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- Are Clonally Expanded Stochastic Mutations Important in Brain Aging?
- Greater Chronic Inflammation Correlates with Greater Cognitive Decline
- Recent Research into the Effects of Obesity on Aging
- Support for Oxidized Cholesterol as a Primary Cause of Atherosclerosis
- Recent Research into the Interaction of Exercise and Aging
- A Demonstration of Regeneration Achieved Using Extracellular Vesicles from Stem Cells
- The Longevity Forum, a Meeting of Science and Society
- Delivery of Noggin to the Brain Improves Stem Cell Function and Neurogenesis in an Accelerated Aging Mouse Model
- A Phase III Trial Based on the Peripheral Amyloid Sink Concept Succeeds in Slowing Alzheimer's Disease
- A Role for Sarcosine in the Benefits of Calorie Restriction
- Combinations of Approaches to Slow Aging are Not Well Explored
- Market Analysts on the Future of Aging
- Final Stretch Goal for the Lifespan.io NAD+ Mouse Study Crowdfunding Event
- Complicating the Correlation Between Wealth and Life Expectancy
- Calorie Restriction Reduces the Inflammation Associated with Arterial Aging
Are Clonally Expanded Stochastic Mutations Important in Brain Aging?
Beyond the risk of cancer, does random mutational damage to nuclear DNA provide a significant contribution to degenerative aging? Mutation counts rise with age, but if it was a case of every cell becoming a little mutated over the course of its duties before it is replaced, than it would be fairly clear that nuclear DNA damage isn't all that important. The vast majority of single mutations have little significant effect within the cell in which they occur, and that cell is just one of countless others. Cells divide, however, and thus mutations spread. Mutations in stem cells and other prolific cell populations can lead to large numbers of cells carrying the same mutation, and even in youth our bodies are a patchwork of such mutant populations.
Is this process of clonal expansion of mutations throughout tissues important in aging, beyond cancer? Does it cause sufficient metabolic disarray over the present human life span to be counted alongside the other contributions to aging? Or would it only cause issues once we have removed those other contributions, and thus live far longer? The consensus is yes, nuclear DNA damage is significant over the present human life span, but definitive proof of that position is elusive. There is plenty of evidence for either side of the debate. In the article here, the focus is on populations of clonally expanded mutant cells specifically in the brain, and whether they might contribute to neurodegeneration.
The results are suggestive, supporting a role for clonally expanded mutant populations in neurodegenerative disease. This is true of other work as well. It remains the case that the next step in any of this research is to figure out how to do better than suggestive results, to produce a compelling proof or disproof of the hypothesis. This will likely require gene therapy technologies that are somewhat more advanced than the present state of the art, but precision approaches with good cell coverage and tissue specificity will arrive in the next decade or two. That may be enough to enable proof of principle animal studies in which localized mutations can be created or removed to a some degree.
Islands of Mutated Neurons Dot the Brain. Are They Bad for Us?
Researchers have long suspected that the brain contains a genomic patchwork of cells harboring mutations that arose at different stages of development. These variants have even been tied to a handful of sporadic cases of neurodegenerative disease. However, due to the localized nature of these mutations throughout the brain, tracking them down, let alone investigating their involvement in disease, requires cutting-edge sequencing, cell isolation, and computational techniques. Using single-cell sequencing, a recent study estimated that each cell in the brain harbors 200-400 somatic mutations that arose during brain development, while another study reported around 1,500 per post-mitotic neuron. The mutation rate of human neurons also reportedly ramps up with age. Yet the cumulative impact of these mutations, and how many cells harbor each one, remains uncertain.
To address these questions, researchers employed ultra-deep sequencing of 56 genes linked to neurodegenerative disease in different regions from postmortem brain samples. The scientists resequenced each sample more than 1,000 times, allowing them to detect variants with high specificity and sensitivity, even for genes that are typically extremely difficult to sequence. Then, using a computational model of brain development, they used their findings to estimate the burden of somatic variation in the entire brain. In all, the researchers found 39 somatic variants among 44 of the 173 brain samples that were taken from from 54 post-mortem brains. Eight variants were in neurodegenerative disease-related genes.
The researchers next sought to extrapolate their findings to estimate the burden of variants in neurodegenerative disease-related genes across the entire brain. Using a cellular barcoding technique, they estimated they had sequenced DNA from around 611,000 cells. They were also able to estimate the proportion of cells in any given region that carried a somatic mutation in a neurodegenerative disease-related gene.
They fed this data into a statistical algorithm that simulated brain development to predict the total number and distribution of mutated cells among the estimated 86 billion in each brain. The answer: 100,000 to 1 million cells carry a somatic mutation in a disease-related gene. Incorporating information about how cells divide, differentiate, and mutate during development, the algorithm also foretold that each person likely had one large island of 10,000 to 100,000 cells that grew from one original mutation in a disease gene, while 10 percent of people had at least one island of more than 200,000 such cells. In addition, each brain contained 75 to 481 smaller islands, each consisting of just more than 100 descendants of a cell carrying a pathological variant. The researchers speculated that these islands of somatic variants trigger sporadic neurodegenerative disease, which reportedly affects roughly 10 percent of the human population.
Greater Chronic Inflammation Correlates with Greater Cognitive Decline
Along with raised blood pressure, chronic inflammation is one of the most important downstream consequences of (a) the causes of aging, (b) harmful environmental factors such as burden of infectious disease, and (c) poor lifestyle choices, such as becoming overweight. Chronic inflammation in and of itself produces a wide range of harmful consequences, accelerating the development and progression of all of the most common fatal age-related conditions. Inflammation disrupts regeneration, guides normally helpful immune cells into harmful activities, and distorts the operation of cellular metabolism in damaging ways.
In the short term, inflammation is a necessary part of the response to injury or infection. It is when it runs on without cease that the problems start. Cells that are constantly acting as if in response to an emergency perform their usual tasks ever more poorly. Many age-related diseases have a strong inflammatory component, and this is the case for most forms of neurodegenerative condition. The immune cells of the brain are somewhat different from those elsewhere in the body, and are arguably far more essential to correct tissue function. They participate in maintenance of synaptic connections, for example.
The study here finds the expected correlation between degree of chronic inflammation and degree of cognitive decline in aging. The authors conclude that suppression of chronic inflammation should be a priority in the treatment of older individuals. The broad range of evidence regarding inflammation and its role in aging suggests that ways to override the inflammatory response could be beneficial even without addressing the underlying causes of inflammation. This sort of outcome was achieved to some degree in the case of raised blood pressure, via antihypertensive medications that override the responses to molecular damage that lead to hypertension, but dealing with blood pressure is a more straightforward challenge than taming the aged, damaged immune system.
Given the complexity of the immune system, approaches that aim at the much simpler root causes of chronic inflammation are much more likely to (a) succeed at a reasonable cost and (b) produce larger gains. Consider senolytic therapies that selectively destroy senescent cells, for example. These errant cells, that accumulate with age, are a significant source of inflammatory signaling. Remove them, and inflammation is reduced. More prosaically, consider loss of visceral fat tissue through the usual approach of eating fewer calories. Visceral far is metabolically active, producing inflammation throughout the body via a range of mechanisms that can all be dialed down just be reducing the amount of fat tissue present in the body.
Systemic Inflammation Is Associated With Longitudinal Changes in Cognitive Performance Among Urban Adults
Chronic systemic inflammation is a risk for neurodegeneration manifesting as Alzheimer's Disease (AD) and age-related cognitive decline. Markers of inflammation are associated with poorer cross-sectional cognitive performance, faster longitudinal decline in various domains of cognition as well as with structural and functional brain changes representing early markers of AD, including brain region activity, regional cortical thickness and white matter microstructural integrity. However, few studies have examined cross-sectional or longitudinal associations of inflammation with cognitive performance in a bi-racial adult cohort, and none have tested effect modification by race, age, and sex in the relationship between systemic inflammation and rate of change in cognitive performance over time while using a large battery of cognitive tests.
The current study examined associations between systemic inflammation and cognitive performance among African Americans and Whites urban adults participating in the Health Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study. Markers known to either increase or decrease during inflammation were tested against cross-sectional and longitudinal cognitive function, stratifying by key sociodemographic factors, including age, sex, and race.
Among key findings, a composite score combining four markers of systemic inflammation was associated with faster decline on a test of visual memory/visuo-constructive abilities, among older men only (over 50 years of age). Many other associations were detected in the expected direction for all markers except for serum iron, whereby a higher inflammatory status was linked to either worse performance at baseline or faster decline over time for specific age, sex and race groups. Most notably, baseline erythrocyte sedimentation rate (ESR) was associated with a faster decline on verbal memory among older men, whereas serum albumin was linked to slower attention decline among older men and over-time improvement in executive function in the total population. In contrast, high sensitivity C-reactive protein associations with cognition were mostly detected at baseline, for global mental status and the domain of attention.
Recent Research into the Effects of Obesity on Aging
It is no big secret that being overweight will harm your future prospects for health and longevity. The more visceral fat tissue, the worse off you will be. Since it is somewhat easier to be in denial on this topic than it is to lose significant amounts of weight, there are a lot of people out there in some state of denial regarding the harm they are doing to themselves. This situation was not made better by flawed epidemiological studies in past years suggesting that overweight people had lower mortality rates in later life. Those studies have since been comprehensively torn apart and their flaws dissected in detail.
People lose weight when they are in the later stages of age-related disease, and thus we must discard every study that failed to distinguish between (a) people who are in a normal weight range because they are dying and (b) people who are in a normal weight range and essentially as healthy as they can be for their age group. Sadly, that is a great many studies, including those that have been adopted as a security blanket by that portion of the public at large who wish to be told something other than that they should strive to lose weight or suffer the consequences. In reality, every increment of visceral fat tissue adds to the risk of age-related disease and early mortality.
Of the two studies I'll point out here, the first is representative of more modern work on the consequences of being overweight, in which the authors take more care with the data, and their conclusions conform to the present consensus. The second is an interesting addition that might be considered to support the idea that the best metric of harm is the amount of excess fat multiplied by how long that level of fat is sustained. So being fat for a few years is bad, and leaves a lasting footprint on your future risk of age-related disease, but being fat for a decade or two is far worse. Like smoking, the best time to stop is always now. Continuing as you are will only make matters worse.
Study of 500,000 people clarifies the risks of obesity
Elevated body mass index (BMI) - a measure of weight accounting for a person's height - has been shown to be a likely causal contributor to population patterns in mortality, according to a new study. Specifically, for those in UK Biobank (a study of middle to late aged volunteers), every 5kg/m2 increase in BMI was associated with an increase of 16 per cent in the chance of death and specifically 61 per cent for those related to cardiovascular diseases.
While it is already known that severe obesity increases the relative risk of death, previous studies have produced conflicting results with some appearing to suggest a protective effect at different parts of the spectrum of body mass index. Until now, no study has used a genetic-based approach to explore this link. The findings which link body mass index and mortality, confirm that being overweight increases a person's risk of death from all causes including cardiovascular diseases and various cancers.
The team applied a method called Mendelian randomization, a technique that uses genetic variation in a person's DNA to help understand the causal relationships between risk factors and health outcomes - here mortality. This method can provide a more accurate estimate of the effect of body mass index on mortality by removing confounding factors, for example, smoking, income and physical activity, and reverse causation (where people lose weight due to ill health), which could explain the conflicting findings in previous observational studies.
Weight Cycling Increases Longevity Compared with Sustained Obesity in Mice
Despite the known health benefits of weight loss among persons with obesity, observational studies have reported that cycles of weight loss and regain, or weight cycling, are associated with increased mortality. To study whether weight loss must be sustained to achieve health and longevity benefits, we performed a randomized controlled feeding study of weight cycling in mice.
In early adult life, obese mice were randomized to ad libitum feeding to sustain obesity, calorie restriction to achieve a "normal" or intermediate body weight, or weight cycling (repeated episodes of calorie restriction and ad libitum refeeding). Body weight, body composition, and food intake were followed longitudinally until death. A subsample of mice was collected from each group for determination of adipose cell size, serum analytes, and gene expression.
Weight loss significantly reduced adipose mass and adipocyte size in both sexes, whereas weight cycling animals regained body fat and cell size during refeeding. Sustained weight loss resulted in a dose-dependent decrease in mortality compared with ad libitum feeding. In conclusion, weight cycling significantly increased life-span relative to remaining with obesity and had a similar benefit to sustained modest weight loss.
Support for Oxidized Cholesterol as a Primary Cause of Atherosclerosis
In the paper I'll point out today, the authors provide evidence in support of the concept that it is specifically oxidized cholesterol that is the primary cause of atherosclerosis rather than the condition resulting from too much cholesterol in general. In atherosclerosis, fatty deposits form in blood vessel walls, weakening them and narrowing the vessels. This ultimately leads to fatal structural failure as stressed blood vessels rupture or are blocked. Atherosclerosis is arguably a condition that arises because the macrophages responsible for removing cholesterol from blood vessel walls become overwhelmed, inflammatory, and incapable of keeping up the work of maintenance and repair. They become foam cells and die, adding their contents and their remnants to grow an atherosclerotic plaque, and attracting more of their fellows to the same location to repeat the cycle.
Here it is argued that this foam cell fate is largely the consequence of oxidized cholesterol. The macrophages are reacting to oxidized cholesterol in ways that sabotage their efforts to remove local deposits of cholesterol. The approach to this condition adopted by the SENS rejuvenation research programs is to find ways to break down the oxidized cholesterol that our cells struggle to deal with. Removing it from the picture should enable cells to continue as they were, and remove the fatty deposits. Researchers associated with the SENS Research Foundation have searched for bacteria capable of consuming these damaged forms of cholesterol, in order to adapt their enzymes into therapeutic molecules. This work has to date largely focused on 7-ketocholesterol, with some early success, but a broader and more heavily funded research program is very much called for.
Modified LDL particles activate inflammatory pathways in monocyte-derived macrophages
One of the main characteristics of atherosclerosis is the accumulation of lipids in the intimal layer of the arterial wall. In atherosclerotic plaques, phagocytic cells, such as macrophages, engulf atherogenic low-density lipoprotein (LDL) particles, but are unable to process them, and thus become foam cells, having cytoplasm packed with lipid droplets. Foam cells are characterized by several typical features: they have decreased ability to migrate, while displaying enhanced production of pro-inflammatory cytokines. Therefore foam cells participate in maintaining chronic inflammation in the lesion.
Previous studies have shown several clusters of genes up- or down-regulated in macrophages in response to oxidized LDL, which is known to be atherogenic. Regarding the inflammatory response, modified LDL appeared to trigger up-regulation of genes with anti-inflammatory activities. We performed a transcriptome analysis of macrophages treated with atherogenic LDL that causes intracellular cholesterol accumulation. We used the strategy of upstream analysis for causal interpretation of the expression changes.
In this study, we discovered 27 transcription factors that were potentially responsible for the changes in gene expression induced by modified atherogenic LDL. These transcription factors were used for identifying the master-regulators (genes and proteins) responsible for regulation of large cascades of differentially expressed genes. In general, the genes that were up-regulated in response to lipid accumulation in macrophages induced by atherogenic LDL were mostly involved in inflammation and immune response, and not in cholesterol metabolism. Our results suggest a possibility that it is not cholesterol accumulation that causes an innate immunity response, but rather the immune response is a consequence of a cellular reaction to modified LDL. These results highlight the importance of the inflammatory component in the pathogenesis of atherosclerosis.
Modified LDL Particles Activate Inflammatory Pathways in Monocyte-derived Macrophages: Transcriptome Analysis
A hallmark of atherosclerosis is its complex pathogenesis, which is dependent on altered cholesterol metabolism and inflammation. Both arms of pathogenesis involve myeloid cells. Monocytes migrating into the arterial walls interact with modified low-density lipoprotein (LDL) particles, accumulate cholesterol and convert into foam cells, which promote plaque formation and also contribute to inflammation by producing proinflammatory cytokines. A number of studies characterized transcriptomics of macrophages following interaction with modified LDL, and revealed alteration of the expression of genes responsible for inflammatory response and cholesterol metabolism. However, it is still unclear how these two processes are related to each other to contribute to atherosclerotic lesion formation.
We attempted to identify the main master regulator genes in macrophages treated with atherogenic modified LDL using a bioinformatics approach. We found that most of the identified genes were involved in inflammation, and none of them was implicated in cholesterol metabolism. Among the key identified genes were interleukin (IL)-7, IL-7 receptor, IL-15, and CXCL8. Our results indicate that activation of the inflammatory pathway is the primary response of the immune cells to modified LDL, while the lipid metabolism genes may be a secondary response triggered by inflammatory signalling.
Recent Research into the Interaction of Exercise and Aging
Today's open access papers touch on aspects of the interaction between exercise and the pace of aging. People age at somewhat different rates, and for the vast majority of us lifestyle is a far greater determinant of that rate than our genes. Until such time as the clinical deployment of rejuvenation therapies is well underway, and in regions of the world sufficiently wealthy to have tamed the majority of infectious disease, it remains the case that our choices regarding our health, such as calorie restriction and exercise, are the most reliable means of improving life expectancy. The size of the effect is not enormous in the grand scheme of things: three quarters of slim, fit, well-considered people die before reaching 90 years of age, after all. You cannot add decades to your life by making incrementally better lifestyle choices.
So why bother? Well, firstly because being increasingly sick for a span of decades at the end of life is a real drag, and exercise and calorie restriction do make a sizable difference to the odds of avoiding much of that fate. But more importantly this is an era of radical, accelerating progress in the life sciences. With every passing year we move closer towards the deployment of real, working rejuvenation therapies. Some of the the first of those, senolytic treatments to clear senescent cells, can already be used by the adventurous. The times are changing rapidly when it comes to medical science. A few years of life gained through exercise, or achieving an extra decade of being fit enough to travel to try new therapies via medical tourism, may well make the difference between considerable benefits and a longer life, or missing out on that chance.
If exercise was incredibly expensive, or if exercise to improve health was only possible at the end of a multi-billion investment in medical research and development, then it wouldn't be worth it. That is the same story as for many lines of development that aim to modestly slow the aging process, those based on replicating calorie restriction, for example. Such treatments will be expensive to create, and the past twenty years tells us that this process has a high rate of failure. It just isn't worth it when other lines of rejuvenation research have far greater expected outcomes in terms of health gained and years added. But exercise is here now, free, and highly reliable. Modest gains achieved at little cost, and that near always work as intended, are not to be ignored. It helps.
The Inherent Human Aging Process and the Facilitating Role of Exercise
Arguably the best available depictions of the global physiological changes produced by age are the profiles of world record performance times in swimming, athletics, and cycling, depicting the trajectory of decline in maximal integrated physiological performance capability. The curves suggest that the aging process produces a synchronized, controlled decrease in physiological performance over the human lifespan. The shape of the performance profile by age is essentially independent of discipline, distance, or phenotype. Importantly, the specific times of performance are not the driving force in the production of the shape of the declining performance profile.
We suggest that in these highly trained individuals the shape of the curve is generated by the aging process operating on a physiology optimized for any given age. We hypothesize that with adequate training this same profile and trajectory, but with lower performance times, would be generated by all individuals who engage in sufficient physical activity/exercise. Unlike performance, data obtained from examining individual physiological systems or tissues do not give information on the unceasing and changing global integrating functions of the aging process. However, these data do give valuable information about the integrity of physiological systems at a particular age and allow a direct comparison to be made between the effects of inactivity and physical activity/exercise.
Being physically active has been shown to have global protective effects on physiological systems and thus facilitates the aging process by maintaining physiological integrity. There is emerging evidence which suggests that physiological regulation of aging may be multi-compartmentalized. We do not advocate exercise as a panacea, but all the evidence indicates that being physically active and exercising is far superior to any other alternative for achieving optimal aging.
Effects of Acute and Chronic Exercise on Immunological Parameters in the Elderly Aged: Can Physical Activity Counteract the Effects of Aging?
Immunosenescence is characterized by deterioration of the immune system caused by aging which induces changes to innate and adaptive immunity. Immunosenescence affects function and phenotype of immune cells, such as expression and function of receptors for immune cells which contributes to loss of immune function (chemotaxis, intracellular killing). Moreover, these alterations decrease the response to pathogens, which leads to several age-related diseases including cardiovascular disease, Alzheimer's disease, and diabetes in older individuals. Furthermore, increased risk of autoimmune disease and chronic infection is increased with an aging immune system, which is characterized by a pro-inflammatory environment, ultimately leading to accelerated biological aging.
During the last century, sedentarism rose dramatically, with a concomitant increase in certain type of cancers (such as breast cancer, colon, or prostate cancer), and autoimmune disease. Numerous studies on physical activity and immunity, with focus on special populations (i.e., people with diabetes, HIV patients) demonstrate that chronic exercise enhances immunity. However, the majority of previous work has focused on either a pathological population or healthy young adults whilst research in elderly populations is scarce. Research conducted to date has primarily focused on aerobic and resistance exercise training and its effect on immunity. This review focuses on the potential for exercise training to affect the aging immune system. The concept is that some lifestyle strategies such as high-intensity exercise training may prevent disease through the attenuation of immunosenescence.
A Demonstration of Regeneration Achieved Using Extracellular Vesicles from Stem Cells
Most present stem cell therapies achieve their positive results through signaling rather than any other action of the transplanted cells. The transplanted cells die fairly rapidly, but their signals change the behavior of native cells for the better for some period of time. Most cell signals are delivered via some form of extracellular vesicle, small membrane-bound packages containing a wide variety of molecules. The contents and variety of vesicles are at this time very poorly cataloged, but it is still possible to make use of them. Vesicles can be harvested from cultured cell populations, and packaging such vesicles as a therapy is somewhat easier than managing cell treatments. As an example of the type, researchers here report on a demonstration in pigs in which they replace the delivery of stem cells with the delivery of extracellular vesicles derived from stem cells, and achieve good results.
Extracellular vesicles are matter that is released by cells. Seen for many years as not having any value, this 'cellular dust' has been studied and presents therapeutic properties similar to their mother cells, without their disadvantages: These vesicles do not divide, limiting the risk of cancer, and do not differentiate either, thus preventing the development of poor function. Furthermore, it appears that they can be produced by a single donor for several patients, and have already demonstrated their therapeutic potential in animals in repairing heart, liver and kidney lesions.
In the case of digestive fistula, in which there is abnormal communication between organs in the digestive tract or with the skin, regenerative medicine is an important therapeutic avenue to explore. Fistulas of this kind respond poorly to current treatments; they can develop following postoperative complications or an autoimmune disorder such as Crohn's disease, which causes digestive tract dysfunction.
For the first time, scientists used extracellular vesicles from stem cells to treat digestive fistula in a swine model. The study reveals that local injections into the fistula of a gel containing these vesicles results in the complete closure of post-operative digestive fistula. Researchers intend to test the new approach in a perineal fistula model found in Crohn's disease, with the hope of replacing the stem cell injections. The vesicle gel could be administered locally and easily and become a simpler, safer and more effective treatment.
The Longevity Forum, a Meeting of Science and Society
Next week, the first Longevity Forum will be held in London. This is a broadening of Jim Mellon's Juvenescence venture, which is a fund that has invested in a number of startups working on therapies to slow or reverse aspects of aging, but perhaps more importantly also a vision for a near future in which aging can be robustly treated as a medical condition, and healthy lives lengthened by many decades as a result. The Juvenescence principals seek not just to invest in a few companies, but to build a new industry: to put in place a supporting ecosystem that can fund the very expensive later stages of development and regulatory approval for entirely new categories of medicine, the suite of rejuvenation therapies that will arrive in the years ahead.
This ambitious project necessarily involves persuading the largest, most conservative and risk-averse institutional sources of funding, those that are capable of devoting hundreds of millions in funding to construct and distribute new medical technologies. Biotechnology startups are just the start of a process, and the rest of society provides the follow-through that leads to widespread availability of better medicine. This goal will involve persuading thought leaders and the public at large of the merits of the vision of longer, healthier lives for all, as large organizations rarely take even a single step beyond the present public consensus of opinions. None of the necessary change will just magically happen. It will all require deliberate effort, and the Longevity Forum is one part of that effort.
We believe that increased longevity presents the biggest opportunity of the 21st century but will require a thoughtful and rapid response to ensure its benefits can be reaped. With every country in the world experiencing an ageing population, the individuals, companies and countries that best adapt will seize a substantial competitive advantage. The Longevity Forum brings together two key pillars of the longevity debate - science and society.
As science catches up with the human aspirations of living longer, a new approach to public health is urgently required. Our Juvenescence agenda advocates a new model for both health promotion and disease prevention which can support healthy longevity, increased life expectancy, improve overall productivity and ensure that healthcare spending is focused on preventing diseases of ageing rather than on curing them.
At the same time, our 100 Year Life agenda recognizes that living healthy and long lives without changes to the three stage structure of life (school, work and retirement) which has defined the 20th century, will not necessarily lead to fulfilled lives. With this in mind, we advocate a move towards a life structure which is better suited to the 21st century, with radical changes to how we approach education, careers, finances, and family life.
Tackling these issues requires a focus not on end of life but all stages of life. We need to ensure that all generations are prepared for a long and healthy life. This new era of longevity requires greater interconnection between education, financial planning, and scientific progress.
Delivery of Noggin to the Brain Improves Stem Cell Function and Neurogenesis in an Accelerated Aging Mouse Model
The challenge when considering any study carried out in an accelerated aging animal model is whether or not the findings have any relevance to normal aging. Aging is at root the accumulation of molecular damage, but this is a specific balance of various forms of damage. Accelerated aging models pile on large amounts of one specific form of molecular damage, usually by suppressing DNA repair mechanisms. The results somewhat replicate the consequences of aging, but they are not aging. Thus one has to understand the fine details of the research in order to have an opinion on whether or not it tells us anything useful about normal aging. This isn't easy for laypeople; even scientists in the field can differ on these matters.
The study here is an example of the type, and a case in which I am not familiar enough with the mechanisms involved to be able to say whether or not the work is helpful. The approach taken by the researchers could just be addressing an aspect of the damage specific to the animal model rather than damage that occurs in aging. Researchers use accelerated aging models because they provide answers more rapidly and at a lower cost. The next step is to take the approach and try it out in normal mice, to see whether or not the results seem similar. It is a good idea to reserve judgement until those results are in hand.
Increasing age is the greatest known risk factor for the sporadic late-onset forms of neurodegenerative disorders such as Alzheimer's disease (AD). One of the brain regions most severely affected in AD is the hippocampus, a privileged structure that contains adult neural stem cells (NSCs) with neurogenic capacity. Hippocampal neurogenesis decreases during aging and the decrease is exacerbated in AD, but the mechanistic causes underlying this progressive decline remain largely unexplored.
We here investigated the effect of age on NSCs and neurogenesis by analyzing the senescence accelerated mouse prone 8 (SAMP8) strain, a non-transgenic short-lived strain that spontaneously develops a pathological profile similar to that of AD and that has been employed as a model system to study the transition from healthy aging to neurodegeneration. We show that SAMP8 mice display an accelerated loss of the NSC pool that coincides with an aberrant rise in BMP6 protein, enhanced canonical BMP signaling, and increased astroglial differentiation.
In vitro assays demonstrate that BMP6 severely impairs NSC expansion and promotes NSC differentiation into postmitotic astrocytes. Blocking the dysregulation of the BMP pathway in vivo by intracranial delivery of the antagonist Noggin restores hippocampal NSC numbers, neurogenesis, and behavior in SAMP8 mice. Thus, manipulating the local microenvironment of the NSC pool counteracts hippocampal dysfunction in pathological aging. Our results shed light on interventions that may allow taking advantage of the brain's natural plastic capacity to enhance cognitive function in late adulthood and in chronic neurodegenerative diseases such as AD.
A Phase III Trial Based on the Peripheral Amyloid Sink Concept Succeeds in Slowing Alzheimer's Disease
Results announced by the sponsors of a recently concluded phase III trial in Alzheimer's patients do not represent a cure, but the treatment did more than halve the progression of the condition. The approach involved removing amyloid-β from the blood rather than from the brain. Levels of amyloid-β are dynamic, and there is an equilibrium between the amount found in the brain and the amount found elsewhere. Past studies have shown that reducing amyloid in the blood can reduce its presence in the brain, the result of a new equilibrium.
This seems like an important confirmation of the amyloid hypothesis of Alzheimer's disease, at a time at which it is coming under increasing attack. The long history of failed attempts to show clinical benefits from clearing amyloid-β have led to a diversity of competing theory and initiatives, and an increased focus on tau aggregration rather than amyloid aggregation as the major cause of pathology in the later stages of the condition. I'd also take this as indirect support for the impaired drainage view of Alzheimer's, in which the paths by which cerebrospinal fluid exits the brain atrophy with age, and thus rates of removal for a range of forms of metabolic waste are reduced.
Alzheimer Management by Albumin Replacement (AMBAR) is an international, multicenter, randomized, blinded, and placebo controlled, parallel group clinical trial that enrolled mild and moderate Alzheimer patients from 41 treatment centers in Europe and the United States. The study was designed to evaluate the efficacy and safety of short-term plasma exchange followed by long-term plasmapheresis with infusion of Human Albumin combined with intravenous immunoglobulin in patients with mild and moderate Alzheimer's disease.
AMBAR is based on the hypothesis that most of the amyloid-beta protein - one of the proteins accumulated in the brains of Alzheimer's patients - is bound to albumin and circulates in plasma. Extracting this plasma may flush amyloid-beta peptide from the brain into the plasma, thus limiting the disease's impact on the patient's cognitive functions. Additionally, Albumin may represent a multi-modal approach to the management of the disease due to it's binding capacity, antioxidant, immune modulatory, and anti-inflammatory properties.
The AMBAR study included 496 mild and moderate Alzheimer patients, randomized in three treatment groups and one control (placebo) group. The participants were 55-85 years old and the efficacy of treatment was measured by changes in cognition and in daily living activities scores. An independent contract research organization (CRO), oversaw the trial's clinical monitoring phase and managed the data collection and analysis stages. The trial employed a randomized and double-blind design, meaning that neither patients nor evaluators knew whether subjects were receiving the treatment or the placebo.
The analysis of AMBAR data in moderate patients has shown positive, highly relevant results in a cohort of patients suffering from moderate Alzheimer's disease. In the three-combination arms the differences to placebo showed between 50 and 75% less decline for the Alzheimer's Disease Assessment Scale-cognitive (ADAS-Cog) in the treated patients and between 42 and 70% less decline for the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) scale. In the arm with all patients treated with plasma exchange the difference to placebo achieved a 66% less decline for the ADAS-Cog scale in the treated patients and a 52% less decline for the ADCS-ADL scale.
A Role for Sarcosine in the Benefits of Calorie Restriction
Calorie restriction slows aging and extends life span in near all species tested to date. Unfortunately the magnitude of life extension declines as species life span increases, and in humans is probably no more than a few years. Nonetheless, the short-term beneficial changes to metabolism are quite evident in human practitioners, the practice of calorie restriction reduces the risk of suffering age-related disease, and it is still the case that for most people the only approaches likely to produce equivalent or greater reliable, sustained health benefits are exercise and the use of senolytic therapies.
Calorie restriction largely functions through upregulation of the cellular maintenance processes of autophagy. This is demonstrated by the fact that models with disabled autophagy do not exhibit extended life spans when subjected to calorie restriction. There are of course also the secondary benefits that derive from a low level of visceral fat tissue that necessarily accompanies a low calorie diet, but the autophagy is nonetheless vital. New discoveries by researcher groups involved in mapping the complex changes induced by calorie restriction are often related to autophagy, and this is the case here.
The metabolomic profile of aging has also been assessed in a number of species, including Drosophila melanogaster, naked mole rat, marmoset, and humans. Tissue-specific metabolomic signatures were reported to correlate with body mass and lifespan across a diverse number of species, and some tissue metabolites were found that discriminated long-lived rodents from controls. Although data on metabolomic shifts with aging and diet are rapidly accumulating, replication across studies has been limited, which has slowed progress toward ascertaining consensus hallmark candidates and signatures that define the aging metabolome across sex, strain, and species. Furthermore, to what extent these metabolomic shifts are merely a consequence of aging per se, as opposed to playing a causal role in the aging process, has been difficult to discern from what has largely been observational data.
Here, we have characterized changes in the metabolome with aging and dietary restriction (DR) using established techniques in a well-characterized hybrid rat model of aging. We have also interrogated the metabolome for shared changes in a set of human samples obtained from a cohort of younger and older subjects consuming a Western or DR diet. We report on some unique shifts in the metabolome, including alterations in glycerophospholipids, biogenic amines, and amino acids with diet and age. In addition, statistical analyses revealed that DR is a stronger driver of the circulating and tissue rat metabolomic phenotype than age.
When screening for metabolites with similar responses between species, we identified circulating sarcosine, a biogenic amine involved in methionine (Met), glycine, and folate metabolism, as decreased with aging per se in rodents and humans and increased by DR in both species. These shifts correlated with changes in rat liver glycine-N-methyltransferase (GNMT) content, which is a known sarcosine-generating enzyme. Long-lived Ames dwarf mice demonstrate significantly elevated sarcosine levels across age, while correlation analysis of metabolites following sarcosine refeeding in old rats prominently places this metabolite as an integral node linking amines, amino acids, glycerophospholipids, and sphingolipids. We also show that sarcosine feeding reduces Met levels in old animals and is a strong activator of macroautophagy in vitro and in vivo.
Taken together, these data identify sarcosine as a potentially important biomarker of diet and aging in mammals and suggest that this metabolite plays a previously unappreciated role in mediating at least some of the beneficial effects attributed to DR on proteostasis.
Combinations of Approaches to Slow Aging are Not Well Explored
Scores of distinct ways to modestly slow aging in short-lived species have been demonstrated in the laboratory over the past decades. Many are redundant, influencing the same underlying mechanism, but others produce effects on the operation of cellular metabolism that are different enough to be synergistic. Unfortunately the research community does very little work on combined therapies; this true for all fields of medicine, not just aging. This is perhaps partially the culture of science, and partially the consequence of heavy handed regulation and intellectual property law. The financial incentives at all level of research and development make it harder to set out to combine therapies or potential therapies than to just work on something else.
Still, some efforts take place, though they fall far short of the "let's try everything at once" concepts that may make sense from a practical point of view. Combining every known method of slowing aging will at the end of the day still fail to produce rejuvenation, as the underlying damage that causes aging is not repaired to any significant extent, but it may well produce enough of a benefit to be worth trying, given that the approaches already exist in some form.
The idea behind the study was to test whether combinations of drugs known to extend healthspan and/or lifespan in animal models could work in synergy and produce even more pronounced effects. The team chose rifampicin, rapamycin, psora-4, metformin, and allantoin. Some of these, namely rapamycin and metformin, are well-known for their connection to lifespan, though their original purposes were somewhat different - rapamycin is used to prevent organ transplant rejection, whereas metformin is a 50-year-old, off-patent drug used to treat type 2 diabetes.
The researchers used C. elegans nematodes as test subjects; their intent was to see which drug combinations, if any, would provide the largest health and lifespan benefits without causing toxicity. While some combinations did turn out to be toxic or no more effective than the single drugs, others proved significantly more effective when used together; In particular, the combination of rapamycin, rifampicin, and allantoin achieved an 89% extension of mean lifespan, whereas rifampicin, psora-4 and allantoin resulted in a 96% increase of mean lifespan - all of which were without any toxicity.
It is also very important to note is that all treated worms of all ages didn't just live longer; rather, they spent a larger portion of their extra lifespan in good health, which constitutes even more evidence that interfering with the aging processes is a promising avenue to obtain significant health gains. Interestingly, comparable effects were observed when testing similar drug cocktails in fruit flies; nematodes and fruit flies are significantly far apart, evolutionarily speaking, which, according to the researchers, suggests that the aging mechanisms targeted by these drug combinations must trace all the way back to an ancient common ancestor of the two species. This is good news for humans, as it increases the likelihood that similar interventions might work in us as well.
Market Analysts on the Future of Aging
Enough funding is now flowing into the clinical development of therapies to slow or reverse aging to ensure that the analysis and white paper industry has started to pay attention. Their efforts are one of the ways in which ideas move through the business community; market analyst organizations play a role somewhat analogous to that of media outlets. Their job is to inform, some are highly opinionated, and their efforts can cause some ideas to be taken more seriously than others.
That analysts are producing materials such as the example noted here is a sign that greater investment in this field is ahead. That said, it remains the case that, absent better guidance, new funding may largely support low-yield efforts that can only modestly slow aging, such as calorie restriction mimetic development, rather than high-yield efforts involving forms of rejuvenation therapy. Providing that guidance is an important function of our advocacy community, as outsiders typically find it challenging to tell the difference between better and worse approaches to the treatment of aging as a medical condition.
Senolytics. Blood transfusions. Placenta stem cells. These are just some of the innovative ways that startups are tackling mortality and increasing the human lifespan. How can we live longer? How do we become healthy enough so that we can extend our lifespans by 5, 10, or even 50 extra years? And it's not just about living longer, but also feeling younger. For example, what if you could feel 25 at the age of 75? These are the big questions that scientists have been trying to answer for decades, with few answers.
Understanding how we age on a physiological level is an incredibly complex topic. It shares many of the cellular and molecular processes that underlie age-related diseases like cancer or Alzheimer's, which continue to elude us in their pathology. While aging itself isn't a treatable disorder or condition, companies and researchers focused on longevity are looking at bodily processes at the cellular level to see how aging progresses and trying to find the right drugs, treatments, and vitamins that might slow these processes down. And as a result, we may discover the key to longevity, or living a longer life.
For instance, a new class of drugs known as "senolytics" are now being touted as the next big thing in anti-aging research for getting rid of decrepit (but harmful) cells that stop dividing as we age, known as senescent cells. And it's not just the biotech or pharma companies looking to combat mortality with novel drug therapies. Wellness companies are developing daily supplements that claim to prolong your lifespan. And some startups are even offering blood transfusions from younger individuals for a "rejuvenating" effect.
In this report, we explore the current landscape of initiatives that aim to slow down the aging process, and in turn, reduce the likelihood of several diseases. We look at how these initiatives could promote longevity and what this market looks like for both investors and consumers.
Final Stretch Goal for the Lifespan.io NAD+ Mouse Study Crowdfunding Event
The latest Lifespan.io crowdfunding project launched last month and is already closing in on the final stretch goal of 75,000; congratulations to everyone involved. The funds will be used to run a mouse study of nicotinamide mononucleotide (NMN) supplementation, one of a number of similar approaches that can increase NAD+ levels in older animals. This in turn improves mitochondrial function, though without addressing any of the underlying causes of mitochondrial decline with aging - it is a way to narrowly compensate for some of the metabolic consequences of aging, or to selectively override some of the reactions to the biochemical damage of aging. It isn't repair, but it clearly produces some benefits. A study of increased NAD+ levels using the alternative approach of nicotinamide riboside supplementation in older humans showed a reduction in blood pressure, most likely by improving the performance of smooth muscle cells in blood vessel walls. The metrics taken over the course of this Lifespan.io funded mouse study will allow researchers to assess the degree to which the NMN intervention can slow aging in mice.
Yesterday, we announced the successful completion of the NAD+ Mouse Project after a great fundraiser, but it seems we are not done yet. The research team at Harvard has announced a new stretch goal for the last two days of the campaign. A new 75,000 goal is to be the final step, and to support that, Dr. David Sinclair is offering to fund match the next 5000 in donations to the project to help it reach this final goal. So, for the next two days, all donations are worth double.
In our project, we will test the hypothesis that by restoring bioavailable NAD+ we can reverse aspects of the aging process. Starting with mice that are 20 months old (roughly equivalent to a 50 year old human), longer-term NMN treatments will be applied in order to restore levels of cellular NAD+ to those found in youthful mice. Your donations will not only allow us to purchase the materials necessary to perform this experiment, but also pave the way for human clinical trials aimed at showing, for the first time, that we can actually slow down human aging.
The final stretch goal will be to add even more comprehensive testing, such as end-of-life pathology (frequency and specificity of neoplasms/tumors/cancer) and MRI diagnostics (body composition, lean-to-fat ratio). This would really allow the researchers to maximize the useful data they collect during the study and help assess any changes to cancer risk, why each animal died, and what age-related diseases were affected by the drug.
Complicating the Correlation Between Wealth and Life Expectancy
In a recent publication, researchers argue that there are flaws in past studies showing that, for the US population, wealth correlates with a sizeable increase in life expectancy. Those studies failed to consider the highly dynamic nature of wealth. Only a fraction of the population maintains a given level of wealth for decades: individual fortunes rise and fall quite rapidly. Taking this into account, the data actually shows that the size of the wealth effect for life expectancy is half of that previously estimated.
This is something of a distraction, however. The only real methodology by which wealth can be used to buy additional years of healthy life is to invest it into the right forms of medical research and development, meaning the establishment of rejuvenation therapies based on the SENS model of damage repair. Unfortunately all too few wealthy individuals have realized that this option is on the table. We can hope that this will change in the years ahead, as the first rejuvenation therapies worthy of the name make their way to the clinic.
New research results challenge previous findings of huge differences in life expectancy between the rich and those at the bottom of the income scale. In real life people don´t necessarily stay poor or stay rich, as assumed in previous research, and economists have now found a way to take this mobility between income-classes into account providing a more realistic way to calculate life expectancy for people from different walks of society. Their results show that in reality the difference between the lifespan of a rich and a poor person is really not that big.
In 2016 a research team showed that high-income people in the US can expect to live 6.5 years longer at age 40 than low-income individuals. The existing method assumes that the poor stay poor and the rich stay rich for the rest of their lives. In reality, however, over a ten-year period half of the poorest people actually move into groups with better incomes and likewise, half of the rich leak down into lower income classes. The mortality of those who move to a different income class is significantly different from those who stay in the same class.
When accounting for income mobility, life expectancy for a 40-year-old man in the upper income groups is 77.6 years compared with 75.2 for a man in poorer groups - a difference of 2.4 years. For women the difference between high and low-income groups is 2.2 years. However, without taking the income mobility into account the life expectancy difference was twice as big - around five years - for both men and women. Using the method, the authors suggest that the difference in the US is three years rather than 6.5.
Calorie Restriction Reduces the Inflammation Associated with Arterial Aging
The practice of calorie restriction slows aging across the board. Near every known measure of aging is diminished in calorie restricted mice, and it produces significant health gains in humans. While the short term benefits of calorie restriction are quite similar in all mammals, the long term gain in life span is only large in short-lived species. Understanding why this is the case will require a near complete understanding of cellular metabolism as a whole. Researchers can pinpoint key controlling mechanisms, but the interaction between cellular metabolism and the pace of aging is enormously complex, and far from fully mapped. This is one of the reasons why progress towards calorie restriction mimetic drugs has been so painfully slow and expensive.
The example here is one of many in which calorie restriction is shown to reduce the extent of an issue that accompanies aging. Chronic inflammation is a dysregulation of the immune system and associated signaling that has serious consequences over time, accelerating the progression of all of the common age-related conditions. It is particularly damaging in the context of blood vessel walls, where the immune cells known as macrophages gather in attempts to clean up the deposits of cholesterol associated with atherosclerosis. Inflammation is well known to speed up the growth of the atherosclerotic plaques that ultimately cause a stroke or heart attack. Less of it is a good thing.
Aging exponentially increases the incidence of morbidity and mortality of quintessential cardiovascular disease mainly due to arterial proinflammatory shifts at the molecular, cellular, and tissue levels within the arterial wall. Calorie restriction (CR) in rats improves arterial function and extends both health span and life span. How CR affects the proinflammatory landscape of molecular, cellular, and tissue phenotypic shifts within the arterial wall in rats, however, remains to be elucidated.
Aortae were harvested from young (6-month-old) and old (24-month-old) Fischer 344 rats, fed ad libitum and a second group maintained on a 40% CR beginning at 1 month of age. Histopathologic and morphometric analysis of the arterial wall demonstrated that CR markedly reduced age-associated intimal medial thickening, collagen deposition, and elastin fractionation/degradation within the arterial walls. Immunostaining/blotting showed that CR effectively prevented an age-associated increase in the density of platelet-derived growth factor, matrix metalloproteinase type II activity, and transforming growth factor beta 1 and its downstream signaling molecules, phospho-mothers against decapentaplegic homolog-2/3 (p-SMAD-2/3) in the arterial wall. In early passage cultured vascular smooth muscle cells isolated from AL and CR rat aortae, CR alleviated the age-associated vascular smooth muscle cell phenotypic shifts, profibrogenic signaling, and migration/proliferation in response to platelet-derived growth factor.
In conclusion, CR reduces matrix and cellular proinflammation associated with aging that occurs within the aortic wall and that are attributable to platelet-derived growth factor signaling. Thus, CR reduces the platelet-derived growth factor-associated signaling cascade, contributing to the postponement of biological aging and preservation of a more youthful aortic wall phenotype.