Can Two Dozen Marginal Ways to Treat Aging be Combined into One Useful Therapy?

Comparatively little work on combinations of therapies takes place in the research community. I suspect this to be a matter of regulatory incentives. For example there is little room for commercial entities to be able to make money by combining established treatments owned by other entities. Similarly for researchers, the world of possible approaches is balkanized by intellectual property, while the disposition of the majority of research funding is ultimately guided by the promise of a pot of gold at the end of the road. That pot of gold is much harder to obtain when someone else owns the therapies involved, and all that is being done is to apply them together. The edifice of intellectual property is a great evil, and this is one of many reasons why that is the case. Given this long-standing state of affairs, there is at present little data to guide our expectations on the bounds of the possible when it comes to combining large numbers of therapies in search of additive and synergistic effects. Some people think that we should forge ahead in the matter of slowing aging: take every intervention with good evidence to date, and run large numbers of them in the same mice to see what happens. Should we believe that various ways of manipulating the operation of cellular metabolism demonstrated to achieve 5-10% life extension in mice can combine to double life span in that species? Intuition suggests not, but I don't think it to be completely out the question. Nor is it unreasonable to try it and see, given a rigorous approach to experimental design. Sadly, no established funding institution would go for this; it would have to be funded through philanthropy. Why do I think that this is unlikely to produce large enough results to make it worthwhile? Because the evidence to date strongly suggests that the scores of methods of manipulating metabolism to modestly slow aging are operating on just a few core processes, such as autophagy. These are the stress responses that produce the lengthening of life observed in calorie restriction, and we know that these mechanisms don't produce anywhere near the same degree of life extension in humans as they do in short-lived species. Everything is connected to everything else in cellular biochemistry. A given interaction between two proteins can be influenced by adjusting levels of any number of other proteins, with widely varying degrees of effectiveness and side-effects. So most methods of slowing aging are different views into the same mechanism of action. The few combinations of approaches tried to date, involving only two methods, have resulted in mixed outcomes. Calorie restriction and mTOR inhibition may be additive, while growth hormone receptor knockout and mTOR inhibition interfere with one another, for example. That gives little insight as to the rest. It is hard to predict other results, beyond noting that a majority of interventions do appear to function through enhanced autophagy, and thus we might expect them not to combine in an additive way to any great degree. What of the SENS rejuvenation biotechnology approach to aging, in which independent fundamental forms of cell and tissue damage are repaired? How will repair therapies combine? In this case we should expect additive effects: removing damage should be beneficial in proportion to the amount removed, at least when considered from a fundamental, reliability theory perspective. The mortality risk and longevity of a complex system of many redundant parts is dependent on its current load of damage. At this point we have no idea as to how that will turn out in practice, however. The contributions of different forms of damage may be significantly larger or smaller than one another. The results of two independent root cause forms of damage are not themselves independent: they interact, and probably significantly. Functional decline in one system spurs greater damage and functional decline in others, which is why age-related degeneration accelerates greatly in later life. It is a complex business. It isn't unreasonable to think that in some circumstances the results of rejuvenation therapies A and B will be indistinguishable from A alone, or that B will never achieve a great deal without being combined with C. Can we envisage a world in which repairing cellular senescence alone produces no extension to life span because other, largely independent chains of damage and consequence are still life-limiting for old humans? That is becoming increasingly hard given the evidence to date for reversal of numerous age-related diseases to result from removal of senescent cells, not to mention the PAI-1 mutants who exhibit increased life span - but we know far more about senescent cell clearance than we do about any of the other SENS strategies. No-one is in a position to do more than make educated guesses about the results of combining senescent cell destruction with removal of mitochondrial DNA damage, or with clearance of specific lysosomal aggregates. Beyond "two should be better than one, but perhaps not in some specific cases" everything else will remain a mystery until the biotechnology is ready and the work is carried out. Making predictions seems a fool's game, given the degree to which the people closest to senescent cell research have been surprised by the scope and size of benefits observed in mice over the past few years.

https://www.fightaging.org/archives/2018/02/can-two-dozen-marginal-ways-to-treat-aging-be-combined-into-one-useful-therapy/

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A Few Recent Advances in Tissue Engineering and Regenerative Medicine

The tissue engineering and regenerative medicine communities are too large and energetic to do more than sample their output, or note the most interesting advances that stand out from the pack. The publicity materials I'll point out here are a recent selection of items that caught my eye as they went past. Dozens more, each of which would have merited worldwide attention ten or fifteen years ago, drift by with little comment every year. The state of the art is progressing rapidly towards both the ability to build complex tissues from a cell sample, such as patient-matched organs for transplantation, and the ability to control regeneration and growth inside the body. Ultimately we may not need transplantation if native organs can be persuaded to repair themselves ... but this will likely also require significant progress towards repairing the cell and tissue damage of aging, the forms of molecular breakage that degrade regenerative capacity. Even though the research community has progressed a long way past the capabilities of even a decade ago, there remains a longer road ahead. Transplants of cell populations are still very challenging; only a small fraction of those cells survive to take up residence and contribute over the long term. The best technology demonstrations manage 10% survival or thereabouts. Standard approaches to finding the best methodology for each cell type and situation have yet to arise. There is a lot of trial and error. Yet replacement of cell populations, reliably, and with high quality, youthful, undamaged cells, is needed to treat many of the consequences of aging. Consider the loss of dopamine-generating neurons in Parkinson's disease, for example, or the wearing down of the stem cell population responsible for generating the immune system, or the structural remodeling and weakening of the heart in response to hypertension. Removing the damage that caused those issues will not automatically restore all of the losses. Researchers report first lung stem cell transplantation clinical trial For the first time, researchers have regenerated patients' damaged lungs using autologous lung stem cell transplantation in a pilot clinical trial. In 2015, the researchers identified p63+/Krt5+ adult stem cells in a mouse lung, which had potential to regenerate pulmonary structures including bronchioles and alveoli. Now they are focusing on lung stem cells in humans rather than mice. The researchers found that a population of basal cells labeled with an SOX9+ marker had the potential to serve as lung stem cells in humans. They used lung bronchoscopy to brush off and amplify these lung stem cells from tiny samples. In order to test the capacity of lung stem cells to regenerate lung tissue in vivo, the team transplanted the human lung stem cells into damaged lungs of immunodeficient mice. Histological analysis showed that stem cell transplantation successfully regenerated human bronchial and alveolar structures in the lungs of mice. Also, the fibrotic area in the injured lungs of the mice was replaced by new human alveoli after receiving stem cell transplantation. Arterial blood gas analysis showed that the lung function of the mice was significantly recovered. The team launched the first clinical trial based on autologous lung stem cell transplantation for the treatment of bronchiectasis. The first two patients were recruited in March 2016. Their own lung stem cells were delivered into the patients' lung through bronchoscopy. One year after transplantation, two patients described relief of multiple respiratory symptoms such as coughing and dyspnea. CT imaging showed regional recovery of the dilated structure. Patient lung function began to recover three months after transplantation, which maintained for one year. Scientists create functioning kidney tissue Kidney glomeruli - constituent microscopic parts of the organ - were generated from human embryonic stem cells grown in plastic laboratory culture dishes containing a nutrient broth known as culture medium, containing molecules to promote kidney development. They were combined with a gel like substance, which acted as natural connective tissue - and then injected as a tiny clump under the skin of mice. After three months, an examination of the tissue revealed that nephrons: the microscopic structural and functional units of the kidney - had formed. Tiny human blood vessels - known as capillaries - had developed inside the mice which nourished the new kidney structures. However, the mini-kidneys lack a large artery, and without that the organ's function will only be a fraction of normal. So, the researchers are working with surgeons to put in an artery that will bring more blood the new kidney. "We have proved beyond any doubt these structures function as kidney cells by filtering blood and producing urine - though we can't yet say what percentage of function exists. What is particularly exciting is that the structures are made of human cells which developed an excellent capillary blood supply, becoming linked to the vasculature of the mouse. Though this structure was formed from several hundred glomeruli, and humans have about a million in their kidneys - this is clearly a major advance. It constitutes a proof of principle - but much work is yet to be done." New tissue-engineered blood vessel replacements closer to human trials Researchers have created a new lab-grown blood vessel replacement that is composed completely of biological materials, but surprisingly doesn't contain any living cells at implantation. The vessel, that could be used as an "off the shelf" graft for kidney dialysis patients, performed well in a recent study with nonhuman primates. It is the first-of-its-kind nonsynthetic, decellularized graft that becomes repopulated with cells by the recipient's own cells when implanted. The researchers generated vessel-like tubes in the lab from post-natal human skin cells that were embedded in a gel-like material made of cow fibrin, a protein involved in blood clotting. Researchers put the cell-populated gel in a bioreactor and grew the tube for seven weeks and then washed away the cells over the final week. What remained was the collagen and other proteins secreted by the cells, making an all-natural, but non-living tube for implantation. To test the vessels, the researchers implanted the 15-centimeter-long (about 5 inches) lab-grown grafts into adult baboons. Six months after implantation, the grafts grossly appeared like a blood vessel and the researchers observed healthy cells from the recipients taking up residence within the walls of the tubes. None of the grafts calcified and only one ruptured, which was attributed to inadvertent mechanical damage with handling. The grafts after six months were shown to withstand almost 30 times the average human blood pressure without bursting. The implants showed no immune response and resisted infection.

https://www.fightaging.org/archives/2018/02/a-few-recent-advances-in-tissue-engineering-and-regenerative-medicine/

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Opioid makers gave millions to patient advocacy groups to sway prescribing

?These financial relationships were insidious, lacked transparency, and are one of many factors that have resulted in arguably the most deadly drug epidemic in American history," said U.S. Sen. Claire McCaskill, who released the report.

https://www.statnews.com/pharmalot/2018/02/12/opioids-patient-groups-funding/

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