The Methuselah Foundation and SENS Research Foundation have sent around the latest edition of the Rejuvenation Biotechnology Update, highlighting and explaining a few of the more interesting research results of recent months. It is a quarterly newsletter for members of the Methuselah 300, a more than decade-old group of advocates and supporters who each pledge to donate $25,000 over 25 years to help fund the development of therapies to treat aging. The first of the 300 helped to launch the Methuselah Foundation, and their continued support drew in the funding needed to eventually spin off the SENS Research Foundation as its own venture. While it was just thirteen years ago that the 300 was first mentioned, a lot has happened since then. Tempus fugit.
Only thirteen years, yes, but for me that seems like a long time past. Back then advocates for longevity science were few in number, working so very hard to raise a few thousand dollars here and a few thousand dollars there, while being roundly mocked for declaring that aging should and could be treated as a medical condition when people did deign to pay attention. How far we've come since then! The entire environment has changed, the attitudes of the scientific establishment are remade, the concept of medicine to address aging is discussed in the media on a regular basis, available funding is greatly multiplied, and the first SENS rejuvenation therapies are moving towards the clinic. There is a still a long way to go yet towards the goal of defeating aging and all age-related disease, but the beginning has been written and done: we have now entered into the next phase.
Transplanted Senescent Cells Induce an Osteoarthritis-Like Condition in Mice.
This study provides evidence that adding senescent cells to a healthy joint can create a constellation of symptoms that resemble osteoarthritis. It is an important step in linking cellular senescence and osteoarthritic joint damage. However, the "smoking gun" that would really implicate senescent cells as a clinically-relevant target for osteoarthritis treatment would be to demonstrate that using senolytic drugs or genetic approaches to remove senescent cells from the joint of an animal with osteoarthritis leads to an improvement in osteoarthritis symptoms and the restoration of joint structure and function. Furthermore, the authors acknowledge that senescent cells may be one cause or a contributor to osteoarthritis, but osteoarthritis may also have other causes or contributing factors (such as chronic inflammation from other causes, mitochondrial dysfunction, and loss of glycosaminoglycans). So, we remain vigilant about the potentially-significant role of senescent cells is in the development of osteoarthritis.
Given that it is becoming increasingly clear that senescent cells significantly contribute to an overall phenotype of age-associated disease and dysfunction, these results are a promising step in the direction of implicating senescent cells as a therapeutic target for osteoarthritis. These findings no doubt hearten our colleagues at UNITY Biotechnology, who have identified osteoarthritis as their first target for senolytic drug therapy. Research on clearance of senescent cells as a strategy to correct aging damage is a high priority to SENS Research Foundation and Methuselah Foundation. Fortunately, this field seems to be advancing significantly and rapidly in the last few years. The company Oisín Biotechnologies (partially funded by SENS Research Foundation and Methuselah Foundation) is pursuing a "transient" (non-integrating) genetic approach to target and remove senescent cells from human bodies.
A single heterochronic blood exchange reveals rapid inhibition of multiple tissues by old blood.
This study represents an important advancement in technology to study blood-borne factors associated with youth and aging. It also contributes important findings that isolate the effect of blood-borne factors on tissue functions and injury repair in the context of aging. The authors anticipated that when the effects of blood alone were isolated, the findings would more relevant to human clinical applications. Some key findings from this study were that, at least when it came to neurogenesis, old blood seemed to inhibit neurogenesis more in young mice than young blood rejuvenated the brains of old mice. This would seem to implicate a greater increase in pro-aging factors, compared to the decrease in anti-aging factors, with age. This finding of old blood inhibiting neurogenesis in the hippocampus may be linked with the observed increase in β-2 microglobulin in young mice who received old blood, which occurred in the brain and muscle. However, the exact mechanism by which β-2 microglobulin levels came to be elevated in young mice who received old blood is still not clear. If it could be clarified, perhaps a potential therapeutic target or targets could be identified to lower β-2 microglobulin and other pro-aging factor levels in aged individuals.
One especially encouraging finding from this study was, as the authors put it, "the plasticity of age" - the observation that changes in tissues took place rapidly and old tissues were restored to a more youthful state within days of when blood exchange took place. And, unlike parabiosis experiments, a therapeutic approach based on blood exchange or blood filtration would be feasible in humans. Exchange transfusion is already an established treatment for several human autoimmune diseases where diluting auto-antibodies out of the circulation is beneficial, and exchange transfusion devices are currently available and FDA-approved for treatment of these diseases. Similarly, hemodialysis is a well-established procedure, and a more selective device that would scrub old blood of excessive "pro-aging" factors could extend this paradigm. The investigators in this study are looking to develop their findings into a clinical application for human patients soon: a startup company founded by a colleague is now preparing a clinical trial to adapt existing medical equipment test this very possibility in aging humans.
Vestibular Perceptual Thresholds Increase above the Age of 40.
The vestibular system in humans senses body motion and positioning of the body in space. The vestibular apparatus in the inner ear consists of a fluid-filled organ lined with sensing cells. The study found that after age 40, in both males and females, vestibular function steadily declined: vestibular perceptual thresholds increased; that is, the older a person gets, the more movement it takes for them to detect a change in position. According to the CDC, 1 out of 4 older Americans falls each year. In older individuals, falling is strongly associated with serious injuries and death. In fact, falls are the leading cause of injury and death from injury in Americans over age 65. The major factors for avoiding falls are functional balance and leg strength. The vestibular system plays a critical role in balance. So, understanding age-related declines in vestibular function may reveal critical insights into how to maintain balance and prevent falls.
Unfortunately, the major thing missing from this study was the identification of a mechanism for the decline in vestibular function after approximately age 40, and evidence supporting the identification of this mechanism. Several other studies have measured the number of vestibular hair cells (sensory cells) at various ages and showed a steady decline every year since birth. At first glance, this data does not seem to fit with the observation that vestibular function only starts to decline after age 40, this may be a case of a common phenomenon in aging that Dr. Aubrey de Grey has referred to as the "threshold of pathology." That is, humans may have enough vestibular hair cells so as to be redundant before age 40. Beyond that age, they may have lost enough cells that vestibular function starts to be affected as more cells die off. The authors speculate that free radical damage may be responsible for the death of vestibular hair cells with age, and further that vestibular function may serve as a reliable marker for the level of aging damage an individual has incurred, which can be measured noninvasively by simply testing vestibular function as they did in the current study.
Although the authors do not have experimental evidence that free radical damage is responsible for declining vestibular function with age, there is a range of evidence supporting the involvement of mutations in mitochondrial DNA and of mitochondrial free radical generation in vestibular damage from other causes. Vestibular damage is a major side-effect of the antibiotic gentamycin and others in its class, and free radicals are thought to be one of the mechanisms. Moreover, people with specific mutations in mitochondrial genes that code for the organelles that assemble proteins that are components of the mitochondrial energy production machinery are unusually vulnerable to this toxicity. Mice with a mutation that prevents the building of one of the complexes of the mitochondrial energy-production line develop vestibular damage, and human patients with the mitochondrial mutation disease Kearns-Sayre syndrome frequently have vestibular dysfunction as one of the many effects of the disease.
One way to address the rise in free radical damage with age is to prevent it at the source. This is the strategy behind SENS Research Foundation's "MitoSENS" program. Briefly: mitochondria in a subset of cells acquire large deletions in their DNA as individuals age, and the abnormal metabolic activity that cells harboring such mitochondria undertake results in a rise in oxidative stress in the body. To fix this problem, mitochondrial genes should be stably expressed in the cell nucleus instead of in the mitochondria, where these genes are more easily damaged. The strategy of MitoSENS is to fix the source of the damage: the inability of these dysfunctional mitochondria to generate the proteins they need to carry out normal metabolism with lower free radical production. If vestibular function is indeed connected to the rise of cells that have been taken over by mitochondria bearing such deletions and creating additional free radicals, this would enhance the value of the goals of the MitoSENS project, which could provide the benefit of preserving vestibular function and prevent the common, dangerous, and deadly scourge of falls.