Life Extension Magazine January 2013
Conference Report: Ellison Medical Foundation Colloquium on Aging
By Ben Best
The Ellison Medical Foundation is the largest private funder of research on aging and the second overall funder—second only to the federal government's National Institute on Aging.
Since its inception in 1998, Ellison's Medical Foundation has provided more than $300 million to fund basic biomedical research on aging, life span, and age-related diseases and disabilities—including telomeres, longevity genes, DNA and mitochondrial damage, Alzheimer's disease, neural development, degeneration, and cognitive decline, and more.
The Ellison Medical Foundation's approach is different, innovative, and bold. As the late Nobel laureate Dr. Joshua Lederberg once described the Ellison Foundation, "Our job is to fund the new, the unconventional, and to take chances that others won't. Our only criterion will be the best science and the best of scientists."
That's why every year, the Ellison Medical Foundation awards a total of $40 million in four-year grants to 25 New Scholars and 25 Senior Scholars for basic research on the biology of aging. At the end of the four years, the scholars present their findings at the Colloquium for New and Senior Scholars.
Below is a sampling of discoveries presented at this year's colloquium. Although they are quite technical in nature, the potential impact they could have on the future of anti-aging research and healthy human life span makes them an important part of Life Extension's mission to provide readers with the very latest scientific information.
All of the research was done on model organisms, which means we don't yet know how these studies will translate into humans. However, using these model organisms, these scientists are paving the way for the future of anti-aging and longevity research—and could very well hold the key to future life-changing discoveries.
The Discovery: Nicotinamide Mononucleotide, a Potential Treatment for Adult-onset Diabetes
It is believed that calorie restriction has the potential to extend life span. One way in which this takes place is by enhancing the activity of the brain hormone orexin. This can be especially beneficial in those with type II diabetes, since orexin improves insulin sensitivity and helps prevent an increase in body fat.1 However, in order for calorie restriction to have these beneficial effects on type II diabetics, two additional factors must be in place.
At this year's Ellison Medical Foundation Colloquium on the Biology of Aging, Dr. Shin-ichiro Imai demonstrated that the protein sirtuin is required in order for calorie restriction to enhance the activity of orexin. But sirtuin alone is not enough. In order for any of these beneficial processes to take place, the coenzyme NAD+ must also be present.
The problem is that cellular NAD+ declines with both aging and a high fat diet. The good news is that Dr. Imai found that feeding mice nicotinamide mononucleotide (NMN)—the precursor to NAD+—promoted NAD+ synthesis. This suggests that NMN could be a potential treatment for type II diabetes.2
Dr. Imai is hopeful that sirtuins will prove to be of value against diseases associated with human aging—particularly type II diabetes.3,4
The Discovery: Resveratrol Can Help Increase Life Span By Relieving Endoplasmic Reticulum Stress, An Underlying Factor in Age-Associated Diseases
Dr. Matt Kaeberlein was a 2008 New Scholar reporting on his four-year grant work at the 2012 Colloquium. Like Dr. Imai, Dr. Kaeberlein was a pioneer in discovering the life-extending effects of sirtuins in yeast.5
Dr. Kaeberlein has recently been studying the relationship between aging and endoplasmic reticulum stress. The endoplasmic reticulum (ER) is a collection of membranes within cells where proteins are created and folded. Chaperone molecules assist with the folding process. Folding of proteins is important because if proteins are not folded into the right shape, they may not function properly. Too many mis-folded proteins in the endoplasmic reticulum results in a phenomenon described as endoplasmic reticulum stress, or "ER stress."
Unrelieved ER stress can lead to massive cell death, and is believed to be an underlying factor in many diseases associated with aging, including atherosclerosis, diabetes, and neurodegenerative disease.6
It is possible that resveratrol can help increase life span by helping the body protect against ER stress. When cells are subject to ER stress, they try to rectify the problem by increasing the number of chaperone molecules and by increasing the size of the endoplasmic reticulum.7 Resveratrol has been shown to extend the life span of nematode worms by helping promote this ER stress protection response.8
New Scholar, Dr. Hyung Don Ryoo, also studied the effect of ER stress on longevity—except he used fruit fly retinas. Dr. Ryoo demonstrated that in addition to increasing chaperone molecules and increasing endoplasmic reticulum volume, cells could also relieve ER stress by inducing increased degradation of the mis-folded proteins.9 Dr. Ryoo showed that unrelieved ER stress can lead to cell death by a particular cell-signaling pathway.10
The Discovery: Innate Immunity is Regulated by a Protein That Controls Gene Expression
A weakened immune system in the elderly plays a significant role in their susceptibility to infection—and in many cases leads to death. A person between 50 and 64 years old is nearly 10 times more likely to die from influenza than a person in the 5-49 age group. A person over 65 years old is more than 10 times more likely to die from an influenza-associated death as a person in the 50-64 age group.11
At the Colloquium, New Scholar Dr. Dennis Kim reported on his studies of the decline in innate immunity with age in nematode worms. Kim showed that as nematodes age, they become increasingly vulnerable to death by bacteria.
He found that innate immunity is regulated by PMK-1 (a protein that controls gene expression12), and he identified genes that PMK-1 regulates.13 Kim discovered that by an age of 15 days, nematodes have less than 16% of the PMK-1 protein seen in the larval stage, and that genes regulated by PMK-1 show sharply reduced expression with aging as well.14
When I asked Kim what causes the decline in PMK-1 protein with age, he replied that this essential question remains to be answered. If there is a human equivalent to PMK-1, and if the cause of PMK-1 decline is discovered, Kim's research could lead to ways to reduce the vulnerability of elderly humans to infectious diseases.
The Discovery: "Jumping Genes" Can Contribute to Cancer and Aging
Nobel laureate Dr. Barbara McClintock won her prize in Physiology or Medicine for her discovery of transposable elements ("jumping genes"), DNA sequences that can change position within the genome of a single cell. At least 25 human genetic diseases have been attributed to "jumping genes."15
New Scholar Dr. Victoria Belancio demonstrated that genomic instability due to "jumping genes" can contribute to cancer as well as aging.16,17
Life Extension® Supports Ongoing Anti-Aging Research
The Life Extension Foundation® is evaluating the anti-aging research projects that are coming to the end of their four-year Larry Ellison grants to see which ones can be extended with new funding from Life Extension®.
If you have any questions on the scientific content of this article, please call a Life Extension® Health Advisor at 1-866-864-3027.
1. Funato H, Tsai AL, Willie JT, et al. Enhanced orexin receptor-2 signaling prevents diet-induced obesity and improves leptin sensitivity. Cell Metab. 2009 Jan 7;9(1):64-76.
2. Yoshino J, Mills KF, Yoon MJ, Imai S. Nicotinamide mononucleotide, a key NAD(+) intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab. 2011 Oct 5;14(4):528-36.
3. Imai S, Guarente L. Ten years of NAD-dependent SIR2 family deacetylases: implications for metabolic diseases. Trends Pharmacol Sci. 2010 May;31(5):212-20.
4. Imai S. Dissecting systemic control of metabolism and aging in the NAD World: the importance of SIRT1 and NAMPT-mediated NAD biosynthesis. FEBS Lett. 2011 Jun 6;585(11):1657-62.
5. Kaeberlein M, McVey M, Guarente L. The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev. 1999 Oct 1;13(19):2570-80.
6. Tabas I, Ron D. Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nat Cell Biol. 2011 Mar;13(3):184-90.
7. Walter P, Ron D. The unfolded protein response: from stress pathway to homeostatic regulation. Science. 2011 Nov 25;334(6059):1081-6.
8. Viswanathan M, Kim SK, Berdichevsky A, Guarente L. A role for SIR-2.1 regulation of ER stress response genes in determining C. elegans life span. Dev Cell. 2005 Nov;9(5):605-15.
9. Kang MJ, Ryoo HD. Suppression of retinal degeneration in Drosophila by stimulation of ER-associated degradation. Proc Natl Acad Sci U S A. 2009 Oct 6;106(40):17043-8.
10. Kang MJ, Chung J, Ryoo HD. CDK5 and MEKK1 mediate pro-apoptotic signaling following endoplasmic reticulum stress in an autosomal dominant retinitis pigmentosa model. Nat Cell Biol. 2012 Mar 4;14(4):409-15.
11. Thompson WW, Shay DK, Weintraub E, et al. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA. 2003 Jan 8;289(2):179-86.
12 Kim DH, Feinbaum R, Alloing G, et al. A conserved p38 MAP kinase pathway in Caenorhabditis elegans innate immunity. Science. 2002 Jul 26;297(5581):623-6.
13. Troemel ER, Chu SW, Reinke V, Lee SS, Ausubel FM, Kim DH. p38 MAPK regulates expression of immune response genes and contributes to longevity in C. elegans. PLoS Genet. 2006 Nov 10;2(11):e183.
14. Youngman MJ, Rogers ZN, Kim DH. A decline in p38 MAPK signaling underlies immunosenescence in Caenorhabditis elegans. PLoS Genet. 2011 May;7(5):e1002082.
15. Hedges DJ, Deininger PL. Inviting instability: Transposable elements, double-strand breaks, and the maintenance of genome integrity. Mutat Res. 2007 Mar 1;616(1-2):46-59.
16. Belancio VP, Roy-Engel AM, Pochampally RR, Deininger P. Somatic expression of LINE-1 elements in human tissues. Nucleic Acids Res. 2010 Jul;38(12):3909-22.
17. Belancio VP, Roy-Engel AM, Deininger PL. All y'all need to know 'bout retroelements in cancer. Semin Cancer Biol. 2010 Aug;20(4):200-10.
18. Wood JG, Rogina B, Lavu S, et al. Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature. 2004 Aug 5;430(7000):686-9.
19. Minor RK, Baur JA, Gomes AP, et al. SRT1720 improves survival and healthspan of obese mice. Sci Rep. 2011;1:70.