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- Just How Dynamic are Cellular Senescence Levels in Old Tissues?
- Cardiac Muscle Cell Therapy Improves Function after Heart Attack in Monkeys
- Prevention of Harmful Astrocyte Activation as a Therapy for Parkinson's Disease
- Can the Top-Down Institutional Approach Promote the Right Sort of Research and Development to Treat Aging?
- The Humble Axolotl and the Quest for Human Organ Regeneration
- Using Age-Related Gene Expression Changes to Search for Drugs to Slow Aging
- A View of Commercial Efforts in Organ Bioprinting and Recellularization
- Chronic Inflammation Correlates with White Matter Damage in the Aging Brain
- Aspirin Enhances Autophagy to Reduce Amyloid in Mouse Models of Alzheimer's
- Adjusting Macrophage Polarization as a Basis for Cancer Immunotherapy
- The Longevity Film Competition, Advocacy for Rejuvenation Research
- Metformin Shown to Attenuate Lung Fibrosis in Mice
- Differences in Macrophage Polarization Between More Healthy and Less Healthy Elders
- Reducing Levels of All Pathological Protein Aggregates Should be a Primary Strategy for Treating Neurodegeneration
- Biomedical Engineering in Medicine and Aging
Just How Dynamic are Cellular Senescence Levels in Old Tissues?
Accumulation of senescent cells is one of the root causes of aging. Based on the comparatively few measures established in old tissues, the proportion of cells that are senescent does not rise to more than a few percent of all cells even in very old individuals. That few percent is enough to wreak havok, however. Senescent cells actively secrete a mix of signals that promote chronic inflammation, destructively remodel tissue structure, and change the behavior of surrounding cells for the worse. They are harmful enough to be a significant direct contribution to many age-related diseases. Data exists for their baleful influence to produce osteoarthritis, fibrosis of the lung and other organs, and many other conditions.
Given all of this, there is considerable enthusiasm for the development of means to selectively destroy these cells: small molecule senolytic drugs, immunotherapies, and suicide gene therapies are all under development, the first now in human trials. Interestingly, despite some years of this active development, the ability to accurately and usefully measure the count and life span of senescent cells in tissue has lagged behind. There are methods that work well enough in animal studies, but few approaches that are useful in human medicine, and none of them are yet widely used. So there is really very little data on the degree to which senescent cell counts rise and fall over time, in response to environmental circumstances. All that is known for certain is that old people have more senescent cells. Are those senescent cells lasting for years? Are they created at a small rate and linger for decades? Is there are a rapid turnover in most tissues, and the increasing number is a function of dysfunction in the processes of removal?
In this context, the research reported in the open access paper here is most interesting. The authors show quite large short-term variations in cellular senescence in muscle tissue in response to strength training in young people. Even given the youth of the subjects, taken on its own it suggests a cautious reevaluation of the idea that all senescent cells accumulate slowly and last for a long time, and thus that senolytic therapies would have to be undertaken only infrequently. (Not to mention posing the question of how much of the way in which strength training improves health in older individuals is due to eliminating senescent cells).
Yet this must be balanced with the established evidence for significant lasting benefits to result from a single senolytic treatment in mice, which seems only possible if senescent cells arrive at a slow rate and linger for a long time following creation. It is possible that there are different populations and types of senescent cells, some dynamic, some not. It is also possible that the standard senescent markers show up in cells that are not senescent in some circumstances. It is likely that senescence dynamics are quite different in different tissue types. Whatever the answers, it seems clear that assessment of senescent cell counts and dynamics is overdue a greater level of attention.
Aged cells in human skeletal muscle after resistance exercise
Most of the cells in the human body are continuously aging, dying and regenerating to gradually evolve a fairly stable size of multicellular system with a wide range of cell ages. Skeletal muscle is the largest tissue of the human body, in which cell lifespan varies considerably among different cell types. For example, myofibers are long-lived, whereas endothelial cells in capillary surrounding myofibers age rapidly with a short half-life around 2 weeks. Selective elimination of senescence cells in skeletal muscle and other tissues has been shown to increase lifespan in mice, suggesting a promising approach for anti-aging intervention. The protein p16Ink4a, a cyclin-dependent kinase inhibitor CDKN2A, is a widely used senescence marker expressed specifically in aged cells. However, p16Ink4a+ senescence cells in human skeletal muscle are rarely studied. It is currently unclear whether senescent cells are accumulated in human skeletal muscle at young age and whether exercise has significant influence on its number.
Senescent cells can be selectively recognized and rapidly cleared by phagocytic macrophages. One way to direct macrophages into skeletal muscle is resistance exercise. After weight loading, phagocytic macrophages (M1 phenotype) infiltrated into damaged sites, followed by protracted presences of regenerative macrophages (M2 phenotype). The cell turnover process instantly demands nitrogen sources from amino acids or proteins for nucleotide synthesis and DNA replication. A delayed protein supplementation after resistance training can significantly undermine muscle hypertrophy, suggesting a far-reaching impact of protein availability in time around exercise challenge on long-term muscle adaptation. It remains uncertain whether protein availability influences macrophage presences and senescent cell clearance in exercising skeletal muscle.
In this study, senescent cell distribution and quantity in vastus lateralis muscle were examined in young human adults after a single bout of resistance exercise. To determine the effects of dietary protein availability around exercise on senescent cell quantity and macrophage infiltration of skeletal muscle, two isocaloric protein supplements (14% and 44% in calorie) were ingested before and immediately after an acute bout of resistance exercise, in a counter-balanced crossover fashion. An additional parallel trial was conducted to compare the outcome of muscle mass increment under the same dietary conditions after 12 weeks of resistance training.
The main findings of the study are as follows: 1) No senescent myofibers are detected in the skeletal muscle of young men aged between 20-25 y; 2) Most of the senescent cells found around muscle fibers are endothelial progenitor cells; 3) A single bout of resistance exercise reduces the senescent endothelial progenitor cells by 48% in challenged muscle and maintains at low levels for 48 hours; 4) Resistance exercise with low protein availability is associated with greater increases in macrophage infiltration and further depletion of senescent endothelial progenitor cells in muscle tissue during recovery, but prevents muscle hypertrophy for a long term. Taken together, these data suggest that senescence cell clearance and muscle mass increment are associated with the magnitude of muscle inflammation after resistance exercise, which can be influenced by protein supplementation around exercise.
Cardiac Muscle Cell Therapy Improves Function after Heart Attack in Monkeys
Cell therapies are thought to have great promise as a way to help repair damaged tissue that will not normally regenerate to any great degree. When it comes to the heart, and following nearly two decades of stem cell and other therapies tested in trials and via medical tourism, the research community is still in search of a reliable, highly effective methodology. Work in the laboratory continues, and researchers have recently reported improvement in heart function following heart attack in Southern pig-tailed macaques.
The approach used here involves generating a sizable cell population of cardiomyocytes, heart muscle cells, from embryonic stem cells. Those cells are then introduced into the heart directly, where a large enough proportion of them survive to produce long term reconstruction and some gain in function - not yet a path back to normal, but better than the alternative. The survival of the transplanted cells is the key to effective regenerative therapies: approaches using patches of lab-grown heart tissue in which there is sizable survival of cells following transplantation have also shown promise in heart repair. First generation stem cell therapies are less effective and reliable when it comes to tissue regrowth precisely because near all the cells die, and the benefits produced are mediated by signaling effects on native cells.
The heart is an organ in which the fine structure matters. Its muscle cells participate in an electrical communication network, ensuring that all beat in unison. If that network is disrupted by haphazard growth, then failure of function can result. Unfortunately, there are the first signs of that in this study. The challenge for heart regeneration is perhaps less that it is naturally one of the least regenerative organs, and more that regeneration must be achieved carefully. Other organs are less of a problem on this front, particularly those that are essentially chemical factories or cell nurseries, and their structure and even location isn't anywhere near as important as is the case for the heart or the brain.
Cardiac Cell Transplants Help Monkeys' Hearts
Injecting human cardiac muscle cells into monkeys that suffered heart attacks helped the animals' damaged hearts pump blood better, researchers report. The treatment is based on the reprogramming of human embryonic stem cells, and the results move the therapy a step closer to clinical trials. "We're talking about the number one cause of death in the world for humans. And at the moment all of our treatments are dancing around the root problem, which is that you don't have enough muscle cells."
When a heart attack goes untreated, blood is blocked from flowing to the heart, which leads to the death of heart muscle cells. There can also be scarring and heart failure - when the heart cannot pump enough blood to the body. In the study, after 9 monkeys were made to have heart attacks, their heart-pumping capacity dropped by more than 30 percent. Injecting 750 million cardiac muscle cells, derived from human embryonic stem cells, into the monkeys' hearts led to the growth of new heart muscle tissue. After four weeks, most monkeys' hearts showed improved pumping capacity, up to a third better than right after the heart attacks, and two monkeys had two-thirds of the lost capacity restored after 12 weeks.
However, some of the monkeys had irregular heartbeats after the cardiac cell transfusion. "That is a very important observation because now you can perhaps begin to design a strategy to get at what is happening. How can we prevent this from happening? That, to me, is the story of this paper."
Human embryonic stem cell-derived cardiomyocytes restore function in infarcted hearts of non-human primates
Pluripotent stem cell-derived cardiomyocyte grafts can remuscularize substantial amounts of infarcted myocardium and beat in synchrony with the heart, but in some settings cause ventricular arrhythmias. It is unknown whether human cardiomyocytes can restore cardiac function in a physiologically relevant large animal model. Here we show that transplantation of ∼750 million cryopreserved human embryonic stem cell-derived cardiomyocytes (hESC-CMs) enhances cardiac function in macaque monkeys with large myocardial infarctions.
One month after hESC-CM transplantation, global left ventricular ejection fraction improved 10.6 vs. 2.5 in controls, and by 3 months there was an additional 12.4% improvement in treated vs. a 3.5% decline in controls. Grafts averaged 11.6% of infarct size, formed electromechanical junctions with the host heart, and by 3 months contained ∼99% ventricular myocytes. A subset of animals experienced graft-associated ventricular arrhythmias, shown by electrical mapping to originate from a point-source acting as an ectopic pacemaker. Our data demonstrate that remuscularization of the infarcted macaque heart with human myocardium provides durable improvement in left ventricular function.
Prevention of Harmful Astrocyte Activation as a Therapy for Parkinson's Disease
Researchers have recently investigated means to interfere in on a one of the later consequences in neurodegenerative conditions, in which the supporting astrocyte cells in the brain become actively harmful to the neurons that they normally aid and protect. Astrocytes are triggered into this state at least in part by the inflammatory dysregulation of microglia, a class of innate immune cells of the central nervous system. Aging brings rising levels of chronic inflammation throughout the body, a consequence of processes such as the accumulation of senescent cells and malfunctioning of the immune system. The evidence clearly shows that this inflammation contributes to the progression of all of the common age-related conditions, and neurodegenerative diseases are no exception.
The focus in the research materials noted here is on Parkinson's disease, but the mechanism is more broadly applicable. All older individuals suffer to some degree from inflammation of the central nervous system, and the more of it there is, the worse off they are. Sabotaging one of the numerous consequences of this inflammatory state is better than nothing, but it isn't as good as finding ways to address the roots of the issue. In this case, that would be the causes of what has come to be known as inflammaging, the decline of the immune system into simultaneous incompetence and excess activity.
There are a number of strategies that could be pursued effectively today, even given the present poor state of knowledge of the precise cellular and biochemical details of later stage aging. Regeneration of the thymus and replacement of hematopoietic stem cells to restore a youthful supply of immune cells; clearance of the existing immune system to remove malfunctioning and maladapted cells; clearance of senescent cells to remove their inflammatory signals; and so forth. While some companies are working in these areas, all in all too little effort is being directed towards these and related strategies that are in principle capable of turning back immune aging.
Experimental Drug Stops Parkinson's Disease Progression in Mice
NLY01 works by binding to glucagon-like peptide-1 receptors on the surface of certain cells. Similar drugs are used widely in the treatment of type 2 diabetes to increase insulin levels in the blood. Though past studies in animals suggested the neuroprotective potential of this class of drugs, researchers had not shown directly how it operated in the brain. To find out, they tested NLY01 on three major cell types in the human brain: astrocytes, microglia, and neurons. They found that microglia, a brain cell type that sends signals throughout the central nervous system in response to infection or injury, had the most sites for NLY01 to bind to - two times higher than the other cell types, and 10 times higher in humans with Parkinson's disease compared to humans without the disease.
Microglia secrete chemical signals that convert astrocytes - the star shaped cells that help neurons communicate with their neighbors - into aggressive "activated" astrocytes, which eat away at the connections between cells in the brain, causing neurons to die off. Researchers speculated that NLY01 might stop this conversion. In a preliminary experiment in laboratory-grown human brain cells, the researchers treated human microglia with NLY01 and found that they were able to turn the activating signals off. When healthy astrocytes were combined with the treated microglia, they did not convert into destructive activated astrocytes and remained healthy neuroprotective cells.
Researchers tested the drug's effectiveness in mice engineered to have a rodent version of Parkinson's disease. They injected the mice with alpha-synuclein, the protein known to be the primary driver of Parkinson's disease, and treated the mice with NLY01. Similar but untreated mice injected with alpha-synuclein showed pronounced motor impairment over the course of six months in behavioral tests. However, the researchers found that the mice treated with NLY01 maintained normal physical function and had no loss of dopamine neurons, indicating that the drug protected against the development of Parkinson's disease.
Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson's disease
Activation of microglia by classical inflammatory mediators can convert astrocytes into a neurotoxic A1 phenotype in a variety of neurological diseases. Development of agents that could inhibit the formation of A1 reactive astrocytes could be used to treat these diseases for which there are no disease-modifying therapies. Glucagon-like peptide-1 receptor (GLP1R) agonists have been indicated as potential neuroprotective agents for neurologic disorders such as Alzheimer's disease and Parkinson's disease.
The mechanisms by which GLP1R agonists are neuroprotective are not known. Here we show that a potent, brain-penetrant long-acting GLP1R agonist, NLY01, protects against the loss of dopaminergic neurons and behavioral deficits in the α-synuclein preformed fibril (α-syn PFF) mouse model of sporadic Parkinson's disease. NLY01 also prolongs the life and reduces the behavioral deficits and neuropathological abnormalities in the human A53T α-synuclein (hA53T) transgenic mouse model of α-synucleinopathy-induced neurodegeneration.
We found that NLY01 is a potent GLP1R agonist with favorable properties that is neuroprotective through the direct prevention of microglial-mediated conversion of astrocytes to an A1 neurotoxic phenotype. NLY01 should be evaluated in the treatment of Parkinson's disease and related neurologic disorders characterized by microglial activation.
Can the Top-Down Institutional Approach Promote the Right Sort of Research and Development to Treat Aging?
Most scientists who spend their professional lives within large institutions, such as the big universities, the National Institute on Aging (NIA), and so forth, tend to favor institutional solutions. In practice that means slow engineering of change within the established hierarchy, rather than stepping outside it, or where a new need is identified, meeting it with the creation of a new institutional edifice much like those that already exist. This is the top down approach to development: structure and delegation, provide big-picture guidance and leave the details up to lower levels of the hierarchy. It is advocated in a recent open access position paper authored by a noted Russian researcher, one of those who led the development of plastinquinone based mitochondrially targeted antioxidants as a potential means to slow the progression of aging.
It is necessary to establish an International Agency for Research on Aging
Extending healthy lifespan is one of the main goals of gerontology and preventive medicine. There are potential interventions which might delay and/or prevent the onsets of many chronic pathologies associated with human aging. The affected pathways have been identiﬁed, and the behavioral, dietary, and pharmacologic approaches to preventing and treating age-related disorders have emerged. Interventions that target the aging process in its entirety appear to be more effective in preventing a broad range of age-related pathologies than specific interventions targeting such pathologies. Development of the new anti-aging drugs opens broad prospects for the pharmaceutical and healthcare industries. However, if human longevity continues to advance, the incidences of age-associated diseases, including cardiovascular diseases, type 2 diabetes, and cancer would also increase thus presenting a tremendous challenge for humankind. The search for adequate models for selecting the effective and safe methods of healthy life extension has become a priority in biology of aging.
There are at least two broadly accepted definitions of pharmacological compounds capable of intervening in aging: a) anti-aging drugs, which presumably reverse the aging process ('rejuvenation'), and b) geroprotectors, which are supposed to prevent premature aging and/or slow down or postpone aging. The term "longevity therapeutics" has been introduced for drugs that can interfere with the process of aging and extend the mean and/or maximum lifespan, preserve physiological functions and mitigate the onset and severity of a broad spectrum of age-associated diseases in mammals. Potential geroprotective agents have been subdivided into several groups: those that demonstrate an anti-aging effect without any evidence of lifespan increase; those that increase lifespan by reducing the incidence of age-associated pathology; and those that extend lifespan presumably by reversing the aging process itself. Most of the evidence related to these definitions and classifications has been gained in animal studies.
The designs of most such studies were found to have various deficiencies which led to confounding results. Therefore, there is the need to work out standard guidelines for testing such drugs and evaluating their life extending potential as well as various late effects, including tumor development. Guidelines for testing should include such significant elements as animal models, testing regimens, and biomarkers/endpoints. To this end, it is necessary to develop international standards for conducting the preclinical and clinical studies of agents intended to be used in pharmacological interventions in aging, as well as for evaluating the results of such studies. In the years to come, a promising agenda could be the development of new biomarkers based mostly on biochemical and genetic tests for short-term screening of potential agents. Collaborative studies of anti-aging drugs and geroprotectors conducted in various laboratories could be particularly promising.
In 2000, an international program on the assessment of the efficacy and safety of geroprotectors was proposed. It was suggested that the proposed program could be established under the auspices of the United Nations Program on Aging, the World Health Organization, and the International Association of Gerontology and Geriatrics. Unfortunately, the proposed program has not been implemented. We believe that it is worth reverting to that earlier proposal. Whereas the main challenge for healthcare in the 20th century had been the rapid increase in morbidity and mortality from malignant neoplasms, in the 21st century the primary challenge will be the effects of global aging on public and individual health. Therefore, the establishment of an International Agency for Research on Aging (IARA) under the auspices of the World Health Organization, similar to the International Agency for Research on Cancer (IARC), is expedient. Similarly to IARC, the objective of IARA should be the promotion of international collaboration in gerontology and geriatrics.
Can this really work, however? The challenge with large institutions is that the natural human inclination to conservatism, to playing it safe, to avoiding change, is magnified tenfold. If you want to maintain the status quo, that might be great, but if you want to change the world, then institutions are usually the enemy. The NIA mission involves "understanding the nature of aging and the aging process, and diseases and conditions associated with growing older, in order to extend the healthy, active years of life." This organization has been in existence since the 1970s; why are we still aging at much the same pace, with none of the fundamental causes meaningfully addressed? All of this funding has certainly led to the accomplishment of a great deal of scientific work, but sadly next to nothing of practical use when it comes to ways to slow or reverse the aging process. This isn't because they have no starting point: many of the root causes of aging have been well described for decades. Yet there is absolutely no danger that the NIA will meaningfully support the best directions for rejuvenation in the near future.
Much the same is true of other large institutions. They favor examination of aging, small changes to aging achieved by tinkering with metabolism, or the safe old school path of palliative methods of making age-related disease slightly less worse. Few exhibit any interest in the well known potential approaches to reversing aging by repairing its root causes. The World Health Organization won't even acknowledge that aging can be treated at all! What one can expect from a sizable institution charged with a specific mission is for its functionaries to pick the smallest possible set of changes they can aim for, and then work ineffectually to achieve those changes.
Senolytic rejuvenation therapies are being pioneered outside the institutions, as they did not support it despite the decades of evidence. The Methuselah Foundation and SENS Research Foundation, instrumental in steering the research community towards better strategies, were created by outsiders because the institutions of aging research would not acknowledge the need and the opportunity for effective rejuvenation development programs. Revolution and new, useful paths forward near always arise outside the mainstream, and are opposed by establishment institutions for as long as possible. That certainly happened, and is still in the process of happening, for rejuvenation research. So I'd say that the support we give to a better future is best directed to bottom-up approaches. Rebels, revolutionaries, startups, and rejuvenation biotechnology. New ideas, new directions, not the same old careful preservation of the status quo that exists in the largest research bodies.
The Humble Axolotl and the Quest for Human Organ Regeneration
The popular science article I'll point out today takes a look at research into axolotl biochemistry. The scientists involved are searching for ways in which they might be able to improve upon mammalian regeneration; the axolotl is one of the few higher species capable of perfect, repeated regeneration of lost limbs and severe damage to other organs. There are limits, of course, and the axolotl is just as mortal as any mammal, but mammals, ourselves included, have in comparison a very poor capacity for regeneration. We can barely grow back a fingertip, and even that only when very young, and not at all reliably. There are tantalizing hints that the capacity for far greater feats of regeneration still lurks within mammals, but disabled, or overridden. Mammals can regenerate during later embryonic development. The MRL mouse lineage can regenerate small injuries without scarring. African spiny mice have evolved to regenerate whole sections of skin perfectly, and don't appear all that different from other rodents in other aspects.
In addition to axolotls, researchers work with zebrafish, newts, and other highly regenerative species. It is an exercise in comparative biology, an effort to reverse engineer the important differences between these species and mammals. Some interesting advances have emerged in recent years. For example the human tumor suppressor ARF shuts down the exceptional regeneration of zebrafish when introduced into that species. This strongly suggests that the majority of higher species that have poor regenerative capacity do so because of evolved defenses against cancer. After all, the controlled cell growth of regeneration versus the uncontrolled cell growth of cancer are two sides of the same coin. Another important discovery centers around the role of macrophages and transient senescent cells in regeneration. The details of the intricate interactions between these and other cell types in injured tissue seems at the center of the choice between scarring or regrowth. Mammals scar, axolotls regrow.
Despite being a focus of attention for the popular science media, the prize here is not really a way to regrow lost limbs. That is a minor benefit. The real prize is a way to repair damage to internal organs, including important aspects of the slow-moving loss of function that arises with age, such as the internal scarring of fibrosis. Enabling axolotl-like proficient regeneration will be a form of therapy that partners well with the restoration of stem cell function in the old. Both lines of research may come to fruition in the clinic on a similar timescale in the years ahead.
Salamander's Genome Guards Secrets of Limb Regrowth
In a loudly bubbling laboratory, about 2,800 of the salamanders called axolotls drift in tanks and cups, filling floor-to-ceiling shelves. Salamanders are champions at regenerating lost body parts. A flatworm called a planarian can grow back its entire body from a speck of tissue, but it is a very small, simple creature. Zebrafish can regrow their tails throughout their lives. Humans, along with other mammals, can regenerate lost limb buds as embryos. As young children, we can regrow our fingertips; mice can still do this as adults. But salamanders stand out as the only vertebrates that can replace complex body parts that are lost at any age, which is why researchers seeking answers about regeneration have so often turned to them.
While researchers studying animals like mice and flies progressed into the genomic age, however, those working on axolotls were left behind. One obstacle was that axolotls live longer and mature more slowly than most lab animals, which makes them cumbersome subjects for genetics experiments. Worse, the axolotl's enormous and repetitive genome stubbornly resisted sequencing. Then a European research team overcame the hurdles and finally published a full genetic sequence for the laboratory axolotl earlier this year. That accomplishment could change everything.
After an amputation, a salamander bleeds very little and seals off the wound within hours. Cells then migrate to the wound site and form a blob called a blastema. Most of these recruits seem to be cells from nearby that have turned back their own internal clocks to an unspecialized or "dedifferentiated" state more like that seen in embryos. But it's unclear whether and to what extent the animal also calls on reserves of stem cells, the class of undifferentiated cells that organisms maintain to help with healing. Whatever their origin, the blastema cells redifferentiate into new bone, muscle and other tissues. A perfect new limb forms in miniature, then enlarges to the exact right size for its owner.
Arms, legs, and tails aren't the only body parts that laboratory axolotls can regrow. They also recover from crushing injuries to their spinal cords. They can regenerate a millimeter-by-2-millimeter square of their forebrain. Scientists don't know whether axolotls use the same mechanisms to regenerate their internal organs as their limbs. They also don't know why an axolotl can grow back an arm many times in a row but not indefinitely - after being amputated five times, most axolotl limbs stop coming back. Another mystery is how a limb knows to stop growing when it reaches the right size. But these may not be mysteries for much longer.
Using Age-Related Gene Expression Changes to Search for Drugs to Slow Aging
Gene expression is the complex, dynamic process by which proteins are produced from their genetic blueprints. It changes constantly due to a shifting pattern of epigenetic decorations attached to DNA. Targeting gene expression changes that take place with age is the path advocated by the minority of researchers who believe that aging is an evolved program, an adaptation in which the damage and decline is selected for. They should favor the sort of work noted here, in which the epigenetic changes of aging are used to steer screening for drug candidates, in search of compounds likely to work in similar ways to metformin, mTOR inhibitors, aspirin, and other existing drugs shown to modestly slow aging in animal studies. There is a great deal of difference in size and reliability of effects between just the three mentioned above, and it isn't at all clear whether or not they are representative of other compounds waiting to be discovered.
If, as the majority of the research community believes, aging is not programmed, not directly selected, and is caused by an accumulation of forms of unrepaired cell and tissue damage, then epigenetic change with aging is a reaction rather than a cause. It is a downstream consequence of the real issues. Adjusting specific gene expression levels should have only small effects on the course of aging because the underlying damage remains to cause all of its other failures and harms. This is why I favor the SENS rejuvenation biotechnology approach over the popular work on mTOR inhibitors and the like - the research community must target the root causes rather than later consequences if the goal is meaningful gains in health and life span.
Pharmacological intervention can extend animal lifespan. The DrugAge database reports drug-induced lifespan extensions - up to 1.5-fold for C. elegans, 1.1-fold for D. melanogaster, and 31% for M. musculus. Some of these chemicals may mimic the effects of dietary restriction (DR). For example, resveratrol, which induces a similar gene expression profile to dietary restriction, can increase lifespan of mice on a high-calorie diet, although not in mice on a standard diet. Rapamycin, directly targets the mTORC1 complex, which plays a central role in nutrient sensing network and has an important role in lifespan extension by DR. Rapamycin extends lifespan by affecting autophagy and the activity of the S6 kinase in flies. However, it can further extend the fly lifespan beyond the maximum achieved by DR, suggesting that different mechanisms might be involved. Nevertheless, the mechanisms of action for most of the drugs are not well known.
Several studies have taken a bioinformatics approach to discover drugs that could extend lifespan in model organisms. For instance, the Connectivity Map, a database of drug-induced gene expression profiles, has been used to identify DR mimetics, and found 11 drugs that induced expression profiles significantly similar to those induced by DR in rats and rhesus monkeys. Although previous studies tried to discover drugs that can affect ageing, they all focus on genes or drugs related to lifespan regulation. The role of these drugs in promoting healthy ageing in humans is still an open question. In this study, using gene expression data for human brain ageing, we aimed to discover not only new pro-longevity drugs but also those that can improve health during ageing. The biological processes showing a change in expression include pathways related to synaptic and cognitive functions as well as proteostasis, suggesting gene expression changes in the ageing brain could be used as a surrogate to find drugs to target detrimental effects.
Using multiple gene expression datasets from brain tissue, taken from patients of different ages, we first identified the expression changes that characterise ageing. Then, we compared these changes in gene expression with drug perturbed expression profiles in the Connectivity Map. We thus identified 24 drugs with significantly associated changes. Some of these drugs may function as anti-ageing drugs by reversing the detrimental changes that occur during ageing, others by mimicking the cellular defense mechanisms. The drugs that we identified included significant number of already identified pro-longevity drugs, indicating that the method can discover de novo drugs that meliorate ageing. The approach has the advantages that, by using data from human brain ageing data it focuses on processes relevant in human ageing and that it is unbiased, making it possible to discover new targets for ageing studies.
A View of Commercial Efforts in Organ Bioprinting and Recellularization
A fair number of companies are at work on various approaches to bioprinting larger tissue structures, stepping stones on the way to the construction of patient-matched organs to order. New organs on demand is clearly the goal on the horizon, but many hard problems have to be solved before that can be accomplished for even relatively less complex internal organs. At the moment, while functional tissues for several organ types can be produced from cells in the lab, in the form of tiny organoid structures, there is no reliable methodology for the production of blood vessel and capillary networks needed to supply large tissue sections. Printing structures of the same complexity as the natural extracellular matrix of decellularized donor organs is also a work somewhere in progress. Nonetheless, a great deal of funding is devoted to these and other challenges; progress is likely over the decade to come.
Last month I had the chance to hold a replica of the upper part of a human airway - the windpipe plus the first two bronchi. It had been made from collagen, the biological cement that holds our bodies together. It was slippery and hollow, with the consistency of undercooked pasta. The structure had emerged from a refrigerator-size 3-D printer at an outpost of United Therapeutics, a company that earns more than a billion a year selling drugs to treat lung ailments. One day, the company says, it plans to use a printer like this one to manufacture human lungs in "unlimited quantities" and overcome the severe shortage of donor organs. Bioprinting tissue isn't a new idea. 3-D printers can make human skin, even retinas. Yet the method, so far, has been limited to tissues that are very small or very thin and lack blood vessels.
United instead is developing a printer that it believes will be able, within a few years, to manufacture a solid, rubbery outline of a lung in exquisite detail, including all 23 descending branches of the airway, the gas-exchanging alveoli, and a delicate network of capillaries. A lung made from collagen won't help anyone: it's to a real lung what a rubber chicken is to an actual hen. So United is also developing ways to impregnate the matrix with human cells so they'll attach and burrow into it, bringing it alive.
United has already made some risky organ bets. One of its subsidiaries, Revivicor, supplies surgeons with hearts, kidneys, and lungs from genetically engineered pigs (these have been used in baboons, so far). Another, Lung Bioengineering, refurbishes lungs from human donors by pumping warm solution into them. About 250 people have already received lungs that would otherwise have been designated medical waste. Don't expect fully manufactured organs soon. United, in its company projections, predicts it won't happen for another 12 years. The printed structure I saw is just a start. Even so, United's effort to print entire organs, which got under way last year, may be the industry's largest.
Chronic Inflammation Correlates with White Matter Damage in the Aging Brain
Here researchers add more evidence to the existing stack of studies linking inflammation to the pace of neurodegeneration, with a focus on white matter damage in the brain in this case. Like raised blood pressure, inflammation is a mediating mechanism that transforms the low-level molecular damage at the root of aging into high-level organ dysfunction and structural damage throughout the body. Chronic inflammation is one of the major reasons why excess visceral fat tissue and exposure to particulates such as smoke are so harmful to long term health. Even the healthy and trim amongst us are faced with the steady rise of inflammation with age, driven by processes such as the accumulation of senescent cells and their inflammatory signals, and the progressive dysfunction of the immune system that is known as inflammaging. The more that can be done to keep chronic inflammation at bay, the better off we are.
"We found that individuals who had an increase in inflammation during midlife that was maintained from mid to late life have greater abnormalities in the brain's white matter structure, as measured with MRI scans. This suggests to us that inflammation may have to be chronic, rather than temporary, to have an adverse effect on important aspects of the brain's structure necessary for cognitive function." Researchers have long gathered evidence that chronic inflammation and the biochemicals associated with it may damage the brain. C-reactive protein, an inflammatory factor made in the liver, for example, already has become a marker for chemical damage to heart and blood vessel tissue indicative of heart attack. So far, however, studies linking inflammation to brain abnormalities have not looked at these factors and features over an extended period of time in the same population.
In the new study, researchers took data from the atherosclerosis risk in communities (ARIC) study that looked at brain structure and integrity, as well as a marker of inflammation over a 21-year period spanning middle age to late life. Specifically, the investigators focused on and compared data on 1,532 participants recruited from 1987 to 1989. At the final visit, participants were an average age of 76. Over the course of the ARIC study, each participant had five visits with study coordinators, averaging every three years. At the last visit, each participant underwent an MRI of their brain to examine evidence of damage to so-called white matter - the part of the brain responsible for transmitting messages. Damaged white matter appears superwhite on a scan, similar to overexposure on a photograph, and was measured using an automated program.
At visits 2, 4 and 5, the researchers took blood samples to measure for high-sensitivity C-reactive protein, a standard measure of inflammation throughout the body. Those with levels below 3 milligrams per liter were considered to have low inflammation, whereas those with 3 or more milligrams per liter of C-reactive protein were considered to have elevated inflammation. Even after adjusting for demographics and cardiovascular disease risk, the researchers found that the 90 people who transitioned from low to persistently elevated C-reactive protein during midlife, indicating increasing inflammation, showed the greatest damage to the white matter in the brain. Because their findings overall showed that increasing and chronic inflammation were associated with the most damage to white matter, there is more reason to infer a cause and effect relationship between growing and persistent inflammation and evidence of dementia.
Aspirin Enhances Autophagy to Reduce Amyloid in Mouse Models of Alzheimer's
A number of groups advocate the use of NSAIDs such as aspirin as a means to reduce risk and postpone the development of Alzheimer's disease, based on the evidence accumulated in the past few decades. Aspirin is considered by some to be a calorie restriction mimetic that enhances autophagy, the cellular housekeeping mechanism that is required for calorie restriction to extend life in laboratory species. That said, I normally mention aspirin as a way to dampen excess enthusiasm for any new calorie restriction mimetic, autophagy-stimulating compound demonstrated to slow aging in the laboratory. After all, aspirin slows aging too, and to a similar degree, when tested in short-lived species. We shouldn't expect any of the current crop of allegedly age-slowing compounds that influence these mechanisms to do much more for human health than aspirin has achieved. All sorts of beneficial effects will be observed, such as the one noted here, but at the end of the day the size of the effect matters greatly.
A regimen of low-dose aspirin potentially may reduce plaques in the brain, which will reduce Alzheimer's disease pathology and protect memory. Alzheimer's disease is a fatal form of dementia that affects up to one in 10 Americans age 65 or older. To date, the FDA has approved very few drugs for the treatment of Alzheimer's disease-related dementia, and the medications that exist can only provide limited symptomatic relief. Poor disposal of the toxic protein amyloid beta in the brain is a leading mechanism in dementia and memory loss. Activating the cellular machinery responsible for removing waste from the brain has emerged as a promising strategy for slowing Alzheimer's disease.
Amyloid beta forms clumps called amyloid plaques, which harm connections between nerve cells and are one of the major signs of Alzheimer's disease. Building on previous studies demonstrating a link between aspirin and reduced risk and prevalence of Alzheimer's disease, researchers were able to show that aspirin decreases amyloid plaque pathology in mice by stimulating lysosomes - the component of animal cells that help clear cellular debris.
A protein called TFEB is considered the master regulator of waste removal. The researchers gave aspirin orally for a month to genetically modified mice with Alzheimer's pathology, then evaluated the amount of amyloid plaque in the parts of the brain affected most by Alzheimer's disease. They found that the aspirin medications augmented TFEB, stimulated lysosomes, and decreased amyloid plaque pathology in the mice.
Adjusting Macrophage Polarization as a Basis for Cancer Immunotherapy
Macrophage polarization is a hot topic of late. The innate immune cells known as macrophages are responsible for a wide range of duties that include destroying errant cells, attacking pathogens, cleaning up waste and debris, and participation in tissue regrowth and regeneration. The polarization of a macrophage describes its state and inclination as to which of those duties it undertakes: M1 macrophages are aggressive and inflammatory, while M2 macrophages tend towards participation in the gentler processes of rebuilding and regeneration. Many of the common inflammatory age-related conditions appear to be characterized by too many M1 macrophages and too few M2 macrophages. Methods by which that balance can be shifted seem promising as a basis for therapy.
Cancer is a different story, however, as is often the case. Many of the issues seen in aging can actually be helpful when it comes to the short-term goals of shutting down and eliminating cancerous tissue. Forcing cancerous cells into senescence is a viable strategy, for example, even though researchers know that senescent cells are one of the root causes of aging, and are working on ways to remove them from normal aged tissues. In this case, the problem of too many M1 macrophages is actually a desirable goal when it comes to attacking cancer. The researchers here are clearly achieving good results via encouraging more macrophages to take up the M1 phenotype in the cancer environment.
Much cancer immunotherapy research has focused on harnessing the immune system's T cells to fight tumors, "but we knew that other types of immune cells could be important in fighting cancer too." Now researchers report that in preclinical models they can amplify macrophage immune responses against cancer using a self-assembling supramolecule. As immune cells, macrophages usually eat foreign invaders including pathogens, bacteria, and even cancer cells, but one of the two types do not always do so. Macrophage type M1s are anti-tumorigenic, but M2s can be recruited by tumor cells to help them grow. Also, tumor cells overexpress a protein that tells the macrophages, "don't eat me." In this way, pro-tumorigenic macrophages may make up 30 to 50 percent of a tumor's mass.
"With our technique, we're re-programming the M2s into M1s by inhibiting the M2 signaling pathway. We realized that if we can re-educate the macrophages and inhibit the 'don't eat me' protein, we could tip the balance between the M1s and M2s, increasing the ratio of M1s inside the tumor and inhibiting tumor growth." The researchers used a multi-component supramolecular system that self-organizes at the nanoscale to deliver an antibody inhibitor plus a drug inside the tumor. This is the first time anyone has combined a drug that targets M2 macrophages and an antibody that inhibits the 'don't eat me signal' in one delivery system.
The researchers tested the supramolecular therapeutic in animal models of two forms of cancer, comparing it directly with a drug currently available in the clinic. Mice that were untreated formed large tumors by Day 10. Mice treated with currently available therapies showed decreased tumor growth. But mice treated with the new supramolecular therapy had complete inhibition of tumor growth. The team also reported an increase in survival and a significant reduction in metastasis. The next steps are to continue testing the new therapy in preclinical models to evaluate safety, efficacy and dosage.
The Longevity Film Competition, Advocacy for Rejuvenation Research
The volunteers at Heales and the International Longevity Alliance last organized a film competition in support of longevity science and longer, healthier lives back in 2015. Now the second competition in this series is underway, with its own website, and the aim of spreading the word about the potential inherent in the treatment of aging as a medical condition. Given enthusiasm and funding, aging might be controlled and halted in the decades ahead, through the development of therapies that repair its root causes. I hope to see a brace of interesting entries as this contest progresses, given the growth in our community over the past few years. If you have an idea and the time to act on it, why not give it a try?
This is an international film competition created to help convey the importance of addressing age related disease. Our jury is composed of filmmakers, scientists, successful entrepreneurs and experts in the fields of regenerative medicine, aging, and longevity. We are living in very interesting times, times of constant change. The scientific community is telling us that soon we could enjoy much healthier and longer lives thanks to technological advancements happening at an accelerated rate. The future can be bright and healthy and we want more people to know about this amazing prospect and want them to get involved in this important mission; the mission of healthy longevity.
However, describing something potentially beautiful is not always easy. We think you can help by making a (very) short movie conveying that a longer and healthier life thanks to sustainable medical interventions, will be a very positive thing for citizens and society alike. Help us spread the word in the right way, help us make sure people understand this is about health and that for the first time in history the possibility of tackling aging is not science fiction, but science fact. Join us in this crusade by entering our competition presented by the SENS Research Foundation, the Healthy Life Extension Society and the International Longevity Alliance and not only potentially help saving lots of lives, but also win the first prize of 10,000! We look forward to your ideas on how to better communicate this important message to the world.
Metformin Shown to Attenuate Lung Fibrosis in Mice
Fibrosis is a form of malfunction in tissue maintenance and regeneration, in which cells inappropriately build scar-like collagen structures that disrupt normal tissue function. It is perhaps most significant in age-related diseases of the lung, heart, and kidney, but it is a general feature of old tissues. There are no effective and approved treatments capable of reversing fibrosis to any significant degree, but good evidence has arrived in recent years to suggest that senescent cells, one of the root causes of aging, are also an important contributing cause of the regenerative dysfunction that leads to fibrosis. Senolytic therapies capable of selectively removing senescent cells from an organ with fibrosis should prove helpful.
In that context, it is interesting to look over this recent demonstration of attenuated lung fibrosis via metformin treatment. Metformin is thought to modestly slow aging, being a form of calorie restriction mimetic, but as such treatments go, it is notably poor and unreliable. The animal data is highly varied when it comes to practical outcomes on aging and longevity. The beneficial effect on fibrosis observed here is thought to be mediated via mitochondrial function. Given what is known of metformin in aging, cellular senescence in fibrosis, and the role of mitochondria in programmed cell death, removing problem cells from tissue, it is tempting to speculate on the destruction of a fraction of the senescent cells in a fibrotic organ. But again, we know that metformin is unreliable in animal studies, while senolytics are exactly the opposite. So other mechanisms seem more likely, such as a change in cell behavior prompted by better function in mitochondria.
Pulmonary fibrosis can develop after lung injuries like infections, radiation, or chemotherapy, or it can have an unknown cause, as in idiopathic pulmonary fibrosis, or IPF. IPF is a progressive, and ultimately fatal, lung disorder. In experiments using lung tissues from patients with IPF, mouse lung fibroblasts, and a murine model of lung fibrosis, a team showed the reversal of lung fibrosis and the underlying cellular mechanisms affected via drug treatment. Interestingly, the drug that accelerated the resolution of lung fibrosis is metformin, which is a safe and widely used agent for non-insulin-dependent diabetes.
The research focused on AMP-activated protein kinase (AMPK), an enzyme that senses energy state in the cell and regulates metabolism. Researchers found that AMPK activity was lower in myofibroblast cells within fibrotic regions of human lung tissue from IPF patients. Myofibroblasts deposit extracellular collagen fiber as part of the fibrosis process. These myofibroblasts were metabolically active and were resistant to the programmed cell death called apoptosis, a natural process that removes more than 50 billion damaged or aged cells in adults each day.
Activation of AMPK in myofibroblasts from lungs of humans with IPF, using the drug metformin or another activator called AICAR, led to lower fibrotic activity. AMPK activation also enhanced the production of new mitochondria, the organelles in cells that produce energy, in the myofibroblasts, and it normalized the cells' sensitivity to apoptosis. Using a mouse model for lung fibrosis elicited by the anti-cancer drug bleomycin, the research team found metformin treatment, starting three weeks after lung injury and continuing for five weeks, accelerated the resolution of well-established fibrosis. Such resolution was not apparent in AMPK-knockout mice, showing that the effect of metformin was AMPK-dependent.
"Together, our studies support the concept that AMPK may function as a critical metabolic switch in promoting resolution of established fibrosis by shifting the balance from anabolic to catabolic metabolism. Additionally, we provide proof-of-concept that activation of AMPK by metformin or other pharmacologic agents that activate these pro-resolution pathways may be a useful therapeutic strategy for progressive fibrotic disorders."
Differences in Macrophage Polarization Between More Healthy and Less Healthy Elders
Macrophages of the innate immune system take on different states known as polarizations depending on their duties. M1 macrophages are aggressive and inflammatory, involved in the destruction of pathogens and harmful cells. M2 macrophages aid in the processes of regeneration. The immune system becomes more inflammatory with advancing age. This chronic inflammation drives progression of most of the common age-related diseases, and an excess of M1 macrophages appears as a feature of many of those conditions. The research community is looking into ways to force more macrophages into the M2 polarization, as a possible approach to override a fraction of age-related immune dysfunction. In this context, researchers here report on their evaluation of differences in the macrophage population between more and less healthy older individuals.
The low-grade, chronic inflammatory state affecting aging organisms - inflammaging - is among the major risk factors for the development of the most common human age-related diseases (ARDs). Increasing evidence suggests that inflammaging is underpinned by monocytes/macrophages, while the acquisition of a senescent phenotype - a phenomenon that has been defined as macroph-aging - impairs the ability of immune cells to cope with stressors, thus contributing to immunosenescence. In this framework, the role of macrophage polarization in the modulation of inflammatory and repair processes is attracting growing interest.
The two main, and opposite activities of macrophages have led them to be classified into pro-inflammatory classically activated macrophages (M1) and anti-inflammatory and immunoregulatory alternatively activated macrophages (M2). Despite its value, this classification is however insufficient to describe the diverse phenotypes and functions of monocytes/macrophages in vivo. Intense research is being devoted to associate the polarization profiles, seen in vitro in relation to specific stimuli, with circulating and/or tissue macrophage polarization in health and disease conditions. Clearly, in vitro models are unable to mimic the complex environment that influences the M1/M2 balance in vivo, and since macrophages can develop mixed M1/M2 phenotypes, novel in vivo detection strategies are required. Several biomarkers have been associated with M1/M2 profiles. CD163, the high-affinity scavenger receptor for the haemoglobin-haptoglobin complex, is selectively expressed on M2 macrophages and monocytes, whereas CD80, a costimulatory signal for T cell activation and survival, is preferentially expressed on M1 macrophages.
Since data on the M1/M2 phenotype of circulating monocytes in healthy aging are not available, this study was undertaken to analyse monocyte profiles in healthy subjects of different ages using flow cytometry. To establish whether an M1/M2 imbalance could be disease-associated, the M1/M2 phenotype of elderly healthy subjects was compared with the one of elderly patients with acute myocardial infarction (AMI). The AMI patients showed a significantly decreased proportion of CD163+CD80+ and an increased proportion of CD163+ and CD163-CD80- cells among classical monocytes, opposite trends to those observed in healthy aging. Moreover, a significantly greater proportion of intermediate and non-classical CD80+ monocytes suggested a shift to a pro-inflammatory phenotype. Overall, CD163/CD80 characterization of circulating monocytes provides additional information about their polarization and could be an innovative tool to monitor aging.
Reducing Levels of All Pathological Protein Aggregates Should be a Primary Strategy for Treating Neurodegeneration
The reasons why restoration of cerebrospinal fluid drainage is a very promising strategy for the treatment of Alzheimer's disease go beyond the compelling direct evidence, into matters of research and development strategy. Numerous proteins that become misfolded or altered in ways that cause them to form solid deposits in the aging brain, surrounded by a halo of harmful secondary biochemistry. To date, serious development efforts that have advanced to clinical trials have focused on clearing only one of these aggregates. That may well never be enough: neurodegeneration appears to be a combination of the effects of many mechanisms of similar weight and consequence.
Thus more researchers are beginning to call for broader efforts that target multiple problem proteins. In this context, the importance of improved cerebrospinal fluid drainage is that it can can reduce the levels of all molecular waste and resulting consequences in the brain, both the well understand and the less well understood alike. It all flows out through the same channels, provided that those channels are working well enough. Unfortunately they decline with age, and that is a comparatively simple, mechanical and structural potential point of intervention. I am looking forward to the data produced by Leucadia Therapeutics as their metholodology for drainage restoration progresses over the years ahead: they should be able to fairly quickly definitively confirm the utility of this strategy.
Nearly all major neurodegenerative diseases - from Alzheimer's to Parkinson's - are defined and diagnosed by the presence of one of four proteins that have gone rogue: tau, amyloid-beta (Aβ), alpha-synuclein (α-syn), or TDP-43. As such, investigational drugs and studies aimed at preventing or slowing the disease often hone in on just one of these respective proteins. However, targeting multiple proteins at once may be the real key, according to a recent study. These so-called "proteinopathies" - misfolded proteins that accumulate and destroy neurons - co-exist in varying degrees across all of the different neurodegenerative disorders and may instigate each other to drive disease severity in many aging patients. The prevalence of these co-pathologies suggests that each disease may ultimately require combination therapy targeting multiple disease proteins, and not just a single therapy, in patients with both early and later-stage disease.
"Historically, the focus of most clinical trials has been on targeting the primary pathological proteins of a given neurodegenerative disease such as deposits of tau and Aβ for Alzheimer's disease, but we see now that many of these disease-related aggregated proteins affect most older patients across a full spectrum of clinical and neuropathological presentations. This gives us additional leverage to find ways to detect patients' specific proteinopathies with increasingly sophisticated biomarker and imaging technologies. This will allow us, and other researchers, to better match participants with specific targeted therapies in clinical trials."
The study analyzed 766 autopsied brains and revealed that patients with more severe forms of their diseases had more co-pathologies. Co-pathologies were common but varied among the disease groups, ranging from 27 to 81 percent of patients having co-pathologies. For example, 52 percent of patients with corticobasal degeneration (CBD), in which tau as the primary protein, had multiple other neurodegenerative disease protein deposits present. Tau was nearly universal, with 92 to 100 percent of all patients having at least one form. Aβ was next, with 20 to 57 percent of patients having at least one type of protein deposit, while α-syn pathology, typically seen in Parkinson's disease, was less common, with 4 to 16 percent. TDP-43 deposits, which are characteristic pathological signatures of frontotemporal lobar degeneration and amyotrophic lateral sclerosis, were the rarest, with 0 to 16 percent of patients having these deposits.
The findings not only show a high prevalence of co-pathologies, but also suggest a patient's primary pathological protein may influence co-pathology prevalence and severity, as shown in patients with Alzheimer's and Lewy body disease patients. These findings support the "proteopathic seeding" hypothesis that has been previously established in model systems of neurodegenerative diseases. Misfolded proteins may directly "cross-seed" other normal, vulnerable proteins to accumulate and clump via a cell-to-cell transfer of toxic proteins.
Biomedical Engineering in Medicine and Aging
Today, the effective treatment of aging can only proceed rapidly as an engineering project. The fine details of the way in which aging progresses at the level of cells and proteins are far from fully understood - but that is not a roadblock to progress. The research community knows enough of the causes of aging to repair them and observe the results. In fact the repair approach, where it has been tried, and as typified by senolytic development to clear senescent cells, is doing far more, with far less expenditure, and in far less time, than other strategies that involve mapping and adjusting the extreme complexity of cellular metabolism.
A good analogy for this situation is that sizable bridges and other large structures were constructed on an empirical basis for millennia prior to a full understanding of materials science, prior to the implementation of computational modeling in architecture. In exactly the same way it is possible to make meaningful progress in the treatment of aging today, and because aging causes far more harm than any other aspect of the human condition, it is our ethical imperative to make that progress rather than waiting on greater understanding of how exactly aging and metabolism interact in detail.
Biomedical gerontologist Aubrey de Grey says he believes that, thanks to imminent advances in technology, the first person to live to age 1,000 likely is alive today. De Grey became interested in studying the biological aspects of aging, he says, because he views its negative effects, such as chronic pain and memory loss, as preventable. While he is focused on improving quality of life, he says longevity is a "side effect" of good health. He helped to found the SENS (Strategies for Engineered Negligible Senescence) Research Foundation, a regenerative medical research nonprofit that focuses on preventing diseases and disabilities related to aging.
Living much longer lives will happen soon, de Grey contends, challenging the notion that aging is inevitable or even natural. Radiologist Joon Yun agrees. Yun is president and managing partner of Palo Alto Investors. His family foundation has sponsored a number of initiatives and made a US 2 million gift to launch the National Academy of Medicine's Healthy Longevity Grand Challenge, to "solve aging" as he puts it. Like de Grey, he says he is focused on improving quality of life so that people will be able to continue their active lifestyles without any trouble, no matter their age.
There are many opportunities in tissue engineering, stem-cell therapy, and immunotherapy. One of the projects the SENS Research Foundation is working on involves "death resistant cells," which cause degenerative aging. These cells cause loss of muscle mass, inflammation, and metabolic changes. The foundation is looking into rejuvenating cellular and molecular structures to keep people young. To restore health and vigor, organizations partnering with the foundation are experimenting with growing organs and cells in labs. That could allow for organs to be custom-made from the recipient's cells. The cells also could be used as neurons for the brain or muscle for the heart. The process might eliminate the need for organ donors or searching for a match. It also would reduce the risk of transplant rejection, and a recipient's organs would be biologically "younger" than those from a donor.
As people get older, they experience a decline in such vital functions as memory, digestion, and blood circulation. Yun is focused on what he calls functional longevity. He is offering a 1 million cash prize to researchers who can "hack the aging code," or find a solution to aging that would prolong lives and maintain quality of life. Yun's approach to prolonging life span is to restore the body's ability to respond to stress, known as homeostatic capacity. As we get older, our capacity declines, causing functions to weaken. Yun is looking for entrepreneurs and engineers who have ideas on how to measure homeostatic capacity. "Rather than thinking about inflammation as a cause of aging, we should think about it as a loss of inflammatory capacity. Instead of thinking that weight gain is just part of aging, think of it as a loss of metabolic capacity."