2016 Conferences on AgingApril 2017
By Ben Best
Aging is damage to tissues and organs that accumulates with time.
There is no single cause of aging, because there are many sources of damage and many kinds of damage. There may be, however, ways to address many of these causes with perhaps one or more therapies.1
Inflammatory factors in the bloodstream increase with age. This chronic inflammation is a cause of cancer and damage to organs and tissues. A major source of this inflammation is cells that cease dividing, a condition known as cellular senescence. Senescent cells secrete inflammatory cytokines, cancer-inducing growth factors, and other harmful substances.
Cellular senescence is caused by DNA damage, shortened chromosome ends (telomeres), and other factors. Cellular senescence and inflammation can result in stem cells ceasing to function. Healthy stem cells heal injuries and replace worn-out cells in the intestines, the skin and the blood (including the white blood cells that provide immunity).2
In 2016, I attended several conferences dealing with aging. In contrast to earlier conferences, I was impressed by how much researchers are now not only discovering new causes of aging or means to slow it, but are also finding ways to reverse aging and significantly extend mammalian life spans.
Interventions Testing Program
Randy Strong, PhD (professor of pharmacology, University of Texas Health Science Center, San Antonio) is one of the Directors of the National Institute on Aging’s Interventions Testing Program (ITP). The ITP tests potential anti-aging substances on mice at three independent laboratories: the University of Texas, the University of Michigan, and the Jackson Laboratory in Maine.3,4
The ITP has been able to report lifespan benefits for a number of substances, but often these were effective only in male mice. Median (but not maximum) lifespan was increased for males by 12% with the antioxidant (nordihydroguaiaretic acid),5 by 8% with aspirin,5 and by 7% using a proprietary blend of milk thistle, bacopa, ashwagandha, green tea, and turmeric extracts.6
Interestingly, an estrogen (17-alpha-estradiol) increased median lifespan by 19% and maximum lifespan by 12% in male mice.6
The antidiabetic drug acarbose increased male mouse median lifespan by 6% and maximum lifespan by 12%, most likely by reducing the amount of glucose absorbed into the bloodstream.6
For female mice, acarbose increased median lifespan by 2% and maximum lifespan by 6%.6
ITP showed rapamycin increased median and maximum lifespan in both male and female mice.7 Insulin resistance and impaired glucose tolerance are associated with poor health and reduced lifespan. Rapamycin has these side effects.8 The combination of metformin and rapamycin increased median lifespan by 23% in both male and female mice.6
Rapamycin as an Anti-Aging Drug
Matt Kaeberlein, PhD (professor of pathology, University of Washington, Seattle) wants to validate rapamycin as an anti-aging drug. In 2009, rapamycin was shown to increase median and maximal lifespan of mice when given at 20 months of age (about equivalent to the age of a 60-year-old human).7 No additional lifespan extension was seen by beginning the rapamycin at 9 months of age, and the earlier (more lengthy) dosing increased the incidence of cataracts and testicular degeneration.9 A three-fold increase in the dose of rapamycin, however, approximately doubled the lifespan extension of 9-month-old mice.10
Rapamycin reduces inflammation, especially in the heart,11,12 and inhibits cells from becoming senescent.13 Rapamycin increases cognitive function in mice.14 A rapamycin-like drug improved the response to influenza vaccination in elderly humans.15
Dr. Kaeberlein’s team showed that a 3-month rapamycin treatment of 20-month-old mice could increase life expectancy by at least 50%.16 Although this experiment indicates that brief exposure (in human time frame) to rapamycin in elderly mice could have substantial long-term benefit, the required dosing period for humans to show a comparable benefit would probably be considerably longer.17
Dr. Kaeberlein believes that substantial benefit without serious side effects can result from large doses of rapamycin given for brief periods.18 He maintains that this prospect is best tested in middle-aged large companion-animal (pet) dogs, because these dogs age about seven times more rapidly than humans.19 He has been actively recruiting owners of pet dogs for participation in this research using the website dogagingproject.com
Sirtuins and NAD+ for Rejuvenation
David Sinclair, PhD (professor in the Department of Genetics at Harvard Medical School and co-director of the Paul F. Glenn Center for the Biological Mechanisms of Aging, Boston, Massachusetts) has been a pioneer in studying the sirtuin anti-aging proteins, as well as substances that activate those proteins (such as resveratrol).20
Sirtuin activators that are hundreds of times more powerful than resveratrol increase insulin sensitivity, and have therefore been proposed as a treatment for type II diabetes.21 Powerful sirtuin-activators have also been shown to improve the general health and lifespan of mice fed a normal diet.22 Sirtuins can rejuvenate cells by stimulating the recycling of damaged cellular components (autophagy).23
Sirtuins require the substance NAD+ to function. Sirtuins are important for DNA repair and for efficient function of the energy-producing cellular organelles, mitochondria.24
NAD+ declines with age because an enzyme in inflammatory cells that destroys NAD+ increases with age.25 Reducing inflammation, inhibiting the inflammatory enzyme, and replacing NAD+ by supplementing with substances (such as nicotinamide riboside) that lead to NAD+ formation, can restore the benefits of sirtuin and NAD+ (improved insulin sensitivity, mitochondrial function, and DNA repair).25 Moreover, NAD+ restoration rejuvenates stem cells, improving the regenerative capacity of organs and tissues.26
Two-Year Study of Calorie Restriction in Normal Humans
Evan Hadley, MD (Director of the Division of Geriatrics and Clinical Gerontology, National Institute on Aging, Bethesda, Maryland) reported on the two-year clinical trial conducted by the National Institute on Aging to determine the effects of calorie restriction on healthy, non-obese adults between the ages of 21 to 50.
Calorie restriction with adequate nutrition (CR) has been shown to increase health and lifespan in a wide variety of organisms, but the benefits have been difficult to prove for humans.27
Subjects in the clinical trial were volunteers randomized to either eat normally or restrict calories by 25%. Average body mass index (BMI) for the subject was 25.1 (on the border between normal and overweight). 218 volunteers began the study, with 82% of the CR group and 95% of the normally eating group completing the two-year study.28
The CR group was able to reduce calories by 19.5% during the first six months, but only by an average of 9.1% for the following 18 months.28 The CR group showed significant reduction of blood cholesterol, triglycerides, and TNF-alpha (an inflammatory protein).28 The stress hormone cortisol was only elevated for the first year.29 The study showed improved quality of life and no harmful outcomes for those in the CR group.30,31
Elimination of Senescent Cells for Rejuvenation
Norman Sharpless, MD (professor of medicine & genetics, University of North Carolina) is concerned with how senescent cells contribute to aging, and with means to eliminate senescent cells. Senescent cells cease dividing due to various defects, including short telomeres. Senescent cells produce inflammatory factors which can trigger their removal by the immune system.2
With age, the immune system becomes increasingly incapable of removing senescent cells, which become a major source of chronic inflammation.32 Chronic inflammation can lead to cancer.33 Senescent cells impair the function of the tissues and organs in which they occur.34 These cells have been shown to accelerate aging in mice (reducing health and shortening lifespan).35
To eliminate senescent cells requires differentiating them from healthy cells in tissues. Unfortunately, there are no markings that are consistently specific to senescent cells as opposed to healthy ones.36
Dr. Sharpless has focused his attention on a protein called p16, which is often seen on senescent cells. He has found that p16 in human body cells increases tenfold over 60 years of adult aging.37 He has found that increased p16 is seen in many aging-associated diseases, including atherosclerosis, diabetes, neurodegeneration, frailty, cancer, and cataracts,38 and that p16 indicates reduced stem cell function.39
Dr. Sharpless has shown increased p16 in smokers40 and patients receiving chemotherapy.41
Injecting mice with a drug that eliminates cells having p16 has been shown to improve function of many organs, including kidney and heart, while increasing lifespan.34 Upregulation of anti-apoptotic proteins is often seen in senescent cells. Targeting cells by inhibiting anti-apoptotic proteins has also been shown to eliminate senescent cells in mice.42
Using the herbal product quercetin and the anticancer drug dasatinib for targeting yet other (non-p16) features of senescent cells has been shown to eliminate senescent cells in mice, improving function in the heart and blood vessels.43
Telomere Lengthening for Rejuvenation
Maria Blasco, PhD (director, Spanish National Centre for Cancer Research, Madrid, Spain) is one of the world’s foremost authorities on the role of telomeres in cancer and aging. Her pro-life extension attitude can be seen in her recent Spanish-language book for laypeople: Dying Young at 140.
Telomeres are repeating DNA sequences that protect the ends of chromosomes the way the caps of shoelaces prevent the laces from fraying. Telomeres shorten each time a cell divides. When telomeres have become too short, the cell usually dies or becomes senescent. Longer telomeres can indicate good health.44
People with short telomeres or high rates of telomere shortening have triple the rate of death from cardiovascular disease.45 People over age 100 with longer telomeres have better cognitive function and fewer age-related diseases.46
Telomeres are lengthened by the enzyme telomerase, which is very active early in fetal development, but absent in most adult cells, the exception being stem cells, where some telomerase is present. But even in stem cells, telomerase activity is inadequate to maintain telomere length.44
Short stem cell telomeres result in insufficient replacement of blood cells,47 brain cells,48 and many other tissues.
Dr. Blasco believes that telomere shortening is a major cause of aging,49 because of loss of stem cell function, loss of cells, increased numbers of senescent cells, and the inflammation produced by senescent cells.50 But she also believes that aging due to telomere loss is reversible.51
Most cancer cells become immortal (prevent themselves from aging) by activating telomerase, and the severity of the cancer often corresponds to the amount of telomerase activity.52
Dr. Blasco’s research team achieved a 24% increase in the lifespan of one-year-old mice by delivering a telomerase gene using a virus that does not incorporate the gene into chromosomes.53 There was no increase in cancer.53 Her team has also used the virus to deliver telomerase genes to increase survival of mice suffering from aplastic anemia,54 and of mice who have suffered a myocardial infarction (heart attack).55
Factors from Young Blood to Rejuvenate the Elderly
Thomas Rando, MD, PhD (professor of neurology, Stanford University Medical Center, Stanford, California) supervised a landmark 2005 study which joined the circulatory system of young and old mice (parabiosis).56
The parabiosis experiment showed that the blood of young mice rejuvenated muscle stem cells in old mice, enhancing muscle regeneration after injury.56 But in the young mice, the stem cells lost some of their regenerative potential from exposure to “old” circulating blood.57
One of the students at the time conducting that experiment (Irina Conboy) later showed that the social bonding hormone oxytocin declines with age and contributes to muscle stem cell rejuvenation in old mice.58 She also showed that the growth factor TGF-beta produced by old muscle cells inhibits muscle stem cell function.59
Another student at the time who had participated in the breakthrough 2005 parabiosis study (Amy Wagers) later showed that the growth factors GDF11 and GDF8 (myostatin) decline with age and rejuvenate old mice when administered to them.60
Dr. Rando himself went on to show that repeated injections of young blood plasma improve cognitive function in old mice.61 He also showed that inflammatory factors in the blood that increase with age, such as CCL11 caused reduction in stem cell activity.62
Proposed Clinical Trial with Young Blood Factors
Dipnarine Maharaj, MD (medical director, South Florida Bone Marrow/Stem Cell Transplant Institute, Boynton Beach, Florida) believes that increasing chronic inflammation as a consequence of aging causes decreasing function of stem cells, thereby impairing the function of bodily organs and tissues.
A study of elderly adults showed that high levels of chronic inflammation were highly predictive of low cognition, low bodily function, and a higher likelihood of impending death.63 Most of the aging-related diseases (cancer, heart disease, stroke, Alzheimer’s disease, arthritis, diabetes, etc.) are associated with chronic inflammation.64
Impairment of stem cell function reduces the ability of body tissues and organs to heal wounds and prevent impaired function due to cell depletion.65 Elderly people become frail not only with respect to weak muscles and bones, but because of a frail brain, frail hormonal system, and frail immune system.66
Adjoining the circulatory system of young mice to old mice (parabiosis) has shown rejuvenation of the old mice due to blood components of the young mice restoring stem cell function in the old mice.67
Dr. Maharaj wants to conduct clinical trials that demonstrate rejuvenation of elderly humans by infusion of stem cell-mobilized plasma from young, healthy humans. He has patented the procedure he would use in these clinical trials (patent 2014/0336443).
His procedure involves stimulating bone growth with oscillating magnetic fields, mobilizing stem cells from young donors by administering G-CSF (granulocyte-colony stimulating factor),68 infusing plasma (not blood cells) containing growth factors mobilized by the G-CSF from the young donors into elderly subjects, and then assessing the youthfulness of the elderly subjects using eight biomarkers. The biomarkers include measures of inflammation, insulin sensitivity, telomere length, etc.
A Method to Evaluate Rejuvenation Therapies
Steve Horvath, PhD, ScD (professor, Human Genetics and Biostatistics, University of California, Los Angeles) has noticed that the addition of methyl groups to DNA increases with age (a process known as epigenetic change). Analyzing 7,844 samples of healthy human tissues, he developed a method of estimating chronological age that is 96% correct.69 Dr. Horvath believes that his method could be useful in evaluating rejuvenation therapies.69
His method demonstrates accelerated aging in HIV infection,70 Parkinson’s disease,71 Down’s syndrome,72 and obesity.73 His method also predicts impending death from any cause.74
Applying his method to the offspring of persons close to 105 years of age, he found the offspring to have an “epigenetic age” about five years younger than age-matched controls.75-77
Based on these findings, we appear to be on the verge of breakthrough methods of rejuvenating human beings.
Sadly, vastly more money is spent on various forms of entertainment than on research to develop these methods.
There are currently initiatives to raise money for this research by the SENS Foundation, Age Reversal Therapeutics, Inc., and other organizations.
Life Extension supporters are encouraged to donate or invest in these organizations for the sake of their health, their longevity, and their survival, and the health, longevity, and survival of their loved-ones.
- Life Extension Foundation. Research Update. March 2017.
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