Life Extension Magazine September 2013
Aging & Diseases of Aging: Conference in Tokyo, Japan
By Ben Best
If you could go back in time, you’d want to have a pint of your blood removed and frozen every few years so that it would be available to be reintroduced into your aging body.
One reason is that your young blood does not have the inflammatory proteins that are found in old blood. These inflammatory factors have been found to inhibit stem cell function. Young blood also contains more youthful immune system cells (T-lymphocytes and B-lymphocytes). Cells in the immune system become less functional with age.
Another benefit of having your youthful blood available is that it contains more youthful stem cells that can provide a systemic rejuvenating effect.
Progressive medical facilities in the United States now offer a service where they temporarily stimulate stem cells in healthy people to boost their white blood cell production (using granulocyte-colony-stimulating factor). After a week’s time, the doctors withdraw your blood and freeze it until a time in the future when you need it to save your life. There is no time limit for how long your blood can remain frozen.
The time and expense involved in this procedure precludes most people from doing it.
Over forty years ago scientists demonstrated that linking the blood circulation of old rats to young rats could extend the life span of old rats by about 20%.1 The rat experiments worked because the rats were genetically identical, despite being different ages. Elderly humans cannot accept the blood of younger people because of immune rejection of the stem cells unless they are a full tissue match.
Only in the last ten years have scientists begun to discover the reason behind the life-extending benefits for old rats sharing blood circulation with young rats. This was one of the many topics covered in the “Aging and Diseases of Aging” conference held in Tokyo, Japan, on October 22-27, 2012.
Research in Tissue Aging
As described by Thomas Rando, PhD, (Professor of Neurology & Neurological Sciences at Stanford University) the technique of shared blood circulation between rodents of different ages was not used again for decades until 2005 when his graduate student, Irina Conboy, showed that the procedure restored the regenerative capacity of muscle stem cells in the older mice.2 It was also demonstrated that the stem cells in the liver, brain, and bone of an old animal could regain regenerative potential by being exposed to the circulating blood of a young animal.2 Later studies have confirmed that molecules in the blood of old animals depress muscle stem cell activity in both young and old animals.3
More recently, Dr. Rando’s laboratory used shared circulation in mice to discover the chemical CCL11 in the blood of old mice responsible for inhibiting stem cells in the brain.4 CCL11 injected into young mice reduced brain stem cell activity, while impairing learning and memory.4 Excessive inflammatory factors in the blood of old animals, notably TGF-1, are responsible for the inhibition of stem cells in muscle.5
Dr. Rando believes that a major cause of tissue aging is the decline in regenerative capacity of the stem cells of those tissues as a result of blood-borne molecules that increase with age and that inhibit stem cells. He has been investigating the mechanisms by which chemicals in the blood reduce stem cell activity, concluding that DNA expression is being altered.6 Every tissue in the body of an animal is different, but all cells making up these tissues have the same DNA code serving as a blueprint for cell function. What makes a liver cell, skin cell, and brain cell different from one another is that different portions of DNA are being expressed for each cell type.
Amy Wagers, PhD (Associate Professor, Harvard Medical School Department of Stem Cell and Regenerative Biology), was a contributor to the 2005 study of shared blood circulation between rodents of different ages. She was also present at this conference, where she reported that shared circulation could stimulate stem cells in old mouse brains to produce new myelin sheaths for neuronal fibers, a technique that could benefit patients suffering from multiple sclerosis.7 Wagers is also researching the use of stem cells from fat tissue to regenerate heart muscle in patients who have suffered from heart failure or heart attack.8
Understanding Senescent Cells
Judith Campisi, PhD (Professor at the Buck Institute for Research on Aging), is interested in the senescent cells that increase with age as a proportion of the total cells in tissues. Cells, like people, can become senescent, and the increasing number of senescent cells contributes to the senescence of people. For cells, senescence means that they stop dividing, usually because their telomeres have become too short, or because of irreparable DNA damage. Cellular senescence is nature’s way of preventing cells from becoming cancerous, but (ironically) cells that have become senescent begin secreting growth factors, proteins, and inflammatory agents that can cause other cells to become cancerous.9,10
Dr. Campisi’s group has identified IL-6 (Interleukin-6) and IL-8 (Interleukin-8) as inflammatory molecules known as cytokines being produced by senescent cells.11 More recently, her group showed that senescent cells resulting from DNA damage are induced to produce pro-inflammatory cytokines by increased activity of the NF-kB pathway.12 Senescent cells are thus in large part responsible for the chronic inflammation of old age that causes so many age-related diseases such as cancer and atherosclerosis. Dr. Campisi noted a discovery made in 2011 of the rejuvenating effects of eliminating senescent cells in mice.13
Dr. Campisi has wondered whether there is any benefit that results from the secretory products of senescent cells. Her conclusion is that in the presence of senescent cells, wound-healing is less fibrous than it would be otherwise due to the presence of protein-digesting enzymes secreted by the senescent cells (along with the other inflammatory molecules).
Juleen Zierath, PhD (Head of the Section of Integrative Physiology, Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden), like Dr. Rando, is interested in control of DNA expression (epigenetics, as distinct from genetics, which studies the effects of DNA differences). Dr. Zierath is specifically investigating the relationship between gene expression and type II (formerly called adult-onset) diabetes.
An important mechanism of epigenetics is addition of methyl molecules (methylation) or removal of methyl molecules (demethylation) to regulatory areas of DNA.14,15 Methylation of biomolecules is an essential biochemical reaction required for maintaining the integrity of biological membranes,16 synthesis of neurotransmitters,16 visual acuity,17 increasing glutathione synthesis in the brain to protect against oxidative stress,18 and protection against depression19 ― among many other vital functions. Methylation and demethylation of DNA is a means by which control is exerted over which genes are expressed and which genes are not. If DNA were completely methylated, no genes would be expressed, whereas if there were no DNA methylation there would be chaotic overexpression of too many genes. Both excessive and inadequate DNA methylation have been associated with cancer.20
Dr. Zierath has been studying DNA methylation effects in type II diabetes. As background, Dr. Zierath described twin studies. Identical twins are genetically identical because they have the same DNA and continue to have the same DNA throughout their lifetimes. Identical twins are epigenetically identical at birth, but become increasingly epigenetically distinct as they become subject to different environmental influences.21 She cited a study which showed that epigenetic effects due to smoking and dietary behavior can be inherited.22
In 2009 Dr. Zierath’s laboratory published a study showing that fatty material in the bloodstream causes methylation of DNA regulatory areas that results in a reduction of mitochondria (and resultant reduction of cellular energy).23 This study was an advance in providing a molecular mechanism that would explain why patients with type II diabetes have fewer mitochondria in their cells. The following year,her team published research indicating that exercise induces epigenetic changes that induce mitochondria function and fat utilization.24
Dr. Zierath has called exercise “the first line of defense against the development of insulin resistance in type II diabetes.” Vigorous exercise at least once per week has been shown to reduce the risk of type II diabetes by 33%.25 Most recently Dr. Zierath’s group published a study showing that exercise increases gene expression of sections of DNA that induce mitochondrial formation.26
Dr. Zierath takes her research personally. When I crossed her path in the hotel gym she asked me, “How’s your methylation?” I did not see anyone else from the conference in the hotel gym.
Eric Verdin, MD (Senior Investigator at the Gladstone Institute of Virology and Immunology at the University of California, San Francisco), discovered in 2002 that the sirtuin SIRT3 is localized in the mitochondria (energy-producing portions of cells).27 Sirtuins are a family of enzymes that modify protein function by removing an acetyl molecule. The seven known sirtuins in mammals are identified by number: SIRT1, SIRT2...SIRT7. SIRT1 is the most famous because (unlike the others) it has been shown to extend the life span of worms and flies.28 Resveratrol activates SIRT1 but not the other sirtuins.
SIRT1 acts primarily by removing acetyl molecules from the proteins surrounding DNA in the cell nucleus, thereby altering gene expression. DNA in the mitochondria is not surrounded by proteins, so Dr. Verdin has spent much of the last decade trying to determine the function of SIRT3. SIRT3 levels in the mitochondria have been shown to be increased in mice on calorie restriction,29 a dietary alteration that extends the life span of rodents. By removing an acetyl group of the mitochondrial antioxidant enzyme SOD2, SIRT3 reduces free radical oxidation.30
A major breakthrough occurred when Dr.Verdin’s research team demonstrated that mice lacking SIRT3 show accelerated obesity, insulin resistance, and other symptoms of the metabolic syndrome when fed a high fat diet.31 A high fat diet normally has this effect on mice,32 but the effect is much greater when SIRT3 is absent. Dr. Verdin’s team also demonstrated that removing a single fat-processing enzyme that SIRT3 affects could rescue the mice from the effects of the high fat diet, even when SIRT3 was absent.31 Dr. Verdin’s team further demonstrated that a mutation in SIRT3 is associated with the metabolic syndrome in humans.31 Dr. Verdin is hopeful that a molecule can be found that stimulates SIRT3 activity, just as resveratrol stimulates SIRT1 activity.
Research on Adiponectin
Takashi Kadowaki, MD, PhD (Professor of Diabetes and Metabolic Diseases, University of Tokyo), has been doing research on adiponectin for over a decade. Adiponectin is a protein secreted exclusively by fat cells. Adiponectin sensitizes the body to insulin, thereby acting as an anti-diabetic agent.33 Insulin resistance (a condition in which cells show reduced insulin-mediated uptake of amino acids, fatty acids, and particularly glucose) precedes and predicts the development of type II diabetes.34 Although adiponectin is produced by fat cells, adiponectin levels are typically low in people who are obese.33 Reduced levels of adiponectin are associated with insulin resistance, lipid dysregulation, and atherosclerosis.33
The first published paper by Dr. Kadowaki on adiponectin reported that adiponectin, particularly when combined with another adipokine known as leptin, could reverse the insulin resistance that a high fat diet produced in mice.35 Kadowski’s research team later demonstrated the key role of adiponectin receptors in mediating the effects of adiponectin suggesting that agents stimulating those receptors could be used to treat insulin resistance and type II diabetes linked to obesity.36 His team has studied the molecular mechanisms behind the reduced mitochondria seen in type II diabetics, linking adiponectin effects to increased activity of the sirtuin SIRT1.37 Mouse experiments suggest that a calorie restricted diet 38 or a EPA/DHA rich omega-3 diet39 can increase blood levels of adiponectin.