In recent years, researchers working on forms of telomerase gene therapy have produced evidence to show that increased levels and activity of telomerase does not raise cancer risk in mice. The open access paper and publicity materials noted below report the latest example. Extra telomerase increases the sort of activities that are beneficial in the context of improved regenerative capacity, but might be thought to raise the risk of cancer when they take place in the damaged environment of old tissue. This means more stem cell activity, more cellular replication, and so forth.

Somatic cells are limited in the degree to which they can replicate by the length of their telomeres, repeated DNA sequences at the ends of chromosomes. A little of that length is dropped with each cell replication, and a cell with short telomeres will become senescent or self-destruct, and in either case cease replicating. The primary function of telomerase is to extend telomeres, so the operation of telomerase in somatic cells will act to push them past their evolved limits to replication. Stem cells, on the other hand, naturally deploy telomerase to bypass the telomere countdown and retain the ability to replicate indefinitely.

All higher animals depend upon this split between a small number of privileged cells and the vast majority of limited cells. It is the primary means by which incidence of cancer is kept to a low enough rate, and pushed off far enough into later life, for evolutionary success. Near all cells that suffer random DNA mutation are somatic cells, and thus are removed from circulation long before they can become damaged enough to be a threat. Unless they are full of telomerase, and replicating for far longer, in which case the odds change for the worse.

Why, then, does telomerase gene therapy in mice fail to increase cancer risk? In fact in some studies it dramatically reduces cancer risk. One theory is that the increased cellular activity and replication in the immune system more than offsets the increased risk elsewhere. Immune cells are an important line of defense against cancer, seeking out and destroying cancerous cells. Cancer risk correlates fairly well with measures of immune system decline with age.

Does this mean that we should embrace telomerase gene therapies for human use, as way to enhance regeneration in the damaged tissues of old individuals? Not yet, I think, or at least not yet if we are cautious. Mice have very different telomere and telomerase dynamics when compared to humans. It is still possible that the balance of evolved cellular metabolism plus added telomerase works out to less cancer in mice, but more cancer in humans. There is work yet to be done, some of which might take the form of more brave individuals self-experimenting with gene therapies, if the last few years are any guide.

Researchers prove that gene therapy vectors carrying the telomerase gene do not increase the risk of cancer in cancer-prone mouse models

For years now researchers have been investigating the possibility of using the enzyme telomerase to treat pathological processes related with telomere shortening, as well as diseases associated with ageing - cardiovascular and neurodegenerative diseases, among others - and even the ageing process itself. In 2012, they designed a highly innovative strategy: a gene therapy that reactivates the telomerase gene using adeno-associated viruses (AAV). These gene therapy vectors do not integrate in the genome of the host cell, thus telomerase only performs its telomere-reparative actions during a few cell divisions before the vector is diluted out. In this manner, a potential risk associated with the activation of telomerase, such as promoting cancer, it is minimized. But to what extent?

The paper being published now specifically tackles this question by applying gene therapy to an animal model, a mouse, which reproduces human lung cancer and which, therefore, already has a greater risk of developing this disease. The results are negative: "The activation of telomerase by means of this gene therapy does not increase the risk of developing cancer", not even in these mice, where tumours are forced to appear in a relatively short time.

"These findings suggests that gene therapy with telomerase appears to be safe, even in a pro-tumour context. In our research, we were already seeing that this gene therapy does not increase the risk of cancer, but we wanted to conduct what is known as a 'killer experiment', an experiment that creates the worst conditions for your hypothesis to hold true; if it survives even under those circumstances, the hypothesis is truly solid. That is why we chose these mice; they are animals that spontaneously develop a type of lung cancer that is very similar to the human form, which normally never appears in normal mice. We can't think of any other experiment that would provide a better demonstration of the safety of this therapy".

AAV9-mediated telomerase activation does not accelerate tumorigenesis in the context of oncogenic K-Ras-induced lung cancer

The ends of our chromosomes, or telomeres, shorten with age. When telomeres become critically short cells stop dividing and die. Shortened telomeres are associated with onset of age-associated diseases. Telomerase is a retrotranscriptase enzyme that is able to elongate telomeres by coping an associated RNA template. Telomerase is silenced after birth in the majority of cells with the exception of adult stem cells. Cancer cells aberrantly reactivate telomerase facilitating indefinite cell division. Mutations in genes encoding for proteins involved in telomere maintenance lead the so-called "telomere syndromes" that include aplastic anemia and pulmonary fibrosis, among others.

We have developed a telomerase gene therapy that has proven to be effective in delaying age-associated diseases and showed therapeutic effects in mouse models for the telomere syndromes. Given the potential cancer risk associated to telomerase expression in the organism, we set to analyze the effects of telomerase gene therapy in a lung cancer mouse model. Our work demonstrates that telomerase gene therapy does not aggravate the incidence, onset and progression of lung cancer in mice. These findings expand on the safety of AAV-mediated telomerase activation as a novel therapeutic strategy for the treatment of diseases associated to short telomeres.

Raised blood pressure is to be avoided; the overwhelming weight of evidence associates it with a higher risk of age-related disease and shorter life expectancy. Some of that is because the proximate causes of raised blood pressure damage long term health in other ways as well, but in and of itself, even if there were no proximate causes, higher blood pressure is harmful. It damages delicate tissues in the brain, kidneys, and other organs. It causes remodeling and weakening of the heart and blood vessels. It increases the pace at which capillaries rupture in the brain, producing tiny areas of damage that contribute to cognitive decline. There is much more - the aforementioned consequences are only a sample of the full range of downstream issues.

The causes of raised blood pressure with advancing age are the mechanisms that produce stiffening of blood vessels, such as loss of elasticity in the extracellular matrix, dysfunction in vascular muscle cells, and so on. They cannot be entirely evaded at the present time, not until the presently very narrow range of available rejuvenation therapies expands considerably, but they can be slowed through lifestyle choices. Don't get fat; avoid smoking and other environmental factors that reliably increase chronic inflammation; the usual suspects, in other words. The research here demonstrates the relationship between excess visceral fat tissue and raised blood pressure.

Body mass index is positively associated with blood pressure, according to the ongoing study of 1.7 million Chinese men and women. In individuals who were not taking an antihypertensive medication, the researchers observed an increase of 0.8 to 1.7 mm Hg in blood pressure per additional unit of body mass index (BMI). Overall, the population had a mean BMI of 24.7 and a mean systolic blood pressure of 136.5, which qualifies as stage I hypertension.

Researchers recorded the participants' blood pressure from September 2014 through June 2017 as part of the larger China Patient-Centered Evaluative Assessment of Cardiac Events (PEACE) Million Persons Project, which captures at least 22,000 subgroups of people based on age (35-80), sex, race/ethnicity, geography, occupation, and other pertinent characteristics - such as whether or not they are on antihypertensive medication. "The enormous size of the dataset - the result of an unprecedented effort in China - allows us to characterize this relationship between BMI and blood pressure across tens of thousands of subgroups, which simply would not be possible in a smaller study."

In China, the frequency of obesity is expected to more than triple in men - from 4.0% in 2010 to 12.3% in 2025 - and more than double in women - from 5.2% to 10.8%. Meanwhile, high blood pressure already affects one-third of Chinese adults, and only about one in 20 of those with hypertension have the condition under control. According to the researchers, one way for the Chinese healthcare system to address these risk factors would be the management of high blood pressure with antihypertensive drugs. A study compared the widespread and successful use of antihypertensive drugs in the United States for blood pressure management to their infrequent use in China, suggesting that by prescribing antihypertensives earlier and more frequently, China might begin to take control of its high blood pressure crisis.

Link: https://news.yale.edu/2018/08/17/body-mass-index-increases-blood-pressure-may-well

Blood vessels stiffen with age, and this appears to be the primary cause of age-related hypertension, or raised blood pressure. That raised blood pressure in turn damages delicate tissues, increasing the pace at which ruptures occur in capillaries throughout the body. In the brain this causes many tiny, silent strokes over the years, adding up to create cognitive decline. Eventually hypertension combines with the corrosive effect of atherosclerosis on blood vessel walls to cause some form of fatal structural failure in a major blood vessel.

The causes of stiffening of blood vessels include cross-linking that disrupts the physical properties of the extracellular matrix, the related loss of elastin in the matrix, and dysfunction in the vascular smooth muscle cells responsible for constriction and dilation of blood vessels. That cellular dysfunction has a whole set of deeper causes, not all of which are well understood at this time. The chronic inflammation and harmful signaling generated by senescent cells seems to be involved, but it isn't the whole story by any means.

Aging is associated with a progressive decline in vasoconstrictor responses in central and peripheral arteries. The mechanism responsible for the age-related decrease in vasoconstrictor function has not been fully elucidated but may involve an impaired ability of vascular smooth muscle (VSM) cells to develop contractile tension. This hypothesis is supported by evidence indicating that myogenic constrictor responses in skeletal muscle arterioles declined with age. In addition, agonist-induced vasoconstrictor responses to norepinephrine (NE), phenylephrine (PE), and angiotensin II (Ang II) were impaired in endothelium intact skeletal muscle feed arteries (SFA) from old rats when compared to young rats.

Arterial aging results in progressive changes in the mechanical properties of the vessel wall leading to increased wall stiffness and an impaired ability of aged blood vessels to control local blood flow and pressure. At the microscopic level, this translates to decreased responsiveness of VSM and endothelial cells to mechanical stimuli. This impairment, in turn, induces compensatory hypertrophic or hyperplastic remodeling of aged arteries. The discrete VSM cell mechanical properties and their ability to adapt to external mechanical signals (e.g., blood pressure and flow) directly contribute to maintaining vessel tone.

Vascular smooth muscle cells play an integral role in regulating matrix deposition and vessel wall contractility via interaction between the actomyosin contractile unit and adhesion structures formed at the cell membrane that mechanically link the cell to the matrix. The actin cytoskeleton is responsible for maintaining cell shape and provides the platform for the distribution of mechanical signals throughout the cell. This mechanical load-bearing cell-matrix interaction is key to maintaining the contractile state of resistance arteries. Most studies to date on arterial aging have focused on the role played by endothelial dysfunction or changes in the extracellular matrix, and less on the contribution of VSM cells that control vessel tone. However, there is emerging interest in the role VSM cells play in regulating vessel wall stiffness.

Link: https://doi.org/10.3389/fphys.2018.00856

Today, I'll point out an open access commentary in which the authors survey a number of lines of research into age-related dysfunction in the liver, all of which lead back to elevated levels of cyclin-dependent kinase 4 (CDK4). Some of this work involves investigation of the mechanisms of fatty liver disease, more properly known as hepatic steatosis. This is most commonly caused by being overweight in this age of cheap calories, but, setting aside the morbidly obese, the condition nonetheless tends to emerge later rather than earlier in life. Other research programs look at more directly age-associated measures of liver function, such as senescent cell burden, changes in gene expression, and proteins and lipids in the bloodstream. Inhibition of CDK4 in late life to some degree reverses many of these declines.

Manipulation of specific proteins and genes is an intervention with widely varying expectations of ease and safety. The ideal gene and its protein product has little influence over anything other than the one disease-associated mechanism of interest. Or at the least, it only has that one relationship in the organ suffering from the disease state, even if it has other roles elsewhere in the body. Unfortunately that can be said for all too few genes. CDK4 is a dangerous-looking target, showing up in considerations of cancer via its close relationship to retinoblastoma proteins, and because it is involved in cell replication. Growth and replication genes tend to be hard to safely target as downstream effects of change are unpredictable, and their influence on cancer risk is one of those unpredictable items. This is the challenge for any gene involved in vital low-level cellular processes, and is one of the reasons why adjusting gene expression to form new metabolic states is an expensive, slow process.

The question remains as to why CDK4 levels rise with age in the liver. This is a reaction to which of the root causes of aging, mediated by which intermediary mechanisms? Just because chronic inflammation is important in liver aging, and the inflammation-producing accumulation of senescent cells is measured here doesn't mean that cellular senescence is the most important of underlying causes. As is usually the case, the approach of fixing root causes and observing the results is likely to be a faster path to answers than working backwards through pathways and relationships in the cell.

Correction of aging phenotype in the liver

The earliest stage of Non-Alcoholic Fatty Liver Disease (NAFLD), hepatic steatosis (or non-alcoholic fatty liver, NAFL) has no evidence of liver injury, but is characterized by an accumulation of triglycerides in hepatocytes. In some patients, NAFL can progress in age-dependent manner to fibrosis and then to non-alcoholic steatohepatitis (NASH) and cirrhosis. Mechanisms of development of hepatic steatosis are not well understood and approaches to treat hepatic steatosis are not developed.

Researchers have investigated the role of the endogenous ligand of growth hormone Ghrelin in development of age-associated hepatic steatosis. The authors clearly demonstrated the deletion of ghrelin prevents development of hepatic steatosis. This prevention is mediated by down-regulation of C/EBPα-p300 axis suggesting that the inhibition of ghrelin activities or C/EBPα-p300 pathway might be considered as a therapeutic approach. In agreement with these findings, other scientists have recently reported that blocking cdk4, a direct activator of C/EBPα-p300 complex, eliminates age-associated hepatic steatosis as well as several age-associated disorders of the liver.

Researchers have investigated age-associated development of hepatic steatosis in mice with deletion of ghrelin. At young age, no significant differences were observed. However, while wild type (WT) mice developed severe steatosis, Ghrelin knockout (KO) mice showed significant inhibition of steatosis. Further studies revealed that the enzyme of the last step of synthesis of triglycerides, DGAT1, is not elevated in livers of Ghrelin KO mice, while it is elevated with age in livers of old mice. Activation of DGAT1 promoter does not occur in ghrelin KO mice due to a lack of C/EBPα-p300 complexes. The lack of these complexes is associated with failure of Ghrelin KO mice to phosphorylate C/EBPα, the event that is required for the formation of C/EBPα-p300 complexes. This phosphorylation is typically under control of cdk4 and it is likely that the deletion of ghrelin leads to the inhibition of cdk4, suggesting that cdk4 is a key mediator of ghrelin-dependent hepatic steatosis.

Researchers examined the role of cdk4 in age-dependent hepatic steatosis using three settings: liver biopsies from old patients with NAFLD, cdk4-resistant C/EBPα-S193A mice, and inhibition of cdk4 in old WT mice. These three experimental settings showed that cdk4 is elevated in old patients and degree of elevation correlates with severity of NAFLD. Work with S193A mice and the inhibition of cdk4, revealed that cdk4 is a key driver of the age-associated hepatic steatosis. Surprisingly, the authors found that inhibition of cdk4 not only eliminates hepatic steatosis, but also corrects several other age-dependent liver disorders including cellular senescence, heterochromatin structures, E2F1 and RB-dependent pathways of proliferation, liver/body weight ratio, and several blood parameters.

We all, to some degree, accumulate harmful protein aggregates in the brain with age, but only some people develop severe neurodegenerative disease as a result. The rest of the population remains mildly impaired. Why is this? Some have suggested that Alzheimer's disease and the like are to some degree lifestyle conditions, aggravated by the presence of excess visceral fat tissue and the abnormal metabolism that results. Alternatively the microbial hypothesis suggests that only some people have sufficient persistent infection by herpesviruses or lyme spirochetes to result in high levels of protein aggregates. Theories of impaired cerebrospinal fluid drainage point to differing levels of structural failure in fluid channels leading from the brain. Researchers here propose another mechanism, in that some people have synapses that are resilient to the harms inflicted by tau aggregation, thought to be the most damaging mechanism in late stage Alzheimer's disease.

People suffering from Alzheimer's disease (AD) develop a buildup of two proteins that impair communications between nerve cells in the brain - plaques made of amyloid beta proteins and neurofibrillary tangles made of tau proteins. Intriguingly, not all people with those signs of Alzheimer's show any cognitive decline during their lifetime. The question became, what sets these people apart from those with the same plaques and tangles that develop the signature dementia?

"In previous studies, we found that while the non-demented people with Alzheimer's neuropathology had amyloid plaques and neurofibrillary tangles just like the demented people did, the toxic amyloid beta and tau proteins did not accumulate at synapses, the point of communication between nerve cells. When nerve cells can't communicate because of the buildup of these toxic proteins that disrupt synapse, thought and memory become impaired. The next key question was then what makes the synapse of these resilient individuals capable of rejecting the dysfunctional binding of amyloid beta and tau?"

The researchers analyzed the protein composition of synapses isolated from frozen brain tissue donated by people who had participated in brain aging studies. The participants were divided into three groups - those with Alzheimer's dementia, those with Alzheimer's brain features but no signs of dementia, and those without any evidence of Alzheimer's. The results showed that resilient individuals had a unique synaptic protein signature that set them apart from both demented AD patients and normal subjects with no AD pathology. "We don't yet fully understand the exact mechanisms responsible for this protection. Understanding such protective biological processes could reveal new targets for developing effective Alzheimer's treatments."

Link: https://www.utmb.edu/newsroom/article11851.aspx

Small, short doses of damaging cellular stress, such as that achieved through the application of heat, toxins, lack of nutrients, or raised levels of oxidative molecules, produce a net benefit to cell and tissue function. This is called hormesis. It occurs because cells react to short periods of stress with a lasting upregulation of maintenance activities and other altered behavior. Hormetic behaviors are the basis for many of the benefits of exercise, calorie restriction, and other related interventions shown to slow aging to some degree in animal studies.

In the research noted here, scientists report on an investigation into the way in which mitochondrial activity changes in response to cellular stress. Mitochondria are the power plants of the cell, and their function is central to cellular health. With age, mitochondria become dysfunctional in a number of different ways. Periodic hormetic stress may slow down or attenuate this progressive decline by, for example, increasing the housekeeping processes of mitophagy, responsible for recycling damaged mitochondria. Other signaling processes that more directly determine mitochondrial function are also likely involved, however.

Researchers report that brief exposures to stressors can be beneficial by prompting the cell to trigger sustained production of antioxidants, molecules that help get rid of toxic cellular buildup related to normal metabolism. Short-term stress to cells leads to remodeling mitochondria, the powerhouses of the cell that deteriorate with age, so they generate fewer toxic byproducts. The findings could lead to new approaches to counter the cellular effects of aging, possibly even extending lifespan.

"The novelty of this study is that we've generated a model in which we can turn off antioxidant production in mitochondria but in a reversible way. So we were able to induce this stress for specific time windows and see how cells responded." In the process of converting food into chemical energy, mitochondria produce a chemical called superoxide, which has a critical role in cells but is toxic if it builds up. For this reason, mitochondria also produce an enzyme - superoxide dismutase, or SOD - to convert superoxide to a less toxic form.

In a group of genetically identical mice in utero, half with a molecular "off" switch for SOD experienced brief stress when the enzyme was deactivated. After the mice were born and continued to grow to adulthood, the two groups looked very similar. But liver samples taken when they were four weeks old told a strikingly different story: the mice whose SOD enzyme had been turned off briefly to trigger stress in mitochondria had - surprisingly - higher levels of antioxidants, more mitochondria and less superoxide buildup than the mice who had not experienced stress.

When the team analyzed which genes were being activated in both the lab dishes and the liver samples of all the mice, they found unexpected molecular pathways at work in the SOD group that were reprogramming mitochondria to produce fewer toxic molecules while simultaneously increaseing the cells' antioxidant capacity. The work suggests that short-term mitochondrial stress may lead to long-term adaptations (a concept called "mitohormesis") that could keep cells healthy longer, staving off aging and disease. Researchers next plan to study whether the mechanism elucidated here can delay the effects of aging in mammals.

Link: https://www.salk.edu/news-release/cells-agree-what-doesnt-kill-you-makes-you-stronger/

The Life Extension Advocacy Foundation (LEAF) volunteers recently interviewed Didier Coeurnelle of the Healthy Life Extension Society (HEALES), a long-standing advocate on the European side of our community who has promoted research and development of therapies to treat aging for many years now.

Insofar as the treatment of aging goes, we are living through the early stages of an enormously important transition, a tipping point in the progress of medicine. It will be of far greater impact than the advent of antibiotics. The development of rejuvenation therapies, treatments that can reverse or repair or bypass the known root causes of aging, will bring sweeping change and improvement to the human condition. The first legitimate, functioning rejuvenation therapies already exist, senolytic drug candidates that can remove a sizable fraction of senescent cells from old tissues. These drugs are in some cases very cheap, being generic and widely manufactured for other uses, but the world at large has not yet caught up to this point. The millions of older individuals who might benefit from removal of senescent cells do not yet appreciate that with just a modest effort, they could most likely experience significantly improved health, a reduction in the burden of aging.

Nothing happens quickly. It will take time for the realization to percolate. For the human trials to complete and be publicized, and then for people to understand the implications of the results. The usual suspects are ahead of the wave, by which I mean some researchers, some self-experimenters, some venture capitalists, some advocates. Their job at the present time is still largely to persuade everyone else, the people who will one day be customers, developers, and investors. An enormous industry is waiting in the wings to come into being. It will ultimately provide the majority of all medicine and medical services, approaches that will control the progression of aging and put an end to age-related disease. It is inevitable, but the necessary steps along this road are running all too slowly, for reasons that have little to do with the technology and everything to do with human nature.

An Interview With Didier Coeurnelle

You have been an advocate for quite some time now; how successful do you think collective advocacy efforts have been over the years?

Not enough yet and not fast enough. The "pro-aging" narrative is, sadly, powerful. Defeating aging looks "too good to be true" and makes people feel uneasy. However, there are changes. For example, in the French-speaking world, sometimes we see articles about "amortalité" (life without senescence) in the press; a few years ago, you would see only articles speculating about billionaires wanting "immortality" (which makes people afraid).

In November, HEALES will organize the next Eurosymposium on Healthy Ageing (EHA). EHA and Undoing Aging each have a section focused on advocacy. Why did you decide to include it?

I think most scientists wanting big progress for longevity know that having public opinion on our side will help. Also, PR is useful in order to raise money. However, many scientists feel uneasy about these issues. That's why we decided to have a day dedicated to social aspects. Not all scientists will stay for the last day, and we will also try to reach a larger public on the last day. Another aspect is that Brussels is the European capital. One of our goals is to convince people there. Let's be honest: there is a long way to go. However, for a year or two now, some European civil servants who have been promoting "healthy aging" (we know it is an oxymoron) seem to be very interested in big data on health and scientific research. We will be keeping an eye on these developments.

You don't need to convince people that saving the lives of children is a good thing to do; however, you do need to convince them that saving elderly lives is a good thing. Why do you think this difference exists?

Nor do you need to convince people that defeating cancer or Alzheimer's disease would be good, but death by old age is a step too far. For me, the fundamental reason is a variant of Stockholm syndrome called the terror management theory. Death by old age is awful and unavoidable. We must think that longevity is not better, otherwise it would be too awful to die. This process is unconscious.

How far do you think we are from the point when people won't need persuading anymore, if ever?

Aubrey de Grey said it will be when a mouse becomes "immortal", because people will feel that rejuvenation therapies will be available soon. I think that it could be sooner if more and more scientists start to speak out more about it.

With some luck, the effects of first-generation rejuvenation therapies, such as senolytics, will be tangible soon. Assuming that the effects are measurably positive, how do you think the world will react to the news, and how do you think that this will affect advocacy?

It would be interesting even if senolytics have only a moderate effect. I think some groups who are not in the "longevity camp" will start asking to use them. Maybe, in some countries, they will even start asking for reimbursement from social security programs. Some groups on the other side will probably ask not to use these products or will stress risks, but it will be especially difficult for "deathists" to fight against senolytics, which are, in a way, very classical drugs.

The involvement of In Silico Medicine in the formation of Napa Therapeutics to run drug discovery based on advances in understanding of mitochondrial metabolism in aging is an example of the premium placed on any approach that might plausibly reduce the cost and time involved in finding drug candidates. We will no doubt see a lot more of this sort of thing as computational methodologies become a plausible replacement for greater portions of the existing costly, hands-on, mechanical screening processes.

Draw a triangle in the present field of aging research with the three points set at calorie restriction mimetics, exercise mimetics, and general tinkering with energy metabolism, then efforts to increase NAD+ levels in mitochondria might be found somewhere in the midst of that space. That line of work is growing in popularity, and the early human trials of compounds like nicotinamide riboside suggest that the effect size might be worth chasing if the costs are low. (Though of course the development costs are never low for any approach that must pass through the full regulatory process).

Helping mitochondria to function more effectively in old tissues may help modestly with a variety of issues, given that faltering energy generation is a feature of aging, though it remains to be seen as to just how large the effect sizes are at the end of the day. This is not rejuvenation; this is pushing a damaged engine a little harder, this is overriding an aspect of the aged state of metabolism without addressing the underlying damage that causes that aged state. Sometimes that can work to some degree, sometimes it doesn't.

The Buck Institute for Research on Aging, Insilico Medicine, and Juvenescence Ltd announced today that they have formed Napa Therapeutics, Ltd to develop drugs against a novel aging-related target. The Buck Institute is one of the leading research centers in the world focused solely on research on aging and the elimination of age-related disease. Insilico Medicine is an AI company focused on a range of verticals devoted to aging. Juvenescence is a company focused on developing drugs to modify aging and the diseases of aging.

Napa Therapeutics is based on groundbreaking research in NAD metabolism conducted in the lab of Eric Verdin, MD, President and CEO of the Buck Institute. The Verdin lab will collaborate with Napa, using Insilico's drug development engine to speed the discovery of new compounds. "I am most excited by this model and the ability to combine the quality science of the Buck Institute with the remarkable deep learning engine at Insilico Medicine. To me this is another big step in the evolving process of using AI with human intelligence to extract the best of both systems. Napa Therapeutics lets Juvenescence deepen our collaboration with the Buck Institute and with Insilico Medicine. We hope to shorten the time required to identify molecules that can be brought to the clinic and most importantly help patients."

Link: https://www.prnewswire.com/news-releases/the-buck-institute-insilico-medicine-and-juvenescence-found-napa-therapeutics-to-develop-drugs-to-impede-age-related-disease-300696495.html

The present consensus on the inheritance of longevity is that genetic influences over aging only rise to importance in later life. Even then it is perhaps more a matter of resistance to accumulated molecular damage and its consequences than a slower pace of aging per se. Environment and choice throughout life are the overwhelming determinants of the course of aging leading into middle age, meaning exposure to pathogens, amount of visceral fat tissue, smoking, and similar line items. That of course raises the question as to the degree to which inherited longevity is a cultural rather than genetic phenomenon. Only a tiny minority of individuals can legitimately blame their genes for the sort of shape they are in at 65. Health and survival status at 95 are a different story, however, and genetics plays a larger role - at least in the context of a world lacking rejuvenation therapies, but that will cease to be the case soon enough.

Researchers report that women whose mothers lived to at least age 90 were more likely to also live to 90, free of serious diseases and disabilities. The study found women whose mothers lived into their ninth decade enjoyed 25 percent increased likelihood of also doing so without suffering from serious or chronic illness, including heart disease, stroke, diabetes, cancer, hip fractures or other debilitating disabilities.

Interestingly, the study also found that if only the father lived to 90, it did not correlate to increased longevity and health in daughters. However, if both the mother and father lived to 90, the likelihood of the daughter achieving longevity and healthy aging jumped to 38 percent. The study did not address parental life span effects on sons. Rather, it analyzed data from approximately 22,000 postmenopausal women participating in the Women's Health Initiative, a large, national study investigating major risk factors for chronic diseases among women. Limitations included no knowledge of the health or cause of death of the participants' parents.

Researchers believe a combination of genetics, environment, and behaviors passed to subsequent generations may influence aging outcomes among offspring. At baseline, the women in the study whose mothers lived to at least 90 were more likely to be college graduates, married with high incomes and incorporated physical activity and a healthy diet into their lives. "We now have evidence that how long our parents live may predict our long-term outcomes, including whether we will age well, but we need further studies to explore why. Although we cannot determine our genes, our study shows the importance of passing on healthy behaviors to our children. Certain lifestyle choices can determine healthy aging from generation to generation."

Link: https://ucsdnews.ucsd.edu/pressrelease/parental_life_span_predicts_daughters_living_to_90_without_chronic_disease_or_disability

Hair cells are the sensors of the ear, picking up vibrations with tiny fibers that give the cells their name. Unfortunately, these cells are not replaced when lost in adult mammals. Loud noise, toxins, and some infectious diseases can cause sufficient loss of hair cells to induce deafness - a condition that currently lacks effective treatments. A sizable fraction of research into the causes of hearing loss has focused on hair cells in the ear, particularly with the growth of the regenerative medicine community. The restoration of lost cell populations is on the horizon, and hair cell regrowth is further advanced than many other lines of work in this field.

Is this approach useful for the types of hearing loss most frequently observed in older individuals, however? The results in today's open access paper can be used to argue that hair cell regrowth may not be sufficient on its own. The authors present evidence for inner hair cells to remain largely intact, while the underlying issue is the death of neurons and their axons connecting these cells to the brain. Reintegration of new hair cells with the complex auditory system of the brain has the look of a much harder problem to solve than the lesser challenge of creating the new hair cells. Rebuilding the connecting axons may not be sufficient on its own, and even that is a hard task to contemplate in comparison to the introduction of new hair cells.

This is one of many examples in which it is an open question as to whether the next generation of regenerative strategies will be sufficient to address specific forms of degeneration that span different organs and tissue types. Will we be fortunate, and find that approaches spurring coordinated localized regrowth do in fact cause reconnection of the nervous system to new tissues and cells? The answer will no doubt be different in each case, and depend on the fine details. The effort must be made, and if it fails, then the more sophisticated efforts of later years will have to be designed, constructed, and take their turn.

Primary Neural Degeneration in the Human Cochlea: Evidence for Hidden Hearing Loss in the Aging Ear

Although sensorineural hearing loss (SNHL) can involve damage to either sensory cells or sensory neurons of the inner ear, a longstanding dogma in acquired SNHL was that loss of sensory cells is the primary event, and that degeneration of auditory nerve fibers (ANFs) occurs only secondarily to the loss of peripheral targets. This view arose because, after cochlear insults such as acoustic injury or ototoxic drugs, the degeneration of sensory cells can be seen within hours post-exposure, whereas degeneration of spiral ganglion cells (SGCs), the cell bodies of the ANFs, is not visible for weeks to months.

Animal work challenged the dogma by showing that hair cell loss in acquired SNHL is neither necessary nor sufficient for loss of ANFs. Firstly, in acoustic injury models, overexposures causing only reversible threshold shifts, and no hair cell loss, can nevertheless cause significant ANF degeneration. The neural damage is visible immediately as loss of synaptic connections between ANFs and inner hair cells (IHCs). In the aging mouse ear, as in the noise-damaged ear, it is the connections between SGCs and IHCs that degenerate first, rather than the hair cells themselves. This primary neural degeneration, or partial de-afferentation of IHCs, has negligible effect on thresholds until it exceeds 80-90%, thus it "hides" behind the audiogram.

The observation that ANF degeneration precedes and/or exceeds hair cell loss in animal models of acquired SNHL has suggested why two people with the same threshold audiogram, whether normal or abnormal, can have very different abilities to understand speech in a noisy environment. i.e. that partial de-afferentation of IHCs, a.k.a. "hidden hearing loss", compromises hearing ability in complex listening environments without changing the ability to detect a pure tone in quiet.

Here we take a direct approach to the question of whether hidden hearing loss is as important in humans as in animal models. We study temporal bones from a group of 20 "normal-aging" humans, ranging in age from birth to 86 years, without any explicit history or ear diseases or ototoxic exposures. We prepare these autopsy specimens in ways that allow us to accurately quantify the survival of hair cells and ANF peripheral axons in the same cochlear regions.

Mean loss of outer hair cells was 30-40% throughout the audiometric frequency range in subjects over 60 yrs, with even greater losses at both apical (low-frequency) and basal (high-frequency) ends. In contrast, mean inner hair cell loss across audiometric frequencies was rarely more than 15%, at any age. Neural loss greatly exceeded inner hair cell loss, with 7 of 11 subjects over 60 years showing more than 60% loss of peripheral axons, and with the age-related slope of axonal loss outstripping the age-related loss of inner hair cells by almost 3:1. The results suggest that a large number of auditory neurons in the aging ear are disconnected from their hair cell targets. This primary neural degeneration would not affect the audiogram, but likely contributes to age-related hearing impairment, especially in noisy environments. Thus, therapies designed to regrow peripheral axons could provide clinically meaningful improvement in the aged ear.

Elephants and whales are in their own way just as interesting a target of study for cancer researchers as naked mole-rats. Cancer risk is a numbers game, based on incidence of mutation and capacity of cancer suppression mechanisms to destroy cancerous cells before they can form a tumor. Given that elephants have many more cells than humans, but a lower rate of cancer, what are the differences in cellular biochemistry that explain that outcome? Might any one or more of those differences form the basis for therapies in human medicine? It is a little early to say at this stage whether or not the comparative biology of cancer will lead to meaningful advances in control over human cancer, but a number of lines of research are underway in this part of the field.

An estimated 17 percent of humans worldwide die from cancer, but less than five percent of captive elephants - who also live for about 70 years, and have about 100 times as many potentially cancerous cells as humans - die from the disease. Humans, like all other animals, have one copy of the master tumor suppressor gene p53. This gene enables humans and elephants to recognize unrepaired DNA damage, a precursor of cancer. Then it causes those damaged cells to die. Unexpectedly, however, researchers found that elephants have 20 copies of p53. This makes their cells significantly more sensitive to damaged DNA and quicker to engage in cellular suicide.

Now, researchers describe a second element of this process: an anti-cancer gene that returned from the dead. "Genes duplicate all the time. Sometimes they make mistakes, producing non-functional versions known as pseudogenes." While studying p53 in elephants, researchers found a former pseudogene called leukemia inhibitory factor 6 (LIF6) that had somehow evolved a new on-switch. LIF6, back from the dead, had become a valuable working gene. Its function, when activated by p53, is to respond to damaged DNA by killing the cell. The LIF6 gene makes a protein that goes, quite rapidly, to the mitochondria, the cell's main energy source. That protein pokes holes in the mitochondria, causing the cell to die.

LIF6 seems to have emerged around the time when the fossil record indicates that the small groundhog-sized precursors of today's elephants began to grow bigger. This started about 25 to 30 million years ago. This supplementary method of suppressing cancer may have been a key element enabling enormous growth, which eventually led to modern elephants. Bigger animals have vastly more cells, and they tend to live longer, which means more time and opportunities to accumulate cancer-causing mutations. When those cells divide, their DNA makes copies of itself. But those copies don't match the original. Errors get introduced and the repair process can't catch up. "Large, long-lived animals must have evolved robust mechanisms to either suppress or eliminate cancerous cells in order to live as long as they do, and reach their adult sizes."

Link: https://www.eurekalert.org/pub_releases/2018-08/uocm-zgp080818.php

Samumed is noteworthy for the breadth of their regenerative medicine development pipeline, based as it is on a single technology platform, the manipulation of Wnt signaling. Their trials to date are attempts to use variations on this approach to increase regenerative capacity in aging and damaged tissues. The company might be viewed as an early example of the fork in the road for the regenerative medicine community, arising after first generation stem cell therapies have matured. Some groups will produce better, more advanced cell therapies, aiming to improve the survival and utility of transplanted cells. Others, like Samumed, will abandon cell transplants in favor of ways to manipulate native cell populations to produce similar outcomes.

At least a few of the future successful companies in the rejuvenation research space should come to look quite similar to Samumed in structure. Most legitimate rejuvenation therapies, those capable of at least partially reversing one of the root causes of aging, will be applicable to scores of age-related diseases. Companies will be limited in size and activity only by the amount of funding they can raise. It will not be unusual to see the likes of Samumed or Unity Biotechnology raising hundreds of millions of dollars for very broad pipelines, with trials of their technology for a dozen or more age-related conditions running in parallel.

Samumed, LLC, announced today that it has closed its A-6 Round of equity issuance with $438 million, bringing its total equity raised to date to more than $650 million.The pre-money valuation for the round was $12 billion. "We appreciate the strong support from our investors, and we are now in a fortunate position to both move our later stage programs to commercialization, as well as expand on our earlier stage science and clinical portfolio."

Samumed is developing small-molecule drugs that target the regenerative potential of the Wnt pathway in order to reverse the progression of various age-related diseases. Its development pipeline includes therapies focused on osteoarthritis, degenerative disc disease, idiopathic pulmonary fibrosis, and Alzheimer's disease. A number of these therapies are currently in human trials, and some of them are currently in phase 2 testing.

The Wnt pathway is a primary signaling pathway that regulates the self-renewal and differentiation of adult stem cells. It plays a key role in tissue repair and upkeep, and it helps the body repair and regenerate following injury. As we age, the Wnt pathway becomes deregulated, which leads to a decline of tissue regeneration and supports the progression of various age-related diseases. Samumed is focused on modulating the Wnt pathway in order to promote the restoration and health of diseased tissues by spurring effective regeneration.

Link: https://www.leafscience.org/samumed/

The protein α-synuclein, like amyloid-β and tau, forms into an increasing amount of solid aggregates in the aging brain. These aggregates and their surrounding biochemistry cause neural dysfunction and cell death. Every older individual has raised levels of these protein aggregates, and the pathology they cause rises to the level of named condition when one or another is present in great enough amounts. The age-related diseases associated with α-synuclein are termed synucleinopathies, though one can argue that all neurodegeneration is to some degree influenced by all protein aggregates. Where the research, medical, and regulatory communities choose to draw the line between "normal" and "pathological" is somewhat arbitrary. If methods of reliably removing protein aggregates existed, every older individual should undergo treatment on a periodic basis, not just people with notably high levels of aggregates.

Parkinson's disease is the best known of the synucleinopathies, alongside dementia with Lewy bodies, and a few other less common conditions. Arguably α-synuclein is a meaningful cause of pathology in Alzheimer's patients as well. It might be better to think of the named conditions as rough, shifting territories outlined on a broad map of brain aging that combines differing levels of protein aggregation, vascular dysfunction, mitochondrial aging, immune system failure, and other causative processes. They are shorthand descriptions for large and varied chunks of a complicated landscape.

In today's open access paper, researchers present evidence for inhibition of TLR2 as a potential strategy to dampen the progression of synucleinopathy. TLR2 is a part of mechanisms that trigger the immune system into action, and in this case the activities of glial cells of the brain are the focus point. Glial cells are known to become dysregulated and inflammatory in the aging brain, and suppressing that inappropriate behavior is one possible path towards a slowing of progression towards pathology. Therapies of this nature don't directly address the underlying damage that causes immune dysfunction, but any effort that at least somewhat sets the immune system back on track may result in increased repair and maintenance by immune cells. The size of the effect is very much dependent on the details of the case at hand, of course.

Immunotherapy targeting toll-like receptor 2 alleviates neurodegeneration in models of synucleinopathy by modulating α-synuclein transmission and neuroinflammation

Following Alzheimer's Disease (AD), synucleinopathies such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are the second most common group of neurodegenerative disorders of the aging population. Overall, they represent heterogeneous group of neurological conditions, characterized by progressive accumulation of α-synuclein in neuronal and glial cells. The mechanisms through which the various species of α-synuclein aggregates lead to selective neurodegeneration and neuroinflammation is not completely understood. Transmission of α-synuclein aggregates from neuron-to-neuron and neuron-to-glia has been suggested as the underlying mechanism of the neurodegeneration and neuroinflammation in synucleinopathy.

We have previously shown that the oligomeric forms of extracellular α-synuclein interact with Toll-like receptor 2 (TLR2) on the surface of neurons and glial cells. This results in neuro-inflammatory responses with TNFα and IL-6 production. TLR2 belongs to a family of pattern recognition receptor which modulate responses to exogenous pathogens as well as endogenous misfolded proteins released following damage and cellular stress. In the central nervous system, TLR2 is expressed in glial cells and neuronal populations, and recent studies have shown that the levels of TLR2 are elevated in neurodegenerative disorders such as AD and PD.

We have recently shown that inhibition of TLR2 by gene deletion or siRNA-mediated knock down rescues the pathology associated with α-synuclein accumulation in cellular models and transgenic mice. Therefore, TLR2 and downstream signaling have been suggested a new therapeutic target for synucleinopathy. Neutralizing TLR2 with a monoclonal antibody has been recently shown to ameliorate the pathology in a murine model of AD.

The main objective of this study was to evaluate the therapeutic effects of targeting TLR2 with a functional inhibitory antibody (anti-TLR2). We show that the administration of anti-TLR2 was able to decrease the accumulation of neuronal and astroglial α-synuclein, resulting in reduced neuroinflammation, neurodegeneration, and behavioral deficits in an α-synuclein transgenic mouse model of PD/DLB. Moreover, the anti-TLR2 blocked neuron-to-neuron and neuron-to-astrocyte α-synuclein transmission and reduced pro-inflammatory responses in a cell based model. Therefore, TLR2 might be a viable target and TLR2 immunotherapy is a novel therapeutic strategy for synucleinopathies of the aging population.

Theory and evidence for persistent infection as a cause of Alzheimer's disease continues to grow in scope and plausibility. In general this supports rather than replaces past thinking on amyloid-β and its role in the development of Alzheimer's. It provides an explanation as to why it is that levels of amyloid-β rise over time to produce the early disruptions and changes in the biochemistry of the brain that are necessary for later neurodegeneration to take place. Other compelling lines of work provide evidence for entirely separate mechanisms by which levels of amyloid-β can grow in later life, such as declining drainage of cerebrospinal fluid. It seems plausible that all may be correct to some degree, and that many of these proposed processes are significant, each adding their own contribution to the progressive decline of the brain.

Alzheimer's disease (AD) is the most frequent type of dementia. The pathological hallmarks of the disease are extracellular senile plaques composed of beta-amyloid peptide (Aβ) and intracellular neurofibrillary tangles composed of phosphorylated tau (pTau). These findings led to the "beta-amyloid hypothesis" that proposes that Aβ is the major cause of AD. Clinical trials targeting Aβ in the brain have mostly failed, whether they attempted to decrease Aβ production by BACE inhibitors or by antibodies. These failures suggest a need to find new hypotheses to explain AD pathogenesis and generate new targets for intervention to prevent and treat the disease.

Many years ago, the "infection hypothesis" was proposed, but received little attention. However, the recent discovery that Aβ is an antimicrobial peptide (AMP) acting against bacteria, fungi, and viruses gives increased credence to an infection hypothesis in the etiology of AD. We and others have shown that microbial infection increases the synthesis of this AMP. Here, we propose that the production of Aβ as an AMP will be beneficial on first microbial challenge but will become progressively detrimental as the infection becomes chronic and reactivates from time to time. Furthermore, we propose that host measures to remove excess Aβ decrease over time due to microglial senescence and microbial biofilm formation. We propose that this biofilm aggregates with Aβ to form the plaques in the brain of AD patients.

Link: https://doi.org/10.3389/fnagi.2018.00224

Persistent cytomegalovirus (CMV) infection is thought to cause a sizable amount of the age-related decline of the immune system. Latent infection by this sort of herpesvirus causes few to no immediate and obvious symptoms in the vast majority of individuals, but the virus cannot be permanently cleared by the immune system. Over time ever more T cells of the adaptive immune system become uselessly specialized to CMV, unavailable for other tasks. Coupled with the much reduced pace of creation of new T cells in later life, this results in an increasingly dysfunctional immune system.

Researchers here point to one specific consequence of the accumulation of a problematic class of T cell noted to occur with aging, increased risk of cardiovascular disease, and present evidence to show that this accumulation occurs because of persistent CMV infection. All told, the evidence for CMV to be a major issue, a slow corrosion of immune function and health, is quite compelling. What to do about it? The most effective approach might not be to tackle CMV directly, but rather to clear out and replace the problem immune cells via some form of targeted cell destruction followed by cell therapy.

A recent publication shows that Cytomegalovirus (CMV) infection increases the risk of cardiovascular death by over 20% but no specific mechanisms explaining this effect were identified. CMV infection, however, is notorious for promoting large expansions of terminally differentiated effector T-cells, including CD4 T-cells. This is particularly observable in older people. Moreover, there is good evidence that terminally differentiated T-cells may cause vascular damage, to the extent that therapies specifically targeting T-cells in advanced atherosclerosis are being developed.

Among activated CD4 T-cells, cardiologists are particularly interested in CD28null CD4 T-cells. These terminally differentiated effector cells do not express CD28, a co-stimulatory receptor molecule, which antigen-presenting cells engage during early T-cell activation. CD28null CD4 T-cells were initially discovered in rheumatoid arthritis, but later associated with unstable angina and coronary artery plaque instability. Multiple links between these cells and cardiovascular complications have since been reported. Down-regulation of CD28 on CD4 T-cells is thought to be triggered by continuous/repetitive antigen exposure, which could be the result of a persistent viral infection, for example with CMV.

CD28null CD4 T-cells accumulate in older people and show reduced proliferative capacity among many other signs of cellular senescence. Large frequencies of these cells are, therefore, primarily attributed to normal (immune system) aging. While an association of CMV infection with increased numbers of CD28null CD4 T-cells was repeatedly reported in the literature, this link is generally considered to be indirect and explained by the fact that older people are more likely to be CMV infected. Nobody has yet studied CD28null CD4 or CD8 T-cells in a large enough number of CMV-seronegative (CMV-) older people to resolve this issue. However, several smaller studies in the fields of autoimmune and cardiovascular disease offer some insight.

It was not the purpose of our work to show that CD28null CD4 T-cells are associated with cardiovascular (CV) morbidity or mortality, since there is overwhelming evidence for this association in the literature. Instead, we examined the frequencies of CD28null CD4 T-cells in 93 CMV- and 122 CMV+ generally healthy older people and a corresponding cohort of young people; CD28null CD8 T-cells were evaluated in parallel. Our investigation was focused on the intriguing possibility that, independently of aging, CMV infection is a major risk factor for the expansion of the highly pro-atherogenic CD28null CD4 T-cell subset.

Our results show that CMV infection is significantly associated with the accumulation of CD28null CD4 T-cells. Our data further suggest that CMV may directly drive this subset with a significant proportion of these cells recognizing CMV-antigens. The frequencies of CD28null CD4 T-cells were an order of magnitude higher in CMV+ compared to CMV- individuals, but only marginally affected by age. These observations seem to refute the idea that accumulation of CD28null CD4 T-cells is a result of normal immune system aging.

Link: https://doi.org/10.7150/thno.27428