Life Extension Magazine June 2014
The 2013 SENS Foundation Conference
By Ben Best
There is probably no conference in the world that attracts so many scientists devoted to human rejuvenation as the SENS (Strategies for Engineered Negligible Senescence) Foundation conference, which is held every two years at Cambridge University in England. As described in the July 2013 issue of Life Extension® magazine, the SENS Foundation is attempting to implement strategies to reverse the seven causes of aging they have identified. Dr. Aubrey de Grey, who is on the Scientific Advisory Board of Life Extension®, co-founded SENS, the SENS Foundation, and the SENS conferences. The September 3-7, 2013 SENS Foundation conference was the sixth SENS conference (SENS6).
Keynote Presentation On Gene Therapy For Rejuvenation
George Church, PhD, (Professor of Genetics, Harvard Medical School, Boston, Massachusetts) was the keynote speaker at SENS6. As described in the May, 2013 issue of Life Extension, Dr. Church is the lead Scientific Advisor in a study of centenarians funded by the Life Extension Foundation®. He is one of the most prominent geneticists in the world.
Dr. Church noted that from the year 1870 to the present, the annual increase in life expectancy has been about 0.28 years per year. 1 This falls short of the one-year gain in life expectancy per year that would be required for unlimited life spans. As a hopeful sign that the long-term trend will be exceeded, he cited the recent fall in cost of sequencing the human genome. DNA sequencing costs had been declining by a steady 1.5-fold per year between years 1965 to 2005. After 2005, DNA sequencing costs plummeted dramatically and they are soon expected to drop to a few hundred dollars per genome.
Moreover, genome sequencing has become faster and more accurate—a 10-fold reduction in point errors (one per million) in the last five years. He is anticipating less than one error per genome in the future.
Dr. Church identified several genes that he believes contributes to extreme health and longevity, including one that protects against HIV and another that delays Alzheimer’s disease by a decade. He is hopeful that gene therapy can be used to make such genes available to everyone. The newest and most effective technology for modifying genes is CRISPR (Clustered Regularly Interspersed Short Palindrome Repeats), a means that bacteria use to protect themselves against viruses. Only in 2013 has the application of CRISPR to gene therapy been appreciated.
Dr. Church has been at the forefront of this technological revolution.2-4 His lecture described testing the function of gene-modified heart cells using organ-on-a-chip technology.5
Longevity Benefits Of Calorie Restriction In Humans
Luigi Fontana, MD, PhD, (Research Associate Professor of Medicine and Co-Director of the Longevity Research Program, Washington University, St. Louis, Missouri) has been looking for evidence that calorie restriction with adequate nutrition will extend life and improve health in humans. Life span studies have shown extended life span from calorie restriction in yeast, worms, flies, rodents, and many other organisms.6
Lifetime studies are not feasible in humans because the studies would require a human lifetime to conduct. Calorie restriction with a vegetarian diet was practiced somewhat involuntarily by the eight participants in Biosphere 2 for two years. Those subjects showed reduced risk factors for atherosclerosis, including large reductions in blood cholesterol, blood pressure, and serum triglycerides.7,8
The number of people who have chosen to practice calorie restriction for extended periods is small, but many of them have cooperated in being subjects for Dr. Fontana’s investigations. Eighteen individuals who had been practicing calorie restriction for an average of six years were compared with 18 individuals on a typical American diet. The calorie restriction group showed reduced triglycerides, reduced blood pressure, and reduced inflammation (extremely low C-reactive protein).9
Another study of 25 calorie-restriction subjects found a reduced age-related decline in heart function (diastolic function).10 A study of 28 calorie-restriction subjects compared to 28 exercisers and 28 controls looked at insulin resistance (measured by HOMA-IR, Homeostasis Model Assessment). The calorie-restriction group showed 34% less insulin resistance compared to the exercisers, and 82% less insulin resistance compared to the controls.11 Low insulin resistance is associated with low risk of diabetes and age-related diseases. High heart rate variability indicated flexible adaptive control of the body (especially the heart) by the brain.12 Heart rate variability normally declines with age, but Dr. Fontana found that subjects practicing calorie restriction had heart rate variability values comparable to healthy adults who were 20 years younger.13 Although there is no direct proof that maximum lifespan will be extended by humans practicing calorie restriction, the risk factors for age-related diseases among these low-calorie consumers are very low.
Improved Survival From Heart Attack
Sam Parnia, MD, PhD, (Assistant Professor of Medicine and Director of Cardiopulmonary Resuscitation Research, State University of New York, Stony Brook, New York) discussed the changing view of death since the discovery of cardio-pulmonary resuscitation (CPR) in the 1960s.
Death is reversible if the heart can be restarted soon after cardiac arrest. He said most physicians still have the outdated idea that brain cells die five minutes after the heart stops. Viable stem cells have been cultured from human brain tissue as long as 20 hours after death.14 There is a much higher survival of out-of-hospital cardiac arrest victims in Seattle than in Alabama, likely due to regional differences in the availability of emergency cardiac care (e.g., bystander CPR, EMS quality, etc.)15
Dr. Parnia is concerned that resuscitation efforts in hospitals are too often done improperly. Resuscitation guidelines often recommend use of 100% oxygen, despite the fact that excessive oxygen exposure during resuscitation nearly doubles the likelihood of death.16 Manual CPR is frequently attempted in hospitals, despite the fact that mechanical chest compression devices give better organ perfusion.17
There is a large variation in the amount of time hospitals will spend attempting resuscitation of a cardiac arrest victim. Patients are much more likely to be revived in hospitals if they are in the highest quartile of time spent attempting resuscitation (25 minutes) rather than in the lowest quartile (16 minutes).18 Dr. Parnia said that most physicians will stop CPR efforts after 20 minutes, even though the survival curve does not flatten until 40 minutes. He also said that despite the fact that a few degrees of lowered temperature has been shown to reduce six month mortality from 55 to 41% in resuscitation survivors,19 hypothermia is rarely used or is inefficiently applied in hospitals.20
Tissue Regeneration From Salamanders
Malcolm Maden, PhD, (Professor, Department of Biology, University of Florida, Gainesville, Florida) studies tissue regeneration in axolotls (Mexican salamanders). His presentation was entitled, “Regeneration in the adult organism—a cure for aging?” To justify the title, he quoted the renowned regeneration biologist Richard J. Goss, who said: “If everything rejuvenated, there would be no death.”
Dr. Maden said that some animals (such as hydra, planarians, and jellyfish) avoid aging or age-related death due to the ability to regenerate all organs. A study of the newt salamander showed no loss of regenerative capacity over a period of 16 years.21 And the Mexican salamander, the axolotl, has the greatest regenerative capacity of any vertebrate animal.22 The axolotl can regenerate every organ in its body: limbs, heart, and large portions of brain tissue without scarring. This regenerative capacity does not decline with age.21
When the limb of an axolotl is severed, a collection of stem cells known as a blastema forms. The blastema cells have de-differentiated, but only to the extent of being a collection of stem cells having different potentials for differentiating into specific tissue types―such as skin, muscle, bone, nerve, blood vessels, etc.23 Dr. Maden has demonstrated regeneration of major portions of injured brain in axolotls.24 He has determined that retinoic acid―the vitamin-A metabolite that facilitates growth and development―plays a key role in regeneration.25 He commented that a human child has an ability to regrow amputated fingertips, and that retinoic acid contributes to this process.
Dr. Maden has shown that applying retinoic acid to the spinal cord of a rodent causes nerve fibers to regrow.26 He explained that depriving rats of vitamin A (retinoic acid) results in symptoms of Alzheimer’s disease. Restoring the retinoic acid reversed the symptoms. Dr. Maden hopes that understanding the process of regeneration in axolotls will lead to the ability to induce wound-healing and tissue regeneration in people without scar formation.
Speakers Receiving Funding From The Life Extension Foundation
Three of the researchers presenting at SENS6 acknowledged the Life Extension Foundation as a source of funding, two of these researchers were featured in the January 2014 issue of Life Extension.
Joao Pedro de Magalhaes, PhD, (Senior Lecturer/Associate Professor, Institute of Integrative Biology, Liverpool University, Liverpool, United Kingdom) has been using funds from the Life Extension Foundation to sequence the genome of the bowhead whale, the longest-living mammal, which lives more than 200 years.27 With more cells in their bodies, larger animals would be expected to have higher rates of cancer.28 Even tall humans have a higher cancer risk than short humans, independent of all other risk factors.29 But a variety of anti-cancer mechanisms allows larger animals to avoid the greater cancer risk that would otherwise accompany their greater size.30 Dr. Magalhaes’s laboratory is uniquely equipped to analyze the genome of the bowhead whale to determine the means by which it achieves such longevity while avoiding cancer.31 He said that such research cannot be funded through conventional funding sources. He expressed appreciation for the Life Extension Foundation grant he received to do this work.
John Furber, MSc, (CEO, Legendary Pharma-ceuticals, Gainesville, Florida) attends many conferences dealing with the biology of aging every year, and he is therefore very well-known among biomedical gerontologists. He has designed a rejuvenation experiment which the Life Extension Foundation is funding. At the time he gave his presentation, he had not yet begun work on the project he was describing.
Lysosomes are the garbage disposal/recycling centers of biological cells. Lysosomes contain enzymes that digest cellular waste products into reusable components. 32 But with time, lysosomes accumulate enzyme-resistant age-pigment molecules known as lipofuscin.33 Some neurons in the brain can contain up to 75% lipofuscin.34 Lipofuscin emits toxic free radicals. Cells loaded with lipofuscin cannot be expected to function very well, so lipofuscin may contribute to the maladies of old age. Furber would like to rejuvenate cells by removing the lipofuscin. By doing an extensive search of scientific literature, he identified some chemicals which induce cells to export lysosomal lipofuscin out of the cell.35
During the question period, Furber was asked whether there would be harmful effects in transferring lipofuscin out of cells, such as causing macrophages to be engorged with undigestible lipofuscin. Furber did not know the answer, but because there is such a great potential benefit he said, “Let’s do the experiment so we can find out.” He is hopeful that if this process is done slowly and carefully, the macrophages will not be overloaded and the circulatory system will not become much more inflammatory.
Justin Rebo, MD, (Research Scientist, SENS Foundation, Mountain View, California) reported on work he had done at Dr. John Schloendorn’s company ImmunePath. Dr. Rebo had been looking for the easiest problems that could be solved in regenerative medicine (“low hanging fruit”).
Cancer victims subjected to chemotherapy or radiation experience severe loss of immune system blood cells that makes them very vulnerable to infection. Such patients can be treated by transplantation of umbilical cord blood stem cells,36 but such cells are very limited in supply, and matching cells with patients to ensure compatibility can be difficult.37 In some cases, stem cells have been multiplied in the laboratory before transplantation, a process that has proved somewhat successful.38,39
Dr. Rebo’s work involved deriving blood cells from pluripotent stem cells in mice. By applying an appropriate cocktail of cell signaling proteins (cytokines), he was able to derive the needed immune system blood cells. Dr. Rebo was able to show that these derived cells would migrate to the bone marrow.
He gave mice sublethal doses of chemotherapy, and the mice treated with the derived immune system blood cells were much more likely to survive. Dr. Rebo will be using Life Extension Foundation funding to investigate in more detail why shared blood circulation between genetically identical mice of different ages rejuvenates the old mouse, and makes the young mouse biologically older.40,41 Blood from a young mouse contains more functional white blood cells and stem cells42 as well as fewer inflammatory proteins.43
Dr. Rebo’s objective is to determine with precision all of the positive components of young blood and all of the negative components of old blood. With this information, he will develop strategies to enhance the positive components as well as to block or remove the negative components. He is hopeful that his results will be ready for clinical application in only a few years.
Mitochondrial Sirtuin Promotes Health And Longevity
Danica Chen, PhD, (Assistant Professor, Nutri-tional Science and Technology, University of California, Berkeley, California) has been investigating the role of sirtuins in aging. There are seven sirtuin enzymes in mammals, identified by number: SIRT1 through SIRT7.44 SIRT1, which is activated by resveratrol, is the most famous sirtuin,45 but Dr. Chen studies SIRT3.
SIRT3 is found in mitochondria, the energy-producing organelles in cells. Removal of SIRT3 from mouse cells has been shown to increase free-radical production by the mitochondria―and to increase cancer incidence.41 Calorie restriction (the most generally accepted means to extend life and health) in mice normally reduces free-radical damage, but not when SIRT3 has been removed.46,47 Calorie restriction has been shown to stimulate SIRT3 and thereby reduce free-radical production by mitochondria.48
Dr. Chen’s team has shown that increased SIRT3 improves the regenerative capacity of blood stem cells.49 Cancer cells normally bypass the use of mitochondria to generate energy, an effect that is opposed by SIRT3.50 By bypassing the mitochondria as an energy source, cancer cells are also bypassing the capacity of mitochondria to kill them (by apoptosis, or cell death). SIRT3 activity declines with age, and long-lived humans have greater expression of SIRT3.51 A compound to stimulate SIRT3 the way resveratrol stimulates SIRT1―or enhances expression of SIRT3―could improve human health and longevity as well as increase cancer resistance.
An Amyloid That Kills The Oldest Old Humans
Brian O’Nuallain, PhD, (Assistant Professor of Neurology, Harvard Medical School, Boston, Massachusetts) is working on the SENS Foundation project to eliminate amyloid protein aggregates. Although aggregation of amyloid-beta protein is believed to cause Alzheimer’s disease,52 the SENS Foundation project is focused on aggregation of the amyloid protein transthyretin (TTR). Deposition of mutant TTR in the heart may lead to cardiac amyloidosis.53,54 Increase in TTR oxidation due to aging might contribute to the onset of TTR amyloidosis. Heparin also leads to increased TTR aggregation.55
In the majority of cases, cardiac amyloidosis is a disease of elderly men.56 Also, about 4% of African-Americans have a mutation that can lead to earlier onset of the disease. 57 Among the oldest of the old (supercentenarians, or people over age 110), the effects of amyloidosis have been described as a leading cause of death.58 Dr. O’Nuallain said that TTR disease is underdiagnosed because diagnosis is so difficult. He explained his efforts have been to develop antibodies that will bind to the TTR protein so that it can be seen as images in patient scans. 59 He is also looking for antibodies that will not only bind to TTR protein, but will enzymatically degrade aggregated TTR.
An Alternate Method For Cancer Cell Survival
Haroldo Silva, PhD, (OncoSENS Research Scientist, SENS Foundation, Mountain View, California) is working to prevent cancer. Cells normally stop dividing when the telomeres at the ends of their chromosomes become too short. Most cancer cells overcome this limitation by invoking an enzyme ( telomerase) that lengthens the telomeres, allowing the cancer cells to divide indefinitely. About 10-15% of cancer cells do not use telomerase, however, but use the Alternate Lengthening of Telomeres (ALT) method to lengthen telomeres.60
Because there are many more researchers studying telomerase than studying ALT, the SENS Foundation has devoted its anti-cancer efforts to ALT. Cells utilizing ALT to lengthen telomeres can be identified by ALT-associated bodies in the cell nucleus.61 SENS Foundation is developing faster means to identify the number of these ALT-associated bodies per cell. ALT cells also contain high levels of telomere-like DNA sequences formed into circles apart from the chromosomes. Because the sequences begin with the nucleotide cytosine, these circles are called C-circles.62 Telomere lengthening by ALT is believed to be in part the result of copying from C-circles.63
The SENS Foundation is building on work determining specific genes that are partially expressed in ALT cells.64 David Halvorsen, a Research Associate working with Dr. Silva at the SENS Foundation, joined Dr. Silva on the stage to explain the role of specific genes and their role in the ALT pathway. The SENS Foundation plans to investigate more genes that are particularly active in ALT cells.