Fight Aging!

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Contents

• Intervene Immune Publishes Thymus Regrowth Trial Results
• Clonal Mutation in Immune Cells Correlates with Epigenetic Age Acceleration
• Lower LDL Cholesterol and Blood Pressure Over a Lifetime Correlate with Greatly Reduced Risk of Cardiovascular Disease
• Short Term versus Long Term Gains in Working Memory Following Exercise
• Embedded 3D Printing Used to Assemble Tiny Organoids into Larger Vascularized Tissue Masses
• Aspirin Use Fails to Postpone Disability and Improve Survival in Older Individuals
• Inhibition of mTORC1 as a Treatment to Slow the Consequences of Muscle Aging
• Long-Lived Dwarf Mice Exhibit an Improved Mitochondrial Stress Response
• Oral Bacteria Mediate Short Term Lowering of Blood Pressure Following Exercise
• Dsyfunctional Autophagy Promotes Cellular Senescence in Long-Lived Neurons
• Upregulation of Autophagy Reverses Age-Related Decline of Memory B Cell Function
• LEAF Interviews David Sinclair
• Repair of a Damaged Cornea Using Cells Derived from Induced Pluripotent Stem Cells
• Senolytic Treatment Reverses Age-Related Loss of Regenerative Capacity in the Liver
• Evidence for an Intestinal Origin of Parkinson's Disease

Intervene Immune Publishes Thymus Regrowth Trial Results
https://www.fightaging.org/archives/2019/09/intervene-immune-publishes-thymus-regrowth-trial-results/

Intervene Immune is the company formed to commercialize the methology for regrowth of thymic tissue used in the small TRIIM (Thymus Regeneration, Immunorestoration, and Insulin Mitigation) trial, a combination of growth hormone, DHEA, and metformin. As I've noted in the past, that the approach involves the use of human growth hormone over an extended period of time makes it less desirable as an intervention, but if one can gain an expectation of some thymic regeneration, leading to an extended improvement in immune function that lasts for years beyond the treatment period, then it might be worth the trade-off. In general, higher growth hormone levels are associated with a worse outcome in the study of aging, while lower levels are associated with a slowing of aging. Using growth hormone for anything other than treating rare clinical conditions of deficiency is something like burning the candle at both ends.

The thymus is an inaccessible organ in the chest responsible for transforming thymocytes created in the bone marrow into T cells of the adaptive immune system. This complicated process takes place in thymic tissue that, unfortunately, atrophies with age, becoming replaced with fat. The less tissue, the fewer T cells are generated, and the worse the function of the immune system over time. The thymus loses much of its mass quite early in life, following childhood, but the later, slower decline over the course of adult life is a different process mediated by chronic inflammation and other factors that arise with old age. The adaptive immune system is vital to health, and thus a great deal of research has taken place over the past few decades into means of thymic regeneration: upregulation of FOXN1 or related genes such as BMP4; engineering of new thymic tissue; delivery of recombinant KGF, delivery of growth hormone; sex steroid ablation; and so forth. Some are more reliable than others, and some, such as KGF, have succeeded in mice and failed in human trials.

The Intervene Immune team has presented a fair amount of data on the results from their trial at recent conferences, including epigenetic age changes, and you'll find it all in the open access paper noted here. The results unfortunately don't include all of the assays of immune cell characteristics one might want in order to be able to compare directly with the effects of sex steroid ablation in human patients, but are intriguing. (In turn the sex steroid ablation trials didn't look at thymic mass in CT scans, an unfortunate omission). Further, it isn't possible to clearly associate all of the outcomes with regrowth of thymic tissue, particularly the epigenetic age effects, given everything else the treatment might be doing. Nonetheless, taken as a whole this is good supporting evidence for those groups working on more direct approaches to the problem of the atrophied thymus, such as Lygenesis and the company Bill Cherman and I founded last year, Repair Biotechnologies.

First hint that body's 'biological age' can be reversed

A small clinical study has suggested for the first time that it might be possible to reverse the body's epigenetic clock, which measures a person's biological age. For one year, nine healthy volunteers took a cocktail of three common drugs - growth hormone and two diabetes medications - and on average shed 2.5 years of their biological ages, measured by analysing marks on a person's genomes. The participants' immune systems also showed signs of rejuvenation.

The latest trial was designed mainly to test whether growth hormone could be used safely in humans to restore tissue in the thymus gland. The gland, which is in the chest between the lungs and the breastbone, is crucial for efficient immune function. White blood cells are produced in bone marrow and then mature inside the thymus, where they become specialized T cells that help the body to fight infections and cancers. But the gland starts to shrink after puberty and increasingly becomes clogged with fat. Evidence from animal and some human studies shows that growth hormone stimulates regeneration of the thymus. But this hormone can also promote diabetes, so the trial included two widely used anti-diabetic drugs, dehydroepiandrosterone (DHEA) and metformin, in the treatment cocktail.

Checking the effect of the drugs on the participants' epigenetic clocks was an afterthought. The clinical study had finished when researchers conducted an analysis. Four different epigenetic clocks were used to assess each patient's biological age, and he found significant reversal for each trial participant in all of the tests. "This told me that the biological effect of the treatment was robust. The effect persisted in the six participants who provided a final blood sample six months after stopping the trial. Because we could follow the changes within each individual, and because the effect was so very strong in each of them, I am optimistic,"

Reversal of epigenetic aging and immunosenescent trends in humans

Thymus regeneration and reactivation by growth hormone administration have been established in aging rats and dogs by restoration of youthful thymic histology and by reversal of age-related immune deficits. The present study now establishes highly significant evidence of thymic regeneration in normal aging men accompanied by improvements in a variety of disease risk factors and age-related immunological parameters as well as significant correlations between thymic fat-free fraction (TFFF) and favorable changes in monocyte percentages and the lymphocyte-to-monocyte ratio (LMR), independent of age up to the age of 65 at the onset of treatment. These observations are consistent with the known ability of growth hormone to stimulate hematopoiesis and thymic epithelial cell proliferation. Our finding of an increase in FGF-21 levels after 12 months of treatment suggests that thymic regeneration by the present treatment may be mediated in part by this cytokine, which we believe is a novel finding.

Treatment-induced increases in naïve CD4 and naïve CD8 T cells were relatively small compared to changes reported in recombinant growth hormone treated HIV patients, but our volunteer population was pre-immunosenescent and not depleted of naïve CD4 and naïve CD8 T cells at baseline. Positive responses also occurred despite potential complications caused by lymph node aging. Therefore, the small increases observed in these cells and in CD4 T-cell recent thymic emigrants are consistent with the ultimate goal of preventing or reversing the normal age-related collapse of the TCR repertoire at ages just above those of our study population.

There may be both immunological and non-immunological mechanisms of epigenetic aging reversal. Growth hormone, DHEA, and metformin have unique effects that are in opposition to aging, and it is possible that the specific combination of these agents activates a broad enough range of therapeutic pathways to account for the previously unpredictable reversal of epigenetic aging, even independently of the immunological markers we have measured.

Clonal Mutation in Immune Cells Correlates with Epigenetic Age Acceleration
https://www.fightaging.org/archives/2019/09/clonal-mutation-in-immune-cells-correlates-with-epigenetic-age-acceleration/

The nuclear DNA encoding near all of the protein machinery necessary to cell function is constantly damaged and constantly repaired. The repair mechanisms are highly efficient, and are backed up by numerous other systems intended to destroy cells that suffer particularly critical DNA damage, mutations that can lead to cancer or severe dysfunction. Nonetheless, damage accumulates. Near all of this damage is irrelevant, as it occurs randomly in single somatic cells with a limited life span, in genes that the cell isn't using. Unfortunately, there are ways for DNA damage to become significant.

The first is obviously cancer, a condition arising from particular combinations of mutational damage that allow a cell to replicate aggressively without limit. The second is when damage occurs in a stem cell or progenitor cell that will create large numbers of descendant somatic cells. A mutation can be spread widely throughout a tissue, and the resulting patchwork of mutations is known as somatic mosaicism. It is thought that somatic mosaicism contributes to the general level of dysfunction in aging tissue, but this is hard to prove at the present time: the compelling experiment that isolates only this class of nuclear DNA damage as a factor and links it to specific aspects of aging has yet to be designed and carried out. It is easy to generate nuclear DNA damage in animal models, via radiation or genetic engineering to disable repair mechanisms, and indeed this causes harm, but it is not the same thing at all.

Today's research is focused on a form of somatic mosaicism in the immune system, known as age-related clonal haemopoiesis (ARCH), this designation limited to mutations in a small range of genes associated with cancer risk. Mutations arise in hematopoietic stem cells or progenitor cells, just as elsewhere, and as a consequence large numbers of immune cells bear those mutations. When this occurs in the ARCH genes related to cancers of the immune system, such as leukemia, it raises the risk of cancer and earlier mortality, the latter possibly due to increased risk of cardiovascular disease. One can speculate on why the increased risk of cardiovascular disease occurs, such as the importance of macrophages to the development of atherosclerosis, but a solid understanding is lacking.

In the same vein, researchers here show that age-related clonal haemopoiesis is correlated with an increased epigenetic age. At this point an acceleration of epigenetic age, to have a higher epigenetic age than chronological age, should probably be expected for any underlying state that raises all cause mortality, given the large amount of evidence for patients with specific age-related diseases to have higher epigenetic age measures. Unfortunately we don't yet have a reliable technology that allows low-risk replacement of hematopoietic stem cell populations: it is possible via hematopoietic stem cell transplantation, but this is a traumatic procedure involving chemotherapy and significant side-effects. But given a way to safely destroy existing hematopoietic cell populations and introduce new undamaged populations, a great many issues in aging might be addressed meaningfully. It is a goal to work towards.

DNA changes accelerate body's ageing

DNA changes throughout a person's life can significantly increase their susceptibility to heart conditions and other age-related diseases, research suggests. Such alterations - known as somatic mutations - can impact the way blood stem cells work and are associated with blood cancers and other conditions. A study says that these somatic mutations and the associated diseases they cause may accelerate a person's biological age - how old their body appears - faster than their chronological age - the number of years they have been alive.

A study examined these changes and their potential effects in more than 1000 older people from the Lothian Birth Cohorts (LBCs), born in 1921 and 1936. The LBCs are a group of people - now in their 80s and 90s - who sat intelligence tests as 11-year olds. They are some of the most-intensively studied research participants in the world. Scientists studied people where the biological and chronological age was separated by a large gap. They found the participants with somatic mutations - around six per cent - had a biological age almost four years older than those with no alterations. Experts say they will now explore the link between these DNA changes and biological ageing acceleration.

Age-related clonal haemopoiesis is associated with increased epigenetic age

Age-related clonal haemopoiesis (ARCH) in healthy individuals was initially observed through an increased skewing in X-chromosome inactivation. More recently, several groups reported that ARCH is driven by somatic mutations, with the most prevalent ARCH mutations being in the DNMT3A and TET2 genes, previously described as drivers of myeloid malignancies. ARCH is associated with an increased risk for haematological cancers. ARCH also confers an increased risk for non-haematological diseases, such as cardiovascular disease, atherosclerosis, and chronic ischemic heart failure, for which age is a main risk factor.

Whether ARCH is linked to accelerated ageing has remained unexplored. The most accurate and commonly used tools to measure age acceleration are epigenetic clocks: they are based on age-related methylation differences at specific CpG sites. Deviations from chronological age towards an increased epigenetic age have been associated with increased risk of earlier mortality and age-related morbidities. Here we present evidence of accelerated epigenetic age in individuals with ARCH.

Lower LDL Cholesterol and Blood Pressure Over a Lifetime Correlate with Greatly Reduced Risk of Cardiovascular Disease
https://www.fightaging.org/archives/2019/09/lower-ldl-cholesterol-and-blood-pressure-over-a-lifetime-correlate-with-greatly-reduced-risk-of-cardiovascular-disease/

Numerous genetic variants correlate with either lower LDL cholesterol or lower blood pressure. Some of these have been shown to result in greatly reduced risk of cardiovascular disease, such as variants in APOB, DSCAML1, ANGPTL4, and ASGR1. Researchers here adopt the position that one can use data on the health of individuals with these and other variants from a large population database as a way to model the outcome should a non-variant individual diligently control LDL cholesterol and blood pressure through lifestyle choices throughout life. This is probably a fair assumption, though it is also fair to suggest that not all of the relevant mechanisms touched on by these genetic variants are fully understood.

As one might expect, based on the results from earlier studies of specific variants and risk of cardiovascular disease, the data here shows a large reduction in risk for people who have one or more of these variants. This can then be associated with the level of reduction in LDL cholesterol and blood pressure needed for a non-variant individual to achieve the same outcome. Assuming, of course, that cholesterol levels and blood pressure are the only relevant mechanisms, or at least the dominant mechanisms. They are undoubtedly influential, given that higher LDL cholesterol accelerates atherosclerosis and higher blood pressure results in all sorts of tissue damage, but they are not the only influential processes in aging.

A life of low cholesterol and BP slashes heart and circulatory disease risk

In this study, researchers studied 438,952 participants in the UK Biobank, who had a total of 24,980 major coronary events - defined as the first occurrence of non-fatal heart attack, ischaemic stroke, or death due to coronary heart disease. They used an approach called Mendelian randomisation, which uses naturally occurring genetic differences to randomly divide the participants into groups, mimicking the effects of running a clinical trial.

People with genes associated with lower blood pressure, lower LDL cholesterol, and a combination of both were put into different groups, and compared against those without these genetic associations. Differences in blood LDL cholesterol and systolic blood pressure (the highest level that blood pressure reaches when the heart contracts), along with the number of cardiovascular events was compared between groups.

A long-term reduction of 1 mmol/L low-density lipoprotein (LDL), or 'bad' cholesterol, in the blood with a 10 mmHg reduction in blood pressure led to an 80 percent lower lifetime risk of developing heart and circulatory disease. This combination also reduced the risk of death from these conditions by 67 percent. The team found that even small reductions can provide health benefits. A decrease of 0.3 mmol/L LDL cholesterol in the blood and 3 mmHg lower blood pressure was associated with a 50 percent lower lifetime risk of heart and circulatory disease.

Association of Genetic Variants Related to Combined Exposure to Lower Low-Density Lipoproteins and Lower Systolic Blood Pressure With Lifetime Risk of Cardiovascular Disease

Numerous randomized trials have demonstrated that treatment for up to 5 years with therapies that reduce low-density lipoprotein cholesterol (LDL-C) and systolic blood pressure (SBP) reduce the risk of cardiovascular events. In addition, mendelian randomization studies suggest that the benefit of exposure to lower LDL-C levels and lower SBP may accumulate over time. Because the biological effects of LDL-C and SBP may be cumulative, long-term exposure to the combination of both could potentially substantially reduce the lifetime risk of cardiovascular disease. However, the association of combined lifetime exposure to both lower LDL-C and lower SBP with the risk of cardiovascular disease has not been reliably quantified.

Ideally, this question would be addressed by conducting a randomized trial to minimize the effect of confounding that can occur in observational studies. However, a randomized trial evaluating the association between maintaining prolonged exposure to both lower LDL-C levels and lower SBP with the risk of cardiovascular disease would take several decades to complete, and therefore is unlikely to ever be conducted.

In an attempt to fill this evidence gap, this study used genetic variants associated with lower LDL-C levels and SBP as instruments of randomization to divide participants into groups with lifelong exposure to lower LDL-C levels, lower SBP, or both; and then compared the differences in plasma LDL-C, SBP, and cardiovascular event rates in each group to estimate the association of combined lifetime exposure with the lifetime risk of cardiovascular disease in a manner analogous to a long-term randomized clinical trial. The primary objective of this study was to assess and quantify the association of prolonged exposure to the combination of both lower LDL-C and lower SBP with the lifetime risk of cardiovascular disease.

Short Term versus Long Term Gains in Working Memory Following Exercise
https://www.fightaging.org/archives/2019/09/short-term-versus-long-term-gains-in-working-memory-following-exercise/

Research has established that exercise rapidly produces an improvement in memory function, within a matter of minutes. It is also the case that regular exercise slows cognitive decline with age and taking up exercise improves cognitive function in older individuals, when considered over the long term rather than immediately following exercise. Given that only a minority of the population in wealthier parts of the world, and particularly the older segment of the population, exercise to the degree recommended to best maintain health, these findings should probably be considered more a case of people doing themselves harm than a case of there being benefits to be obtained.

Today's research materials are interesting for directly comparing the short term and long term benefits of exercise to the operation of working memory in older people. The effect size is about the same, in that the same degree of improvement is observed immediately following exercise versus after a period of regular exercise, but the former benefit is very short-lived, while the latter benefit is sustained over time. The short-term benefit is also only observed in some people, and those differences correlated with structural differences in the brain. Is this all of any practical use at the present time, beyond being yet another recommendation to undertake more exercise? Probably not, but in the long term there is no such thing as useless knowledge.

New study suggests exercise is good for the aging brain

Researchers have found that a single bout of exercise improves cognitive functions and working memory in some older people. In experiments that included physical activity, brain scans, and working memory tests, the researchers also found that participants experienced the same cognitive benefits and improved memory, for a short time, from a single exercise session as they did in a sustained fashion from longer, regular exercise.

Previous research has shown exercise can confer a mental boost. But the benefits vary: One person may improve cognitively and have improved memory, while another person may show little to no gain. Limited research has been done on how a single bout of physical activity may affect cognition and working memory specifically in older populations, despite evidence that some brain functions slip as people age. Researchers wanted to tease out how a single session of exercise may affect older individuals. The team enrolled 34 adults between 60 and 80 years of age who were healthy but not regularly active. Each participant rode a stationary bike on two separate occasions - with light and then more strenuous resistance when pedaling - for 20 minutes. Before and after each exercise session, each participant underwent a brain scan and completed a memory test.

After a single exercise session, the researchers found in some individuals increased connectivity between the medial temporal lobe (which surrounds the brain's memory center, the hippocampus) and the parietal cortex and prefrontal cortex, two regions involved in cognition and memory. Those same individuals also performed better on the memory tests. Other individuals showed little to no gain. The boost in cognition and memory from a single exercise session lasted only a short while for those who showed gains, the researchers found.

The participants also engaged in regular exercise, pedaling on a stationary bike for 50 minutes three times a week for three months. One group engaged in moderate-intensity pedaling, while another group had a mostly lighter workout in which the bike pedals moved for them. Most individuals in the moderate and lighter-intensity groups showed mental benefits, judging by the brain scans and working memory tests given at the beginning and at the end of the three-month exercise period. But the brain gains were no greater than the improvements from when they had exercised a single time.

Acute Exercise Effects Predict Training Change in Cognition and Connectivity

Previous studies report memory and functional connectivity of memory systems improve acutely after a single aerobic exercise session or with training, suggesting the acute effects of aerobic exercise may reflect initial changes that adapt over time. In this trial, for the first time, we test the proof-of-concept of whether the acute and training effects of aerobic exercise on working memory and brain network connectivity are related in the same participants. Cognitively normal older participants (N=34) were enrolled in a randomized clinical trial. Participants completed fMRI resting state and a working memory task acutely after light and moderate intensity exercise and after a 12-week aerobic training intervention.

Functional connectivity did not change more after moderate compared with light intensity training. However, both training groups showed similar changes in cardiorespiratory fitness (maximal exercise oxygen uptake, VO2peak), limiting group-level comparisons. Acute effects of moderate intensity aerobic exercise on hippocampal-cortical connections in the default network predicted training enhancements in the same connections. Working memory also improved acutely, especially following moderate intensity, and greater acute improvements predicted greater working memory improvement with training. Exercise effects on functional connectivity of right lateralized fronto-parietal connections were related to both acute and training gains in working memory.

Embedded 3D Printing Used to Assemble Tiny Organoids into Larger Vascularized Tissue Masses
https://www.fightaging.org/archives/2019/09/embedded-3d-printing-used-to-assemble-tiny-organoids-into-larger-vascularized-tissue-masses/

For as long as I have been watching progress in tissue engineering, the primary and most important barrier to building organs to order has been the inability to construct vascular networks. A network of capillaries must exist for blood, and thus nutrients and oxygen necessary to cell survival, to reach more than a few millimeters into a tissue. In live tissues, hundreds of minuscule capillaries pass through every square millimeter, considered in cross-section. Replicating this level of capillary density in engineered tissue has yet to be accomplished, with even the more advanced technology demonstrations falling well short of this goal.

Well funded initiatives such as the effort to produce genetically engineered pigs with organs that can be decellularized for transplantation into humans, or the application of decellularization to donor human organs, should be considered as attempts to work around the vascular challenge. That is why they exist. If a suitable vascular network cannot be produced from scratch, then the existing vascular network in an existing organ is the only viable alternative. It remains to be seen as to how long these approaches will be needed, how long it will take the research community to be able to grow larger tissues with sufficient vascular networks for practical use in medicine.

As the research community continues to wrestle with the production of vascular networks, scientists have become ever more proficient in the production of small sections of organ tissue from the starting point of a cell sample, known as organoids. Given the ability to reprogram patient cells into induced pluripotent stem cells, which can then be used to produce cells of any type, building functional organoids only requires a suitable protocol: the right signals and conditions to convince cells to form tissue as they do in the body. Discovering how to do this for the more important internal organs has proceeded apace over the past decade: livers, kidneys, lungs, the thymus, and more. As soon as a viable approach to vascularization of tissue emerges, scaled up and fully functional organs made to order will soon follow.

Sacrificial ink-writing technique allows 3D printing of large, vascularized human organ building blocks

Artificially grown human organs are seen by many as the "holy grail" for resolving the shortage of donor organs for transplant, and advances in 3D printing have led to a boom in using that technique to build living tissue constructs in the shape of human organs. However, all 3D-printed human tissues to date lack the cellular density and organ-level functions required for them to be used in organ repair and replacement. Now, a new technique called SWIFT (sacrificial writing into functional tissue) overcomes that major hurdle by 3D printing vascular channels into living matrices composed of stem-cell-derived organ building blocks (OBBs), yielding viable, organ-specific tissues with high cell density and function.

"This is an entirely new paradigm for tissue fabrication. Rather than trying to 3D-print an entire organ's worth of cells, SWIFT focuses on only printing the vessels necessary to support a living tissue construct that contains large quantities of OBBs, which may ultimately be used therapeutically to repair and replace human organs with lab-grown versions containing patients' own cells."

SWIFT involves a two-step process that begins with forming hundreds of thousands of stem-cell-derived aggregates into a dense, living matrix of OBBs that contains about 200 million cells per milliliter. Next, a vascular network through which oxygen and other nutrients can be delivered to the cells is embedded within the matrix by writing and removing a sacrificial ink. "Forming a dense matrix from these OBBs kills two birds with one stone: not only does it achieve a high cellular density akin to that of human organs, but the matrix's viscosity also enables printing of a pervasive network of perfusable channels within it to mimic the blood vessels that support human organs."

Biomanufacturing of organ-specific tissues with high cellular density and embedded vascular channels

Engineering organ-specific tissues for therapeutic applications is a grand challenge, requiring the fabrication and maintenance of densely cellular constructs. Organ building blocks (OBBs) composed of patient-specific-induced pluripotent stem cell-derived organoids offer a pathway to achieving tissues with the requisite cellular density, microarchitecture, and function. However, to date, scant attention has been devoted to their assembly into 3D tissue constructs.

Here, we report a biomanufacturing method for assembling hundreds of thousands of these OBBs into living matrices with high cellular density into which perfusable vascular channels are introduced via embedded three-dimensional bioprinting. The OBB matrices exhibit the desired self-healing, viscoplastic behavior required for sacrificial writing into functional tissue (SWIFT). As an exemplar, we created a perfusable cardiac tissue that fuses and beats synchronously over a 7-day period. Our SWIFT biomanufacturing method enables the rapid assembly of perfusable patient- and organ-specific tissues at therapeutic scales.

Aspirin Use Fails to Postpone Disability and Improve Survival in Older Individuals
https://www.fightaging.org/archives/2019/09/aspirin-use-fails-to-postpone-disability-and-improve-survival-in-older-individuals/

Aspirin is arguably a calorie restriction mimetic, in that it boosts the operation of the cellular maintenance processes of autophagy to some degree. Increased autophagy is a feature of many of the interventions, such as calorie restriction, that slow aging in various animal models. Aspirin can extend life in short-lived species. The fact that an ongoing trial shows it to do no such thing in humans is just one more of the many pieces of evidence to demonstrate that short-lived and long-lived species have a very different plasticity of longevity in response to upregulation of stress response systems such as autophagy. The effect size of benefits resulting from aspirin in old humans is small enough to be overwhelmed by harmful side-effects in a sizable fraction of the population - this is exactly the sort of marginal medical technology that should be sidelined in favor of better approaches to the treatment of aging.

European guidelines on the prevention of cardiovascular disease (CVD) do not recommend aspirin for individuals free from CVD due to the increased risk of major bleeding. This advice was subsequently supported by results in moderate risk patients (ARRIVE trial), diabetic patients (ASCEND trial), and in people over 70 (ASPREE trial), which demonstrated that modest reductions in CVD risk were outweighed by the increased bleeding hazard.

The primary finding from the ASPREE randomised trial was that in people aged 70 years or over with no known CVD, there was no effect of 100 mg of daily aspirin on the composite primary endpoint of disability-free survival (defined as those not reaching a primary endpoint of dementia or persistent physical disability or death). The primary endpoint was chosen to reflect the reasons for prescribing a preventive drug in an otherwise healthy elderly population.

The investigators calculated ten-year CVD risk probabilities at baseline for the 19,114 ASPREE participants using the Framingham score (up to 75 years) and the atherosclerotic cardiovascular disease (ASCVD) pooled cohort risk equations (up to 79 years) and divided them into thirds. As there are no CVD risk scores available beyond the age ranges specified in the equations, they also classified participants according to the presence of 0 to 1, 2 to 3, or more than 3 CVD risk factors. Overall rates of disability-free survival, mortality, major bleeding, and CVD were examined for each risk group and outcomes were compared for those treated with aspirin or placebo.

For participants in the lowest third of CVD risk, by both Framingham and ASCVD scores, there was no disability-free survival or cardiovascular benefit from aspirin. This group also had the highest likelihood of bleeding. In contrast, those in the highest third of CVD risk, by both Framingham and ASCVD scores, had significantly lower CVD event rates on aspirin with similar rates of bleeding. Hazard ratios for CVD reduction with aspirin version placebo were 0.72 for the group classified as high risk by the Framingham score and 0.75 for those defined as high risk by the ASCVD equations. However, this reduction in CVD did not translate to a significantly improved disability-free survival.

"The findings emphasise that the risk-benefit trade-off for aspirin use in healthy older men and women varies across levels of cardiovascular risk. It also indicates that the reduction in CVD events in the highest risk groups using current stratification methods does not identify individuals in whom this advantage translates into longer disability-free survival. Based on the results of the main ASPREE trial, daily low-dose aspirin cannot be recommended in healthy people over 70 - even in those at the greatest CVD risk. Today's analysis indicates that more refined methods are needed to pinpoint a subgroup who might gain from preventive therapy."

Inhibition of mTORC1 as a Treatment to Slow the Consequences of Muscle Aging
https://www.fightaging.org/archives/2019/09/inhibition-of-mtorc1-as-a-treatment-to-slow-the-consequences-of-muscle-aging/

Inhibition of mTOR, and more specifically only its activities as a part of the mTORC1 protein complex, has been shown to slow aging in mice. This is a class of calorie restriction mimetic treatment, in that it works through many of the same beneficial stress response mechanisms as does a restricted nutrient intake. Many of the specific effects of mTORC1 inhibition in various different tissues in the body are still incompletely investigated, however. Researchers here discuss the effects of mTORC1 inhibition on the aging of muscle tissue. With age, muscle mass and strength are lost, leading to the onset of sarcopenia and contributing greatly to the condition of age-related frailty. Means to prevent this deterioration of muscle would provide a great benefit to the older population, but mTORC1 inhibition is unfortunately only a small step towards that goal.

A decade ago, rapamycin, an mTORC1 inhibitor, was reported to extend the lifespan of mice. Consistent with this, rapamycin and other mTORC1 inhibitors also protect several organs and tissues against age-related functional decline. Rapamycin's effect on aging skeletal muscle, however, was not explored until recently. It has long been known that mTORC1 activity is induced in aging muscle. Two recent reports with genetic and pharmacological evidence reveal important findings: 1) Chronic activation of mTORC1 stimulates progressive muscle damage and loss, and 2) Inhibition of mTORC1 with rapamycin prevents age-related muscle loss.

Consistent with the observation that the hyperactive mTORC1 induces muscle damage and loss, inhibition of mTORC1 activity with rapamycin or rapalogs protects aging muscle from atrophy in mice and rats. For example, treatment with rapamycin from 9 months to 30 months of age reduced apoptosis and promoted retention of peripherally located nuclei, and this was associated with reduced fiber loss in aging skeletal muscle. In a separate study, a shorter duration of rapalog treatment for 6-weeks, starting from 22 month of age, preserved both fiber size and muscle weight. These data suggest that mTORC1 is necessary and sufficient to drive skeletal muscle aging.

Do these findings conflict with the current understanding of the anabolic function of mTORC1? We do not think so. We believe the ultimate effect of mTORC1 depends upon: 1) how mTORC1 is activated, and 2) for how long mTORC1 remains activated. Akt-dependent, short-term activation of mTORC1 appears usually to be beneficial to cells, whereas Akt-independent, chronic activation of mTORC1 appears to be detrimental to cells. Akt-independent activation of mTORC1 induces catabolism in addition to its conventional anabolic activity. The progressive myopathy seen in the mTORC1-hyperactive muscle is the net outcome of a complex process that perturbs the balance between anabolism and catabolism, with catabolism winning out and leading to muscle fiber damage and loss.

Long-Lived Dwarf Mice Exhibit an Improved Mitochondrial Stress Response
https://www.fightaging.org/archives/2019/09/long-lived-dwarf-mice-exhibit-an-improved-mitochondrial-stress-response/

Snell dwarf mice in which growth hormone has been disabled live significantly longer than their peers. Suppression of growth hormone activity is one of the better studied interventions known to slow aging in mice, and, like calorie restriction, has led to a strong focus on stress response mechanisms in the aging research community. A majority of the means of slowing aging in short-lived laboratory species are characterized by increased cellular maintenance activities that are triggered into greater efforts by cellular stresses: heat, cold, lack of nutrients, an excess of toxic or reactive molecules, and so forth.

Declining mitochondrial function is a characteristic of aging, as quality control mechanisms falter in their operation with advancing age. Researchers here show that one of the mechanisms associated with maintaining correct mitochondrial function, the unfolded protein response, is more active in Snell dwarf mice. This is consistent with what is already known of the slowed aging in this and similar lineages, and of the importance of cellular maintenance and mitochondria in aging.

Prolonged lifespan and improved health in late adulthood can be achieved by partial inhibition of mitochondrial proteins in yeast, worms, fruit flies, and mice. Upregulation of the mitochondrial unfolded protein response (mtUPR) has been proposed as a common pathway in lifespan extension induced by mitochondrial defects. However, it is not known whether mtUPR is elevated in long-lived mouse models.

Here, we report that Snell dwarf mice, which show 30%-40% lifespan extension and prolonged healthspan, exhibit augmented mitochondrial stress responses. Cultured cells from Snell mice show elevated levels of the mitochondrial chaperone HSP60 and mitochondrial protease LONP1, two components of the mtUPR. In response to mitochondrial stress, the increase in Tfam (mitochondrial transcription factor A), a regulator of mitochondrial transcription, is higher in Snell cells, while Pgc-1α, the main regulator of mitochondrial biogenesis, is upregulated only in Snell cells. Consistent with these differences, Snell cells maintain oxidative respiration rate, ATP content, and expression of mitochondrial-DNA-encoded genes after exposure to doxycycline stress.

In vivo, compared to normal mice, Snell mice show stronger hepatic mtUPR induction and maintain mitochondrial protein stoichiometry after mitochondrial stress exposure. Overall, our work demonstrates that a long-lived mouse model exhibits improved mitochondrial stress response, and provides a rationale for future mouse lifespan studies involving compounds that induce mtUPR. Further research on mitochondrial homeostasis in long-lived mice may facilitate development of interventions that blunt mitochondrial deterioration in neurodegenerative diseases such as Alzheimer's and Parkinson's and postpone diseases of aging in humans.

Oral Bacteria Mediate Short Term Lowering of Blood Pressure Following Exercise
https://www.fightaging.org/archives/2019/09/oral-bacteria-mediate-short-term-lowering-of-blood-pressure-following-exercise/

One of the benefits of exercise is improved cardiovascular function, and one of the ways in which this manifests is a reduced blood pressure. Maintaining a lower blood pressure is very influential over the course of aging; age-related hypertension is very damaging. Exercise tends to exhibit short term benefits immediately following a session, and then similar long term benefits when exercise is regular. Here, researchers show that the short term reduction in blood pressure following exercise is mediated in large part by oral bacteria, a most interesting finding. Whether this holds up over the long term and regular use of antibacterial mouthwash at times unrelated to exercise is another question entirely, of course. If anything, modern dentistry is the story of a futile struggle to keep any sort of oral bacteria population suppressed for any length of time.

Scientists know that blood vessels open up during exercise, as the production of nitric oxide increases the diameter of the blood vessels (known as vasodilation), increasing blood flow circulation to active muscles. What has remained a mystery is how blood circulation remains higher after exercise, in turn triggering a blood-pressure lowering response known as post-exercise hypotension. Previous research has suggested that nitric oxide was not involved in this post-exercise response - and only involved during exercise - but the new study challenges these views.

"It's all to do with nitric oxide degrading into a compound called nitrate, which for years was thought to have no function in the body. But research over the last decade has shown that nitrate can be absorbed in the salivary glands and excreted with saliva in the mouth. Some species of bacteria in the mouth can use nitrate and convert into nitrite - a very important molecule that can enhance the production of nitric oxide in the body. And when nitrite in saliva is swallowed, part of this molecule is rapidly absorbed into the circulation and reduced back to nitric oxide. This helps to maintain a widening of blood vessels which leads to a sustained lowering of blood pressure after exercise."

Twenty-three healthy adults were asked to run on a treadmill for a total of 30 minutes on two separate occasions, after which they were monitored for two hours. On each occasion at one, 30, 60 and 90 minutes after exercise they were asked to rinse their mouths with a liquid - either antibacterial mouthwash (0.2 per cent chlorhexidine) or a placebo of mint-flavoured water. Their blood pressure was measured and saliva and blood samples were taken before exercise and at 120 minutes after exercise. No food or drink except water was allowed during exercise and the recovery period, and none of the study participants had any oral health conditions.

The study found that when participants rinsed with the placebo, the average reduction in systolic blood pressure was -5.2 mmHg at one hour after exercise. However when participants rinsed with the antibacterial mouthwash, the average systolic blood pressure was -2.0 mmHg at the same time point. These results show that the blood pressure-lowering effect of exercise was diminished by more than 60 per cent over the first hour of recovery, and totally abolished two hours after exercise when participants were given the antibacterial mouthwash. Previous views also suggested that the main source of nitrite in the circulation after exercise was nitric oxide formed during exercise in the endothelial cells (cells that line the blood vessels). However, the new study challenges this. When antibacterial mouthwash was given to the participants, their blood nitrite levels did not increase after exercise.

Dsyfunctional Autophagy Promotes Cellular Senescence in Long-Lived Neurons
https://www.fightaging.org/archives/2019/09/dsyfunctional-autophagy-promotes-cellular-senescence-in-long-lived-neurons/

Senescent cells cause harm to surrounding tissue when they linger over time, evading the usual fate of self-destruction or destruction by the immune system. They secrete inflammatory and other signals that rouse the immune system into a state of chronic inflammation, destructively remodel nearby tissue, and encourage other cells to become senescent. The presence of senescent cells is a significant cause of aging and age-related disease, as demonstrated by studies in which senolytic therapies are used to selectively remove some portion of the burden of senescent cell in old tissues.

Researchers here show that long-lived non-dividing cells in the brain also become senescent, and that a faltering of the cell maintenance processes of autophagy is important in this process. One of the reasons why autophagy declines with age, particularly in long-lived cells, is the build up of hardy metabolic waste products that clutter the recycling structures called lysosomes, making them inefficient and bloated. More effort should be devoted towards building therapies capable of breaking down the waste products that our biochemistry struggles with.

Senescent cells accumulate in various tissues and organs with aging altering surrounding tissue due to an active secretome, and at least in mice their elimination extends healthy lifespan and ameliorates several chronic diseases. Whether all cell types senesce, including post-mitotic cells, has been poorly described mainly because cellular senescence was defined as a permanent cell cycle arrest. Nevertheless, neurons with features of senescence have been described in old rodent and human brains.

In this study we characterized an in vitro model useful to study the molecular basis of senescence of primary rat cortical cells that recapitulates senescent features described in brain aging. We found that in long-term cultures, rat primary cortical neurons displayed features of cellular senescence before glial cells did, and developed a functional senescence-associated secretory phenotype able to induce paracrine premature senescence of mouse embryonic fibroblasts but proliferation of rat glial cells.

Functional autophagy seems to prevent neuronal senescence, as we observed an autophagic flux reduction in senescent neurons both in vitro and in vivo, and autophagy impairment induced cortical cell senescence while autophagy stimulation inhibited it. Our findings suggest that aging-associated dysfunctional autophagy contributes to senescence transition also in neuronal cells.

Upregulation of Autophagy Reverses Age-Related Decline of Memory B Cell Function
https://www.fightaging.org/archives/2019/09/upregulation-of-autophagy-reverses-age-related-decline-of-memory-b-cell-function/

Memory B cells undertake some of the more important tasks in coordination of an effective immune response, circulating in the body to accelerate the deployment of other resources in the immune system to tackle a specific threat. Dysfunction in B cells is a significant component of the onset of age-related immunosenescence, the progressively greater incapacity of the immune system. Selectively removing and replacing B cells has been shown to improve matters, but here researchers identify failing autophagy as an important factor. B cells are long-lived, and long-lived cells tend to build up metabolic waste that is resilient to the enzymes available to break it down. This gums up the structures and systems used in autophagy, causing it to fail, and the cells to thus become ever more cluttered with damaged protein machinery and other harmful waste. This in turn degrades function.

During a regular influenza season, about 90% of the deaths occur in people older than 65 years. Immune responses to vaccines are known to be particularly ineffective in the elderly population. A major correlate of protection for vaccinations is the specific antibody titer generated by long-lived plasma B cells. With a lifespan of several decades, long-lived lymphocytes are particularly prone to accumulation of intracellular waste. Autophagy recycles unwanted cytoplasmic material. Autophagy-deficient lymphocytes are unable to generate adequate responses, in particular long-lived lymphocytes, memory T cells, memory B cells, and plasma B cells.

Here we show that reduced autophagy is a central molecular mechanism underlying immune senescence. Autophagy levels are specifically reduced in mature lymphocytes, leading to compromised memory B cell responses in old individuals. Spermidine, an endogenous polyamine metabolite, induces autophagy in vivo and rejuvenates memory B cell responses. Mechanistically, spermidine post-translationally modifies the translation factor eIF5A, which is essential for the synthesis of the autophagy transcription factor TFEB. Spermidine is depleted in the elderly, leading to reduced TFEB expression and autophagy. Spermidine supplementation restored this pathway and improved the responses of old human B cells. Taken together, our results reveal an unexpected autophagy regulatory mechanism that is mediated by eIF5A at the translational level, which can be harnessed to reverse immune senescence in humans.

LEAF Interviews David Sinclair
https://www.fightaging.org/archives/2019/09/leaf-interviews-david-sinclair/

David Sinclair recently published a new book to assist in publicizing his present research directions, companies, and thinking on aging, and is here interviewed by the Life Extension Advocacy Foundation (LEAF) volunteers. The work presently underway includes supplements to increase levels of NAD+ in mitochondria and, separately, partial reprogramming of cells in a living individual in order to gain some of the effects of full reprogramming, particularly restoration of mitochondrial function. Fully reprogramming cells into induced pluripotent stem cells has been shown to clear out dysfunctional mitochondria and reset epigenetic markers of age to a more youthful configuration.

It is worth noting that this strategy will not be able to fix a great many of the issues that arise in cells with age, such as the accumulation of metabolic waste that even youthful cells cannot break down effectively. If it can be used to safely restore mitochondrial function in old tissues for an extended period of time, however, then that is certainly interesting enough to chase aggressively in and of itself. Mitochondrial dysfunction is a noteworthy aspect of aging, and is involved in numerous age-related diseases.

Currently, medicine treats the symptoms, not the causes, of age-related diseases. Do you think that we might soon reach the point where therapies will be taken in a preventive manner to delay the onset of age-related diseases?

Well, there's a subset of the population, particularly in the US, but increasingly around the world, who are using the internet to educate themselves and are trying to take action before they become sick. Sometimes with medical supervision, sometimes not. It's a grassroots movement right now; for it to become mainstream, the regulations would have to change so that doctors can feel comfortable prescribing medicines to prevent diseases. But, if we don't change, then we will continue to practice whack-a-mole medicine and only treat one disease at a time after it's already developed.

You are very well known for your work with NAD+ and its precursors; we're often asked whether nicotinamide riboside or nicotinamide mononucleotide is better?

They're very similar molecules, and both have been shown to provide a variety of health benefits in mice. That doesn't mean either of them will work to slow aging in humans, and that's why placebo-controlled clinical trials are required to know if one of them, or both of them, will work in certain conditions. Those studies began over a year ago, and they are currently Phase 1 safety studies in healthy volunteers. Next year, the plan is to test the pharmaceutical product in a disease area, most likely a rare disease, but also in the elderly to see if we can recapitulate some of the results we've seen in mice, such as increased blood flow and endurance.

Another area that you are involved in is partial cellular reprogramming to reverse age-related epigenetic alterations in cells and tissues. Please tell us a little bit about this approach and the approach that you are taking and how you're progressing so far?

For 20 years, we've been working on epigenetic changes as a cause of aging, starting with work in yeast and now in mammals. We've developed viral vectors and combinations of reprogramming factors that appear to be much safer than past approaches, and we've used them to reprogram the eye to restore vision in mice with glaucoma and in very old mice. Currently, it is believed that the epigenetic clock is just an indicator of age and not part of the actual aging process, but our recent work strongly suggests that the process of reversing the clock doesn't just change the apparent age of the body, it actually reverses aging itself by restoring the function of the old cells to behave as though they're young again. Therefore, the clock may not just be telling time; it may actually be controlling time.

Could you please tell us a little bit about your book and what the readers should look forward to?

"Lifespan: Why We Age and Why We Don't Have To" takes the reader on a journey through history, looking at the endeavor of humans to try to live longer and using that historical perspective to look at today's situation and project into the future. The book also takes readers on a journey through the very cutting edge of aging research and things that the reader can do right now to take advantage of these new discoveries in their daily lives with changes in their daily activity, what they eat, when they eat, but also medicines that are currently available on the market that may extend lifespan. The last chapter is about where we are headed, what are the medicines that are in development, and then when these drugs become available, what does the world look like? Is it a better place or a worse place, and how will our lives change?

Repair of a Damaged Cornea Using Cells Derived from Induced Pluripotent Stem Cells
https://www.fightaging.org/archives/2019/09/repair-of-a-damaged-cornea-using-cells-derived-from-induced-pluripotent-stem-cells/

Since the discovery of induced pluripotency more than a decade ago, researchers have been working towards the use of this technology to produce cells for use in tissue engineering and regenerative therapies. Induced pluripotent stem cells are functionally equivalent to embryonic stem cells; given suitable recipes and methods for the surrounding environment and signals, they can be made to generate any of the cell types in the body. The cornea of the eye is a comparatively simple starting point for tissue engineering, easier to work with in many ways, in generating tissues and in delivering cells to the patient. Here, the first repair of a human cornea is reported, using tissue structures produced from induced pluripotent stem cells.

A Japanese woman in her forties has become the first person in the world to have her cornea repaired using reprogrammed stem cells. The woman has a disease in which the stem cells that repair the cornea, a transparent layer that covers and protects the eye, are lost. The condition makes vision blurry and can lead to blindness. To treat the woman, researchers created sheets of corneal cells from induced pluripotent stem (iPS) cells. These are made by reprogramming adult skin cells from a donor into an embryonic-like state from which they can transform into other cell types, such as corneal cells.

The woman's cornea remained clear and her vision had improved since the transplant a month ago. Currently people with damaged or diseased corneas are generally treated using tissue from donors who have died, but there is a long waiting list for such tissue in Japan. Japan has been ahead of the curve in approving the clinical use of iPS cells, which were discovered by stem-cell biologist Shinya Yamanaka. Japanese physicians have also used iPS cells to treat spinal cord injury, Parkinson's disease, and another eye disease. The Japanese health ministry gave permission to try the procedure on four people. The team is planning the next operation for later this year and hope to have the procedure in the clinic in five years.

Senolytic Treatment Reverses Age-Related Loss of Regenerative Capacity in the Liver
https://www.fightaging.org/archives/2019/09/senolytic-treatment-reverses-age-related-loss-of-regenerative-capacity-in-the-liver/

You might recall a paper published last year in which the authors reported that cellular senescence is a primary cause of declining capacity in liver regeneration with age. Here the obvious next step is taken, and a senolytic therapy is tested for its ability to restore the capacity of the aging liver to regenerate by clearing senescent cells. Improvement in all sorts of measures that normally decline with age is the expected result of senolytic treatment at this point, given the extensive evidence accumulated to date. Senescent cells are a cause of aging and age-related decline, they actively maintain a dysfunction state of metabolism via their secretions, and thus of course getting rid of them helps. Though, as noted in this paper, things are never as simple as we might hope them to be.

Many tissues, including the liver, heart and limbs possess a limited regenerative capacity in newborn or young mice, but which is lost upon maturation. As far as we are aware, misregulation of senescence has not been causally linked to such loss of regenerative capacity. Here, we first assessed the dynamic patterns of senescence markers during liver regeneration in young and adult mice. Although a transient p53-independent increase in p21 is well described following partial hepatectomy, its precise functions remain unclear, and loss of p21 does not seem to adversely impact regeneration in young animals. However, in models of advanced aging and severe liver damage, aberrantly expressed senescence markers, including p21 and p16Ink4a have been reported to impede liver regeneration. For example, in models of liver fibrosis, a robust senescence response is induced primarily in the stellate cells, which serves to limit fibrosis. Other models of severe liver damage induce a pronounced p21-expressionin hepatocytes, which results in decreased regeneration, senescence,and senescence-spreading.

We find that following partial hepatectomy, the senescence markers p21, p16Ink4a, and p19Arf become dynamically expressed at an age when regenerative capacity decreases. In addition, we demonstrate that treatment with a senescence-inhibiting drug improves regenerative capacity, through targeting of aberrant p21 expression. Surprisingly, we also find that the senescence marker p16Ink4a is expressed in a different cell-population to p21, and is unaffected by senescence targeting. This work suggests that senescence may initially develop as a heterogeneous cellular response, and that treatment with senolytic drugs may aid in promoting organ regeneration.

Senolytic treatment is increasingly shown to have beneficial effects in enhancing tissue function and alleviating disease symptoms in a variety of tissues. However, in many cases, the specific cellular targets or molecular mediators in vivo remain to be identified. Our study suggests that p21-positive cells may be a primary target. This is supported by the findings that protection from apoptosis is a main function of p21, including in senescent cells, and many senolytics, including the one used here, work by blocking anti-apoptotic pathways. In addition,as p21 functions to protect cells from damage, prolonged loss of p21 in aging mice predisposes to cancer through loss of this cytoprotective effect.

Interestingly, our study suggests that a one-time removal of p21 positive cells using a senolytic has a beneficial effect on regeneration, but probably without the long-term consequences of p21-loss. Surprisingly however, we see no effect of senolytic treatment on the increased expression of p16Ink4a that is present prior to hepatectomy, and which becomes detectable at the same stage as the decrease in regenerative capacity. Many studies show how targeting p16Ink4a expression has beneficial effects on aged and damaged tissue. However, in most cases, this also results in reduction of p21 and p19Arf, making it difficult to discern specific effects of each gene.

As p16Ink4a and p21 are expressed in different cell populations in our study, this hints that p16Ink4a, at this level of expression at least, may have beneficial effects in the liver also. However, why senolytic treatment seems to eliminate p16Ink4a positive cells in other contexts and not here remains unknown, but probably relates to the level of p16Ink4a-expression or co-expression with other senescence genes, as p16Ink4a levels become increasingly higher with age. Perhaps with advanced age or chronic damage, p21 and p16Ink4a become co-expressed, and at higher levels in the same cell types, resulting in a full-senescence response, and what we witness here is an early stage in a cumulative and progressive decline that becomes more complex over time.

Evidence for an Intestinal Origin of Parkinson's Disease
https://www.fightaging.org/archives/2019/09/evidence-for-an-intestinal-origin-of-parkinsons-disease/

As is the case for many neurodegenerative conditions, Parkinson's disease is associated with the spread of protein aggregation. Specific proteins become changed in ways that cause them to form solid deposits, surrounded by a halo of associated toxic biochemistry that harms neurons. The aggregates in Parkinson's patients are formed from α-synuclein, and here, researchers provide evidence for the origins of α-synuclein related neurological dysfunction to begin in the intestine, and only later migrate to the brain.

Parkinson's disease is characterised by a slow destruction of the brain due to the accumulation of the protein alpha-synuclein and the subsequent damage to nerve cells. The disease leads to shaking, muscle stiffness, and characteristic slow movements of sufferers. In a new research project, scientists used genetically modified laboratory rats which overexpress large amounts of the alpha-synuclein protein. These rats have an increased propensity to accumulate harmful varieties of alpha-synuclein protein and to develop symptoms similar to those seen in Parkinson's patients. The researchers initiated the disease process by injecting alpha-synuclein into the small intestines of the rats.

"After two months, we saw that the alpha-synuclein had travelled to the brain via the peripheral nerves with involvement of precisely those structures known to be affected in connection with Parkinson's disease in humans. After four months, the magnitude of the pathology was even greater. It was actually pretty striking to see how quickly it happened."

Patients with Parkinson's disease often already have significant damage to their nervous system at the time of diagnosis, but it is actually possible to detect pathological alpha-synuclein in the gut up to twenty years before diagnosis. "With this new study, we've uncovered exactly how the disease is likely to spread from the intestines of people. We probably cannot develop effective medical treatments that halt the disease without knowing where it starts and how it spreads - so this is an important step in our research. Parkinson's is a complex disease that we're still trying to understand. However, with this study and a similar study that has recently arrived at the same result using mice, the suspicion that the disease begins in the gut of some patients has gained considerable support."