Understanding the Genetics of CentenariansOctober 2016
By Chancellor Faloon
The Albert Einstein College of Medicine has been conducting research evaluating the blood and genes of over 500 centenarians age 95-112 years old and their children. The team of researchers has discovered specific longevity genes and healthy blood markers they believe to be the cause of their longevity.1
Nir Barzilai, MD, is spearheading the centenarian study at Einstein but is also currently leading a large scale trial to test the anti-aging effects of the drug metformin.2
He has specific motivation for conducting this trial because of the numerous studies showing that metformin can extend life.3 In fact, one of these compelling studies found that 78,241 adults with type II diabetes who were prescribed metformin lived longer than nondiabetics not taking metformin.4
This article will discuss what has been learned from research regarding the genetics of centenarians.
Lower IGF-1 Levels Associated with Longevity
Several studies have been released on mice, flies, and worms showing that when they’ve been adjusted to have lower expression of IGF-1 and closely related genes their lifespans are extended by as much as 50%.5-9
IGF-1 (insulin like growth factor-1) is a hormone similar to insulin that is produced by the liver. It is released by the liver in response to elevated amounts of growth hormone. IGF-1 levels are highest during puberty as they are responsible for much of our growth.10,11
Studies on centenarians have shown that they and their offspring have lower IGF-1 levels.12-14 Barzilai and his team discovered that lower levels present in centenarians were attributed to specific genetic variants they carried.15,16
It has been reported in studies that having lower levels of IGF-1 is not always favorable because of the side effects of fatigue, decreased muscle mass, and sexual function.7 However, these centenarians did not have these side effects. Many of them were still employed, actively exercised, and challenged their brains by reading articles and completing crossword puzzles.1
A separate study, published in the journal Aging Cell, evaluated the relationship between IGF-1 levels and longevity. The researchers tested 184 nonagenarians (individuals from 90 to 99 years old) and found that they have lower levels of IGF-1, leading the authors to conclude that “…low IGF-1 levels predict life expectancy in exceptionally long-lived individuals.”14
These and others studies have led the way for researchers to find methods to modulate IGF-1. Calorie restriction and the antidiabetic drug metformin have emerged as promising candidates.17
A recent study revealed that metformin may protect women with breast cancer from metastasis through its ability to decrease IGF-1 and increase an important IGF-1 binding protein. The study tested 102 women who were divided into a control group (chemo + hormone therapy) and a metformin group (chemo + hormone therapy + metformin).18
Compared to the control group, the women who received metformin had significantly fewer metastases. The researchers believed this to be caused by the increase in an important IGF-1 binding protein, IGFBP-3 (IGF binding protein-3), which has been documented as an inhibitor of cell growth and inducer of apoptosis.18,19
Caloric Restriction Benefits
In general, consuming lower calorie meals has been shown to increase longevity. This is because when we calorie restrict, longevity enzymes called sirtuins are activated.20-22
Numerous studies demonstrate that reductions in sirtuin enzymes lead to neurodegeneration of the brain, vascular inflammation, increased fat storage and production, insulin resistance, fatigue, and loss of muscle strength.23-31
Sirtuin enzymes are activated by NAD+ (nicotinamide adenine dinucleotide), a cellular compound that is found in every cell in the body and is essential to life.32,33 In fact, NAD+ enables the transfer of energy from the foods we eat to vital cell functions. Unfortunately, as we age, NAD+ levels decline.34
Together with calorie restriction, a natural way to boost NAD+ levels is through supplementation with a form of vitamin B3 called nicotinamide riboside. Studies have shown that this form of vitamin B3 converts into NAD+, making it an effective strategy for promoting youthful vitality by preventing the natural decline in cellular energy.
Studies have also shown that nicotinamide riboside extends lifespan, increases endurance, improves cognitive function, switches “off” the genes of aging, activates sirtuins, and enhances cellular energy.35,36
A study on mice fed a high-fat diet found that nicotinamide riboside supplementation improved insulin sensitivity, prevented weight gain, and on a treadmill test they ran 33% longer than the control mice.36
Longevity Gene Variants Identified
In studies conducted by Barzilai’s research team, identification of certain genetic variants within the CETP and ADPOC3 genes were found to be present in both long-lived individuals and their offspring. These genetic variants relate to longevity, cardiovascular health, favorable lipoprotein profile, and insulin sensitivity.37,38
In another study, the same team of researchers found that centenarians and their offspring also had present a genetic variant of the ADIPOQ gene, which expresses higher amounts of the hormone adiponectin. This hormone is secreted by fat cells (adipocytes) and helps regulate glucose levels by increasing insulin sensitivity and reducing the amount of glucose produced by the liver. In addition, higher amounts of adiponectin have also been shown to protect against atherosclerosis.39
Studies have also shown that metformin can increase adiponectin levels, which is just one of the many ways it provides antidiabetic effects.40
Alive for Over a Century and Still Working!
In particular, one fascinating centenarian Dr. Barzilai studied was Irving Kahn, who was the world’s oldest active living working professional. Kahn had a very optimistic view on life. He said that he woke up every morning with something to look forward to. Unfortunately, Kahn died last year at the age of 109 but continued to actively work until his death.1
What makes Irving Kahn even more interesting is that he had three sisters who all lived to be over a 100 years old, even though one sister smoked for 80 years of her life.
What was particularly fascinating was that all these centenarians were still very active. They were engaged, passionate, and very happy. They woke up every morning and set goals. Peers of these centenarians say that their zest for life was an inspiration to them all.
The identification of genetic variants by Barzilai’s research team could facilitate the development of new drug therapies that might help people live longer, healthier lives by preventing or delaying age-related diseases. This is why he has teamed up with several other well-respected researchers to conduct the first anti-aging study to be done on metformin. The study will follow 3,000 adults between the ages of 65-79 for a minimum of 5 years to see if metformin can prevent disease. If the study is successful, metformin could be the first drug approved to fight aging.3
Metformin has been extensively studied because it can mimic the benefits received from exercise and calorie restriction through activating AMPK as well as other mechanisms. Studies continue to come out that show activating AMPK increases longevity.41-43
Life Extension® has published significant research and introduced numerous nutrients that can help promote longevity, reduce the biomarkers of aging and maintain healthy levels of triglycerides, glucose, cholesterol, and insulin.
The blood markers discussed in this article are just some of what has to be taken into account to optimally increase longevity and prevent disease. A new hypothesis that will be discussed in a future issue of Life Extension magazine will describe the potential benefit of using carefully-controlled growth hormone over a limited time to regenerate the thymus gland. Restoration of thymic activity would induce profound anti-aging effects including partial reversal of immune senescence.
If you have any questions on the scientific content of this article, please call a Life Extension® Wellness Specialist at 1-866-864-3027.
- Available at: https://www.einstein.yu.edu/centers/aging/longevity-genes-project/. Accessed July 11, 2016.
- Barzilai N, Crandall JP, Kritchevsky SB, et al. Metformin as a Tool to Target Aging. Cell Metab. 2016;23(6):1060-5.
- Available at: http://www.sciencemag.org/news/2015/09/feature-man-who-wants-beat-back-aging. Accessed July 11, 2016.
- Bannister CA, Holden SE, Jenkins-Jones S, et al. Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls. Diabetes Obes Metab. 2014;16(11):1165-73.
- Bartke A, Chandrashekar V, Bailey B, et al. Consequences of growth hormone (GH) overexpression and GH resistance. Neuropeptides. 2002;36(2-3):201-8.
- Broughton SJ, Piper MD, Ikeya T, et al. Longer lifespan, altered metabolism, and stress resistance in Drosophila from ablation of cells making insulin-like ligands. Proc Natl Acad Sci U S A. 2005;102(8):3105-10.
- Sonntag WE, Csiszar A, deCabo R, et al. Diverse roles of growth hormone and insulin-like growth factor-1 in mammalian aging: progress and controversies. J Gerontol A Biol Sci Med Sci. 2012;67(6):587-98.
- Halaschek-Wiener J, Khattra JS, McKay S, et al. Analysis of long-lived C. elegans daf-2 mutants using serial analysis of gene expression. Genome Res. 2005;15(5):603-15.
- Kenyon C, Chang J, Gensch E, et al. A C. elegans mutant that lives twice as long as wild type. Nature. 1993;366(6454):461-4.
- Annunziata M, Granata R, Ghigo E. The IGF system. Acta Diabetol. 2011;48(1):1-9.
- Pan Z, Zhang J, Zhang J, et al. Expression Profiles of the Insulin-like Growth Factor System Components in Liver Tissue during Embryonic and Postnatal Growth of Erhualian and Yorkshire Reciprocal Cross F1 Pigs. Asian-Australas J Anim Sci. 2012;25(7):903-12.
- Vitale G, Brugts MP, Ogliari G, et al. Low circulating IGF-I bioactivity is associated with human longevity: findings in centenarians’ offspring. Aging (Albany NY). 2012;4(9):580-9.
- Bucci L, Ostan R, Cevenini E, et al. Centenarians’ offspring as a model of healthy aging: a reappraisal of the data on Italian subjects and a comprehensive overview. Aging (Albany NY). 2016;8(3):510-9.
- Milman S, Atzmon G, Huffman DM, et al. Low insulin-like growth factor-1 level predicts survival in humans with exceptional longevity. Aging Cell. 2014;13(4):769-71.
- Tazearslan C, Huang J, Barzilai N, et al. Impaired IGF1R signaling in cells expressing longevity-associated human IGF1R alleles. Aging Cell. 2011;10(3): 551-4.
- Suh Y, Atzmon G, Cho MO, et al. Functionally significant insulin-like growth factor I receptor mutations in centenarians. Proc Natl Acad Sci U S A. 2008;105(9):3438-42.
- Anisimov VN, Bartke A. The key role of growth hormone—insulin—IGF-1 signaling in aging and cancer. Critical reviews in oncology/hematology. 2013;87(3):201-23.
- El-Haggar SM, El-Shitany NA, Mostafa MF, et al. Metformin may protect nondiabetic breast cancer women from metastasis. Clin Exp Metastasis. 2016;33(4):339-57.
- Lee HY, Chun KH, Liu B, et al. Insulin-like growth factor binding protein-3 inhibits the growth of non-small cell lung cancer. Cancer Res. 2002;62(12):3530-7.
- Available at: http://www.lifeextension.com/Magazine/2014/11/The-Youth-Restoring-Benefits-Of-NAD/Page-01. Accessed July 11, 2016.
- Lu SP, Kato M, Lin SJ. Assimilation of endogenous nicotinamide riboside is essential for calorie restriction-mediated life span extension in Saccharomyces cerevisiae. J Biol Chem. 2009;284(25):17110-9.
- Morris KC, Lin HW, Thompson JW, et al. Pathways for ischemic cytoprotection: role of sirtuins in caloric restriction, resveratrol, and ischemic preconditioning. J Cereb Blood Flow Metab. 2011;31(4):1003-19.
- Imai S, Guarente L. NAD+ and sirtuins in aging and disease. Trends Cell Biol. 2014;24(8):464-71.
- Sebastian C, Satterstrom FK, Haigis MC, et al. From sirtuin biology to human diseases: an update. J Biol Chem. 2012;287(51):42444-52.
- Min SW, Sohn PD, Cho SH, et al. Sirtuins in neurodegenerative diseases: an update on potential mechanisms. Front Aging Neurosci. 2013;5:53.
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- Ahn J, Lee H, Jung CH, et al. MicroRNA-146b promotes adipogenesis by suppressing the SIRT1-FOXO1 cascade. EMBO Mol Med. 2013;5(10):1602-12.
- Pang W, Wang Y, Wei N, et al. Sirt1 inhibits akt2-mediated porcine adipogenesis potentially by direct protein-protein interaction. PLoS One. 2013;8(8):e71576.
- Feige JN, Lagouge M, Canto C, et al. Specific SIRT1 activation mimics low energy levels and protects against diet-induced metabolic disorders by enhancing fat oxidation. Cell Metab. 2008;8(5):347-58.
- Green MF, Hirschey MD. SIRT3 weighs heavily in the metabolic balance: a new role for SIRT3 in metabolic syndrome. J Gerontol A Biol Sci Med Sci. 2013;68(2):105-7.
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- Barzilai N, Atzmon G, Schechter C, et al. Unique lipoprotein phenotype and genotype associated with exceptional longevity. Jama. 2003;290(15):2030-40.
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- Atzmon G, Pollin TI, Crandall J, et al. Adiponectin levels and genotype: a potential regulator of life span in humans. J Gerontol A Biol Sci Med Sci. 2008;63(5):447-53.
- Su JR, Lu ZH, Su Y, et al. Relationship of Serum Adiponectin Levels and Metformin Therapy in Patients with Type 2 Diabetes. Horm Metab Res. 2016;48(2):92-8.
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