organism as a whole. Heat shock proteins (a.k.a. HSPs) help all other proteins maintain their proper 3-dimensional structure in the cell which is important for the specific function of each protein. The 3-dimensional is also very important for the normal half-life of a protein. Damage as a consequence of normal metabolism and immune function damages proteins and disrupts their structure and can lead to protein misfolding…this can prevent a protein from being properly degraded which can lead to protein aggregation.

Protein aggregation is associated with neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease and cardiovascular disease. Increased expression of heat shock proteins from heat exposure help repair proteins that have been damaged and this prevents protein aggregation. HSPs have also been shown to protect against neurodegenerative diseases. What is interesting is that in addition to heat stress increasing HSPs (to help prevent from misfolding) Gordon mentions that heat also activates autophagy…which makes sense you might want to clear away any damaged cells that have misfolded proteins accumulating in them that were not already sufficiently mitigated by HSPs.

This research may also have relevance to humans. Heat shock proteins that are activated by heat and one study has that humans that use a 163F sauna for 30 minutes increased their heat shock protein levels 49% over baseline and these elevations persist for 48 hours. Other associative studies in humans have shown that using the sauna 2-3 times per week was associated with a 24% lower all-cause mortality and 4-7 times per week was associated with a 40% lower all-cause mortality. There was also a strong inverse association between sauna use and dementia and Alzheimer’s disease. Using the sauna 2-3 times per week was associated with a 20% lower Alzheimer’s risk and 4-7 times per week with a 66% lower risk of Alzheimer’s disease.

Iron Overload And Aging

Iron plays a very important role in allowing red blood cells to transport oxygen to all tissues. It also plays a very import role in the mitochondria because it is a cofactor for metabolic enzymes that produce energy from glucose and fatty acids. Just because iron is important for health does not mean you want more or it. Too much iron can lead to free iron which has been shown to increase the production of reactive oxygen species and results in the formation of the highly reactive hydroxyl radical through something called the Fenton reaction. Gordon’s research found that worms that were fed excess dietary iron for a couple of days had an increase in insoluble, aggregated proteins. The iron did not make new proteins insoluble, but it accelerated the aging phenotype of proteins that already become insoluble with age and the iron also shortened their lifespan. He found that feeding the worms a chelator along with the dietary iron was able to ameliorate these effects. Alpha-lipoic acid is a well-known chelator of iron and it would be interesting to see if it could also ameliorate the negative effects of excess dietary iron but that remains to be shown.

Plausible Human Relevance

The RDA for adult males is 8 mg and for pre-menopausal women it is 18mg. A lot of iron is lost during menstruation, which is why menstruating women are at a higher risk for iron deficiency. Pregnancy also changes the RDA for iron since more iron is needed for proper fetal development. Too much dietary iron having negative health consequence may also have human relevance. There are a few common gene polymorphisms in genes that encode for proteins that bind iron and people that are homozygous for the right combination can have hemochomatosis, which can cause the body to absorb too much iron and can lead to all sorts of health problems.

Additionally, there is another a cluster of gene polymorphisms in the transferrin gene (which is a gene that encodes for specialized proteins that bind to free iron) and the hemochromatosis gene that affects free iron levels and is associated with a 5-fold increased risk of Alzheimer’s disease. For those of you that have done 23andMe genetic testing and are interested, from a non-medical informational only stand-point, in learning about whether you might have some of the specific combinations of gene polymorphisms discussed with Gordon in the transferrin gene and the hemochromatosis gene, you can actually find out what your genotype is by running the raw data through the genetic tool on my website. It is very easy to do and very quick.

Vitamin D And Aging

Believe it or not, worms that are fed dietary vitamin D3 are able to produce the active vitamin D steroid hormone, 1,25 hydroxy-vitamin D3. In their natural environment, C. elegans live on rotting fruit in the soil and so it is possible that they even produce vitamin D3 from UVB radiation from sunlight but that remains to be tested. Gordon investigated how vitamin D3 affected protein aggregation in worms. These worms can be used to study diseases that involve protein aggregation many of which happen to be neurodegenerative diseases, for example, Alzheimer’s disease, which involves the aggregation of the amyloid beta-42 peptide. Worms are engineered to have human amyloid beta-42 in their muscle cells and this accumulates with age and eventually causes the muscles to dysfunction and they become paralyzed.

Gordon fed these worms vitamin D3 (not the active steroid hormone 1,25 hydroxy-vitamin D3) and this delayed the onset of paralysis in these worms and there was a huge suppression of the formation of insoluble proteins. Additionally, Gordon fed vitamin D3 to normal worms and it extended their lifespan. Interestingly, the lifespan extension appeared to be dependent on the worm homolog of the Nrf2 gene, which is a master regulator of over 200 different genes, many anti-inflammatory and antioxidant genes.

Plausible Human Relevance

Obviously, worms are a long way from humans. Vitamin D has also been shown to reduce amyloid plaques and improve cognition in mice that have been engineered to get something similar to Alzheimer’s disease. Several studies have linked higher levels of vitamin D to decreased dementia risk and randomized controlled trials have shown that high-dose vitamin D supplementation in the range of 2,000 IU to 4,000 IU per day improves cognition in adults. The has not been found for lower doses closer to the RDA. Additionally, all-cause mortality studies showing that people with blood levels between 40-60 ng/ml have the lowest all-cause mortality…people that are deficient in vitamin D have a higher all-cause mortality. Similar studies have shown the same thing with telomeres…twins with high vitamin D have longer telomeres compared to those with lower vitamin D.

Search For Longevity Compounds

As mentioned earlier, Gordon directs the Caenorhabditis Intervention Testing Program, which aims to find compounds that can extend the lifespan in a variety of different worm species with the hope of later testing these compounds in mice and then in clinical studies. This program is in its infancy but so far 10 compounds have been investigated. These compounds include thioflavin T (a dye widely used to visualize and quantify the presence of misfolded protein aggregates called amyloids.), alpha-ketogluterate (a substrate used by mitochondria to produce energy), alpha lipoic acid, curcumin and more. Gordon talks a little bit about the preliminary findings including how thioflavin T has the most potential for increasing lifespan in a wide variety of different species of worms.

Podcast Outline

00:00:27 – The various qualities of C. elegans, especially as related to science’s deep knowledge of the organism, that makes it a perfect fit for this type of research.
00:01:40 – Some of the early experiences that actually lead to my early interest in the aging field and how it actually holds a little in common with Gordon.
00:03:15 – The role of protein aggregation as a possible fundamental mechanism of aging… even beyond its more established role in neurodegenerative diseases.
00:07:41 – Some of the fascinating research surrounding mild heat stress as a means to increase lifespan in lower organisms.
00:16:00 – Some of Gordon’s research into the effects of metal accumulation, particularly iron, on aging in lower organisms and how, in humans, it may be important to approach the intake of these minerals with care.
00:17:57 – The interplay between genes that influence iron-binding and the development of Alzheimer’s disease in humans.
00:21:35 – Some of Gordon’s research into the (perhaps surprising) effect of vitamin D on aging in C. elegans and, particularly, on the solubility of proteins… the loss of which is a feature of aging of particular interest.
00:23:22 – The critical involvement of the Nrf2 stress-response pathway in conferring benefits of vitamin D in worms… a pathway many of you may know about from previous discussions of sulforaphane[1][2], a robust activator of Nrf2 in humans.
00:31:53 – The story behind the Caenorhabditis Intervention Testing Program, a multi-institutional effort using the advantages of C. elegans short lifespan to screen for potential compounds that may increase lifespan. We also discuss the more expensive-but-closer-to-humans version of this program known just the Intervention Testing Program.
00:33:00 – Some of the challenges encountered with ensuring standardization of protocols across all of the participating labs in the Caenorhabditis Intervention Testing Program.
00:32:20 – The amazing genetic diversity represented in soil-dwelling nematodes and how this is also an advantage in longevity research.
00:37:08 – The synergistic way in which research in lower organisms (C. elegans in this case) works together with rodent research to better understand the biology of aging and identify potential therapeutics.
00:38:05 – The interesting possibility that certain compounds may have a different overall effect on lifespan or healthspan that is dependent within certain contexts (e.g. environmentally stressed or not)… this may add a little bit more complexity!

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About Dr. Rhonda Patrick

Perciavalle Patrick has a Ph.D. in biomedical science from the University of Tennessee Health Science Center, Memphis TN and St. Jude Children’s Research Hospital, Memphis TN. She also has a Bachelor’s of Science degree in biochemistry/chemistry from the University of California, San Diego. She has done extensive research on aging, cancer, and nutrition. She did her graduate research at St. Jude Children’s Research Hospital where she investigated the link between mitochondrial metabolism, apoptosis, and cancer. Her groundbreaking work discovered that a protein that is critical for cell survival has two distinct mitochondrial localizations with disparate functions, linking its anti-apoptotic role to a previously unrecognized role in mitochondrial respiration and maintenance of mitochondrial structure. Her dissertation findings were published in the 2012 issue of Nature Cell Biology.

Dr. Patrick trained as a postdoctoral fellow at Children’s Hospital Oakland Research Institute with Dr. Bruce Ames. She investigated the effects of micronutrient (vitamins and minerals) inadequacies on metabolism, inflammation, DNA damage, and aging and whether supplementation can reverse the damage. In addition, she also investigated the role of vitamin D in brain function, behavior, and other physiological functions and has published papers in FASEB on how vitamin D regulates serotonin synthesis and how this relates to autism and other neuropsychiatric disorders.

Dr. Patrick has also done research on aging at the Salk Institute for Biological Sciences. At the Salk, she investigated what role insulin signaling played in protein misfolding, which is commonly found in neurodegenerative diseases such as Alzheimer’s disease.

She frequently engages the public on topics including the role micronutrient deficiencies play in diseases of aging, the role of genetics in determining the effects of nutrients on a person’s health status, benefits of exposing the body to hormetic stressors, such as through exercise, fasting, sauna use or heat stress, or various forms of cold exposure, and the importance of mindfulness, stress reduction, and sleep. It is Dr. Patrick’s goal to challenge the status quo and encourage the wider public to think about health and longevity using a proactive, preventative approach.

Publications:

* Vitamin D and the Omega-3 Fatty Acids Control Serotonin Synthesis and Action, Part 2: Relevance for ADHD, Bipolar, Schizophrenia, and Impulsive Behavior FASEB Journal
* Vitamin D Hormone Regulates Serotonin Synthesis. Part 1: Relevance for Autism FASEB Journal
* Requirement for Anti-Apoptotic MCL-1 in the Survival of BCR-ABL B-Lineage Acute Lymphoblastic Leukemia Blood
* Delving Deeper: MCL-1′s Contribution to Normal and Cancer Biology Trends in Cell Biology
* Anti-Apoptotic MCL-1 Localizes to the Mitochondrial Matrix and Couples Mitochondrial Fusion to Respiration Nature Cell Biology
* Ubiquitin-Independent Degradation of Anti-Apoptotic MCL-1 Molecular and Cellular Biology
* Opposing Activities Protect Against Age-Onset Proteotoxicity Science