Fight Aging! Newsletter, March 20th 2017

Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.

This content is published under the Creative Commons Attribution 3.0 license. You are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!

To subscribe or unsubscribe please visit:


  • A Potentially Useful New Finding in the Biochemistry of Amyloid-β
  • An Update on the Use of Gene Therapies to Convert Retinal Cells
  • Failure of Mitophagy and Mitochondrial Function in Kidney Disease
  • Can Pregnancy Effects be Used to Argue For Changes in Cell Signaling as an Effective Approach to Treating Aging?
  • More on PCSK9 Inhibition to Dramatically Reduce Cholesterol Levels, Lowering the Risk of Later Cardiovascular Disease
  • Latest Headlines from Fight Aging!
    • Hypotension Evidence Supports Views of Blood Supply as Important in Dementia
    • Evidence for Senescent Cells to Promote Vascular Calcification
    • DrugAge Database Announced
    • Evidence for RNA Quality Control to be Among the Determinants of Longevity
    • An Interview with Kelsey Moody of Ichor Therapeutics
    • Prototyping a Basis for the Next Generation of Retinal Prostheses
    • RNA Interference as a Treatment for Transthyretin Amyloidosis
    • Trials of Autophagy Enhancement to Treat Parkinson's Disease
    • Stochastic Nuclear DNA Damage in Aging
    • The Influence of Children on Late Life Mortality in Humans

A Potentially Useful New Finding in the Biochemistry of Amyloid-β

The research quoted below is illustrative of a great deal of investigation into Alzheimer's disease and related amyloid biochemistry. There is a vast depth of detail remaining to be explored, even in areas thought to be comparatively well-mapped. While much of that exploration is business as usual, leading to expected destinations and anticipated confirmations, there is always the chance of upheaval, as might be the case here. Alzheimer's disease, like many neurodegenerative conditions, is characterized by the aggregation of solid deposits of misfolded or otherwise altered proteins in brain tissue: amyloid-β and phosphorylated tau. Once established, these deposits generate a complicated halo of surrounding biochemistry that is harmful to brain cells and their activities. In fact, pretty much everything to do with Alzheimer's disease is ferociously complex and nowhere near as well understood as researchers would like it to be.

Most efforts in Alzheimer's disease are presently directed towards ways to safely remove amyloid-β, with programs aiming to remove tau also underway. Removal has the advantage of needing less progress towards complete understanding of the biochemistry of the aged, diseased brain. Unfortunately even this shortcut has proven to be far more challenging than hoped. The past decade is littered with failed efforts to remove amyloid in the immunotherapy space, for example. Only very recently has success of any sort been demonstrated in human patients. The lack of tangible progress in amyloid clearance has spurred a great deal of exploration in the field, among researchers who believe that failure indicates not unexpected difficulty but that amyloid isn't the right target. There are dozens of newer theories on Alzheimer's disease floating around with varying degrees of support in the research community. So far this hasn't made much of a dent in the primacy of amyloid clearance efforts, but the clock is clearly ticking when it comes to the balance of funding and interest.

As is the case for many new discoveries in Alzheimer's biochemistry, the researchers use this one to suggest a different direction for the development of practical therapies. Here, the intent would be to replicate work from a related field and stabilize a precursor to amyloid, in theory preventing it taking the next step that produces the excess amyloid-β found in diseased brains. This isn't completely new in Alzheimer's disease research; inhibition of amyloid creation has been suggested as an approach at other stages along the road to amyloid formation. It isn't clear that there is any better evidence for effectiveness to date than there is for amyloid clearance, however. From a high-level perspective, if amyloid is the problem, then periodic removal should be a better class of therapy than continual suppression. This is only true if it can be made to work at all, of course.

Never before seen images of early stage Alzheimer's disease

It is a long-held belief in the scientific community that the amyloid-β plaques appear almost instantaneously. New infrared spectroscopy images, however, revealed something entirely different. The researchers could now see structural, molecular changes in the brain. "No one has used this method to look at Alzheimer's development before. The images tell us that the progression is slower than we thought and that there are steps in the development of Alzheimer's disease that we know little about. This, of course, sparked our curiosity." What was happening at this previously unknown phase? The results revealed that the amyloid-β did not appear as a single peptide, a widely held belief in the field, but as a unit of four peptides sticking together, a tetramer.

This breakthrough offers a new hypothesis to the cause of the disease. The abnormal separation of these four peptides could be the start of the amyloid-β aggregation that later turns into plaques. "This is very, very exciting. In another amyloid disease, transthyretin amyloidosis, the breaking up of the tetramer has been identified as key in disease development. For this disease, there is already a drug in the clinic that stabilizes the tetramers, consequently slowing down disease progression. We hope that stabilizing amyloid-β in a similar fashion may be the way forward in developing future therapies." The discovery could therefore alter the direction of therapy development for the disease. The aim of most clinical trials today is to eliminate plaques. Researchers will now try to understand the interaction patterns of amyloid-β preceding the aggregation process. Finding the antidote to whatever breaks the amyloid-β protein apart could open doors towards a major shift in­ the development of therapies for Alzheimer's disease.

Pre-plaque conformational changes in Alzheimer's disease-linked Aβ and APP

Reducing levels of the aggregation-prone amyloid-β (Aβ) peptide that accumulates in the brain with Alzheimer's disease (AD) has been a major target of experimental therapies. An alternative approach may be to stabilize the physiological conformation of Aβ. To date, the physiological state of Aβ in brain remains unclear, since the available methods used to process brain tissue for determination of Aβ aggregate conformation can in themselves alter the structure and/or composition of the aggregates.

Here, using synchrotron-based Fourier transform infrared micro-spectroscopy, non-denaturing gel electrophoresis and conformational specific antibodies we show that the physiological conformations of Aβ and amyloid precursor protein (APP) in the brains of transgenic mouse models of AD are altered before formation of amyloid plaques. Furthermore, focal Aβ aggregates in brain that precede amyloid plaque formation localize to synaptic terminals. These changes in the states of Aβ and APP that occur prior to plaque formation may provide novel targets for AD therapy.

An Update on the Use of Gene Therapies to Convert Retinal Cells

A few years back, researchers reported on a novel approach to treating the degenerative blindness of retinitis pigmentosa, an inherited condition in which the rod photoreceptor cells responsible for low-light and peripheral vision become progressively more dysfunctional, eventually leading to the death of other retinal cells. The researchers found that tinkering with levels of Nrl in retinal tissues can make rod cells transform into something more like the cone cells responsible for color vision. In normal development of retinal photoreceptor cells, those with a lot of Nrl become rods, while those with less become cones, but as demonstrated by this team, adult photoreceptors can be coerced into taking on the character or one or the other. While this isn't as good as fixing the underlying problem that causes rod cell dysfunction, it so far appears to be a potentially beneficial approach.

This is far from the only situation in the human body in which some form of conversion of adult cells might be helpful as a palliative or compensatory treatment, in absence of a true cure that addresses root causes. There are many examples of specialist cell populations impacted by aging or disease, arising from a common progenitor and thus closely related to surrounding cells. Dopaminergenic neurons, islet cells, and so on through a long list of cell types. I don't think that researchers should be starting out with this sort of approach as the end goal of their work medicine - that end goal should be to fix the underlying cause of the problem and thus effect a complete cure. But if it becomes feasible along the way, then why not?

Today I noticed a recent update on this line of research, now moved to CRISPR-based gene therapy in mice. Given the advent of CRISPR and the great reduction in the cost and difficulty of gene therapies, I have to wonder why there isn't more of a thrust towards treating the genetic cause of this condition. While the number of specific mutations thought to relate to the condition is quite large and varied - it isn't a nice, neat single gene inherited disease - it is no longer enormously costly and challenging to deliver correct versions of multiple genes to just the retina. In many ways retinal conditions are as close to an ideal testing ground for gene therapies as you are likely to find in the human body, given the relative isolation of the eye from other tissues, and the distinctive differences in those tissues that enable accurate targeting via a number of methods. Still, people more familiar than I with the costs have decided that a more general and compensatory approach makes sense.

CRISPR-Based Therapy Prevents Retinal Degeneration

Retinitis pigmentosa, which affects around one in 4,000 people, causes retinal degeneration that eventually leads to blindness. The inherited disorder has been mapped to more than 60 genes (and more than 3,000 mutations), presenting a challenge for researchers working toward a gene therapy. The results of this latest study suggest that a broader, gene-editing-based therapeutic approach could be used to target many of the genetic defects underlying retinitis pigmentosa. "This combination of CRISPR technology with an adeno-associated virus vector, a system tried and true for delivering genetic information to the retina, may represent the first step in a global treatment approach for rod-mediated degenerative disease."

Researchers designed a CRISPR single guide RNA (sgRNA) to target a retinal transcription factor, Neural retina leucine zipper (Nrl), which specifies rod cell fate during retinal development and maintains rod cells within the mature retina. The team delivered the Nrl-targeted sgRNA and the Cas9 endonuclease directly to the retina of mice on two separate adeno-associated virus (AAV) vectors. The advantage of an AAV vector is the ability to maintain long-term gene expression in non-dividing cells, such as those of the retina.

Retinitis pigmentosa causes gradual cell death - first of rod cells, responsible for night vision, followed by the more scarce cone cells, which enable color and daylight vision. Rod cells also provide structural and nutritional support to cone cells. Researchers showed that targeting Nrl could preserve the functions of cone cells in mice. Using a Cre-based recombination system, the team found that eliminating Nrl could partially convert rod cells into cone-like cells, preventing their deaths as well as the secondary cone cell death seen in retinitis pigmentosa. "The idea is that we do not turn rods into real cone cells, but for the rod cells to gain some cone feature so that they will resist the mutation effects that cause them to eventually die."

Because the Cre-recombination approach is not readily translatable into humans, researchers looked to the CRISPR system instead. The team first injected the retinas of 2-week-old wild-type mice with the experimental therapy vectors, then observed the mice for three to four months. The researchers saw reduced Nrl expression in the animals that received the therapy compared to mice injected with control vectors. At six weeks after injection, the treated animals' rod cells had downregulated rod genes and upregulated cone genes. The treatment did not result in any deleterious effect on cone cells, the researchers reported.

Nrl knockdown by AAV-delivered CRISPR/Cas9 prevents retinal degeneration in mice

In retinitis pigmentosa, loss of cone photoreceptors leads to blindness, and preservation of cone function is a major therapeutic goal. However, cone loss is thought to occur as a secondary event resulting from degeneration of rod photoreceptors. Here we report a genome editing approach in which adeno-associated virus (AAV)-mediated CRISPR/Cas9 delivery to postmitotic photoreceptors is used to target the Nrl gene, encoding for Neural retina-specific leucine zipper protein, a rod fate determinant during photoreceptor development.

Following Nrl disruption, rods gain partial features of cones and present with improved survival in the presence of mutations in rod-specific genes, consequently preventing secondary cone degeneration. In three different mouse models of retinal degeneration, the treatment substantially improves rod survival and preserves cone function. Our data suggest that CRISPR/Cas9-mediated NRL disruption in rods may be a promising treatment option for patients with retinitis pigmentosa.

Failure of Mitophagy and Mitochondrial Function in Kidney Disease

We modern humans are comparatively lightly affected when it comes to kidney failure as an age-related cause of death; it ranks fairly low in the list. We are primarily killed by cardiovascular issues and cancer. In some other species, such as domestic cats, kidney failure is a leading cause of mortality, and near all older individuals are significantly impacted by the consequences of declining kidney function whether or not it is the final cause of death. Still, a comparatively low toll for humans is no great comfort to the many who suffer, especially since there is little in the way of medical technology available at present that can address the causes of kidney failure in any meaningful way. Treatments are compensatory or palliative, attempts to slow down progression only. This may start to change soon given the advent of methods to clear senescent cells from aged tissues, as senescent cells contribute to age-related fibrosis, a dysfunction of regenerative processes in which forms of scar tissue are created in place of functional tissue. Fibrosis impacts many organs, but is notably important in age-related kidney disease. Thus we might hope that removal of senescent cells will product benefits for patients - human and feline.

In past years, researchers have considered that failure of mitochondrial function might feature as a cause of age-related kidney disease. There are arguments to be made for this conclusion, but as ever it is challenging to put the many attributes and changes observed in aged tissues and organs into a definitive order of cause and effect. Aging involves changes in near every aspect of an enormously complex and still incompletely mapped set of interdependent systems. Mitochondria are the power plants of the cell, responsible for producing chemical energy stores, among many other duties. Should they fail, cells cannot function correctly. In the SENS rejuvenation research program, damage to mitochondrial DNA in a minority of cells is implicated as a significant root cause of aging. More general and widespread mitochondrial decline may also occur for other reasons, however, such as changes in the cellular signaling environment that take place in old tissues, reactions to higher levels of molecular damage and metabolic wastes of various sorts.

In the research noted below, the authors argue for kidney disease to be caused by mitochondrial decline, which is in turn caused by an age-related failure of cellular quality control processes. Mitophagy is the name given to a collection of mechanisms responsible for removing damaged and malfunctioning mitochondria before they can cause further harm. If mitophagy declines in efficiency, then cells will become stressed and malfunction as damage builds up in the population of mitochondria. Again, where this fits in the chain of cause and consequence - that starts with the molecular damage listed in the SENS vision for rejuvenation therapies - is something of an open question. Cells communicate in many ways, and that communication reflects the state of aging in a tissue. Tracing these changes back to their root causes is very challenging; research groups can spend years proving a single step in the lengthy chain. Since there is an established list of root causes, it is probably much more efficient to build repair therapies for those root causes and see what happens as a result.

Mitochondria Play a Significant Role in Age-Associated Kidney Disease

Researchers have published findings that may provide a new approach to preventing kidney injury after ischemia. "We've shown that it's possible to prevent kidney damage by its preliminary 'training' with short periods of ischemia (blocking of blood supply). However, our main discovery is the fact that this mechanism is disabled in old animals and, as a result, a kidney becomes unprotected. It is an extremely important problem as the major part of clinical cases of renal failure occurs in aged patients. To afford the protection of their kidneys would be a great success for medicine."

In the current study, scientists developed assays that compared data from young and old rats. The scientists revealed that a considerable number of mitochondria in older rats had a lower transmembrane potential - inevitably leading to cell death. Since kidney cells cannot proliferate, their death becomes irreplaceable, leading to increasing symptoms of renal injury. This scenario leads to the kidneys being unable to fulfill their main function of removing products of metabolism from the organism, many of which are quite toxic. The researchers suggest that's why such "bad" mitochondria should be removed in the process of quality control. In a young kidney, quality control depends on the transmembrane potential of mitochondria. When the potential drops below the critical value for a long time, a mitochondrion gets a "black label" in the form of a special protein - PINK-1. Such a labeled mitochondrion undergoes a process of self-destruction (autophagy) and is destroyed within the cellular organelles called lysosomes. In cells of old kidneys, this process is not only broken, with low-potential damaged mitochondria not being destroyed - they actually increase in number.

"There is the following process: we block blood supply of the kidney (namely, we deprive it of oxygen and substrates), and under these conditions, the weakest mitochondria in cells lose their potential and are immediately removed by the quality control system. As a result, the 'renewal', or just 'purges', of the mitochondrion population takes place, and only the healthy ones survive. That's why in young rats and the case of severe kidney ischemia, mitochondria can cope with the damage and they survive. And what happens in old rats? We do kidney preconditioning, mitochondria lose their potential, but they aren't removed as the clean-up system operates poorly. As a result of such training, 'bad' mitochondria are only accumulated in an old cell, and in the case of kidney ischemia everything gets even worse. This project opens a prospect for renal failure treatment. Moreover, mechanisms that we discovered are quite universal, so it's obvious that they are also applicable not only to kidney ischemia but also to other renal pathologies."

The age-associated loss of ischemic preconditioning in the kidney is accompanied by mitochondrial dysfunction, increased protein acetylation and decreased autophagy

In young rats, ischemic preconditioning (IPC), which consists of 4 cycles of ischemia and reperfusion alleviated kidney injury caused by 40-min ischemia. However,old rats lost their ability to protect the ischemic kidney by IPC. A similar aged phenotype was demonstrated in 6-month-old OXYS rats having signs of premature aging. In the kidney of old and OXYS rats, the levels of acetylated nuclear proteins were higher than in young rats, however, unlike in young rats, acetylation levels in old and OXYS rats were further increased after IPC.

In contrast to Wistar rats, age-matched OXYS demonstrated no increase in lysosome abundance and LC3 content in the kidney after ischemia/reperfusion. The kidney LC3 levels were also lower in OXYS, even under basal conditions, and mitochondrial PINK1 and ubiquitin levels were higher, suggesting impaired mitophagy. The kidney mitochondria from old rats contained a population with diminished membrane potential and this fraction was expanded by IPC. Apparently, oxidative changes with aging result in the appearance of malfunctioning renal mitochondria due to a low efficiency of autophagy. Elevated protein acetylation might be a hallmark of aging which is associated with a decreased autophagy, accumulation of dysfunctional mitochondria, and loss of protection against ischemia by IPC.

Can Pregnancy Effects be Used to Argue For Changes in Cell Signaling as an Effective Approach to Treating Aging?

Over the past decade, a few research groups have provided evidence to suggest that pregnancy can enhance regeneration in the mother. The proposed mechanisms have largely involved capable stem cells from the fetus acting as a mild form of stem cell therapy when they find their way into the mother's tissues. Since then, however, parabiosis research has taken off, in which an old and a young animal have their circulatory systems joined. This has a beneficial effect on the older animal, and researchers have spent a great deal of effort investigating signal molecules in the bloodstream that differ between old and young animals. The initial focus was on finding youthful signals that might help turn back some of the detrimental changes that take place in old tissues, such as loss of regenerative capacity and decline in stem cell activity.

Perhaps unfortunately, the latest update in this line of research puts something of a damper on the idea that young signals can rejuvenate old tissues, and proposes that the effect is achieved through dilution of harmful signals or waste in the old tissues and bloodstream. Still, now that everyone is as much focused on signals as they are on stem cells, it is perhaps time to look back at the evidence for pregnancy effects. Is there anything there that might be used to argue in one direction or another when it comes to the signal environment, aging, and potential therapies? From where I stand the existing evidence looks a little sparse to be building anything atop it, but it doesn't seem like an unreasonable angle to pursue further - at least for those researchers who are focused on slowing aging through forcing change on the signaling environment. That said, there is no necessary reason why these two situations, parabiosis and pregnancy, should in the end turn out to have much in common; it could just as easily be the case that the placental barrier rules out all of the interesting exchanges that take place in parabiosis.

Why does signaling change in old tissues? Those who see aging as an accumulation of molecular damage would say it is a consequence of increased levels of damage. Cells react to their environment, and it is unfortunately the case that some of those reactions go on to cause further harm. See, for example, cells becoming senescent. There is another viewpoint, that of programmed aging, which considers signaling changes a primary cause of aging, and altered cellular behavior then in turn leads to damage. After some years of reading around that area of theory, I still think its proponents have a tough hill to climb in order to make that case. Fortunately, the development of working rejuvenation theories will settle the right and wrong of things more rapidly than the slow battles over theory; practical efforts will come to an answer in the next ten to fifteen years, I'd say. Therapies based on damage repair and therapies based on alteration of signaling are both imminent; one approach will work far better than the other, and that will be that.

Molecular and Cellular Interactions between Mother and Fetus - Pregnancy as a Rejuvenating Factor

Prevention or even reversal of aging have become topics of numerous studies. The discovery of rejuvenating factors, if they exist and are of chemical nature, would become a breaking point in solving many problems in gerontology. Scientists periodically report a discovery of such factors; however, careful examination of their data and technical details of these studies raise doubts if the discovered factors indeed possess rejuvenating properties. In particular, when the circulatory systems of two animals of different ages are connected in a heterochronic parabiotic model, the older partner undergoes rejuvenation. Some recent studies aimed to identify the chemical factor that enters the older organism from the younger one suggested that this rejuvenating factor is GDF11, a differentiation growth factor that circulates in the common blood stream of parabiotic partners. However, more detailed studies failed to unambiguously confirm that GDF11 is responsible for the rejuvenating effect.

The rejuvenating effect of pregnancy remains a subject for discussion. We find it promising to view pregnancy as a parabiotic system in which organisms of different age (young fetus and mature mother) are functionally connected and exchange factors that affect both, in either positive or negative manner. Pregnancy is a great burden for the maternal organism and carries a risk of numerous complications. Hence, for many years, both clinical medicine and academic research have concentrated mostly on negative effects of pregnancy on the mother's health. However, recent studies have shown that pregnancy might have positive effects on the physiological state of many organs and on maternal longevity in general, especially in the absence of pregnancy-accompanying complications. Some studies even discussed the "rejuvenating" effect of pregnancy on the maternal organism.

The regenerative capacity of liver (estimated from the rate of liver regeneration after removal of 2/3 of its volume) in 10-12-month-old mice was four times lower than in young (3-month-old) animals. However, when old mice were in the third trimester of pregnancy, their rate of liver regeneration after hepatectomy was like that in young animals: in both young non-pregnant mice and aged pregnant mice, liver regenerated to its initial volume ~2 days after the surgery, while in old non-pregnant animals, liver volume remained less than 50% of the original one. Another common object for studying regeneration and its decline with age is a skeletal muscle. The regeneration index in 20-month-old mice was almost 10 times lower than in 3-month-old mice. The effects of pregnancy on skeletal muscles were like those observed in liver: pregnancy enhanced two-fold the regeneration of muscles in both aged (10-month-old) and young animals. The number of satellite cells (muscle stem cells) did not differ between the groups, which indicates that deterioration of the regenerative functions was not due to the exhaustion of the pool of these cells. The decline in the regenerative capacity of muscle tissue with aging is believed to be related to changes in regulation, in particular, to inactivation of the Notch signaling pathway. Pregnancy reverses these changes in aged animals and restores the activity of this pathway to the levels typical for young individuals.

The rejuvenating effect of pregnancy might be explained by the donation of fetal cells capable to differentiate. The regenerative properties of stem cells are well known, and therapeutic effects of stem cells injection after brain, liver, or kidney damage have been well described. Some fetal cells enter the maternal circulation and tissues - a phenomenon known as microchimerism. Fetal cells could be found in the mother's blood and tissues several decades after pregnancy. At present, there is no consensus on the mechanisms that would explain the effects of microchimeric cells on the maternal organism. Two main possibilities are discussed: the first one is regulatory interactions, and the second is direct differentiation of microchimeric cells into a type of cells required for the mother's regeneration. In the first case, a limited number of fetal cells act as coordinators of the regenerative process. For example, fetal cells are believed to regulate inflammatory response by downregulating TGF-β biosynthesis and by directing maternal regeneration toward scar-less fetal-like wound healing. A direct contribution of microchimeric multipotent cells to regeneration has been demonstrated in a damaged heart model. Fetal cells actively migrated into the damaged area of the mother's heart, where they differentiated into fully functional cardiomyocytes that contracted synchronously with surrounding cells. In the absence of damage, the number of fetal cells in the heart was 20-fold less.

A major question remains: what exactly is the contribution of each of the factors to the rejuvenating effect of pregnancy on the maternal organism? The answers to this question will allow to develop clinical approaches for protection of pregnant women and health improvement in the human population in general.

More on PCSK9 Inhibition to Dramatically Reduce Cholesterol Levels, Lowering the Risk of Later Cardiovascular Disease

There is good evidence for at least some methods of achieving dramatic reductions in blood cholesterol in humans to be safe and reduce the risk of age-related cardiovascular issues. To pick one of the underlying mechanisms involved in these benefits, the common age-related condition of atherosclerosis is at root caused by interactions between damaged cholesterol and the cells of blood vessel walls. Cells become irritated by the presence of that cholesterol, and this begins a series of overreactions and unfortunate events that leads to the generation of fatty plaques that narrow blood vessels and weaken blood vessel walls. In conjunction with the raised blood pressure present in older individuals, this eventually leads to the dramatic structural failure of a stroke or heart attack, when a large blood vessel is blocked or ruptures. If there is less cholesterol in the bloodstream, however, the whole chain of cause and effect slows down. That slowing isn't as good as fixing the issue, such as by effectively sabotaging any one of the bad cellular behaviors that combine to lead to the growth of plaques, but it is certainly a lot better than nothing.

Statins are the obvious item to point out when thinking about cholesterol, aging, and cardiovascular disease. The widespread use of this class of drug has done much to reduce the incidence and mortality of cardiovascular disease. These days, however, researchers are looking into more targeted means of reducing cholesterol levels, forms of therapy that suppress specific genes to achieve much larger reductions than is possible with statins. There are a number potential targets for gene therapies, RNA interference approaches, and the like, such as an ASGR1 mutation that occurs in small number of humans, who have less cholesterol and much lower rates of atherosclerosis. The story is much the same for an ANGPTL4 mutation, also present in a small number of people and associated with significantly reduced cholesterol and cardiovascular risk. For today, however, I'll note a brace of publicity materials on recent attempts to target PCSK9 with the aim of permanently lowering blood cholesterol by a large amount. Several distinct teams appear to have timed their press for the same scientific conference, so all the results appeared in public at much the same time.

New 'gene silencer' drug injections reduce cholesterol by 50% in early research

The first in a new class of gene-silencing drugs, known as inclisiran, has halved cholesterol levels in patients at risk of cardiovascular disease. The findings come from the largest trial yet to test the safety and effectiveness of this kind of therapy. The technique, known as RNA interference (RNAi) therapy, essentially 'switches off' one of the genes responsible for elevated cholesterol, PCSK9. The twice-a-year treatment could be safely given with or without statins, depending on individual patient needs. Eventually, inclisiran could help to reduce the risk of heart attacks and stroke related to high cholesterol. "We appear to have found a versatile, easy-to-take, safe, treatment that provides sustained lowering of cholesterol levels and is therefore likely to reduce the risk of cardiovascular disease, heart attacks, and stroke. These reductions are over and above what can be already be achieved with statins alone or statins plus ezetemibe, another class of cholesterol-lowering drug."

In the study, researchers gave 497 patients with high cholesterol and at high risk of cardiovascular disease either inclisiran at varying doses, or placebo. Seventy-three per cent of these patients were already taking statins, and 31 per cent were taking ezetimibe. Participants, who were recruited from Canada, USA, Germany, Netherlands, and the UK, were excluded if they were taking monoclonal antibodies for cholesterol lowering. Patients were given different doses of inclisiran or placebo via subcutaneous injection, either via a single dose, or via a dose on day one and another at three months. They were followed up regularly for a subsequent eight months and tested for blood cholesterol and side effects. The researchers found that just one month after receiving a single treatment of inclisiran, participants' LDL cholesterol levels had reduced by up to 51 per cent.

PCSK9 Inhibitor Evolocumab Significantly Reduces Adverse Cardiovascular Events When Added to Statin Therapy With No Major Safety Concerns

A new class of cholesterol lowering drugs known as PCSK9 inhibitors has emerged as an effective treatment for drastically lowering LDL cholesterol beyond what is possible with statin therapy alone. Previous research demonstrated that evolocumab, a member of this new class of drugs, effectively reduces LDL cholesterol by approximately 60 percent. Evolocumab is a fully human monoclonal antibody that works by blocking proprotein convertase subtilisin-kexin 9 (PCSK9), a protein that reduces the liver's ability to remove LDL cholesterol from the blood. The FOURIER trial (Further Cardiovascular OUtcomes Research with PCSK9 Inhibition in subjects with Elevated Risk) was designed to determine whether evolocumab, when added to statin therapy, would reduce adverse cardiovascular events.

In this randomized, double-blind, placebo-controlled multinational clinical trial, 27,564 patients aged 40-85 were studied. All trial participants had stable atherosclerotic vascular disease, defined as a medical history of heart attack, stroke or symptomatic peripheral artery disease. On a background of high or moderate intensity statin therapy patients had a LDL cholesterol level of at least 70 mg/dl. Patients received either evolocumab (140mg every two weeks or 420mg every month) or placebo. Similar to data from previous lipid lowering trials, researchers report that evolocumab reduced LDL cholesterol by 59 percent, in this case from a median of 92 mg/dL to a median of 30 mg/dL. The LDL cholesterol lowering effect remained constant over the duration of the trial.

Researchers report that patients treated with evolocumab had a 15 percent reduction in the risk of major cardiovascular events, defined as the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization (occurring in 9.8 percent of patients treated with evolocumab vs. 11.3 percent of patients treated with placebo). Additionally, evolocumab reduced the more serious key secondary endpoint, which was a composite of heart attack, stroke or cardiovascular death, by 20 percent (occurring in 7.9 percent of patients treated with evolocumab vs. 9.9 percent in the placebo group). This reduction in risk improved over time, increasing from 16 percent in the first year to 25 percent after the first year.

PCSK9 Inhibitior Bococizumab Produces Varying Results

New results from the clinical trial program, SPIRE (Studies of PCSK9 Inhibition and the Reduction of Vascular Events), which sought to determine the effect of bococizumab, a PCSK9 inhibitor, on LDL cholesterol levels and clinical outcomes in high-risk patients already taking statin therapy, have been presented. Researchers report that bococizumab had short-term benefits on lowering cholesterol levels and significantly reduced the risk of cardiovascular events by 21 percent compared to placebo among those who had baseline LDL cholesterol levels of greater than 100 mg/dL. However, the cholesterol lowering effect tended to diminish over time in some patients and bococizumab did not reduce cardiovascular event rates among those with LDL levels lower than 100 mg/dL.

The SPIRE program involved eight double-blind, placebo controlled clinical trials that were conducted simultaneously. Six lipid-lowering trials randomized 4,449 patients, who previously had a heart attack or stroke or had extremely high baseline cholesterol levels and were on statin therapy, to receive either bococizumab (150 mg subcutaneously every 2 weeks) or placebo to determine the effects on LDL levels. Two other multi-national trials randomized 27,438 patients to either bococizumab or placebo and were designed to evaluate the impact of the drug on cardiovascular outcomes, including nonfatal heart attack and stroke, hospitalization for unstable angina requiring urgent revascularization, or cardiovascular death. Almost all the patients were on statin therapy.

On November 1, 2016, the entire SPIRE clinical trials program was stopped when the sponsor, Pfizer, who manufactures bococizumab, discontinued the development of the drug when initial results from the LDL cholesterol lowering trials indicated that some trial participants had developed anti-drug antibodies, an immunologic response to the drug. Further analysis indicated that bococizumab effectively reduced LDL cholesterol levels by an average of 56 percent after 14 weeks; however, the immunologic reaction attenuated the reduction in LDL cholesterol in approximately 15 percent of those who received the drug. Data also show that there was a wide variation in the magnitude of cholesterol reduction that patients achieved with bococizumab, even among patients who did not develop the immunologic response. Bococizumab is a humanized antibody therapy that works by blocking proprotein convertase subtilisin-kexin 9 (PCSK), a protein that reduces the liver's ability to remove LDL cholesterol from the blood. "We believe that the attenuation of LDL lowering over time in the treatment group was likely due to the fact that bococizumab, a humanized antibody, led to an immunologic response in some patients. The alternative PCSK9 inhibitors evolocumab and alirocumab, which have already been approved for use, are fully human antibodies and do not have this adverse effect."

If this were a better world, the next stage in this process would be the development of one-off gene therapies for use by all adults, carried out long before old age rolls around. That is unlikely to happen any time soon within the bounds of the present regulatory environment, however. Waiting until the damage is underway and the disease process in its comparatively late stages before acting is the great failing of modern medicine and regulation of its use. So much more could be done to slow down and prevent aging by intervening sooner with these new technologies, in adults who are still young and healthy. Acting too late is always a poor strategy in comparison.

Latest Headlines from Fight Aging!

Hypotension Evidence Supports Views of Blood Supply as Important in Dementia

The evidence presented here is supportive of views on neurodegeneration that place an emphasis on blood supply to the brain. Certainly, the aging of the cardiovascular system is strongly implicated in some forms of dementia, but not always necessarily because of a lessening supply of oxygen and nutrients. The more common picture is of small amounts of damage caused by tiny blood vessel ruptures that add up over time, but the brain is an energetic organ; it is very possible that declining supply from the circulatory system is a contributing factor.

Middle-aged people who experience temporary blood pressure drops that often cause dizziness upon standing up may be at an increased risk of developing cognitive decline and dementia 20 years later. Findings suggest that these temporary episodes - known as orthostatic hypotension - may cause lasting damage, possibly because they reduce needed blood flow to the brain. Previous research has suggested a connection between orthostatic hypotension and cognitive decline in older people, but this appears to be the first to look at long-term associations. "Even though these episodes are fleeting, they may have impacts that are long lasting. We found that those people who suffered from orthostatic hypotension in middle age were 40 percent more likely to develop dementia than those who did not. It's a significant finding and we need to better understand just what is happening."

For the study, the researchers analyzed data from the Atherosclerosis Risk in Communities (ARIC) cohort, a study of 15,792 residents in four communities in the United States, who were between the ages of 45 and 64 when the study began in 1987. For this study, they focused on the 11,503 participants at visit one who had no history of coronary heart disease or stroke. After 20 minutes lying down, researchers took the participants' blood pressure upon standing. Orthostatic hypotension was defined as a drop of 20 mmHg or more in systolic blood pressure or 10 mmHg or more in diastolic blood pressure. Roughly six percent of participants, or 703 people, met the definition. These participants, who were on average 54 years old upon enrolling in the study, continued to be followed over the next 20 or more years. People with orthostatic hypotension at the first visit were 40 percent more likely to develop dementia than those who did not have it. They had 15 percent more cognitive decline.

It is not possible to tease out for certain whether the orthostatic hypotension was an indicator of some other underlying disease or whether the drop in blood pressure itself is the cause, though it is likely that the reduction in blood flow to the brain, however temporary, could have lasting consequences. It also wasn't clear, she says, whether these participants had repeated problems with orthostatic hypotension over many years or whether they had just a brief episode of orthostatic hypotension at the original enrollment visit, as patients were not retested over time.

Evidence for Senescent Cells to Promote Vascular Calcification

The progressive stiffening of blood vessels is an important proximate cause of age-related hypertension and cardiovascular disease. One cause of this stiffening is a process of calcification, deposition of calcium into the tissues of blood vessel walls. Recent evidence shows that this process is caused by changes in cellular behavior, which opens up a range of potential targets for therapy and prevention. Here, researchers further demonstrate that the activities of senescent cells are probably involved in this picture. This is good news if validated, as targeted clearance of senescent cells as an approach to the treatment of aging is already heading towards the clinic, under active development at a number of companies.

Vascular calcification is an undervalued risk factor for the appearance of cardiovascular disease (CVD). Regarded as a surrogate marker for atherosclerosis, a condition that frequently precedes coronary events, calcification is commonly seen in the vasculature of elderly subjects, and in middle-aged subjects with premature vascular disease associated to chronic kidney disease. Hitherto, vascular calcification was thought to be a consequence of simple, physical mineral deposition in the vessel walls. New evidence, however, has revealed a highly regulated cellular response to be involved, and that calcification is the result of an imbalance between the inhibitors and inducers of calcium (Ca) deposition.

Microvesicles (MVs) - also named microparticles - are a subset of extracellular vesicles. Recent studies have shown that MVs produced by smooth muscle cells, can carry Ca as well as molecules that act as calcification nucleation sites. They may therefore also be involved in initiating vascular calcification. Endothelial senescence is known to be involved in the initiation of certain CVDs such as atherosclerosis and hypertension; the MVs produced by senescent endothelial cells (ECs) might therefore play an important role in their onset. Previous studies by our group have shown that microparticles produced by ECs in response to inflammatory stimuli, promote a calcifying response in vascular smooth muscle cells. The aim of the present study was to determine: 1) whether MVs produced by senescent, cultured ECs, plus those found in the plasma of elderly subjects, promote calcification in human aortic smooth muscle cells (HASMC), and 2) to determine which contents of such MVs might be involved.

The present results suggest that the MVs circulating in the plasma of elderly subjects contribute towards the calcification of vascular smooth muscle cells. In addition, those obtained for the in vitro-generated human umbilical vein endothelial cells (HUVEC) MVs strongly support the idea that calcification associated with aging is triggered by the MVs produced by senescent ECs. Certainly, the senescent HUVEC MVs contained increased amounts of Ca and bone-associated proteins. Compared to the younger subjects, the plasma of the elderly subjects contained a larger number of MVs in general, and of EC-produced MVs in particular. Only the MVs from the plasma of elderly subjects, and from senescent HUVEC, promoted the calcification of HASMC. It was very difficult to isolate sufficient bona fide EC-derived MVs from the plasma in order to confirm their having a role in vascular calcification. However, more than sufficient such MVs were isolated from senescent HUVEC.

The present results suggest that, with age, the number of MVs in the plasma increases, promoting vascular calcification. These MVs are likely produced by senescent ECs. Clinical studies are required to determine whether the number of calcifying MVs correlates with vascular calcification in elderly patients, and in those with premature vascular disease. The results also suggest that MVs could be used as markers of vascular calcification; their detection might be used to identify patients at risk of CVD and/or follow the clinical course of their disease. They also suggest that MVs might offer a therapeutic target for the control of vascular calcification and associated CVD.

DrugAge Database Announced

To add to the existing set of online databases relevant to aging research at, the DrugAge database was recently announced. This contains a list of interventions that modestly slow aging in various species, along with degree of life extension obtained and references. You might compare this effort with the similar geroprotectors database. The databases are an interesting resource, but it is worth noting that from the perspective of the SENS rejuvenation research programs next to none of this data is all that relevant to the future of human healthy life extension. None of the various compounds so far shown to slow aging in other species should be expected to produce gains in humans that are significantly greater than can be obtained by lifestyle choices such as exercise and calorie restriction. To do better than that requires targeted repair of the molecular damage that causes aging, not merely slowing down the accumulation of that damage a little.

Scientists have announced a database of lifespan-extending drugs and compounds called DrugAge. The database has 418 compounds, curated from studies spanning 27 different model organisms including yeast, worms, flies and mice. It is the largest such database in the world at this time. Significantly, the study found that the majority of age-related pathways have not yet been targeted pharmacologically, and that the pharmacological modulation of aging has by and large focused upon a small subset of currently-known age-related pathways. This suggests that there is still plenty of scope for the discovery of new lifespan-extending and healthspan-extending compounds.

DrugAge is the latest of a number of valuable resources freely available on the Human Aging Genomic Resources (HAGR) website. Other resources available through HAGR include GenAge (a database of age and longevity-related genes in humans and model organisms), AnAge (a database on ageing, longevity records and life-history featuring over 4000 species), GenDR (a database of genes associated with the life extending effects of dietary restriction), and LongevityMap (a database of over 2000 human genes and genetic variations associated with longevity). The database is freely available to the public, and is searchable according to compound name, species and effect on lifespan. The data can be presented as both tables and interactive charts. Functional enrichment analysis of the targets of the database's compounds was performed using drug-gene interaction data, which revealed a modest but statistically significant correlation between the cellular targets of the database's compounds and known age-related genes.

"DrugAge represents a landmark resource for use in the biogerontology community. It is the largest database of lifespan-extending compounds compiled to date, and will surely come to be recognized as an extremely valuable resource for biogerontologists. Analysis performed using the database has already revealed interesting trends, including a modest but statistically significant overlap between lifespan-extending drugs and known age-related genes, a strong correlation between average/median lifespan changes and maximum lifespan changes, a strong correlation between the lifespan-extending effects of compounds between males and females, and perhaps most significantly that most known age-related pathways have yet to be targeted pharmacologically. More broadly, an understanding of the comparative effects of geroprotectors upon the lifespan of a variety of different model organisms is important both for basic research into the biology of ageing, demonstration of lifespan plasticity via modulation of a variety of distinct biomolecular targets as proof to regulators that healthspan extension is a viable paradigm for disease treatment and prevention, and for the eventual clinical translation of potential geroprotectors."

Evidence for RNA Quality Control to be Among the Determinants of Longevity

Cellular quality control mechanisms such as autophagy are observed to be influential in determining natural variations in longevity. Increased autophagy, meaning that cells are working harder to recycle damaged structures and proteins, is a prominent feature of many of the interventions shown to modestly slow aging in laboratory species over the past twenty years. As a further example, autophagy appears to be required for the enhanced health and longevity produced by the practice of calorie restriction. There are other forms of quality control process beyond autophagy, however, and here researchers provide evidence to suggest that those focused on RNA molecules are also important:

DNA, RNA, and proteins carry the genetic instructions within all known living organisms. Existing research has collectively shown that organisms with long lifespans tend to have more stringent DNA and protein quality control. In other words, deterioration of DNA and protein quality control is centrally correlated with aging and age-related diseases. However, the role of the RNA quality control in aging remained almost unexplored.

Researchers have now shown that RNA quality control affects aging. The research team concentrated on a specific RNA quality control mechanism called nonsense-mediated mRNA decay (NMD), a key pathway which degrades both abnormal as well as some normal RNAs. The team has successfully shown that NMD is crucial for longevity in the roundworm called C. elegans, a popularly used animal for aging research. They first discovered that NMD activity decreases during aging. The team then discovered that enhanced NMD underlies the longevity of famous C. elegans strains called daf-2 mutants, which have reduced insulin hormone signaling.

Since the main role of NMD is degradation of its target messenger RNAs (mRNAs), the team focused on mRNAs that were downregulated in daf-2 mutants. Their research showed substantially decreased levels of a gene yars-2, an NMD target, are at least partially responsible for long lifespan in daf-2 mutants. In other words, research data collectively suggest that NMD-mediated RNA quality control is critical for longevity in C. elegans. The researchers anticipate that the discovery of the causal relationship between RNA quality control and longevity will play a significant role in shedding light on the mechanisms behind aging and eventually contribute to curing and even preventing age-related diseases.

An Interview with Kelsey Moody of Ichor Therapeutics

The Life Extension Advocacy Foundation here interviews Kelsey Moody of Ichor Therapeutics, a company working on clinical translation of the SENS rejuvenation research approach to clearing one of the forms of persistent metabolic waste that causes aging and age-related disease. In this case, it is a type of waste product that is generated in the energetic cells of the retina; as it accumulates, it leads to macular degeneration and progressive blindness:

New medical technologies need bold researchers to make the leap from the laboratory table to hospitals and clinics where they can improve or even save lives. Kelsey Moody is one such researcher. Currently research into age-related diseases takes up huge amounts of funding, however very few of these approaches aim to treat the root causes - the processes of aging - and this is why they are not successful. Moody's focus in the past few years has been developing an effective treatment for age-related macular degeneration (AMD), a leading cause of vision loss among people over 50. The experimental treatment he's working on, called LYSOCLEAR, is currently being tested for validity at Ichor Therapeutics, a startup Moody founded in 2013. LYSOCLEAR is based on the LysoSENS approach advocated for by the SENS Research Foundation, where Moody worked as an academic coordinator first in 2008-2010 and as a research scientist in 2012.

How did you learn about the SENS approach?

I first came across SENS during an online review on regenerative medicine, and this initiated my interest in the study human aging. At the time, I had no formal training in science. However, Aubrey de Grey's approach made sense to me at face value, so I purchased his book, Ending Aging, to study it further. After completing the book, I felt I did not have sufficient knowledge to know whether or not his ideas were worthy of serious pursuit, but I was intrigued. I added a major in biochemistry, and reasoned to myself that I would commit to the study of aging until such a time as it was clear to me that such a pursuit was not feasible or a worthwhile use of my time and resources. Now a decade later, I have graduate level training in research, business, and medicine. While the conversation has become much more sophisticated, the original plan holds true. I have not reached a point where I believe SENS is unworthy of serious study. I have focused my company on translational research because I believe this is the area where we can have the greatest impact and where the largest deficits exist among the various longevity organizations, both nonprofit and commercial.

How easy (or difficult) would it be to adapt LYSOCLEAR to target different types of waste products in lysosomes of different tissues?

The idea of LYSOCLEAR is based on enzyme replacement therapy, which has already been used extensively in a clinical setting for the treatment of lysosomal storage diseases. In principle, the concept of "upgrading lysosomes" can be extended to numerous diseases of aging. The challenge is almost always in identifying ways to efficiently and specifically target the payload to its destination. This is somewhat easier when your target cells are well studied and express receptors known to facilitate efficient targeting, such as monocytes or (in our case) retinal pigmented epithelial cells. It is a harder technical problem for other tissue types. Broadly though, I am optimistic that this approach can be repurposed for other diseases, either by our team or others. Atherosclerosis immediately comes to mind, and SENS Research Foundation has funded research to identify enzymes capable of degrading plaque components, such as 7-ketocholesterol.

What are the main obstacles you have met at the early stage of your project?

The recurring challenge I see in the aging space is that the overwhelming majority of "anti-aging" researchers have little to no formal scientific training or wet lab experience, (and it shows), or are basic scientists. Virtually none have translational experience - that is, experience moving benchtop discoveries into a path towards commercialization. Conversely, the translational scientists I have interacted with over the years are almost transactional, and seem to be lacking the creativity and imagination of how new technologies could be applied to solve complex medical problems. So most of the people with ideas cannot execute, and most of the people who can execute lack vision. We try to address this issue as a company by having one foot firmly in the fringe, and the other firmly in the mainstream. For example, about half of our staff are futurists with a passion for anti-aging and SENS, but we balance that with experienced pharmaceutical professionals who keep us grounded and focused on actionable discoveries and a legitimate translational strategy. Likewise, all of our drug development programs include a far reaching "moonshot" opportunity, but also a highly conservative disease indication.

Prototyping a Basis for the Next Generation of Retinal Prostheses

Current approaches to prosthetic sight involve connecting an grid of electrodes implanted in the retina to an external camera. The electrodes stimulate the production of glowing phosphenes, a crude visual representation of what the camera sees. It is simple and in no way real sight, but a great improvement over being completely blind. Researchers here present work on the next generation of technology for artificial substitutes to replace natural vision, removing the camera and shifting towards more miniaturized electronics:

Researchers have developed a new type of retinal prosthesis that brings research a step closer to restoring the ability of neurons in the retina to respond to light. The new prosthesis relies on two groundbreaking technologies. One consists of arrays of silicon nanowires that simultaneously sense light and electrically stimulate the retina accordingly. The nanowires give the prosthesis higher resolution than anything achieved by other devices - closer to the dense spacing of photoreceptors in the human retina. The other breakthrough is a wireless device that can transmit power and data to the nanowires over the same wireless link at record speed and energy efficiency. One of the main differences between the researchers' prototype and existing retinal prostheses is that the new system does not require a vision sensor outside of the eye to capture a visual scene and then transform it into alternating signals to sequentially stimulate retinal neurons. Instead, the silicon nanowires mimic the retina's light-sensing cones and rods to directly stimulate retinal cells. Nanowires are bundled into a grid of electrodes, directly activated by light and powered by a single wireless electrical signal.

The power provided to the nanowires from the single wireless electrical signal gives the light-activated electrodes their high sensitivity while also controlling the timing of stimulation. Power is delivered from outside the body to the implant through an inductive powering telemetry system. The device is highly energy efficient because it minimizes energy losses in wireless power and data transmission and in the stimulation process, recycling electrostatic energy circulating within the inductive resonant tank, and between capacitance on the electrodes and the resonant tank. Up to 90 percent of the energy transmitted is actually delivered and used for stimulation, which means less RF wireless power emitting radiation in the transmission, and less heating of the surrounding tissue from dissipated power.

For proof-of-concept, the researchers inserted the wirelessly powered nanowire array beneath a transgenic rat retina with rhodopsin P23H knock-in retinal degeneration. The degenerated retina interfaced in vitro with a microelectrode array for recording extracellular neural action potentials (electrical "spikes" from neural activity). The horizontal and bipolar neurons fired action potentials preferentially when the prosthesis was exposed to a combination of light and electrical potential - and were silent when either light or electrical bias was absent, confirming the light-activated and voltage-controlled responsivity of the nanowire array.

RNA Interference as a Treatment for Transthyretin Amyloidosis

In this paper, the authors discuss RNA interference (RNAi) as the basis for therapies to treat transthyretin amyloidosis. In this condition, as in other forms of amyloidosis, solid deposits of misfolded or otherwise damaged proteins known as amyloid accumulate with age, causing various forms of dysfunction in tissues. In the case of transthyretin amyloid, these solid aggregates contribute to heart failure and other cardiovascular conditions, and are thought to be involved in a range of other, less immediately pressing age-related conditions. Studies of supercentenarians suggest that transthyretin amyloidosis leading to heart failure is the predominant cause of death in that population. Any comprehensive toolkit of rejuvenation therapies must include a way to clear amyloids, and thus remove their contribution to aging and age-related disease.

Transthyretin (TTR) is a transport protein that is primarily expressed in the liver. Its primary function is to transport Vitamin A (retinol) through its interaction with the retinol binding protein. Although the majority of newly synthesized TTR protein folds and functions properly, TTR protein misfolding can occur. TTR misfolding is exacerbated by destabilizing mutation and proteolysis and, if left uncorrected, misfolded TTR has a propensity to form pathologic amyloid fibrils. TTR-mediated amyloidosis (ATTR amyloidosis) is a progressive, systemic and ultimately fatal disease resulting from the damage caused by the deposition of insoluble TTR fibrils. TTR-containing amyloid fibrils can deposit in peripheral and central nervous systems, the gastrointestinal tract, eye, kidney and/or the heart. In contrast to hereditary ATTR amyloidosis, wild-type ATTR amyloidosis results from the misfolding of wild-type TTR protein with deposition occurring predominantly in the heart. Clinical presentation of wild-type ATTR amyloidosis, which includes carpal tunnel syndrome and cardiomyopathy, typically occurs much later in life relative to the hereditary forms, and likely reflects the fact that wild-type TTR is less prone to misfolding than other, mutated variants present in the hereditary form of the condition.

Although disease manifestation varies across the different forms of ATTR amyloidosis, the common feature of these diseases is the misfolding of TTR protein that ultimately results in amyloid formation and deposition. As such, mitigation of TTR amyloid deposition is crucial to the development of any successful therapeutic treatment for all forms of ATTR amyloidosis. Tetramer stabilizers are a class of small molecule therapies currently under development and even approved in certain geographic locales for the treatment of ATTR amyloidosis. These modalities aim to limit TTR aggregation by binding and stabilizing the properly folded tetramer, thereby decreasing the concentration of aggregation-prone species. To date, data from clinical trials suggests that this approach can slow the rate of ATTR amyloidosis progression. Regardless, there is still a need for effective treatments for ATTR amyloidosis.

RNA interference (RNAi) is a naturally occurring biological process by which small interfering RNA (siRNA) can direct sequence-specific degradation of mRNA, leading to inhibition of synthesis of the corresponding protein. Recent advances in the efficient and specific delivery of siRNA to the liver have paved the way for development of RNAi-based therapeutics for disease targets expressed in the liver. As such, an RNAi therapeutic strategy is well-suited to the treatment of ATTR amyloidosis. Specifically, the therapeutic hypothesis behind this strategy predicts that silencing TTR gene expression will reduce the total amount of TTR protein, both folded and misfolded, that becomes a substrate for amyloid fiber formation, thereby reducing tissue burden and the consequences thereof. Given the vast majority of pathogenic protein in ATTR amyloidosis originates in the liver, liver specific gene silencing enabled by current delivery technologies should result in nearly complete reduction of systemic TTR levels. Finally, given the ability to silence all known disease causing TTR variants, including wild-type, an RNAi therapy may be not only an effective approach for the treatment of ATTR amyloidosis but also more generally applicable.

siRNA formulations targeting TTR resulted in robust knockdown of hepatic TTR mRNA and serum protein in transgenic mice. Further, RNAi-mediated knockdown of hepatic TTR inhibited TTR protein deposition and promoted the regression of existing TTR deposits in pathologically relevant tissues. Finally, the extent of regression of TTR tissue deposits correlated with the extent of reduction in serum TTR exposure. Together, these data suggest that RNAi-mediated knockdown of hepatic TTR expression, by virtue of significantly reducing the systemic concentration of the precursor to the protein aggregate, can prevent the formation of new deposits and thereby allow an otherwise overwhelmed endogenous repair process to reverse the consequences of protein misfolding. Further, while maximal protein knockdown would be ideal, the data suggests that lower levels of knockdown also have potential to result in clinical benefit.

Trials of Autophagy Enhancement to Treat Parkinson's Disease

Researchers are planning trials of a repurposed drug in order to test the effectiveness of enhanced autophagy to treat Parkinson's disease, a condition characterized by loss of the small population of dopaminergenic neurons in the brain. Autophagy is a cellular housekeeping method, and the various genes associated with Parkinson's suggest that the underlying disease mechanism is made worse by inadequate clearance of damaged mitochondria in neurons. Beyond Parkinson's disease, methods of producing increased autophagy are of general interest to those who would like to slow the aging process. Greater levels of autophagy are observed in many of the interventions demonstrated to modestly slow aging in laboratory species, but despite that there has been so far little progress in moving towards clinical therapies based on enhanced autophagy. We should probably expect only marginal results from this particular trial, but it will hopefully help to pave the way for future efforts that do more to boost autophagy in a targeted, deliberate way.

Scientists are hoping that a single drug can treat two devastating brain diseases: Parkinson's and Alzheimer's. The drug is nilotinib, which is approved to treat a form of leukemia. In late 2015, researchers found that small doses of the drug appeared to help a handful of people with Parkinson's disease and a related form of dementia. They'd tried the unlikely treatment because they knew nilotinib triggered cells to get rid of faulty components - including the ones associated with several brain diseases. Results of that preliminary study generated a lot of excitement, but many researchers were cautious. "It was such a small trial, there was no placebo control and it really wasn't designed to assess efficacy." So the original researchers are launching two larger and more rigorous trials of nilotinib, both designed with input from the Food and Drug Administration. One of the trials will enroll 75 patients with Parkinson's disease, the other will enroll 42 patients with Alzheimer's.

Nilotinib seems to work by eliminating toxic proteins that build up in the brains of people with Parkinson's and Alzheimer's. The drug activates a mechanism in brain cells that acts like a sort of garbage disposal. "Our drug goes into the cells to turn on that garbage disposal mechanism. And if we're able to degrade these proteins, we could potentially stop the progression of this disorder." The primary goal of the studies is to learn whether this powerful cancer drug is safe enough for patients with brain diseases. But the new studies should also provide better evidence about whether the drug really works. There's good reason for patients with Parkinson's, Alzheimer's and other neurodegenerative diseases to be optimistic these days. Drugs like nilotinib are coming along because years of research have provided a much better understanding of how these conditions damage the brain. "Now we're in the payoff phase."

Stochastic Nuclear DNA Damage in Aging

Nuclear DNA in every cell accumulates random mutational errors over time. DNA repair mechanisms are highly efficient, but nonetheless, some damage slips through. It is still an open question as to whether this damage is important over the course of the present human life span, at least beyond the matter of cancer risk, where it is well proven that more mutational damage means more cancer. Putting aside cancer for the moment, is there enough random DNA damage occurring in normal individuals to produce enough dysregulation of cellular behavior to in turn lead to meaningful levels of other forms of harm and lost function in tissues? The consensus among researchers is that this is the case, and nuclear DNA damage is listed in the noted hallmarks of aging paper, but that consensus has been challenged. This is largely a debate over theory and indirect evidence at the present time, however: is difficult to produce an animal study in which only random DNA damage is altered in degree, so as to definitively establish differences in outcome. There have been a few promising starts in that direction in the past few years, but much more work remains to be accomplished.

The cells in our bodies are constantly churning out proteins and other structures, built according to the blueprints contained in their DNA, which are crucial to supporting those cells' functions. And while in each cell most of the information contained in its DNA will be ignored, if an area of the genome important to the cell's function is damaged or develops mutations, the cell may produce misshapen proteins or simply stop functioning altogether. The effects of misshapen proteins can range from useless to actively harmful, as when neurons in a brain with Alzheimer's disease produce excessive amounts of the neurotoxic protein amyloid beta.

A few dysfunctional cells here and there don't pose much of a problem, but as more and more cells in a tissue accumulate damage over time, the health of the entire tissue or organ may be compromised. The body's normal way of dealing with such cells is to remove them through a type of programmed self-destruction called apoptosis, making way for new cells. Some cells, however, fail to die and enter a state of senescence, where they are incapable of replicating but are still left to take up space in the tissue. But especially dangerous is the case of a cell with damaged DNA that doesn't enter either apoptosis or senescence: damage drives mutation rate up each time the cell replicates, and if a mutation provides a survival advantage or switches off the cell's protective mechanisms against tumor formation, this can eventually lead to cancer. Cells that divide frequently, such as skin or lung cells, are most susceptible to this danger.

Our bodies may have evolved an impressive variety of damage repair mechanisms, but with increasing exposure to damage-causing agents in the environment and the damages caused by our own internal processes, compounded with the declining effectiveness of our protective mechanisms over time, DNA damage and mutations are bound to accumulate as we age. Some evidence suggests that caloric restriction may mitigate these effects. However, since no drugs yet exist that will prevent or repair DNA damage, all we can do at the moment is try our best to avoid harmful agents like excessive sun exposure and smoking.

The Influence of Children on Late Life Mortality in Humans

Researchers here examine mortality data from one of the wealthier parts of the world, where more people have chosen not to have children, and thus there is a large enough data set to make useful comparisons between older people with and without children. The researchers show that having children adds a few years to life expectancy, conforming to similar past results. The demographic data offers little when it comes to support for any one possible mechanism over others, but some of the options are discussed in the paper. The primary focus is on increased support from children, financial and otherwise, once the parents have entered the frail and vulnerable final stage of aging.

It is well established that parents live longer than non-parents, but the underlying mechanisms are unclear and it is not known how the association changes over the life course. In Sweden and the other Nordic countries, there is an overall trend of increasing levels of childlessness across birth cohorts. It may therefore be valuable to improve our understanding of how childlessness is linked to health and survival chances in old age. We hypothesise that support from adult children to their ageing parents may be of importance for parental health and longevity.

However, there are of course several alternative explanations. For example, the timing and number of children could affect the mortality risk of women through biological pathways. Still, a protective effect of parenthood has been found for mothers and fathers, which may suggest that the biological mechanisms that apply to women is not the only explanation to the association, and other factors matter as well. One such factor could be various types of support from adult children to their ageing parents, such as informational, emotional and social support. In addition, parents have on average more healthful behaviours than childless individuals. It is also possible that the survival advantage of parents over non-parents is due to confounding from biological or social factors influencing the chances of having children and the risk of death. Health-related selection may be important at any phase during the life course, but it seems reasonable that the influence would not increase when parents become very old, but rather being more significant before average life expectancy (LE) as frailer individuals tend to die off. The need for social support from family members may, on the other hand, increase when parents age because ill health becomes more common with increasing age and the ability of self-care may decrease.

How the mortality advantage of parents over non-parents changes over the life span is not known. Previous studies have mainly examined associations between parity and subsequent mortality from 40 years of age up to around 60 years of age. This study closely examines the association between parenthood and longevity, with specific focus on the strength of the association in old age, and with absolute and relative measures. More specifically, we investigate; (1) the association between having a child alive in old age and the risks of death among Swedish men and women, (2) whether the association increases with age of the parent and (3) whether the association persists when stratifying for marital status (taking into account the possible confounding effect of having a partner cohabiting).

This study found an inverse association between having a child and death risks in old age, and, importantly, that the death risk differences between parents and non-parents increased with age of the parent, among men and women. Further, the differences in death risks between individuals with and without children were somewhat larger for men than for women. Our finding that the association grew stronger when parents became older is further in agreement with research suggesting that childless people face support deficits only towards the end of life. However, selective elements and alternative explanations, for example, that parents have more healthy behaviours than non-parents, are not ruled out. The association between having children and mortality persisted when stratifying for marital status, taking into account the possible confounding effect of having a partner. Two of our findings may be interpreted as working against the hypothesis about the importance of social support in older ages: the lack of a stronger mortality association for parents whose children lived fairly close, and the insignificant results for the gender of the child.


Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.