The Most Obvious Tau Aggregates in Tauopathies, the Neurofibrillary Tangles, are not the Primary Cause of Harm

Altered proteins build up in the aging brain, forming solid deposits. The most prominent of them are amyloid-β, altered forms of tau, and α-synuclein, giving rise to amyloidosis, tauopathies, and synucleinopathies respectively. Some conditions mix and match: Alzheimer's disease is both an amyloidosis and a tauopathy. To further muddy the waters, any aging brain far enough along in the process to exhibit full-blown neurodegeneration will also exhibit significant levels of all of the other forms of dysfunction caused by aging.

Present thinking on the roots of protein aggregation conditions is fairly diverse. Insofar as there is a consensus, the root causes are considered to include issues such as failing cellular maintenance processes, failure of the drainage of cerebrospinal fluid as a way to export waste to the rest of the body, infection by pathogens capable of generating more of these unwanted proteins, and failure of the immune system - in defending against those pathogens, in generating inflammation that causes all sorts of breakage and change in cellular behavior, and in cleaning up the waste and debris produced by other cells. Amyloid-β, altered tau, and α-synuclein are all produced in some amount by normal, healthy, young people, but clearly they do not suffer for it, and nor does it build up. Any hypothesis of disease progress must account for what changes in older individuals.

An interesting point of commonality between the various forms of aggregated protein in the brain is that the largest and most obvious deposits, neurofibrillary tangles in the case of tau, are not the worst of the problem. You might think of them as the result of our biology trying to build ever bigger middens to cope with the waste that piles up. Cells dump it into the surrounding environment, or become overridden with garbage that they sequester into lumps when they can't even keep up with that. This is harmful, but as it turns out not as harmful as the surrounding halo of related biochemistry: for the most part it isn't the garbage in the middens that causes cell death and dysfunction, but rather a collection of associated proteins and their subtle interactions with cells. This is well established for amyloid-β, and the paper noted here makes an argument for this to be the case for tau as well.

Researchers describe new biology of Alzheimer's disease

Scientists have known for a long time that two proteins, β-amyloid and tau, clump and accumulate in the brains of Alzheimer patients, and this accumulation is thought to cause nerve cell injury that results in dementia. Recent work by these researchers has shown that the clumping and accumulation of tau occurs as a normal response to stress, producing RNA/protein complexes termed "stress granules," which reflect the need for the brain to produce protective proteins. The persistence of this stress response leads to excessive stress, the accumulation of pathological stress granules, and the accumulation of clumped tau, which drives nerve cell injury and produces dementia.

In the current study, the researchers use this new model and show that reducing the level of stress granule proteins yields strong protection, possibly by reducing persistent pathological stress granules as well as changing the type of tau clumping that occurs. The team hypothesized that they could delay the disease process by reducing stress granules and decreasing this persistent stress response by genetically decreasing TIA1, which is a protein that is required for stress granule formation. Reducing TIA1 improved nerve cell health and produced striking improvements in memory and life expectancy in an experimental model of AD.

Although the experimental models had better memory and longer lives, the team observed more clumped tau in the form of neurofibrillary tangles. To explain how this might be associated with a better outcome, the researchers looked at the type of tau pathology and showed that reducing TIA1 dramatically lowered the amount of tiny clumps, which are termed tau oligomers and are particularly toxic. "Reducing TIA1 shifted tau accumulation from small to large clumps, decreasing the amount of small tau clumps and producing a proportional increase in the large tau clumps that generate neurofibrillary tangles and are less toxic."

Reducing the RNA binding protein TIA1 protects against tau-mediated neurodegeneration in vivo

Emerging studies suggest a role for tau in regulating the biology of RNA binding proteins (RBPs). We now show that reducing the RBP T-cell intracellular antigen 1 (TIA1) in vivo protects against neurodegeneration and prolongs survival in transgenic P301S Tau mice. Biochemical fractionation shows co-enrichment and co-localization of tau oligomers and RBPs in transgenic P301S Tau mice. Reducing TIA1 decreased the number and size of granules co-localizing with stress granule markers. Decreasing TIA1 also inhibited the accumulation of tau oligomers at the expense of increasing neurofibrillary tangles.

Despite the increase in neurofibrillary tangles, TIA1 reduction increased neuronal survival and rescued behavioral deficits and lifespan. These data provide in vivo evidence that TIA1 plays a key role in mediating toxicity and further suggest that RBPs direct the pathway of tau aggregation and the resulting neurodegeneration. We propose a model in which dysfunction of the translational stress response leads to tau-mediated pathology.

Recent Research Implicates Astrocytes in the Progression of Alzheimer's Disease

Astrocytes are one of a number of different classes of supporting cells of the brain, and researchers here investigate how they might be involved in the progression of Alzheimer's disease - though with the caution they they are looking at early-onset Alzheimer's linked to specific mutations. These variants of the condition may be accelerated by processes that are not relevant in the more common form. Either way, Alzheimer's disease is an enormously complex condition; all cell types in the brain change their behavior or are impacted in some way by inflammation, rising levels of protein aggregates such as amyloid-β, or other aspects of aging. Separating cause and effect of the disease state from everything else is a challenging undertaking, not least because the animal species used in the laboratory do not naturally suffer any sort of condition resembling Alzheimer's. So there is always the question of whether or not the very artificial animal models of the disease are close enough to the human condition to steer research in the right direction. This is the case for the biology of astrocytes in particular, and so the researchers here adopt a more modern approach of generating cells for study from human patients.

Alzheimer's disease (AD) is the most common dementia type, with no treatment to slow down the progression of the disease currently available. The mechanisms of AD are poorly understood, and drug therapy has focused on restoring the normal function of neurons and microglia, i.e. cells mediating brain inflammation. The new study shows that astrocytes, also known as the housekeeping cells of the brain, promote the decline of neuron function in AD. The findings suggest that at least some familial forms of AD are strongly associated with irregular astrocyte function, which promotes brain inflammation and weakens neurons' energy production and signalling.

Astrocytes are important brain cells, as they support neurons in many different ways. Astrocytes are responsible, for example, for the energy production of the brain, ion and pH balance, and they regulate synapse formation, the connections between neurons. Recent evidence suggests that human astrocytes are very different from their rodent counterparts and thus, it would be essential to use human cells to study human diseases. However, the availability of human astrocytes for research has been very limited. The study used the induced pluripotent stem cell technology, which enables the generation of pluripotent stem cells from human skin fibroblasts. These induced stem cells can then be further differentiated to brain cells, e.g. neurons and astrocytes, with the same genetic background as the donor had. The study compared astrocytes from familial AD patients carrying a mutation in the presenilin 1 gene to astrocytes from healthy donors, and the effects of these cells on healthy neurons were also analysed.

The researchers found out that astrocytes in patients with Alzheimer's disease produced significantly more beta-amyloid than astrocytes in persons without AD. Beta-amyloid is a toxic protein that is known to accumulate in the brains of AD patients. In addition, AD astrocytes secreted more cytokines, which are thought to mediate inflammation. AD astrocytes also showed alterations in their energy metabolism which likely led to increased production of reactive oxygen species and reduced production of lactate, an important energy substrate for neurons. Finally, when astrocytes were co-cultured with healthy neurons, AD astrocytes caused significant changes on the signaling activity of neurons when compared to healthy astrocytes.

Link: http://www.uef.fi/-/aivojen-astrosyyteilla-havaittiin-yhteys-alzheimerin-tautiin

Failing Mitochondria and Cellular Senescence in the Aging Lung

Mitochondrial dysfunction and cellular senescence are two of the root causes of aging targeted by the SENS rejuvenation research programs. They overlap at least a little, in that one might cause the other, but it is unclear as to whether this is significant for the specific types of mitochondrial damage considered important in the SENS view of aging. The open access paper here walks through this territory in the case of the aging lung; in recent years, it has become clear that senescent cells are important in the development of fibrosis in lungs and other organs, as well as in other aspects of aging in lung tissue. The present development of various forms of senolytic therapies to remove these cells should result in treatments capable of turning back lung aging to some degree, as well as treating presently intractable lung conditions such as idiopathic pulmonary fibrosis.

Cellular senescence is generally defined as irreversible cell-cycle arrest. Importantly, senescence is characterised by the development of a pro-inflammatory secretory phenotype, termed the senescence-associated secretory phenotype (SASP). The SASP is thought to be important for the immune-mediated clearance of senescent cells, however, may also be a contributor to tissue dysfunction. Evidence suggests that accumulation of senescent cells with time, leads to age-related loss of tissue function. Accordingly, senescent cells are found at sites of chronic age-related disease and have been causally implicated in the development of osteoarthritis, atherosclerosis, liver steatosis and pulmonary fibrosis.

The lung is particularly affected by the ageing process, showing clear decline in structure and function with age. Moreover, the ageing lung is characterised by the presence of senescent cells and several respiratory diseases have been identified as diseases of accelerated lung ageing. Chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are classic examples of respiratory diseases that increase in prevalence with age and have been associated with senescence.

The mitochondria can impact on aspects of the senescence phenotype in a number of possible ways and it has been suggested that dysfunctional mitochondria are an additional feature of senescent cells that enable them to mediate paracrine effects. Mitophagy, the selective degradation of defective mitochondria by autophagy, is reduced in senescent cells. This could, in part, be responsible for the increase in mitochondrial mass that has been described in senescence. The accumulation of the mitochondrial compartment and of dysfunctional mitochondria in particular, may be an important contributor to the pro-inflammatory aspects of cellular senescence.

It has been shown that mitochondrial dysfunction induced by mitochondrial DNA depletion, knockdown of mitochondrial sirtuin 3 (SIRT3), or through inhibition of the electron transport chain (ETC) induces senescence with a distinct phenotype, termed MiDAS (mitochondrial dysfunction-associated senescence). Our group recently designed a proof-of-principle experiment, which interrogated whether mitochondria are truly necessary for senescence. Utilising the parkin-mediated mitophagy system to completely remove mitochondria upon their depolarisation, we found that following a variety of senescence triggers (e.g. oxidative stress and oncogene activation) features of cellular senescence, including Sen-β-Gal activity and the SASP, were suppressed. The mitochondria may therefore be key to the regulation of some aspects of cellular senescence, such as the pro-inflammatory phenotype, and may be promising targets for SASP modulation.

Link: https://doi.org/10.1016/j.pharmthera.2017.10.005

Are Low Levels of Physical Activity Significant in Health and Longevity?

Mapping the dose-response curve for exercise, its effects on health and life expectancy, is of great interest to the research community. Given the significant time and effort required to make progress via epidemiological studies, this mapping will no doubt still be an ongoing concern even after the first rejuvenation therapies are widely available. The best we can expect from present day data on physical activity in humans are broad conclusions, such as that regular moderate exercise is good for you, while being sedentary is not, and a highlighting of areas of uncertainty.

One of these areas of uncertainty is the question of low level activity: walking around the house, gardening, shopping, and so forth. Things that don't rise to the level of deliberate physical exercise. Do these activities have a noticeable impact on health and longevity? Is it a case of more is better? Prior to the creation of small accelerometers, of the sort found inside every mobile device these days, there was simply no way to tell. Studies used self-reported data, which is unreliable enough to obscure small differences. With accelerometers, the first studies appeared to suggest that yes, low levels of exercise do correlate with better health in later life. Human epidemiology can rarely do more than point out correlations, but animal studies of exercise definitively show causation of improved health. There is every reason to believe that the observed human data is due to exercise causing improved health.

Not all accelerometer studies produce results that support the hypothesis that benefits arise from low levels of physical activity, however. A paper from earlier this year reported finding no association between low level physical activity and mortality rate, for example. This is a slow-moving part of the field, in which one has to weigh the balance of many studies carried out over a decade or more. At the present time the scales tip towards casual activity providing a modest benefit; more papers arrive with conclusions akin to the one noted here. Still, by the time all is said and done, a couple of decades from now at the present pace, degree of exercise will be nowhere near as influential on your health as whether or not you have access to rejuvenation therapies after the SENS model of periodic damage repair. It is still a good plan to exercise, as it would be foolish to turn down highly reliable, free benefits to health, even if they are modest in comparison to the rewards the future will bring.

For older women, every movement counts, new study finds

Folding your laundry or doing the dishes might not be the most enjoyable parts of your day. But simple activities like these may help prolong your life, according to the findings of a new study in older women. In the U.S. study of more than 6,000 white, African-American and Hispanic women ages 63 to 99, researchers reported significantly lower risk of death in those who were active at levels only slightly higher than what defines being sedentary. Women who engaged in 30 minutes per day of light physical activity - as measured by an accelerometer instead of a questionnaire - had a 12 percent lower risk of death. Women who were able to do a half-hour each day of moderate to vigorous activity had a 39 percent lower mortality risk.

For the age group in this study, light physical activities include regular chores such as folding clothes, sweeping the floor or washing the windows. Activities like these account for more than 55 percent of how older people spend their daily activity. Moderate to vigorous activities would be brisk walking or bicycling at a leisurely pace. The bottom line? "Doing something is better than nothing, even when at lower-than-guideline recommended levels of physical activity."

Even when researchers simultaneously accounted for the amount of each type of activity (light and moderate-to-vigorous) a woman did, they still observed significantly lower mortality associated with each time, independently of the other. "Current public health guidelines require that physical activity be of at least moderate or higher intensity to confer health benefits. Our study shows, for the first time in older women, that health is benefitted even at physical activity levels below the guideline recommendations. The mortality benefit of light intensity activity extended to all subgroups that we examined, and was similar for women younger than 80 compared to women over the age of 80. It was similar across racial/ethnic backgrounds, and among obese and non-obese women. Perhaps most importantly for this population, the mortality benefit was similar among women with high and low functional ability."

Accelerometer-Measured Physical Activity and Mortality in Women Aged 63 to 99

Age-related deterioration in health is associated with a reduction in physical activity (PA). U.S. and international guidelines on PA and public health recommend that healthy older adults perform at least 2.5 hours/week of moderate-intensity or 1.25 hours/week of vigorous-intensity aerobic PA for health benefits, a target that few older U.S. adults meet, often because they are not capable of engaging in moderate- to vigorous-intensity PA (MVPA). Substantially lower all-cause mortality risk is associated with relatively high MVPA levels (3-5 times guideline recommended) assessed using questionnaires. The extent to which this extends to older adults is unclear.

Typically, self-reported activity explains only 10% to 20% of the variance in device-measured PA. PA misclassification is large in older adults, especially for light-intensity PA, which these individuals commonly perform but is currently not recommended for public health. Use of accelerometers to measure PA is novel in prospective studies on older adults and provides the ability to calibrate the effect of PA much better than with self-report, especially for light-intensity PA. We examined associations between mortality and accelerometer-measured PA using age-relevant intensity cutpoints in older women of various ethnicities.

The results support the hypothesis that higher levels of accelerometer-measured PA, even when below the moderate-intensity threshold recommended in current guidelines, are associated with lower all-cause and CVD mortality in women aged 63 to 99. Our findings expand on previous studies showing that higher self-reported PA reduces mortality in adults aged 60 and older, specifically in older women, and at less than recommended amounts. Moreover, our findings challenge the conclusion of recent meta-analyses that MVPA, measured by to self-report, is required to offset mortality risk in adults.

First, absolute rates of all-cause and cardiovascular disease mortality were at least 50% lower in cohort members in the middle tertile of each PA exposure than in those in the lowest tertile. This is particularly impressive when considering the small mean differences between these tertiles of 50 minutes/day for low light-intensity PA, 33 minutes/day for high light-intensity PA, and 20 minutes/day for MVPA. Use of accelerometers enhanced accurate quantification of such small differences in usual daily PA, which is not possible using questionnaire assessments. Small increases in daily PA, which older adults can achieve, could have a substantial effect on mortality in later life. Even in the oldest cohort members, ages 80-89 and ≥90 years, absolute rates of all-cause mortality were 44% and 15% lower, respectively, when comparing the middle and lowest total PA tertile.

Bisphosphonates May Act to Reduce Mortality through Vascular Mechanisms

Bisphosphonates are used as a treatment for osteoporosis. Like most pharmaceutical therapies for age-related disease, they have a set of unpleasant side-effects, but a couple of studies have found evidence for long-term bisphosphonate use to reduce mortality in older individuals. In one case the effect was quite large, a dramatic decrease in mortality versus the expected rates. I think there remains some skepticism about an effect of that size resulting from commonly used medications, versus it being an accident of the data or the study group or some other correlated but unrecorded difference, at least until further studies with larger patient groups take place.

What might the mechanism be, however? Past work suggests that bisphosphonates have some beneficial effect on stem cell activity, which might be a viable explanation, given better evidence in patients. The paper here is focused instead on cardiovascular issues, such as (a) the calcification of blood vessels that contributes to hypertension, and (b) the development of atherosclerosis, in which fatty plaques form to narrow and weaken blood vessels, ultimately causing death when one of these weak points ruptures. These are prominent issues in aging, and given strong evidence for bisphosphonates to produce benefits on this front, it would be a plausible mechanism for reduced mortality. The open access review paper here walks through the current evidence for this hypothesis.

In the past, osteoporosis and atherosclerosis were considered as separate entities with a similar increasing prevalence with aging. Recently, studies have outlined that patients with low bone mineral density (BMD) are at significantly greater risk of developing cardiovascular disease (CVD) as well as unexpected cardiovascular events, more severe coronary atherosclerosis and vascular calcification. In addition, it is known that postmenopausal women with osteoporosis have an increased risk of developing cardiovascular events and that the increased risk is proportional to the severity of osteoporosis. These data have also suggested a possible influence of drugs affecting bone metabolism on lipid and atherosclerosis mechanisms, or that drugs effective on the atherosclerosis process could also be efficacious in fracture prevention.

An initial interesting theory was that CVD and osteoporosis were linked by a common denominator, such as serum lipid profile, which could act in parallel on both vascular and bone cells. However, an interesting observational study showed that in a multiple regression analysis, lipid profile did not predict osteoporosis or fracture risk, whereas aortic calcification severity significantly explained BMD at the hip. On the other hand, low BMD at the distal radius was found to be associated with increased risk of stroke and CVD mortality.

The common finding of simultaneous vascular calcification and osteoporosis in individual patients suggests that local tissue factors could have a crucial role in the regulation of mineralization and cell differentiation. Cardiovascular calcification was conventionally viewed as an inevitable consequence of aging, but some landmark studies have demonstrated that it is a highly regulated process of mineralization which involves cellular and molecular signaling processes similar to those found in normal osteogenesis. The similarity of the molecular mechanisms in osteogenesis and vascular calcification has led to the knowledge that atherosclerotic calcification is an actively regulated process, not a passive mineralization.

The growing evidence that atherosclerosis and osteoporosis share several pathophysiologic mechanisms reinforces the interest in pharmacologic agents which could inhibit bone loss and also provide benefits in terms of slowing the progression of atherosclerosis. At present, only bisphosphonates (BPs), currently considered the drug of choice for the prevention and treatment of osteoporosis, could have this potential.

The interest in the relationships between BPs and atherosclerosis has recently shown a further increase after the publication of the results of the HORIZON study which reported a 28% reduction in mortality in hip fracture patients treated with an annual i.v. dose of zoledronic acid. In another study, it was revealed that patients who received BP therapy for osteoporotic fracture had a lower hazard of myocardial infarction during the 2-year follow-up period with respect to controls. Moreover, two recent studies have reported that oral BPs reduce mortality in osteoporotic patients and that the reduction in mortality could be mainly due to cardiovascular and cerebrovascular deaths.

To sum up, the BPs seem to have the potential of influencing atherosclerosis and calcium homeostasis at the level of vascular walls with several possible mechanisms which may differ according to the type, potency, dosage and administration route of BPs. However, until the present time, it is not yet clear which of these above-mentioned mechanisms may be the most important in humans and additional studies are needed to specifically address the mechanism by which BPs use could influence cardiovascular morbidity and mortality.

Link: https://doi.org/10.2147/CIA.S138002

To What Extent are Gut Bacteria Involved in the Benefits of Fasting?

Calorie restriction improves health and extends life in most species and lineages tested, while both Protein restriction and intermittent fasting can provide similar but usually lesser packages of benefits. Once delving into the details of the biochemistry involved, however, the picture becomes very complex, and is still quite uncertain. These strategies probably work through overlapping collections of mechanisms that in turn interact with one another. Intermittent fasting and protein restriction still provide some benefits even when calorie level is kept constant, for example, and assays of epigenetic changes look fairly different for each of these dietary strategies.

Part of the challenge inherent in investigating calorie restriction, protein restriction, and intermittent fasting lies in the fact that near everything in the operation of metabolism changes in response. To the degree that these approaches modestly slow aging, near every measure of aging is affected. How to pinpoint root causes, or important causes, or chains of cause and effect? It isn't easy, as demonstrated by the very slow progress on this front despite a great deal of investment in time and effort over the past three decades.

The scope of "near everything" certainly includes the behavior and distribution of gut bacteria, and in recent years researchers have devoted increasing attention to their role in health and aging. That may well turn out to be in the same ballpark of importance to life expectancy as, say, exercise, but the degree to which it is entirely secondary to dietary choice or other factors in aging - such as immune dysfunction - is an interesting question. Certainly in the case of calorie restriction there is strong evidence for the benefits to be near-completely a function of increased autophagy, and thus there is little room for gut bacteria in that picture.

What about intermittent fasting, however? Researchers here demonstrate the ability to replicate at least some measures observed in intermittent fasting in mice by transplanting gut microbiota from fasting mice into non-fasting mice. This is quite interesting as a point of comparison for what we think we know about how calorie restriction works. It suggests that intermittent fasting with overall calorie restriction is probably quite a different beast from intermittent fasting without overall calorie restriction.

Obesity and related metabolic disorders are growing health challenges; they mainly result from an imbalance between energy intake and energy expenditure. Emerging evidence suggests that non-shivering thermogenesis can re-establish energy balance and therefore counter the effects of elevated energy intake. This process is mediated primarily by the thermogenic activity of uncoupling protein 1 (UCP1), mainly in brown and beige fat cells. In this context, activating brown adipose tissue (BAT) or browning of white adipose tissue (WAT) could be a promising therapy for obesity and related metabolic diseases.

Recently, intermittent fasting was demonstrated to optimize energy metabolism and promote health. However, the mechanism for these benefits is unclear. Notably, one study found that time-restricted feeding can counteract obesity without reducing energy intake. Although perturbation of circadian rhythm was considered as a significant contributor to the increased energy expenditure, the possibility exists that white adipose browning would be a more direct mechanism. Therefore, in the current study, mice were placed on an every-other-day fasting (EODF) regimen to explore its effect on white adipose beiging and metabolic disorders. Evidence suggests that EODF selectively activates beige fat thermogenesis and ameliorates obesity-related metabolic diseases, probably via a microbiota-beige fat axis.

Gut microbiota play a critical role in energy metabolism and lipid homeostasis, and germfree or microbiota-depleted rodents have decreased susceptibility to diet-induced obesity and metabolic syndrome. Based on the above findings, EODF treatment could alter the microbiota compositions and prevent high-fat-diet-induced obesity and metabolic disorders. To further clarify the role of gut microbiota in mediating the beneficial effects of EODF regimen on metabolic diseases, the effect of EODF in control and microbiota-depleted high-fat-diet-induced obesity mice was compared. EODF treatment significantly reduced obesity and hepatic steatosis and improved insulin sensitivity in control mice, but not in microbiota-depleted mice, indicating that the effects of EODF depend on gut microbiota.

To examine whether gut microbiota are sufficient to replicate the effects of EODF, microbiota-depleted mice with high-fat-diet-induced obesity were transplanted with microbiota from ad libitum (AL) feeding and EODF mice, respectively. Compared with the AL microbiota-transplanted group, EODF microbiota transplantation did mimic all the beneficial effects of EODF treatment on metabolic dysfunctions.

In summary, the present work uncovered novel perspectives on beige-fat development in white adipose tissue. EODF was shown to selectively activate beige fat, probably by re-shaping the gut microbiota, which led to increases in the beiging stimuli acetate and lactate. EODF also dramatically ameliorated metabolic syndrome in a mouse model of obesity. This alternative beige fat activation by EODF offers new insights into the microbiotabeige fat axis and provides a novel therapeutic approach for the treatment of obesity-related metabolic disorders.

Link: http://dx.doi.org/10.1016/j.cmet.2017.08.019

Defenestration and the Roots of Age-Related Insulin Resistance

Defenestration is apparently a word with two meanings. The second, a scientific term, is the removal or loss of fenestrations. Let it never be said that this is not a place of learning. What, one might ask, are fenestrations? This is another word adopted by the scientific community and given an additional meaning: it refers to a collection of small openings or pores in our biology. The particular small openings or pores that concern us today are those found in the blood vessels of the liver, one of the organs involved in the development and progression of type 2 diabetes.

While we might tend to think of type 2 diabetes as a disease caused by excess fat tissue, and for more than 90% of patients in our modern era of cheap calories this is entirely true, it is also the case that the damage of aging ultimately leads to a similar dysfunction in insulin metabolism. The path to the same end is quite different, however. While even the comparatively late stages of visceral-fat-induced diabetes can be reversed through a sustained low-calorie diet and loss of that fat, there is nothing much that can yet be done to effectively deal with purely age-related diabetes. This is just one of the many age-related conditions we'd like to reverse through rejuvenation therapies based on the SENS research programs.

The short open access commentary below summarizes some of the mechanisms involved in loss of insulin sensitivity in the old, distinct from those losses caused by fat tissue. This is where the fenestrations of blood vessels in the liver enter the picture. The authors present evidence to suggest the loss of fenestrations - defenestration - increasingly blocks the passage of insulin to where it is needed, producing what is in effect insulin resistance and all of its secondary consequences. To me the interesting questions attend the cause of this change: is it a form of dysfunction in tissue maintenance of the sort that arises due to growing inflammation in aging tissues? Is it some other secondary effect, a change in signaling that disrupts whatever cellular coordination is needed to form fenestrations? Further research is needed.

It's the holes that matter

Before circulating insulin can interact with membrane bound insulin receptors and trigger downstream signalling it must first cross the endothelium of the blood vessels in the target tissue. This transfer across the endothelium from the blood is recognised as a rate limiting step in insulin action in muscle and fat in humans, but the role of the liver endothelium in insulin uptake has not been examined previously. Recent research explores the contribution of insulin transfer from the blood, across the liver sinusoidal endothelium and to the insulin receptors on the hepatocytes as a mechanism for the development of hyperinsulineamia and insulin resistance, as identified as a major risk factor for the development of age-related disease in humans.

The sinusoids, or blood vessels of the liver are lined by specialized endothelial cells that are very thin and perforated with transcellular holes or pores that traverse the entire cell. These pores, known as fenestrations, have no diaphragm and are patent passages through the cell. The fenestrations provide efficient ultrafiltration of small material from the blood into the liver. Coupled with very little extracellular matrix and a highly adapted hepatocyte membrane, uptake of substrates, such as nutrients, toxins, and insulin into the liver for metabolism, detoxification, and signalling is rapid and regularly overlooked. However, in older age, the morphology of the liver sinusoids and the endothelium changes significantly. The cells become thicker, and the diameter and number of fenestrations is reduced by up to 50% (known as defenestration), there is extracellular matrix deposition and evidence of loss of hepatocyte microvilli. Collectively, these changes have been called pseudocapillarization. It has previously been shown that these changes reduce hepatocyte uptake of lipoproteins and some drugs.

In the current work, the hepatic and systemic disposition of insulin was explored in young and old animals and insulin resistance was confirmed to be present in the older animals. Critically, using multiple indicator techniques insulin transfer across the liver endothelium was shown to be significantly impaired. The 20% reduction in insulin's volume of distribution in the liver was consistent with limited transfer across the sinusoidal endothelium and retention of insulin in the sinusoid. In concordance with these changes, there were very high circulating insulin levels indicative of both increased secretion and impaired clearance. Despite normal glucose tolerance tests in the older animals, insulin resistance was present. Of key importance, insulin and glucose uptake into muscle and fat was shown to be unchanged with age, suggesting age related insulin resistance was most likely being driven by impaired hepatic uptake and clearance.

This work suggests that defenestration and pseudocapillarization of the liver sinusoidal endothelium seen in aging prevents the access of insulin to the insulin receptor on the hepatocyte membrane through impaired transfer across the endothelium. This results in hyperinsulinemia, impaired hepatic insulin signalling and insulin resistance. Further the work demonstrates that the liver endothelium does not provide a barrier for the uptake of insulin under normal conditions. In summary, patent fenestrations are required for hepatic insulin uptake, clearance, and signalling and loss of fenestrations is a probable causative mechanism for insulin resistance and diabetes seen with aging. This work provides evidence that maintaining the integrity of the liver sinusoidal endothelium into old age may prevent age-related insulin resistance and excitingly, introduces a novel therapeutic target.

Towards Better Artificial Alternatives to Cartilage Tissue

It will be interesting to watch the accelerating development of biological versus non-biological replacements for damaged tissue over the next few decades. Both are improving at a fair pace, and there is a sizable area of overlap between the two sides of the field. If a nonbiological alternative gets the job done, then why not use it in place of engineered tissue? At the moment, new patient-matched engineered tissue would be a better long term alternative, considering the various challenges that result from introducing long-term implants into the body, but in near all cases that is not yet an option. Twenty years from now, however, many forms of replacement will have competing tissue engineered and wholly artificial alternatives available in the market, and the trade-offs will be more subtle.

The liquid strength of cartilage, which is about 80 percent water, withstands some of the toughest forces on our bodies. Synthetic materials couldn't match it until "Kevlartilage" was developed. Many people with joint injuries would benefit from a good replacement for cartilage, such as the 850,000 patients in the U.S. who undergo surgeries removing or replacing cartilage in the knee. While other varieties of synthetic cartilage are already undergoing clinical trials, these materials fall into two camps that choose between cartilage attributes, unable to achieve that unlikely combination of strength and water content.

The other synthetic materials that mimic the physical properties of cartilage don't contain enough water to transport the nutrients that cells need to thrive. Meanwhile, hydrogels - which incorporate water into a network of long, flexible molecules - can be designed with enough water to support the growth of the chondrocytes cells that build up natural cartilage. Yet those hydrogels aren't especially strong. They tear under strains a fraction of what cartilage can handle.

The new Kevlar-based hydrogel recreates the magic of cartilage by combining a network of tough nanofibers from Kevlar with a material commonly used in hydrogel cartilage replacements, called polyvinyl alcohol, or PVA. In natural cartilage, the network of proteins and other biomolecules gets its strength by resisting the flow of water among its chambers. The pressure from the water reconfigures the network, enabling it to deform without breaking. Water is released in the process, and the network recovers by absorbing water later. This mechanism enables high impact joints, such as knees, to stand up to punishing forces. Running repeatedly pounds the cartilage between the bones, forcing water out and making the cartilage more pliable as a result. Then, when the runner rests, the cartilage absorbs water so that it provides strong resistance to compression again.

The synthetic cartilage boasts the same mechanism, releasing water under stress and later recovering by absorbing water like a sponge. The nanofibers build the framework of the material, while the PVA traps water inside the network when the material is exposed to stretching or compression. Even versions of the material that were 92 percent water were comparable in strength to cartilage, with the 70-percent version achieving the resilience of rubber. As the nanofibers and PVA don't harm adjacent cells, researchers anticipate that this synthetic cartilage may be a suitable implant for some situations, such as the deeper parts of the knee.

Link: http://ns.umich.edu/new/releases/25262-kevlar-based-artificial-cartilage-mimics-the-magic-of-the-real-thing

Stem Cell Therapy Partially, Unreliably Repairs Spinal Cord Injuries in Rats

Engineering regeneration of an injured spinal cord is one of the fields to watch as a marker of capabilities in stem cell medicine. There is a fair amount of funding and effort directed towards this goal, and it requires overcoming a number of issues that are relevant to other types of regenerative medicine. These include overcoming scarring, inducing healing in tissues that normally do not regenerate in adults, ensuring the reliability of the outcome, and so forth. As the study here indicates, reliability remains a challenge. In all stem cell therapies, the factors that affect patient outcomes are still poorly understood.

Engineered tissue containing human stem cells has allowed paraplegic rats to walk independently and regain sensory perception. The implanted rats also show some degree of healing in their spinal cords. Spinal cord injuries often lead to paraplegia. Achieving substantial recovery following a complete spinal cord tear, or transection, is an as-yet unmet challenge. The researchers implanted human stem cells into rats with a complete spinal cord transection. The stem cells, which were derived from the membrane lining of the mouth, were induced to differentiate into support cells that secrete factors for neural growth and survival.

The work involved more than simply inserting stem cells at various intervals along the spinal cord. The research team also built a three-dimensional scaffold that provided an environment in which the stem cells could attach, grow and differentiate into support cells. This engineered tissue was also seeded with human thrombin and fibrinogen, which served to stabilize and support neurons in the rat's spinal cord.

Rats treated with the engineered tissue containing stem cells showed higher motor and sensory recovery compared to control rats. Three weeks after introduction of the stem cells, 42% of the implanted paraplegic rats showed a markedly improved ability to support weight on their hind limbs and walk. 75% of the treated rats also responded to gross stimuli to the hind limbs and tail. In addition, the lesions in the spinal cords of the treated rats subsided to some extent. This indicates that their spinal cords were healing. In contrast, control paraplegic rats that did not receive stem cells showed no improved mobility or sensory responses. While the results are promising, the technique did not work for all implanted rats. An important area for further research will be to determine why stem cell implantation worked in some cases but not others.

Link: https://www.eurekalert.org/pub_releases/2017-11/f-prw111617.php

Mild Mitochondrial Stress Found to Prevent Some of the Age-Related Declines in Cellular Maintenance in Nematodes

Hormesis is a near ubiquitous phenomenon in living organisms and their component parts: a little damage, a short or mild exposure to damaging circumstances, can result in a net benefit to health and longevity. Cells respond to damage or stress by increasing their self-repair efforts for some period of time, maintaining their function more effectively than would otherwise have been the case. At the high level, the outcomes of hormesis have been measured for a wide variety of stresses and systems, from individual cells to entire organisms. At the low level of specific biochemical processes and interaction of components inside the cell, there is a lot more mapping and cataloging to be accomplished, however.

The research noted below is an example of the this sort of exploration. It is an interesting study for demonstrating that some forms of stress response can turn back a fraction of the age-related decline in cellular maintenance processes, at least temporarily. It is well known that cellular maintenance falters in later life. This is in some cases a form of unhelpful reaction or side-effect caused by rising levels of damage and dysfunction, and in others it is a direct consequence of damage to the systems responsible for maintenance and repair. As an example of the second type, the lysosomes responsible for recycling broken molecules and structures in the cell can become clogged with rare, resilient waste compounds that they cannot process. The whole process of repair runs down when that happens.

The research here appears to touch on the first type of decline, demonstrating that controlling signals can be overridden to turn on the repair machinery once more. In the nematode worms the researchers work with, the species Caenorhabditis elegans, the result is a fair-sized increase in life span. Based on the results of numerous other interventions that increase the activities of cellular maintenance processes, this sort of outcome is expected. It is worth noting that very large increases of this nature in nematode life span - or indeed in any short-lived species - do not map to noteworthy increases in human life span. Our life spans are far less plastic in response to circumstances, despite benefiting from similar types of intervention. Calorie restriction is one of the better known ways to spur greater cellular maintenance activity, and while it certainly improves human health, it doesn't make us live significantly longer, as is the case in short-lived species.

Mitochondrial stress enhances resilience, protects aging cells and delays risk for disease

In a genetic study of the transparent roundworm C. elegans, a research team found that signals from mildly stressed mitochondria (the cellular source of energy) prevent the failure of protein-folding quality-control (proteostasis) machinery in the cytoplasm that comes with age. This, in turn, suppresses the accumulation of damaged proteins that can occur in degenerative diseases, such as Alzheimer's, Huntington's and Parkinson's diseases and amyotrophic lateral sclerosis (ALS).

"People have always known that prolonged mitochondrial stress can be deleterious. But we discovered that when you stress mitochondria just a little, the mitochondrial stress signal is actually interpreted by the cell and animal as a survival strategy. It makes the animals completely stress-resistant and doubles their lifespan. It's like magic. Our findings offer us a strategy for looking at aging in humans and how we might prevent or stabilize against molecular decline as we age. Our goal is not trying to find ways to make people live longer but rather to increase health at the cellular and molecular levels, so that a person's span of good health matches their lifespan."

The study builds on earlier work in which the researchers reported that the molecular decline leading to aging begins at reproductive maturity due to inhibitory signals from the germ line cells to other tissues to prevent induction of protective cell stress responses. In C. elegans, this is between eight and 12 hours of adulthood, yet the animal will typically live another three weeks. The researchers screened the roundworm's approximately 22,000 genes and identified a set of genes, called the mitochondrial electron transport chain (ETC), as a central regulator of age-related decline. Mild downregulation of ETC activity, small doses of xenobiotics and exposure to pathogens resulted in healthier animals, the researchers found.

Mitochondrial Stress Restores the Heat Shock Response and Prevents Proteostasis Collapse during Aging

Old age is the primary risk factor for many human diseases, but the overarching principles and molecular mechanisms that drive aging remain poorly understood. Aging has long been thought of as a stochastic process that is characterized by the gradual accumulation of cell damage. However, recent evidence suggests that aging arises, at least in part, from programmed events early in life that promote reproduction. In the nematode Caenorhabditis elegans, the ability to prevent metastable proteins from misfolding and aggregating fails early in adulthood, resulting in the appearance and persistence of protein aggregates in multiple tissues before animals have ceased reproduction.

Proteostasis is routinely maintained through the activity of constitutive and inducible stress response pathways. Among these, the transcription factor HSF-1 promotes the expression of molecular chaperones and enhances protein-folding capacity in the cytosol and nucleus through the heat shock response (HSR). During C. elegans adulthood, the HSR undergoes rapid repression as animals commence reproduction, thereby leaving cells vulnerable to environmental stress and proteostasis collapse well before overt signs of aging are distinguishable. This suggests that precise regulatory switches actively repress the HSR early in life as part of programs that promote reproduction at the cost of proteostasis.

To this end, we performed an unbiased genetic screen to identify genes whose knockdown maintains resistance to thermal stress and prevents repression of the HSR in reproductively active adults. We identified the mitochondrial electron transport chain (ETC) as a robust determinant of the timing and severity of the decline in the HSR and show that mild mitochondrial stress increases HSF-1 binding at target promoters, maintains the HSR, and preserves proteostasis in reproductively active animals. These beneficial effects were achieved without the severe physiological defects typically associated with impaired mitochondrial function, suggesting that modulation of mitochondrial activity is a physiologically relevant determinant of the timing of repression of the HSR and cytosolic proteostasis collapse with age.

The Results of Most Potential Biomarkers of Aging Vary Considerably

As expected, a study finds that the numerous candidate biomarkers of aging vary widely in their assessments of biological age. This makes complete sense, as (a) aging is caused by a number of distinct processes of damage accumulation, and (b) most of the assessments measure one or more metrics that are more influenced by some forms of damage than by others. To pick an easy example, when measuring aging by skin-related metrics such as wrinkles, appearance, and elasticity, what is seen is primarily the consequences of cross-linking. If measuring fibrosis in organs, then that is primarily cellular senescence and immune system dysfunction. If measuring grip strength, falling numbers here are caused by the contributions to sarcopenia, which so far appears to be caused primarily by failing stem cell activity.

Of all of the potential biomarkers of aging, I would hypothesize that those based on patterns of DNA methylation are the best to date, as they likely measure blended cellular responses to all of the forms of damage that cause aging. That said, it is thought-provoking to see the evidence here suggest that a suitable combination of simple measures such as grip strength and bloodwork is more effective. The conclusion that biomarkers of aging are still a work in progress is no doubt an accurate one.

A head-to-head comparison of 11 different measures of aging, including blood and chromosome tests like those being sold commercially, has found that they don't agree with one another on how fast a given person is growing older. This comparison is based on a life-long study of nearly 1,000 people in Dunedin, New Zealand who have been studied extensively from birth to age 38. Researchers working with this study cohort had earlier reported that a panel of 18 biological measures might be used to predict the pace of aging, based on how these markers had changed from age 26 to 38 in a given individual. But when they expanded their analysis to look at whether these measures and others all pointed in the same direction at age 38, the picture was much less clear.

"People age at different rates and geriatric medicine needs a way to measure that, but when measuring all sorts of different aspects of a person's physiology, from genes to blood markers to balance and grip strength, you see a lot of disagreement. Based on these results, I'd say it's premature to market aging tests to the public."

For comparisons, the researchers drew on physical measures of aging collected from the Dunedin study group, including balance, grip, motor coordination, physical limitations, cognitive function and decline, self-reported health and facial aging as judged by others. Measuring the length of telomeres, protective caps of DNA at the end of chromosomes that unravel as we age, turned up no evidence of the ability to predict physical or cognitive changes, except possibly facial aging. "Telomeres are a fundamental mechanism of aging and cancer prevention, that's true. But saying it's useful to measure in a 50-year-old to see whether they're aging is a different matter."

The team also examined hundreds of locations in the genome to see changes in the patterns of DNA methylation, molecular controls that govern whether a gene is active or not. These epigenetic patterns have been studied by other researchers as clocks thought to measure the aging rate. The researchers measured the clocks when people were 26 and again when they were 38 and found the expected 12 years of progress. The good news is that the three different epigenetic clocks they tested seem to keep time pretty well. "But the clocks were less clearly related to changes in people's physiology or problems with physical or cognitive performance. That raises questions about whether they could be used to survey patients or populations to predict health span."

The team also applied algorithms developed by other teams to analyze a large collection of physiological measures, including blood markers and tests of heart and lung function, and found a somewhat stronger signal. When they statistically examined all of their tests against each other to see whether biological aging measures could predict physical changes or mental changes, they found that the physiological measures performed somewhat better than telomeres or epigenetic clocks. But none of the measures performed well enough to argue for including them in an annual physical exam. The search will continue. As scientists investigate therapies to slow aging, "we'd like to know in less than 30 years whether the treatment works." Ideally, such a measure would be related to chronological age and would be inexpensive and non-invasive so it could be given to people before and after testing an anti-aging therapy to see whether it's working.

Link: https://today.duke.edu/2017/11/aging-tests-yield-varying-results

A Profile of James Clement's Supercentenarian Research

Should James Clement's name remain well-known in association any of the present day work on human longevity, one would hope it will be as one of the pioneers to first organize trials of senolytic therapies in humans, via his Betterhumans organization. This is far from the only research interest of this citizen scientist, however, and in past years he has put in a great deal of time and effort to expand what is known of the genetics and biochemistry of supercentenarians, rare individuals who survive past the age of 110. That is the focus of the article here.

For my part I think that the genetics of supercentenarians are not the place to look for meaningful therapies to lengthen life. After all, these individuals are still very frail, enormously impacted by the damage of aging. So far as past genetic assessments have shown, there isn't much of a difference between the survivors and the dead in any given birth year. A tiny fraction of people beat the odds even when the odds are long, and that may well be all there is to it: chance in complex system. Still, rare discoveries such as that announced yesterday keep the hope alive that there is some genetic rarity in supercentenarians that might be more relevant to future medicine. Regardless, I see the path forward as something other than genetic mapping. Instead it is that of senolytics and other forms of therapy that aim to periodically repair the damage that causes aging before it rises to pathological levels, to prevent and turn back aging, not just slow it a little.

The full genetic sequences of some three dozen genomes of North American, Caribbean, and European supercentenarians being made available this week by a nonprofit called Betterhumans to any researcher who wants to dive in. A few additional genomes come from people who died at 107, 108 or 109. If unusual patterns in their three billion pairs of A's, C's, G's and T's - the nucleobases that make up all genomes - can be shown to have prolonged their lives and protected their health, the logic goes, it is conceivable that a drug or gene therapy could be devised to replicate the effects in the rest of us.

The rare cache of supercentenarian genomes, the largest yet to be sequenced and made public, comes as studies of garden-variety longevity have yielded few solid clues to healthy aging. Lifestyle and luck, it seems, still factor heavily into why people live into their 90s and 100s. To the extent that they have a genetic advantage, it appears to come partly from having inherited fewer than usual DNA variations known to raise the risk of heart disease, Alzheimer's disease and other afflictions.

That is not enough, some researchers say, to explain what they call "truly rare survival," or why supercentenarians are more uniformly healthy than centenarians in their final months and years. Rather than having won dozens of hereditary coin tosses with DNA variations that are less bad, scientists suggest, supercentenarians may possess genetic code that actively protects them from aging. But the effort to find that code has been "challenged," as a group of leading longevity researchers put it in a recent academic paper, in part by the difficulties in acquiring supercentenarian DNA.

The DNA sequences being released this week were acquired almost single-handedly by James Clement, 61. A professed citizen-scientist, Mr. Clement collected blood, skin, or saliva from supercentenarians in 14 states and seven countries over a six-year period. The usefulness of such a small group for a genetic study is unclear, which is one reason Mr. Clement's company Androcyte, now defunct, has turned into a crowdsourcing project. So despite the limitations of Mr. Clement's database, several prominent researchers have already expressed interest in it. "This could show the utility of starting a bigger collection."

There was, nominally, the prospect of making money. But with a business plan that, even to some of his investors, sounded more like a research project, Mr. Clement seems to have undertaken the task largely because it provided the chance to act on a longstanding interest in human longevity, including his own. A self-described transhumanist who eats mostly low-glycemic vegetables and nuts and walks seven miles a day, Mr. Clement has accumulated an eclectic résumé that includes starting a brew pub, practicing international tax law, and cofounding a futurist magazine. He harbors what he prefers to call a "healthy love of life," rather than an aversion to death, and he is possessed of an apparently genuine conviction that longer lives would make humans more humane.

"My hat was off to someone who was willing to take the time out of his life to go get these precious specimens," said Dr. George Church, the Harvard geneticist, who has devoted a portion of his laboratory to research into the reversal of aging. The kind of ultrarare mutations that supercentenarians might harbor, Dr. Church believed, were not likely to be detected with standard techniques, which scan only the places in the genome where DNA is already known to vary between individuals.

To look for as-yet-uncataloged variations would require sequencing all of the supercentenarians' six billion genetic letters, a far more expensive procedure. When he and Mr. Clement first discussed the idea in 2010, the cost was about $50,000 per genome. But the price was falling. And with the financial support of a handful of like-minded wealthy individuals who agreed to invest in the exploratory phase of the project, "it just seemed," Mr. Clement said, "like something I could do."

Link: https://www.nytimes.com/2017/11/13/health/supercentenarians-genetics-longevity.html

Human PAI-1 Loss of Function Mutants Found to Live Seven Years Longer than Peers

Researchers have found a noteworthy effect on longevity in a small study population that includes the only known individuals with a loss of function mutation in plasminogen activator inhibitor-1 (PAI-1). Individuals with the mutation live seven years longer on average than near relatives without it. Repeating the study with larger groups of people obviously isn't a practical option in the case of rare mutations - we're stuck with the family trees that the research community is fortunate enough to identify - but one nonetheless has to wish for more individuals, in order to obtain a more reliable confirmation, when an effect of this size is reported. It means taking a step back to revisit questions we've asked ourselves about the odds of finding significant longevity-enhancing mutations in our species, based upon the absence of results for the past twenty years of searching.

This is also a finding that can and probably should be taken as support for current work on elimination of senescent cells as a potential rejuvenation therapy. PAI-1 isn't a gene pulled from thin air in this context. It is well studied for its influence on aging, and appears to be one of the driving regulators of the harmful effects of cellular senescence. Lingering senescent cells accumulate with age, and secrete a mix of damaging signal molecules that produce chronic inflammation, damage tissue structure, and alter the behavior of nearby cells for the worse. This is known as the senescence-associated secretory phenotype (SASP), and PAI-1 is involved in both the SASP and in some of the processes by which cells become senescent. Studies show that inhibition or loss of PAI-1 reduces some of the harms now known to be associated with senescent cell presence, and in doing so slows measures of aging.

There is all sorts of past research into PAI-1 and senescent cells that we might choose to draw lines between. To pick one example, PAI-1 inhibition can slow atherosclerosis, just as can removal of senescent foam cells in atherosclerotic plaque. There are no doubt overlapping mechanisms here, though it seems clear that reducing PAI-1 levels has a variety of other effects as well. Those effects can't be all that terrible given the existence of a lineage of thriving human mutants lacking PAI-1, something that is always a good demonstration to have in hand. There are a few other beneficial mutations with a small human population to examine, such as those related to reduced blood lipids; we may see many of these lines of research result in therapies in the years ahead. And yet! While there will no doubt be an avalanche of funding into bringing PAI-1 inhibitors to the clinic, ask yourself this: if tinkering with a fraction of the harmful secretions of senescent cells is this beneficial, how much better will it be to remove these damaging cells entirely via senolytic therapies? All of those involved in this field should spend more time than they do on work with a higher expectation value, I believe.

Genetic mutation in extended Amish family in Indiana protects against aging and increases longevity

The first genetic mutation that appears to protect against multiple aspects of biological aging in humans has been discovered in an extended family of Old Order Amish. An experimental "longevity" drug that recreates the effect of the mutation is now being tested in human trials to see if it provides protection against some aging-related illnesses. Indiana Amish kindred (immediate family and relatives) with the mutation live more than 10 percent longer and have 10 percent longer telomeres (a protective cap at the end of our chromosomes that is a biological marker of aging) compared to Amish kindred members who don't have the mutation.

Amish with this mutation also have significantly less diabetes and lower fasting insulin levels. A composite measure that reflects vascular age also is lower - indicative of retained flexibility in blood vessels in the carriers of the mutation - than those who don't have the mutation. These Amish individuals have very low levels of PAI-1 (plasminogen activator inhibitor,) a protein that comprises part of a "molecular fingerprint" related to aging or senescence of cells. It was previously known that PAI-1 was related to aging in animals but unclear how it affected aging in humans.

"For the first time we are seeing a molecular marker of aging (telomere length), a metabolic marker of aging (fasting insulin levels) and a cardiovascular marker of aging (blood pressure and blood vessel stiffness) all tracking in the same direction in that these individuals were generally protected from age-related changes. That played out in them having a longer lifespan. Not only do they live longer, they live healthier. It's a desirable form of longevity. It's their 'health span.'"

The researchers have partnered with another group in the development and testing of an oral drug, TM5614, that inhibits the action of PAI-1. The drug has already been tested in a phase 1 trial in Japan and is now in phase 2 trials there. The team will apply for FDA approval to start an early phase trial in the U.S., possibly to begin within the next six months. The proposed trial will investigate the effects of the new drug on insulin sensitivity on individuals with type 2 diabetes and obesity because of the mutation's effect on insulin levels in the Amish.

A null mutation in SERPINE1 protects against biological aging in humans

Aging remains one of the most challenging biological processes to unravel, with coordinated and interrelated molecular and cellular changes. Humans exhibit clear differential trajectories of age-related decline on a cellular level with telomere attrition across various somatic tissues and on a physiological level across multiple organ systems. In addition to telomere length, researchers have proposed several molecular drivers of aging, including genomic instability, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. Despite knowledge of these potential molecular causes of aging, no targeted interventions currently exist to delay the aging process and to promote healthy longevity.

In the United States, cardiometabolic disease influences life span as a leading cause of death and disability in adult men and women. Cardiometabolic disease is associated with a shorter leukocyte telomere length (LTL). Telomere shortening, which results from replication of somatic cells in vitro and in vivo, may cause replicative senescence. Senescent cells and tissues exhibit a distinctive pattern of protein expression, including increased plasminogen activator inhibitor-1 (PAI-1) as a part of the senescence-associated secretory phenotype (SASP).

PAI-1, which is encoded by the SERPINE1 gene, is the primary inhibitor of endogenous plasminogen activators and is synthesized in the liver and fat tissue. In addition to its role in regulating fibrinolysis, PAI-1 also contributes directly to cellular senescence in vitro. Genetic absence or pharmacologic inhibition of PAI-1 in murine models of accelerated aging provides protection from aging-like pathology, prevents telomere shortening, and prolongs life span. Cross-sectional human studies have demonstrated an association of plasma levels of PAI-1 with insulin resistance. Large genome-wide association studies (GWAS) provide an additional supportive evidence for a casual effect of PAI-1 on insulin resistance and coronary heart disease.

The role of the SASP, in general, and specifically PAI-1 in longevity in humans is uncertain. We have previously reported the identification of a rare frameshift mutation in the SERPINE1 gene in the Old Order Amish (OOA), living in relative geographic and genetic isolation; this mutation results in a lifelong reduction in PAI-1 levels. Therefore, we tested the association of carrier status for the null SERPINE1 mutation with LTL as the prespecified primary end point in the only known cohort with a SERPINE1 null mutation. The central findings of our study are that heterozygosity for the null SERPINE1 gene encoding PAI-1, which is associated with a lifelong reduction in PAI-1, is associated with longer LTL, a healthier metabolic profile with lower prevalence of diabetes, and a longer life span. The Amish kindred provide an unprecedented opportunity to study the biological effects of a private loss-of-function mutation with a large effect on circulating PAI-1 on longevity in humans.

The current study builds upon the available cellular and animal evidence supporting the role of PAI-1, the product of SERPINE1, as an important contributor to aging. PAI-1 expression is increased in senescent cells and tissues and is a fundamental component of the SASP. There is a compelling evidence that senescent cells accumulate in the tissues and contribute to the aging process. In addition to contributing to the molecular fingerprint of senescence, PAI-1 is necessary and sufficient for the induction of replicative senescence in vitro and is a critical downstream target of the tumor suppressor p53. The contribution of PAI-1 to cellular senescence is broadly relevant in the organism as a whole.

The Limits to Human Longevity, or Lack Thereof

This open access paper is a good resource if you happen to want a list of references to the mainstream scientific discussion of the past twenty years regarding trends in human life expectancy, and the predicted future of those trends. It is somewhat myopic beyond that in the sense that it gives little credit to the idea that the trend might continue or increase, as a result of future technological progress in medicine. The trend is an artifact of human efforts, and as such the size of the trend is entirely dependent on how well medicine can be made to address the causes of aging.

In the past, no effort at all was directed towards treating the causes of aging, and the small degree of extended healthy life with each passing year was an entirely accidental benefit. We are now at a point in time in which the scientific community is transitioning into making deliberate efforts to treat the causes of aging, with increasing enthusiasm and funding. Therefore expecting the future trend to look like the past trend, or even slow down, or thinking that we are in any way approaching a limit to human life span, appears to me to be a nonsensical position. We can understand why human life span is limited today, and why it was limited in the past: it does not follow that it will be limited in the future, because medical science will address the biological mechanisms involved, the accumulation of cell and tissue damage that causes aging.

How long can we live? How fast can we run or swim? Demographers disagree about the lifespan trend and its potential limit, while sports scientists discuss the frontiers of maximal physical performance. Such questions stimulate large and passionate debates about the potential of Homo sapiens and its biological upper limits. Historical series, defined as the measurable data collected since the nineteenth century for lifespan, sport, or height provide crucial information to understand human physiology and the form and nature of our progression over the last 10 generations.

Recent studies about lifespan trends increased interest about the possible ceilings in longevity for humans. This long-lasting debate increased in strength at the beginning of the 1990s. Using biological and evolutionary arguments, the first leading opinion postulated an upper limit for life expectancy at birth and maximal longevity. These limits may have already been approached: around 85-95 years for life-expectancy and 115-125 years for maximal longevity, as a result of nutritional, medical, societal, and technological progress. A second school of thought considered that life expectancy may continue to progress indefinitely at a pace of 2 to 3 added years per decade. They claim that most of the babies born during the 2000s, "if the present yearly growth in life expectancy continues through the twenty-first century," will celebrate their 100th birthday or, potentially reach physical immortality due to undefined scientific breakthroughs.

Human life-expectancy and maximal lifespan trends provide long historical series. Similar to sport achievements, though somewhat less precisely measured, it followed an unprecedented progression during the twentieth century supported by major nutritional, scientific, technological, societal, and medical innovations. From 1900 to 2000 in the majority of high-income countries, life expectancy at birth increased by ~30 years, mostly due to a reduction of child mortality through nutrition, hygiene, vaccination, and other medical improvements.

Concerning the future, trends oscillate, from pessimistic to optimistic views, but recent data suggest a slow-down in the progress of life-expectancy related to the stabilization of a very low level of infant mortality (0.2-1% of births in the healthiest countries in the world). The present slow progress in high-income countries is mostly due to reduced mortality rates of chronic non-communicable diseases, principally among cardiovascular diseases and cancers. However, those advancements have a much lower impact on life-expectancy as compared to vaccination campaigns.

Predicting a continuous linear growth of life-expectancy in the long term may probably not be relevant if the major progresses have already been accomplished. Beyond the fittest mathematical model for estimating future trends, we need to carefully examine the consistency with structural and functional limits determining maximal lifespan related to life-history strategies and evolutionary and environmental constraints. For example, aging is an irreversible process: it is complex as it concerns all physiological functions, organs, and maintenance systems. But, it also has universal characteristics, showing a continuous exponential decline starting in the third decade for all maximal indicators with an accelerated loss of physical performance until death. No escape from decline is observed, despite the best efforts of the oldest old.

Similarly, maximal lifespan increased slightly during the last two centuries, but since 1997, nobody has lived for more than 120 years. Surpassing mathematical models, projecting 300 years into the future without biological considerations, most recent data showed evidence of a lifespan plateau around 115-120 years, despite a sharp increase in the number of centenarians and supercentenarians. Jeanne Calment with 122.4 years has certainly come close to the potential biological limit of our species in term of longevity, at the benefit of an extremely rare long-lived phenotype supported by a specific lifestyle and chance.

Link: https://doi.org/10.3389/fphys.2017.00812

Libella Gene Therapeutics Plans Human Telomerase Gene Therapy Trial

My attention was recently directed to another new group planning patient paid human trials of telomerase gene therapy. This is a company associated with Sierra Sciences and the RAAD Festival crowd, meaning the Life Extension Foundation principals. These folk have of late started to fund a number of interesting efforts, such as the Betterhumans senolytics trials. This is another in that series.

Is telomerase gene therapy a useful treatment for aging? In mice it extends life span, most likely through effects such as greater immune activity and greater stem cell activity, but possibly also via other mechanisms. Telomerase acts to lengthen telomeres at the ends of chromosomes, but it also has a range of other functions, some of which might positively impact mitochondrial function. Average telomere length in tissues falls with age: it is a function of the rate of cell division, as telomeres shorten every time a cell divides, and stem cell activity, as stem cells produce daughter cells with long telomeres. So telomere length is very much an assessment of some of the processes of aging, not a cause of aging. In turn, telomerase gene therapy is not a means of targeting the causes of aging - rather, it is one of the more effective classes of compensatory treatment identified to date, alongside forms of stem cell therapy.

Whether telomerase gene therapy will have the same sort of risk and benefit profile in humans as it does in mice is something of an open question. Mice have very different telomere dynamics in comparison to humans, and the risk of cancer may well be quite different as well. Counterintuitively, in mice that risk actually appears to be reduced by introduction of telomerase, though the mechanisms involved are not well understood. We might hypothesize that increased immune system efficiency in removing potentially cancerous cells counterbalances the telomerase-induced tendency for those cells to become more active. Still, how do you find out other than by trying? Making the attempt is the most cost-effective means of obtaining human data.

Our mission is to reverse aging and cure all age-related diseases, starting with Alzheimer's. Libella Gene Therapeutics has exclusively licensed the technology of Sierra Sciences to conduct a human research project. We believe we have the scientist, the technology, the physicians, and the lab partners, all of which are necessary to get this done. By activating telomerase, we hope to lengthen telomeres in the body's cells. To have an effective delivery system for the telomerase to reach every cell in the body, quadrillions of gene therapy particles must be produced for each test subject. The production of enough gene therapy particles to treat one person takes anywhere from four months to a year to complete. Because of the demands on production, we will have a limited number of tests available. We anticipate having around 50 spots over the next 12 months.

We believe the most expedient way to test revolutionary evidence-based technology, such as gene therapy, is a pay to play model. The FDA passed legislation in 2009 allowing for patients to pay for their care when other viable options are not available. Libella Gene Therapeutics (LGT) strongly believes an informed choice is a right, not a privilege. LGT believes that "pay to play" is ethical. The data has continued to mount that telomerase activation and lengthening of telomeres may be the most exciting and disruptional breakthrough in the history of medicine. LGT is committed to bringing telomerase therapy to the world.

Today the majority of human clinical studies are performed outside of the United States. 65% of clinical studies are performed off shore. Typically it is cheaper, quicker, and involves less regulation. LGT believes it is most ethical to conduct our studies outside of the United States where we can move faster, and at a lower cost, as long as there is no reduction in quality or safety for our study participants.

Link: http://www.libellagenetherapeutics.com/mission/