Today's open access paper provides an interesting visualization of the slow upward trend in life expectancy that has taken place over the last 60 years. A plot of the distribution of human mortality by age over the last third of life results in a wave-like curve, peaking at around 90 years of age. But those are today's numbers. In the 1960s, the curve had much the same shape, but the peak was at 80 years of age. Life was shorter, but the distribution of mortality at the end of life was much the same.

This is the case despite large changes in the causes of death over this span of decades. Mortality risk due to heart disease has diminished greatly, for example, thanks to the advent of statins and similar treatments. The slow march of medicine - meaning control of infection and improved health throughout life, not just incrementally better ways to treat age-related disease - has resulted in life expectancy at birth increasing by two years every decade. Remaining life expectancy at 65 has increased by about a year with every passing decade.

These trends are now a matter of history, and will not continue as they have. The advent of senolytic therapies to selectively remove senescent cells, one of the causes of aging, will cause an upward leap in life expectancy at 65. Other rejuvenation therapies that arrive in the decades ahead will result in further gains. The era of slow, incidental increases in life span is over. The era of deliberately engineered longevity has started, but it will most likely take two decades or more for the results of present clinical development to start to appear in population-wide demographic data. There is a lot of work left to accomplished not just in development but also for distribution of rejuvenation therapies: senolytics already exist, but next to no-one is using them, for example. This must change.

Advancing front of old-age human survival

We conclude that an advancing old-age front characterizes old-age human survival in 20 developed countries. The long-term speed of the advancing front is ≃0.12 year per calendar year, about 3 years per human generation. The location of the survival front is the 25th percentile of mortality. Thus, the front implies that, e.g., age 68 years today is equivalent, in terms of mortality, to age 65 years a generation ago. Our findings echo aspects of an earlier proposal that mortality hazards have, over the years, shifted rigidly to older ages. Our analysis of percentiles makes no assumptions about the pattern of mortality at young or old ages and focuses on older deaths. However, our finding of a shifting front in the percentiles of death at old age is consistent with some patterns of shifts in old-age mortality hazards.

Our findings provide no support for an impending limit to human lifespan, certainly not at an age that affects the movement of the survival front (between the 25th and 90th percentiles). To the extent that we can rely on the long-term speeds of percentiles above the 90th, the oldest deaths are being compressed in some countries but definitely not in others. Here again we find no support for an approaching limit to human lifespan. Nor do our results suggest that endowments, biological or other, are a principal determinant of old-age survival. The advancing survival front that we find suggests that the effects of inequality on mortality may be much smaller among old-aged adults than among younger adults.

Our analyses use period life tables, not cohorts, and suggest that continued mortality improvement depends largely on period processes such as economic growth, investment and advances in health science research and practice, and increases in the age of transition to disability. Our results also constrain biological arguments about the causes of death, especially the plasticity of death rates in response to environmental factors. Our moving survival front is consistent with a plateau in mortality rates, but implies that the location and possibly the level of the plateau change over time.

Aging is a phenomenon affecting all organs and systems throughout the body, driven by rising levels of molecular damage. The variation in aging between individuals is largely determined by variations in the overall burden of such damage, the compound interest of small differences arising from lifestyle choices and happenstance such as infection in the first half of life. Thus for any given individual, manifestations and measures of aging tend to be fairly well correlated. That doesn't necessarily tell us anything about causation. So in this study, in which the researchers look at two very high level manifestations of aging, menopause and life span, there is probably no direct thread of causation at all. These are downstream manifestations of the summed effects of every cause of aging.

It is a well-accepted fact in the medical community that both type 2 diabetes and early onset of natural menopause may be associated with early death. Emerging evidence shows an association between age at menopause and diabetes, with studies reporting almost a two-fold increased risk of type 2 diabetes with early onset of menopause. To date, however, there are no other known studies that have quantified (calculated the number of years lived with and without diabetes) the combined association of early menopause and type 2 diabetes with life expectancy.

In this study involving 3,650 postmenopausal women, the difference in life expectancy was compared in women experiencing early, normal, and late menopause, as well as in those with and without diabetes. Compared with late menopause (defined as menopause that occurs at age 55 years and older), the difference in life expectancy for women who experienced early menopause (defined as menopause that occurs at age 44 years or younger) was -3.5 years overall and -4.6 years in women without diabetes. Compared with age at normal menopause (defined as menopause that occurs at 45-54 years of age), the difference in life expectancy for women who experienced early menopause was -3.1 years overall and -3.3 years in women without diabetes.

The authors suggest the need for future research to examine the mechanisms behind this association to help tailor prevention and treatment strategies that improve women's health across all age categories of menopause.

Link: https://www.eurekalert.org/pub_releases/2018-10/tnam-eoo101618.php

Evolution requires happenstance mutation in order to progress, but too much of this random mutation leads to cancer or other forms of dysfunction sufficient to reduce reproductive fitness. The result is our present balance: enough mutation to make cancer a major cause of death, to ensure that mitochondria contribute to aging via mutation of mitochondrial DNA, and to produce some level of general dysfunction in aged tissues due to the accumulated mutational burden. The research noted here is one representative example of a range of research that seeks to quantify the degree to which our cells exhibit random mutational damage as we age. You might compare it with another set of results published recently on competition between mutations in skin, and how this paradoxically manages to suppress cancer risk.

Every person accumulates genetic changes, or mutations, throughout their lifetime. These mutations in normal tissue, called somatic mutations, are key to understanding the first steps to cancer and likely contribute towards ageing, but are uncharted territory due to technical limitations. For the first time, scientists have uncovered that on average, healthy cells in the oesophagus carry at least several hundred mutations per cell in people in their twenties, rising to over 2,000 mutations per cell later in life. Only mutations in a dozen or so genes seem to matter however, as these give the cells a competitive advantage allowing them to take over the tissue and form a dense patchwork of mutations.

The team used targeted and whole-genome sequencing to map groups of mutant cells in normal oesophageal tissue from nine individuals aged 20 to 75 years. The individuals' oesophageal tissues were considered healthy as none of the donors had a known history of oesophageal cancer, nor were taking medication for problems relating to the oesophagus. The study also casts new light on the mutations that are found in the squamous kind of oesophageal cancers. One mutated gene, TP53, which is found in almost all oesophageal cancers is already mutated in 5-10 per cent of normal cells, suggesting that cancer develops from this minority of cells.

In contrast, mutations in the NOTCH1 gene, known to control cell division, were found in nearly half of all cells of normal oesophagus by middle age, being several times more common in normal tissue than cancer. This observation suggests that researchers need to reconsider the role of some genes recurrently mutated in cancer in the light of mutations in normal tissue, and raises the possibility that the NOTCH1 mutation may even protect cells against cancer development. "This study shows that some genetic changes linked to cancer are present in surprisingly large numbers of normal cells. We still have a long way to go to fully understand the implications of these new findings, but as cancer researchers, we can't underestimate the importance of studying healthy tissue."

Link: https://www.sanger.ac.uk/news/view/mutant-cells-colonise-our-tissues-over-our-lifetime

The SENS Research Foundation year end fundraiser has started. From now until the end of 2018, every new monthly donor will have the next year of their charitable donations to the SENS Research Foundation matched from our $54,000 challenge fund. The fund sponsors, Josh Triplett, Christophe and Dominique Cornuejols, and Fight Aging! challenge you to fund the development of rejuvenation therapies: sign up as a recurring donor, and we will match your donations for the next year.

Collectively, the SENS programs provide a path to comprehensive human rejuvenation. The SENS Research Foundation asks us to reimagine aging, to give our support to building a future in which being old does not have to mean being frail, sick, suffering, and diminished. This is not just theory. After years of effort, the work of our community of scientists, advocates, and philanthropists is paying off with the existence of working rejuvenation therapies that are well on their way to the clinic. The first rejuvenation therapies based on the SENS model, those that selectively destroy senescent cells, have been proven in mice and are presently undergoing heavily funded, rapidly expanding clinical development in multiple startup companies. Clinical trials in patients are underway.

So far, so good, but this is just the first step. The progress to date proves that the SENS vision of rejuvenation through damage repair is correct, but even as senescent cell clearance receives the attention and funding that it merits, a score of other equally important lines of research and development continue to languish, lacking resources. It is our job to provide those resources, the funding that can be used to bring these areas of research towards proof, widespread support, and active clinical development. The SENS Research Foundation has demonstrated its ability to make very good use of our charitable donations: you won't find a better way to change the world than this opportunity.

Reimagine Aging: the Campaign Begins Now

Thank you for your dedicated support of SENS Research Foundation's mission to end age-related disease. We know you share our passion and vision for a world with extended, healthy lifespans for all. How much human suffering would be alleviated if science and medicine could comprehensively treat the diseases of aging at their root cause?

Our donors are making this a reality. With your support, we are conducting and funding research, educating new scientists, and engaging in outreach to the public and industry partners. Research focuses on a unique damage-repair approach to treat diseases of aging. Education engages the next generation of rejuvenation biotechnology professionals. Outreach encourages and inspires the general public, policymakers, and academia to Reimagine Aging.

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Researchers here suggest that the protein chrdl1 plays an important role in the regulation of synaptic plasticity, the ability of the brain to generate new connections between neurons. Synaptic plasticity declines with age, and is important in cognitive function. There is thus considerable interest in ways to enhance plasticity, not just to turn back this aspect of aging, but also potentially as a form of enhancement therapy to improve memory or other aspects of the mind.

Researchers have shown that astrocytes - long-overlooked supportive cells in the brain - help to enable the brain's plasticity, a new role for astrocytes that was not previously known. The findings could point to ways to restore connections that have been lost due to aging or trauma. "To investigate this role, we used a lot of techniques in the lab to identify a signal made by astrocytes that's very important for brain maturation."

The signal turned out to be a protein astrocytes secrete called Chrdl1, which increases the number and maturity of connections between nerve cells, enabling the stabilization of neural connections and circuits once they finish developing. To further understand the role of Chrdl1, the team developed mouse models with the gene disabled by introduced mutations. These mice had a level of plasticity in their brains that was much higher than normal. Adult mice with the Chrdl1 mutation had brain plasticity that looked very much like that of young mice, whose brains are still in early stages of development.

Not much is known about the role of Chrdl1 in humans, but one study of a family with a Chrdl1 mutation showed they performed extremely well in memory tests. Other studies have shown the level of the gene encoding Chrdl1 is altered in schizophrenia and bipolar disorder, suggesting that Chrdl1 may have important roles in both health and disease. Future research by the team will dive deeper into the relationships between astrocytes and neurons and look for potential ways to use astrocytes as therapy. "We're interested in learning more about what the astrocytes are secreting into the brain environment and how those signals affect the brain. We plan to look at this relationship both early in development and in situations where those connections are lost and you want to stimulate repair, like after someone has had a stroke."

Link: https://www.salk.edu/news-release/brain-cells-called-astrocytes-have-unexpected-role-in-brain-plasticity/

Alzheimer's disease starts with a slow rise in levels of amyloid-β present in the brain, an imbalance between dynamic processes of creation and clearance. This produces a state of mild biochemical and cognitive dysfunction that sets the stage for the later, much more destructive phase characterized by chronic inflammation, deposition of altered tau protein, and cell death. The roots of Alzheimer's must lie in the early mechanisms, in the poorly studied initial years of the condition, that cause some people to accumulate amyloid-β at a faster pace. In recent years evidence has emerged for persistent viral infection to play a role. Amyloid-β is coming to be seen as an anti-viral mechanism, and its creation and aggregation is prompted by the presence of viral particles.

Strong evidence has emerged recently for the concept that herpes simplex virus type 1 (HSV1) is a major risk for Alzheimer's disease (AD). This concept proposes that latent HSV1 in brain of carriers of the type 4 allele of the apolipoprotein E gene (APOE-ε4) is reactivated intermittently by events such as immunosuppression, peripheral infection, and inflammation, the consequent damage accumulating, and culminating eventually in the development of AD.

Population data to investigate this epidemiologically, e.g., to find if subjects treated with antivirals might be protected from developing dementia - are available in Taiwan, from the National Health Insurance Research Database, in which 99.9% of the population has been enrolled. This is being extensively mined for information on microbial infections and disease. Three publications have now appeared describing data on the development of senile dementia (SD), and the treatment of those with marked overt signs of disease caused by varicella zoster virus (VZV), or by HSV. The striking results show that the risk of SD is much greater in those who are HSV-seropositive than in seronegative subjects, and that antiviral treatment causes a dramatic decrease in number of subjects who later develop SD.

It should be stressed that these results apply only to those with severe cases of HSV1 or VZV infection, but when considered with the over 150 publications that strongly support an HSV1 role in AD, they greatly justify usage of antiherpes antivirals to treat AD.

Link: https://doi.org/10.3389/fnagi.2018.00324

One of the more interesting aspects of the various epigenetic clocks that have been developed in recent years is that it is still largely unknown as to what exactly it is that they are assessing in our aging biochemistry. These clocks are weighted measures of epigenetic markers, such as DNA methylation, over a comparatively small number of genes. The resulting number certainly reflects chronological age, with the best clocks having a margin of error of a few years when assessed over a group of people. There is also sound evidence for it to reflect biological age, the burden of damage and dysfunction, which varies between individuals. Some people are more burdened by aging than others, and it is thought that these clocks can assess that difference.

But what underlying processes of aging are driving the results? That isn't clear at all. It is quite possible that an epigenetic clock measures the changes resulting from only a limited subset of the full range of age-related damage and dysfunction. Because aging is a global phenomenon in which all of its aspects tend to be fairly well correlated with one another, the clock nonetheless works well as a measure of overall aging. We will only find out whether or not this is the case as rejuvenation therapies start to emerge, treatments that very selectively address one and only one of the root causes of aging. Does treatment with senolytics to reduce the number of lingering senescent cells reverse the epigenetic clock measure, for example? We'll know the answer to that question in the near future, but for now those studies are still underway or pending publication.

Researchers here perform an preliminary investigation of what happens to epigenetic age in cells in which telomerase is at work. Telomerase acts to extend cell life by extending telomeres. Telomeres are the caps at the end of chromosomes, and are reduced in length with each cell division. This is a part of the countdown mechanism that leads to the Hayflick limit, preventing normal somatic cells from replicating indefinitely. Once they reach the limit, they self-destruct, or become senescent and are then destroyed by the immune system. Stem cells can replicate indefinitely because they use telomerase, and their role is to create new somatic cells with long telomeres to replace those lost over time. This split between a few privileged cells and the vast majority of limited cells is the way in which cancer risk is kept low enough for evolutionary success in higher animals.

A faction in the research and development communities are quite enthusiastic about telomerase gene therapy as a means to extend life, based on results from animal studies over the past decade or more. This most likely produces benefits through enhanced cell activity, and particularly stem cell activity, in a context in which the evolved balance of declining cell activity with age, most likely a defense against cancer, has some wiggle room. It appears possible to produce greater regeneration in later life without greatly raised risk of cancer by pressing damaged cells into undertaking more work. As is discussed by the authors of the paper below, this may also have something to do with reduced levels of senescent cells: a damaged cell that continues operating might, on average, be less immediately harmful than a lingering senescent cell, even though one would imagine this to raise cancer risk. The degree to which these and other mechanisms might contribute to the improved health and extended life observed in mice as a result of telomerase gene therapies has not yet been rigorously determined. But what does this do to epigenetic age? Running studies in cells doesn't really tell us what happens in animals; it is more a way to get a handle on the basics that can then be used to argue one position or another.

Epigenetic ageing is distinct from senescence-mediated ageing and is not prevented by telomerase expression

Ectopic expression of hTERT, the catalytic sub-unit of telomerase, which can preserve telomere length and avert senescence of some cells. It was initially thought that the functional and physical deterioration that characterise organismal ageing are a result of insufficient replenishment of cells due to telomere-mediated restriction of cellular proliferation. Senescent cells, which accumulate increasingly in tissues in function of age, were assumed to be passive and merely a consequence of the above-described processes. This notion was short-lived when senescent cells were found to secrete molecules that are detrimental to cells and tissues.

As such, it would follow that if cells were prevented from becoming senescent in the first place, ageing could be avoided. Although there are external instigators such as stress and DNA damage that can also cause cells to become senescent, replicative senescence is particular in that it is an intrinsic feature that is part of cellular proliferation and occurs even in an ideal environment. As expression of hTERT has been repeatedly demonstrated to prevent replicative senescence of many different cell types, it is reasonable to consider ectopic expression or re-activation of endogenous hTERT expression as potential means to prevent replicative senescence, delay ageing, and improve health.

The above proposition would be valid if senescent cells were indeed the only cause of ageing. Relatively recently, an apparently distinct form of ageing, called epigenetic ageing was described. This discovery stems from observations that the methylation states of some specific cytosines that precede guanines (CpGs) in the human genome changed rather reliably and strictly with age. This allowed supervised machine learning methods to be applied to DNA methylation data to generate an DNA methylation-based age estimator, which in the majority of the human population is similar with chronological age. Epigenetic age is not merely an alternative means of determining chronological age but is to some degree a measure of biological age or health; a proposition that is further supported by the impressive demonstration that acceleration of epigenetic ageing is associated with increased risk of all-cause mortality.

We recently developed a new epigenetic age estimator, referred to as skin and blood clock that is more accurate in estimating age of different cell types including fibroblasts, keratinocytes, buccal cells, blood cells, saliva and endothelial cells. Studies employing skin and blood clock and the pan-tissue epigenetic age clock revealed a startling consistency of epigenetic age across diverse tissues from the same individual, even though cellular proliferation rates and frequencies of these tissues are not the same. This suggests that the ticking of the epigenetic clock is not a reflection of proliferation frequency, which is in stark contrast to telomere length, which enumerates cellular division. It would therefore appear that the process of epigenetic ageing is distinct from that which is driven by telomere-mediated senescence.

To understand their relationship or interaction, if one indeed exists, we set out to test the impact of hTERT on epigenetic ageing. To this end we employed wild type hTERT that can prevent telomere attrition and its mutants that cannot, with some still able to nevertheless prolong cellular lifespan. Expressing these hTERT constructs in primary cells from numerous donors, ages and cell types, we observe that while hTERT expression can indeed prevent cellular senescence, it does not prevent cells from undergoing epigenetic ageing and that extension of cellular lifespan is sufficient to support continued epigenetic ageing of the cell. These simple observations provide a very important piece to the puzzle of the ageing process because it reveals the distinctiveness of epigenetic ageing from replicative senescence-mediated ageing. They provide further empirical support to the epidemiological observation that hTERT variant that is associated with longer telomeres are also associated with greater epigenetic ageing.

Many other species are more regenerative than we are, and mammals in general are less regenerative than is the case for some other clades. It is too early to say whether ongoing investigations of the basis for proficient regeneration will lead to ways to safely adjust our biochemistry to perform greater feats of healing. Even simple mechanisms, if found, may be turn out to be very hard to introduce into humans. Everything in cellular biochemistry is connected to everything else; nothing can be changed in isolation. The greatest hope is that mechanisms of regeneration that are active in other species are merely dormant in mammals, but again it is too early to say with any confidence as to whether or not this is the case, despite promising signs in recent years.

Hearing impairment has long been accepted as a fact of life for the aging population - an estimated 30 million Americans suffer from some degree of hearing loss. However, scientists have long observed that other animals - namely birds, frogs, and fish - have been shown to have the ability to regenerate lost sensory hair cells. "It's funny, but mammals are the oddballs in the animal kingdom when it comes to cochlear regeneration. We're the only vertebrates that can't do it."

In 2012 researchers identified a family of receptors - called epidermal growth factor (EGF) - responsible for activating support cells in the auditory organs of birds. When triggered, these cells proliferate and foster the generation of new sensory hair cells. The researchers speculated that this signaling pathway could potentially be manipulated to produce a similar result in mammals. "In mice, the cochlea expresses EGF receptors throughout the animal's life, but they apparently never drive regeneration of hair cells. Perhaps during mammalian evolution, there have been changes in the expression of intracellular regulators of EGF receptor family signaling. Those regulators could have altered the outcome of signaling, blocking regeneration. Our research is focused on finding a way switch the pathway temporarily, in order to promote both regeneration of hair cells and their integration with nerve cells, both of which are critical for hearing."

In a new study, researchers tested the theory that signaling from the EGF family of receptors could play a role in cochlear regeneration in mammals. The researchers focused on a specific receptor called ERBB2 which is found in cochlear support cells. One set of experiments involved using a virus to target ERBB2 receptors. Another involved mice genetically modified to overexpress an activated ERBB2. A third experiment involved testing two drugs, originally developed to stimulate stem cell activity in the eyes and pancreas, that are known activate ERBB2 signaling. The researchers found that activating the ERBB2 pathway triggered a cascading series of cellular events by which cochlear support cells began to proliferate and start the process of activating other neighboring stem cells to become new sensory hair cells. Furthermore, it appears that this process not only could impact the regeneration of sensory hair cells, but also support their integration with nerve cells.

Link: https://www.urmc.rochester.edu/news/story/5448/study-points-to-possible-new-therapy-for-hearing-loss.aspx

Adult, or somatic, stem cells support surrounding tissues by delivering a supply of daughter somatic cells, ready to replace those lost over time. This stem cell activity declines with age, and in the best studied stem cell populations this appears to be more a matter of signaling than a matter of inherent dysfunction. Stem cells react to rising levels of damage in tissues, or rather to the changes in signaling that result from that damage. Old stem cells put into a young environment perform as well as their younger counterparts. This decline with age may have evolved to limit cancer risk, but it brings the certainty of a slow decline into organ failure.

Many research groups are searching for the signals responsible for adjusting stem cell activity. The scientists here demonstrate that the autonomic nervous system makes important contributions to this signaling environment, and thus specific neurotransmitters may be a useful target for therapies to suppress or enhance stem cell function in various contexts. When it comes to aging, the function of the autonomic nervous system is known to change in later life, but more work is needed to solidify how this new research fits in to the bigger picture.

Somatic stem cells are microscopic workhorses, constantly regenerating cells throughout the body: skin and the lining of the intestine, for example. Researchers have demonstrated for the first time that stem cell proliferation is directly controlled by the autonomic nervous system (ANS). The ANS controls all of our unconscious functions: breathing, blood flow, digestion, and so forth. Its two major networks of nerve fibers run from the brain through the entire body, with neurons reaching into nearly every organ. These neurons release chemicals called neurotransmitters, which can affect target cells directly or indirectly.

When neurotransmitters bind to receptors in the membranes of certain cells, they elicit a direct response within the cell. But changes in cells can also occur when neurotransmitters induce a general state of inflammation or alter blood flow, an indirect route of action for the ANS. Scientists had suspected the ANS was involved in stem cell proliferation, but they didn't know if the relationship was direct or indirect. A direct relationship could have greater implications for drug interventions to treat medical conditions. "If you wanted to change the regeneration potential of an organ, for example, you wouldn't have to stimulate or suppress the activity of those neurons. Instead, you could just figure out what neurotransmitters are controlling proliferation and then get that chemical to those stem cells with targeted drug delivery."

To demonstrate that stem cell behavior was changing as a result of ANS stimulation, the researchers grew intestinal epithelial cells in the lab and exposed them to high levels of two neurotransmitters, norepinephrine and acetylcholine. Norepinephrine is a major neurotransmitter of the sympathetic nervous system, or "fight or flight" branch of the ANS, while acetylcholine is produced by the parasympathetic nervous system, or "rest and digest" branch. When the researchers simulated activation of either of those systems, they saw a decrease in stem cell proliferation. This suggests the body may avoid putting energy into making new cells when the fight or flight system is active.

Link: https://www.eurekalert.org/pub_releases/2018-10/uoic-isf101718.php

CPHPC, now called miridesap, is a cautionary tale of what all too often happens to promising approaches in the field of medical development, once they advance to the point of expensive clinical trials and the requirement for partners with deep pockets to fund those trials. Miridesap was one of the earlier methodologies demonstrated to clear out transthyretin amyloid from tissues. This form of amyloid appears to be an important contribution to risk of cardiovascular disease, as well as a factor in osteoarthritis, and the evidence suggests it is the majority cause of death in supercentenarians. Its accumulation in old tissues is a form of damage, one of the root causes of aging. Ways to remove transthyretin amyloid should be pursued aggressively, but so far most of the effort in the research community has focused on the inherited form of transthyretin amyloidosis, using therapies that are not all that helpful for the age-related form of amyloidosis.

The first attempt to develop miridesap with a major pharmaceutical concern failed in the 1990s and early 2000s. The company founded to develop miridesap, Pentraxin Therapeutics, then partnered with Glaxosmithkline, GSK, at which point it took something like nine years to get to the point of running a small trial in 2015. That trial was successful, but thereafter GSK discontinued the work. The problem is less that initiatives sometimes fail, and more that (a) major pharmaceutical entities do not have the right incentives operating in order to carry out development programs rapidly and reliably, and (b) their ownership of intellectual property rights prevents anyone else from trying variants on the same approach, even when very little is being done, or the research is entirely halted. While in principal it is possible to obtain rights to a moribund program, in practice that is far from easy, and too expensive for most of the people who would consider trying it. This might all be seen as a symptom of excessive regulatory costs. Either way, research and development languishes.

Miridesap has a third act, however, one that has been in the works for a few years now. Those involved are attempting to use it as a way to remove amyloid-β in Alzheimer's disease, and are organizing a trial that is now recruiting. It will be interesting to see whether this works well enough to make it competitive. It is certainly less harsh on patients in comparison to the immunotherapies that make up the majority of attempts to treat Alzheimer's disease. Perhaps if this works, then the rights for use against transthyretin amyloid can be wrested from GSK, or GSK might be convinced to proceed again with that line of development.

NIHR-backed trial to test miridesap in Alzheimer's

Mark Pepys, who has been working on amyloidosis for 43 years, discovered way back in the 1980s that SAP, a normal, nonfibrous circulating plasma glycoprotein, is involved in the formation of amyloid deposits. He went on to show it is always present as a minor component of human amyloid deposits of all types, and that it prevents amyloid fibrils from being cleared via opsonization and phagocytosis. Despite attracting the interest of big pharma, attempts to translate those insights to the clinic have been slow to bear fruit.

A collaboration with Roche Holding AG that started in 1993 led to the discovery of miridesap (then known as CPHPC). When tested in the rare disease systemic amyloidosis, miridesap removed SAP from the blood, but could not shift large deposits of amyloid from organs. Amyloidosis patients treated with miridesap remained stable, but the deposits did not disappear. After Roche handed back rights in 2008, Pepys formed a collaboration with Glaxosmithkline to develop miridesap in combination with an anti-SAP antibody for treating amyloidosis. The rationale was to remove SAP from the blood and then use the antibody to target SAP in amyloid, activating the complement system to clear the deposits. That played out in a phase I study published in 2015, but a phase II, 30-patient study of the combination therapy recently was suspended by GSK.

Meanwhile, Pepys has been pursuing development of miridesap as a monotherapy in Alzheimer's disease. His basis for thinking miridesap can remove amyloid from the brain when it was not effective in removing it from other organs, is related to the much lower level of SAP that needs to be sponged up. SAP is generated and catabolized only in the liver and is not expressed in the brain. In a mouse model of Alzheimer's that is genetically engineered to generate human SAP, depleting SAP in the bloodstream removed all detectable SAP from amyloid in the brain.

The study is funded with $6.2 million in grants from NIHR. GSK has no commercial interest, but has assisted with the logistics of setting up the Despiad (Depletion of serum amyloid P component in Alzheimer's disease) trial. Patients in the trial will be required to inject miridesap three times a day over 12 months and to undergo a wide range of tests, including PET scans, lumbar punctures, and cognitive assessments. Pepys hopes the 100-patient, double-blind, placebo-controlled Despiad trial, will show the reduction in SAP levels translates into clinical benefit.

Researchers here describe one very thin slice of the sweeping metabolic changes produced by exercise and calorie restriction. Both interventions act to reduce blood pressure, most likely through numerous distinct mechanisms. One of those mechanisms involves raised levels of β-hydroxybutyrate, an effect that can in principle be mimicked or enhanced via carefully designed therapies. The raised blood pressure that occurs with age is one of the more destructive changes that take place with aging; it is in effect a way to translate accumulating damage and dysfunction at the cellular level into a physical bludgeon that destroys delicate structures throughout the body. Blood pressure is so influential in aging that current pharmacological methods that force a lowered blood pressure result in sizable reductions in disease incidence and mortality even though they fail to address the underlying damage of aging in any way.

Hypertension is a modifiable risk factor for cardiovascular disease and exercise is widely recommended for hypertensive patients as a lifestyle modification because of the well-documented beneficial effect of exercise on lowering blood pressure (BP). Similarly, calorie restriction, although not widely recommended for patients, is also documented to lower hypertension. Interestingly, both exercise and calorie-restriction are associated with increased circulating levels of ketone bodies such as β-hydroxybutyrate (βOHB). βOHB is produced predominantly in the liver, transported to other tissues, and traditionally recognized as a vital alternative metabolic fuel during times of starvation. However, contemporary evidence indicates that apart from serving as energy fuels, ketone bodies such as βOHB block inflammasome-mediated inflammatory diseases and thereby play a prominent role in maintaining physiological homeostasis.

In contrast to exercise and calorie-restriction, consumption of high salt promotes hypertension. Studies on the effects of dietary salt have focused mainly on organs and tissues relevant to BP regulation such as kidney, vasculature, heart, and brain. A recent report suggests that a reduction in salt intake serves as an additional interventional approach for reducing the risk for developing metabolic syndrome, of which, hypertension is one of the hallmark features. Taken together, these studies point to an intriguing possibility that a high salt diet induced a deleterious effect on hypertension and could mechanistically represent the opposite scenario to that of the protective effects of exercise and calorie-restriction on hypertension by altering the levels of metabolites such as ketone bodies.

Here, we examined this possibility, first by an untargeted mass spectrometry-based plasma metabolomics study and discovered altered ketogenesis and over-activation of renal Nlrp3 as a key mechanistic link between high salt and hypertension. These results indicated that a high salt diet has mechanistically opposite effects of exercise and calorie-restriction on BP. Next, we demonstrated that nutritional intervention with 1,3-butanediol, a precursor of the endogenous ketone body, βOHB, reversed the adverse effects of high salt induced renal Nlrp3-mediated inflammation, fibrosis, and hypertension. Based on these observations in the Dahl S rat, which is a salt-sensitive pre-clinical model of hypertension, we propose dietary intervention with 1,3-butanediol as an intriguing strategy for the clinical management of salt-sensitive hypertension.

Link: https://doi.org/10.1016/j.celrep.2018.09.058

This open access paper is an example of a model of future life expectancy that projects existing trends, with a little variation in here and there based on whether or not public health measures related to smoking and diet prove to be more successful or less successful. It predicts an average global increase in life expectancy of 4 to 5 years by 2040. In recent years I would have said that this is probably incorrect. I think we are at the point now in the development of rejuvenation therapies at which I can say that it is definitely incorrect. Any study that fails to consider progress in the treatment of aging as a medical condition is disconnected from reality.

Twenty years from now senolytic drugs will be used by a sizable percentage of the world's population, and will cost cents per dose. They will dramatically reduce the suffering and death resulting from inflammatory age-related diseases by removing some fraction of lingering senescent cells from old tissues. The first such therapies already exist today, are easily available, and some cost a few hundred dollars per dose or less. It isn't hard to see that the use of senolytics will spread like wildfire just as soon as the first clinical trials report their results over the course of 2019. Further consider that this is just one branch of rejuvenation biotechnology. Numerous other branches are under development today, and will certainly be clinically available by the late 2020s. The historical trend in life expectancy will be smashed; life expectancy will jump upward quite dramatically.

This was the first study to forecast a comprehensive set of cause-specific and all-cause mortality and associated indicators using a framework that allows for exploring different scenarios for many risk factors and other independent drivers. In our reference scenario, life expectancy was forecasted to continue increasing globally, and 116 of 195 countries and territories were projected to have significant advances in life expectancy by 2040. Gains were projected to be faster among many low-to-middle SDI countries, indicating that inequalities in life expectancy could narrow by 2040.

As shown by the better health scenarios, greater progress might be possible, yet for some drivers such as high body-mass index (BMI), their toll will rise in the absence of intervention. We forecasted global life expectancy to increase by 4.4 years for men and 4.4 years for women by 2040, but based on better and worse health scenarios, trajectories could range from a gain of 7.8 years to a non-significant loss of 0.4 years for men, and an increase of 7.2 years to essentially no change (0.1 years) for women.

In 2040, Japan, Singapore, Spain, and Switzerland had a forecasted life expectancy exceeding 85 years for both sexes, and 59 countries including China were projected to surpass a life expectancy of 80 years by 2040. At the same time, Central African Republic, Lesotho, Somalia, and Zimbabwe had projected life expectancies below 65 years in 2040, indicating global disparities in survival are likely to persist if current trends hold.

Taken together, our forecasts point to a world where most populations are living longer and many health improvements are likely to occur if current trajectories hold; at the same time, such gains are not without potential important social consequences, particularly if long-term planning and policy design are not fully considered today.

An important finding is that in the reference scenario, we forecasted slower progress in 2040 than that achieved in the past; however, in the better health scenario, global life expectancy improvements exceeded gains that occurred from 1990-2016. This forecasted slowdown in the reference scenario is rooted in a combination of several factors. First, some risks were projected to worsen in the future, most notably high BMI. Second, past progress on other leading risk factors for premature mortality, namely tobacco and ambient particulate matter air pollution, was highly variable and thus such heterogeneity was projected through 2040. Third, several countries that have already achieved higher levels of life expectancy have also had stagnated gains.

Link: https://doi.org/10.1016/S0140-6736(18)31694-5

This open access paper reviews the interactions between cellular senescence, autophagy, and immunosenescence, with chronic infection as a mediating mechanism. Given the present state of knowledge and biotechnology, it is challenging enough to look at any two aspects of the aging body and consider how they might interact in isolation, but this can only ever be a thin slice of the bigger picture. All systems and states in our biochemistry interact with one another in some way, directly or indirectly, and examining ever larger sets of relationships between greater numbers of systems and states is the path to greater understanding of aging as a phenomenon. It is also somewhat beyond present capabilities, a complex, challenging endeavor for the scientists of future decades, which is why bypassing the need for this sort of understanding is highly desirable when working towards therapies to treat aging. We cannot afford to wait for a near complete knowledge of the progression of aging.

The state of cellular senescence, in which replication is shut down, can be a reaction to damage. It is one of the ways in which cancer risk is sufficiently minimized to allow higher forms of multicellular life to exist. Senescent cells are unfortunately harmful to surrounding tissues, and their accumulation with age is one of the root causes of degenerative aging. Autophagy is a collection of cellular damage control processes, responsible for recycling broken and unwanted proteins or structures in the cell. Loss of autophagy to the point of excessive accumulation of molecular damage is one way for cells to become senescent, and unfortunately autophagy declines with age. Immunosenescence is the aged state of the immune system, characterized by chronic inflammation and incapacity. In later life, the immune system becomes far less effective in removing damaged cells, such as senescent cells, as well as less effective when it comes to a defense against invading pathogens.

Even when simply considering just these three line items, the potential interactions are complex and challenging to rigorously prove. The authors of this paper advance the common view that chronic infection impairs autophagy, and thus in turn generates increased numbers of senescent cells, which accelerates the progression of immunosenescence.

Chronic Infections: A Possible Scenario for Autophagy and Senescence Cross-Talk

Cellular senescence is induced as a consequence of cellular damage accumulation, with the extent of activation directly depending on a fine-tuned balance between cellular conditions generating damage and those involved in counteracting them. The autophagic pathway plays a key role in preventing cell damage accumulation, however, the aging process leads to a decrease in autophagy capacity, and therefore also its effectiveness. In this context, senescence activation shows a more preponderant protective role.

The immune system does not escape from aging effects and displays senescence characteristics in aged individuals. Immunosenescence refers to the state of dysregulated immune function that contributes to the increased susceptibility to infections, autoimmune diseases, or cancer. Aged individuals are predisposed to more severe symptoms from certain infections and they do not mount an effective immune response upon vaccination. In general, aged populations fail to generate an appropriate innate and adaptive immune response against microorganisms, thus it becomes clear that senescence is involved in this failure.

Besides the normal occurrence of immunosenescence, several pathogen microorganisms accelerate the activation of senescence and predisposal to premature immunosenescence. For instance, hosts infected with bacteria such as P. aeuruginosa, M. tuberculosis, or H. pylori, some viruses, including HCMV, or the parasite T. cruzi, show characteristics of immunosenescence. A common issue of all of these pathogens is that they are able to generate chronic infections. In each of these, regardless of the fact that the host is faced with the same antigen several times during its lifetime, the immune response is inefficient. Furthermore, data shows that this condition generates an immune exhaustion and immunosenescence seems to be the major causative factor offering the pathogens an extra advantage since their elimination by the host tends to be even less effective.

Interestingly, a common characteristic of chronic infections is the autophagy blockage that usually occurs during autophagosome maturation, representing a factor that could contribute to or accelerate immunosenescence activation since it predisposes cells to damage accumulation. Deeper exploration to elucidate whether the activation of senescence in chronic infection is a consequence of autophagy impairment produced by pathogens to avoid degradation or, alternatively, whether it is a mechanism employed by the host to diminish infection spreading when the degradation of the pathogens has been halted. This exploration is needed to further understand the infection-autophagy-senescence relationship. With the available data, we hypothesize that chronic infections induce senescence with similar characteristics of aging, i.e., increase of inflammatory state and autophagy inhibition.

There is plenty of evidence for exercise of all sorts to improve cognitive function in later life. That outcome might be mediated via increased blood supply to the brain, which is a particularly energy-hungry organ. Or it might be mediated via improved mitochondrial function, for much the same underlying reasons relating to energy demands. Or via any one of a number of other related mechanisms that one can link to exercise. Strength training is thought helpful in yet another way, via building or retaining muscle mass that then in turn alters metabolism in favorable ways (that usually lead back to blood flow and mitochondrial function in some way).

There is some overlap between researchers interested in strength training and those interested in ischemic conditioning, a form of intermittent restriction of blood flow that appears synergistic with exercise. One can view this all from the perspective of triggering stress responses. Exercise triggers stress responses, and so does transient ischemia. The former is far more explored, and the latter is harder to undertake safely. One might also view this area of research as the preliminary exploration that leads to drug candidates somewhere down the line, ways to artificially trigger beneficial stress responses, but I think that the past few decades of work on calorie restriction have demonstrated that to be slow, expensive, and challenging.

The integrity of the musculature and the muscle strength is of great importance throughout the entire life span. Age-related decreases in muscle mass and strength are also associated with morphological losses in the brain and decreased cognitive functions. There is growing evidence with respect to positive effects of physical activity preventing and treating morphological and functional losses in muscles and the brain. In recent years, evidence has emerged emphasizing the existence of a bidirectional relationship between physical performance and brain health. The bidirectional relationship suggests that physical training may be a valuable intervention strategy to decelerate not only physical but also cognitive decline in old age. However, the exercise type (e.g., resistance training, endurance training) and exercise variables (e.g., load, duration, frequency), which would be optimal to efficiently enhance cognitive performance are largely unknown.

A promising and cost-effective physical intervention strategy which preserves and enhances both, physical performance (especially with regard to the musculature) and cognitive functions, is resistance training (also known as strength training). A relative new method in the field of resistance training is blood flow restriction training (BFR). While resistance training with BFR is widely studied in the context of muscular performance, this training strategy also induces an activation of signaling pathways associated with neuroplasticity and cognitive functions. Based on this, it seems reasonable to hypothesize that resistance training with BFR is a promising new strategy to boost the effectiveness of resistance training interventions regarding cognitive performance.

Link: https://doi.org/10.3390/jcm7100337

Members of the research community have in recent years exhibited a growing interest in the analysis of gut microbes in the context of metabolism and the pace of aging. Some inroads are being made into better understanding helpful versus unhelpful microbial populations and behaviors, and how exactly their activities might influence health over the long term. It is unclear as to how large this influence is. Perhaps it is in the same ballpark as exercise, but perhaps not. The usual problems arise when comparing results between species, in that short-lived species have greater plasticity of life span, their length of life more readily extended or shortened in response to changing circumstances. It should be no great surprise to find that the practice of calorie restriction, well known to slow aging in near all species tested to date, induces changes in gut microbial populations that conform to alterations that are seen as being helpful for health in other contexts.

The gut microbiota (GM) largely derives nutrients from dietary intake. In this respect, a large number of studies have been reported on the variations of the GM composition occurring according to different diets. The majority of these studies have focused on the comparison of low vs. high energy density (i.e., high fat or high sugar) diets in animals fed ad libitum (AL), showing an increase in the Firmicutes/Bacteroidetes ratio and the proliferation of pro-inflammatory Proteobacteria in the latter condition.These changes occur rapidly and can be partially restored by reverting to the control diet. Animal experimental data also agree with observational studies in humans, where similar taxonomic features were found to be changed between obese and lean individuals.

In addition, the GM composition varies rapidly and significantly in response to macronutrient changes, even when equal numbers of calories are provided. This clearly suggests that the relative abundance of the specific GM members strongly depends on the quality of nutrients they have access to. Hence, given the strong relationship among diet, GM and health, there is a growing interest in developing novel dietary strategies to modulate the composition and, possibly, the metabolic functions of the GM.

Among dietary interventions, caloric restriction (CR) is well known for the health-promoting impact on lipid metabolism and longevity. CR is generally applied without changing the macronutrient composition and solely reducing the caloric intake compared to the AL condition. As a consequence, in experimental models, caged individuals fed a CR diet consume completely their food and then fast for several hours before the next feed administration. We have recently reported that CR induces a rapid change (as early as after 3 weeks of CR) of the GM composition in young rats, that parallels a reduction of triglycerides and cholesterol levels in the blood, and that these changes are maintained up to mid age. In particular, a CR diet enabled the expansion of Lactobacillus rapidly and persistently up to adulthood. CR-induced variation of the GM composition might then play a role in helping extend lifespan and delay the onset of age-related disorders by preserving gut homeostasis. However, the precise biochemical changes the GM undergoes during CR are still undetermined, in the short and in the long term.

Here, we investigated the short- and long-term effects of CR on the rat GM using a metaproteogenomic approach. We show that a switch from ad libitum (AL) low fat diet to CR in young rats is able to induce rapid and deep changes in their GM metaproteomic profile, related to a reduction of the Firmicutes/Bacteroidetes ratio and an expansion of lactobacilli. Specifically, we observed a significant change in the expression of the microbial enzymes responsible for short-chain fatty acid biosynthesis, with CR boosting propionogenesis and limiting butyrogenesis and acetogenesis.

Link: https://doi.org/10.1038/s41598-018-33100-y