Fight Aging! Newsletter, August 27th 2018

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.

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  • Inhibition of CDK4 Reverses Measures of Aging in the Liver
  • Additional Evidence to Demonstrate that Telomerase Gene Therapy Does Not Increase Cancer Risk in Mice
  • First Videos from the 2018 Ending Age-Related Diseases Conference
  • Clearing Senescent Cells from the Brain Reduces Tau Aggregation and Improves Function in Mouse Models of Alzheimer's Disease
  • The Many Successes in Mice that Fail to Translate to Human Medicine
  • Hormesis Produces Benefits via Altered Mitochondrial Activity
  • The Synapses of Some Individuals Appear Resilient to Age-Related Protein Aggregation
  • A Look at the Functional Decline of Smooth Muscle Cells in Aging Blood Vessels
  • Body Mass Index Correlates with Raised Blood Pressure
  • Scaffolds Protect Transplanted Stem Cells to Increase Therapeutic Benefit
  • The Antidepressant Fluoxetine Restores Some Lost Neuroplasticity in Old Mice
  • Four Immunotherapies Now Proven to Reduce Amyloid-β in the Aging Brain
  • The Blatant, Accepted Fraud of the "Anti-Aging" Marketplace Will Eventually Evaporate
  • A Review of the Effects of MitoQ on Biomarkers Related to Aging
  • Cell Reprogramming In Situ Generates Photoreceptor Cells to Treat Blindness in Mice

Inhibition of CDK4 Reverses Measures of Aging in the Liver

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.

Additional Evidence to Demonstrate that Telomerase Gene Therapy Does Not Increase Cancer Risk in Mice

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.

First Videos from the 2018 Ending Age-Related Diseases Conference

The Life Extension Advocacy Foundation volunteers hosted their first conference, Ending Age-Related Diseases 2018, in New York City a month ago. It was attended by a mix of advocates, scientists, entrepreneurs, and investors, all interested in seeing greater progress take place in the field of rejuvenation research. For those of us starting or running biotech companies to work on ways to treat aspects of aging, it was a good opportunity to network and make connections.

The presentations given at the conference were recorded, and are being tidied up and released for general viewing, as is the case for most of the conferences in our community. There was a greater emphasis on the business side of the house than usual at this event, and it is certainly the case that commercial biotechnology is becoming ever more important to efforts to treat aging as a medical condition. All of the fields of damage and damage repair described in the SENS rejuvenation research proposals are arguably at the stage where at least some part of the program might be commercially developed, given suitable levels of funding, or is being actively pursued by one or more companies.

Keith Comito at Ending Age-Related Diseases 2018 - One Second, One Life

Keith Comito, President of the Life Extension Advocacy Foundation and the crowdfunding platform, discusses the emerging longevity biotech landscape at the Ending Age-Related Diseases conference in NYC.

Dr. Aubrey de Grey at Ending Age-Related Diseases 2018 - Rejuvenation is Finally an Industry

Some people in our community make the mistake of jumping right into a conversation about repairing the damage of aging without considering if the listener has any prior knowledge of the subject. Dr. Aubrey de Grey begins, as all good speakers should, in a mixed audience of experienced hands and those totally new to the topic of aging, with the basics about aging and works towards more complex topics. If you're familiar with his work, you may wish to skip to around the 17:55 mark, where he talks about new developments in the field and topics you may not have heard before.

Steven A. Garan at Ending Age-Related Diseases 2018 - Silicon Valley's Role in Fighting Aging

Steven A. Garan is the Director of Bioinformatics at the Center for Research and Education on Aging (CREA) and a researcher at UC Berkeley National Laboratory. In his talk at Ending Age-Related Diseases, he discussed the impact of various present and future Silicon Valley technology breakthroughs on overcoming aging. He gave a somewhat future-facing talk at the conference, which may surprise some people given his senior position at Berkeley. Ten years ago, talking about ending aging would potentially have damaged your career and gotten you unfairly labeled as fringe, much as Dr. Aubrey de Grey was for many years until many others joined his crusade to end aging. It was therefore refreshing to hear Steven talk so positively about the future of biomedical science and about doing something about aging itself in order to end age-related diseases.

Kelsey Moody at Ending Age-Related Diseases 2018 - Antibody Mimetic for Parkinson's Disease

Kelsey Moody is a process-oriented biotechnology executive who has specialized in the study of aging and aging mechanisms for over a decade. Since 2013, he has successfully built Ichor Therapeutics from a living room start-up into a premier, vertically integrated contract research organization that focuses on preclinical research services for aging pathways. Proceeds from this work are used to self-fund initiatives that constitute Ichor's portfolio companies in enzyme therapy (Lysoclear), small molecule drug discovery (Antoxerene), and protein engineering (RecombiPure). In this talk, Kelsey discusses Ichor's protein engineering platform, how Ichor has used it, and Ichor's plans for using it to discover new classes of drugs for age-related diseases.

Clearing Senescent Cells from the Brain Reduces Tau Aggregation and Improves Function in Mouse Models of Alzheimer's Disease

Over the past few years researchers have demonstrated, numerous times, that using senolytic therapies to remove a significant fraction of senescent cells from old tissues in mice can reverse aspects of aging, successfully treat multiple age-related diseases that presently have no viable treatment options, and extend healthy life. In an exciting recent addition to this field of research, scientists used the dasatinib and quercetin combination in mouse models of Alzheimer's disease. The result is a restoration of function and a reduction of the characteristic tau aggregation that is a feature of this condition. The researchers in fact report that there is a two-way relationship between tau aggregation and cellular senescence: targeting either one reduces the other.

Even allowing for the fact that mouse models of Alzheimer's are highly artificial, as no such analogous condition naturally occurs in that species, this might be taken as good evidence for senescent cell accumulation to provide a meaningful contribution to neurodegeneration. Further, I think it important to note that the particular senolytics used here are very cheap. Dasatinib is a generic drug with years of human usage data resulting from the treatment of cancer, and can be obtained for a cost of 100-200 per senolytic dose from some sources. Add an equal amount to pay for validation of the identity of the ordered compound via mass spectroscopy. One dose every few years will probably be optimal for this class of drug; more frequent dosing likely wouldn't help much. These economics mean that self-experimentation with senolytics continues to look ever more like an interesting option, at least for those people willing to carefully think about the trade-off between risk and benefit, and accept responsibility for their actions.

In this context, here is an interesting question: given a working, first generation rejuvenation therapy that targets a fundamental cause of aging and is piling up considerable evidence for impressive across-the-board benefits in diseases of aging in animal studies, how long will it take the tens of millions of older people who could easily obtain and use dasatinib and quercetin to actually start obtaining and using these compounds in large numbers? I feel that the basis for some form of revolutionary change in the relationship between regulators and regulated is brewing. FDA functionaries are unlikely to allow widespread off-label use of dasatinib without a fight, but can any authority really stop a cheap, mass-produced compound from being widely available? History suggests no.

Stressed, toxic, zombie cells seen for 1st time in Alzheimer's

Cellular senescence is associated with harmful tau protein tangles that are a hallmark of 20 human brain diseases, including Alzheimer's and traumatic brain injury. Researchers have identified senescent cells in postmortem brain tissue from Alzheimer's patients and then found them in postmortem tissue from another brain disease, progressive supranuclear palsy. "When cells enter this stage, they change their genetic programming and become pro-inflammatory and toxic. Their existence means the death of surrounding tissue."

The team confirmed the discovery in four types of mice that model Alzheimer's disease. The researchers then used a combination of drugs to clear senescent cells from the brains of middle-aged Alzheimer's mice. The drugs are dasatinib, a chemotherapy medication that is U.S. Food and Drug Administration-approved to treat leukemia, and quercetin, a natural flavonoid compound found in fruits, vegetables, and some beverages such as tea.

After three months of treatment, the findings were exciting. "The mice were 20 months old and had advanced brain disease when we started the therapy. After clearing the senescent cells, we saw improvements in brain structure and function. This was observed on brain MRI studies and postmortem histology studies of cell structure. The treatment seems to have stopped the disease in its tracks. The fact we were able to treat very old mice and see improvement gives us hope that this treatment might work in human patients even after they exhibit symptoms of a brain disease."

In Alzheimer's disease, patient brain tissue accumulates tau protein tangles as well as another protein deposit called amyloid beta plaques. The team found that tau accumulation was responsible for cell senescence. Researchers compared Alzheimer's mice that had only tau tangles with mice that had only amyloid beta plaques. Senescence was identified only in the mice with tau tangles. In other studies to confirm this, reducing tau genetically also reduced senescence. The reverse also held true. Increasing tau genetically increased senescence. Importantly, the drug combination reduced not only cell senescence but also tau tangles in the Alzheimer's mice. This is a drug treatment that does not specifically target tau, but it effectively reduced the tangle pathology.

Tau protein aggregation is associated with cellular senescence in the brain

Tau protein accumulation is the most common pathology among degenerative brain diseases, including Alzheimer's disease (AD), progressive supranuclear palsy (PSP), traumatic brain injury (TBI) and over twenty others. Tau-containing neurofibrillary tangle (NFT) accumulation is the closest correlate with cognitive decline and cell loss, yet mechanisms mediating tau toxicity are poorly understood. NFT formation does not induce apoptosis, which suggests secondary mechanisms are driving toxicity. Transcriptomic analyses of NFT-containing neurons microdissected from postmortem AD brain revealed an expression profile consistent with cellular senescence. This complex stress response induces aberrant cell cycle activity, adaptations to maintain survival, cellular remodeling, and metabolic dysfunction.

Using four AD transgenic mouse models, we found that NFTs, but not amyloid-β plaques, display a senescence-like phenotype. Cdkn2a transcript level, a hallmark measure of senescence, directly correlated with brain atrophy and NFT burden in mice. This relationship extended to postmortem brain tissue from humans with PSP to indicate a phenomenon common to tau toxicity. Tau transgenic mice with late stage pathology were treated with senolytics to remove senescent cells. Despite the advanced age and disease progression, MRI brain imaging and histopathological analyses indicated a reduction in total NFT density, neuron loss, and ventricular enlargement. Collectively, these findings indicate a strong association between the presence of NFTs and cellular senescence in the brain, which contributes to neurodegeneration. Given the prevalence of tau protein deposition among neurodegenerative diseases, these findings have broad implications for understanding, and potentially treating, dozens of brain diseases.

The Many Successes in Mice that Fail to Translate to Human Medicine

There are many failures on the path from early study in cells to successful medical technology applied to humans. A success in cell cultures often turns out to be infeasible in animals, as cells in culture are not a part of a larger tissue and organism and thus not subject to the same signals, stresses, and influences. Work in organoids, tiny sections of living tissue, can certainly help to bridge this gap, but even an organoid that accurately reflects the structure and function of an organ is still not subject to the real ebb and flow of a living animal, all of the interactions with other tissues and systems.

Success in animal studies, usually carried out in mice, can fail in larger mammals for any number of reasons. While there are many similarities between mammals, there are just as many differences. The popular science article below focuses on the biochemical differences between species as a reason for the leap between mice and humans to fail so often. I think it overemphasizes the point, and fails to offer viable suggestions for an alternative. In the field of aging, I'd have to say that there are two important factors for a high failure rate, only one of which is really an issue of species differences, and both can be traced back to a poor high level strategy for the development of means to treat aging and age-related disease.

The first is that short-lived species exhibit vastly greater slowing of aging and life extension when stress response mechanisms are upregulated. So calorie restriction, increased autophagy, heat stress, and other hormetic effects produce sizable gains in life span, up to 40% or more in mice. Where direct comparisons can be made, we know that these methods produce no such result in humans. While beneficial for health, the existence of effect sizes of larger than five years of additional life is very implausible given the existing data. Yet members of the aging research community continue to put the majority of their effort into developing therapies that boost these stress responses. Results fail to translate because effect sizes in humans are much smaller and much less reliable, and clinical trials are looking for sizable, reliable outcomes.

The second issue is that most of the work on age-related conditions starts with the end stage disease state and works backward. Researchers end up trying to develop therapies based on manipulating proximate causes that are very late in the development of pathology, far removed from root causes. This tinkering with the operation of the disease state is far more vulnerable to small differences in cellular biochemistry between species, and tends to produce marginal results at the best of times. Small benefits based on tinkering with a complex, disarrayed biochemistry have a way of vanishing or becoming highly unreliable firstly in the move between species, and secondly in clinical trials once larger numbers of people and their individuals differences become involved. Again, this is a problem that exists because of the way in which research and development is conducted: it is the result of a poor choice of strategy.

The right approach to aging is to target and repair the known root causes. Many of these are the same in their important aspects in all mammals, such as the accumulation of senescent cells, or the class is the same and only the importance of different members of the class varies, such as accumulation of cross-links or lipofuscin, in which the specific molecules to target are different in mice and humans. Further, the effect sizes resulting from successfully reversing root causes of aging and age-related disease should be larger and more reliable in any species: it covers many downstream consequences, and even if those consequences are different in different species, they will still be reduced. This gives a greater expectation of success in future human clinical trials based on the existence of mouse data only.

Don't believe the mice

When you read that a lab animal with a human disease has been cured with a new drug candidate, do not get your hopes up. The stats for converting these successes into human patients are appalling. Results in animals are often the opposite of those seen in humans. For example: corticosteroids were shown to treat head injuries in animals, but then increase deaths in new-born babies in trials. This is a big deal. A staggering 95% of drugs tested in patients fail to reach the market, despite all the promising animal studies that precede their use in humans. "There are lots of reasons why, but in essence we are not 70 kilogram rats and we are not inbred strains."

Mice are the most popular lab animals, but their brains and biology are quite different from our own. Surprisingly, rats and mice predict each other for complex measures with only 60%. Different animals, different effects. Newspapers headlines heralding cures for Alzheimer's to autism, on the back of rodent studies, can be taken with a pinch of salt. Neurodegenerative disorders such as Alzheimer's were one of the first areas to turn against the animal models. "It was shown that the animal tests were misleading with respect to what is a cure and what is not." After hundreds of human trials for promising treatments for Alzheimer's, almost none helped patients. This is a colossal waste of money. Industry has noticed. "The pharma industry is now using about one-sixth the number of animals that they used in the past for drug studies. They go very late into these models."

One problem is that scientists often take a simple approach to mimicking a disease in mice, by just finding a gene that when knocked out stamps the mice with hallmarks of the human disease. This is how the first Alzheimer's disease mouse was created, but the animal did not reflect the true Alzheimer's condition of most patients. "Single gene mouse models are different from the illness that we experience in humans. This has been a failed strategy."

Sometimes scientists discover therapies to cure mice, but not people. The record for inflammatory disease is especially striking. More than 150 trials have tested agents to block inflammation in critically ill patients. The candidates worked in animals, but all failed in patients. With this in mind, researchers decided to compare how all genes in mice and all genes in people react when they encounter trauma, burns or bacterial toxins. There was almost no connection whatsoever. Mice genes did one thing; human genes did another.

Hormesis Produces Benefits via Altered Mitochondrial Activity

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.

The Synapses of Some Individuals Appear Resilient to Age-Related Protein Aggregation

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."

A Look at the Functional Decline of Smooth Muscle Cells in Aging Blood Vessels

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.

Body Mass Index Correlates with Raised Blood Pressure

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.

Scaffolds Protect Transplanted Stem Cells to Increase Therapeutic Benefit

One of the major areas of focus in regenerative research is finding ways to enhance the ability of transplanted cells to integrate with tissue, survive, and induce healing and growth. In early, first generation stem cell therapies, near all cells die quite quickly. The span of benefits that result is a reaction of native cells to the molecular signals briefly generated by the transplanted cells. The anti-inflammatory effects of mesenchymal stem cell therapies as presently practiced is a good example.

One way to improve cell survival is to build an artificial environment that to some degree mimics the extracellular matrix. Given that starting point, however, one can start adding additional features, such as molecular signals that enhance cell resilience, or structures that isolate cells for a time from hostile surroundings. Scaffolding materials are evolving to primarily provide protection for transplanted cells, rather than just a familiar three-dimensional structure.

A car accident leaves an aging patient with severe muscle injuries that won't heal. Treatment with muscle stem cells from a donor might restore damaged tissue, but doctors are unable to deliver them effectively. A new method may help change this. Researchers engineered a molecular matrix, a hydrogel, to deliver muscle stem cells called muscle satellite cells (MuSCs) directly to injured muscle tissue in patients whose muscles don't regenerate well. In lab experiments on mice, the hydrogel successfully delivered MuSCs to injured, aged muscle tissue to boost the healing process while protecting the stem cells from harsh immune reactions. The method was also successful in mice with a muscle tissue deficiency that emulated Duchenne muscular dystrophy.

Simply injecting additional muscle satellite cells into damaged, inflamed tissue has proven inefficient, in part because the stem cells encounter an immune system on the warpath. "Any muscle injury is going to attract immune cells. Typically, this would help muscle stem cells repair damage. But in aged or dystrophic muscles, immune cells lead to the release a lot of toxic chemicals like cytokines and free radicals that kill the new stem cells. "Our new hydrogel protects the stem cells, which multiply and thrive inside the matrix. The gel is applied to injured muscle, and the cells engraft onto the tissues and help them heal."

"Muscle satellite cells are resident stem cells in your skeletal muscles. They live on muscle strands like specks, and they're key players in making new muscle tissue. As we age, we lose muscle mass, and the number of satellite cells also decreases. The ones that are left get weaker. It's a double whammy. At a very advanced age, a patient stops regenerating muscle altogether. With this system we engineered, we think we can introduce donor cells to enhance the repair mechanism in injured older patients. We also want to get this to work in patients with Duchene muscular dystrophy."

The Antidepressant Fluoxetine Restores Some Lost Neuroplasticity in Old Mice

There is a fair amount of evidence in mice for antidepressants to work via increased plasticity in the brain. This means greater generation and integration of new neurons, and more restructuring of synaptic connections between neurons. In mice, plasticity is lost with age, and here researchers show that a commonly used antidepressant can restore some of that loss. It remains an interesting question as to how much of this mouse research does in fact translate to humans; of late the data regarding plasticity of the human brain has been mixed, suggesting that there may be significant differences between humans and mice in this matter.

In the study the researchers focused on the aging of inhibitory interneurons which is less well understood than that of excitatory neurons, but potentially more crucial to plasticity. The team counted and chronically tracked the structure of inhibitory interneurons in dozens of mice aged to 3, 6, 9, 12 and 18 months (mice are mature by 3 months, live for about 2 years, and 18-month-old mice are already considered quite old). Previous work has shown that inhibitory interneurons retain the ability to dynamically remodel into adulthood. But the team now shows that new growth and plasticity reaches a limit and progressively declines starting at about 6 months. The study also shows that as mice age there is no significant change in the number or variety of inhibitory cells in the brain.

While the decline of dynamic remodeling and plasticity appeared to be natural consequences of aging, they were not immutable, the researchers showed. Prior work had shown that fluoxetine promotes interneuron branch remodeling in young mice, so they decided to see whether it could do so for older mice and restore plasticity as well.

To test this, researchers put the drug in the drinking water of mice at various ages for various amounts of time. Three-month-old mice treated for three months showed little change in dendrite growth compared to untreated controls, but 25 percent of cells in six-month-old mice treated for three months showed significant new growth (at the age of 9 months). But among 3-month-old mice treated for six months, 67 percent of cells showed new growth by the age of 9 months, showing that treatment starting early and lasting for six months had the strongest effect.

"Our finding that fluoxetine treatment in aging mice can attenuate the concurrent age-related declines in interneuron structural and visual cortex functional plasticity suggests it could provide an important therapeutic approach towards mitigation of sensory and cognitive deficits associated with aging, provided it is initiated before severe network deterioration."

Four Immunotherapies Now Proven to Reduce Amyloid-β in the Aging Brain

Immunotherapies that target aggregation of amyloid-β in order to treat Alzheimer's disease have a long and expensive history of failure. The tide finally seems to be turning, however, with the advent of several treatments that can reduce amyloid-β levels without resulting in an unacceptable level of risk for the patients. This newfound incremental success is taking place at the same time as the years of frustration with the lack of progress have finally blossomed into a variety of alternative theories on the causes of Alzheimer's disease, such as blocked drainage of cerebrospinal fluid or persistent microbial infection, some of which have advanced to the point of development of therapies.

The challenge for amyloid-β clearance therapies is now to show benefits in patients, and there are good reasons to believe that this will be challenging in the late disease state. The present consensus on Alzheimer's disease is that amyloid-β accumulation is an early phase, damaging yes, but nowhere near as damaging as the tau aggregation that occurs later on. Further, Alzheimer's patients also tend to have other forms of neurodegeneration, such as vascular dementia, that are unlikely to be greatly affected by amyloid-β clearance. It is a challenging business: therapies for neurodegeneration will most likely have to tackle most or all of the important mechanisms in the aging brain in order to be reliably beneficial.

After years of fits and starts, anti-amyloid immunotherapies are finally hitting their target effectively. At least four drugs have now demonstrated the ability to clear plaques from the brain: aducanumab, gantenerumab, Lilly's LY3002813, and BAN2401. At the Alzheimer's Association International Conference, held in July, researchers presented new data from gantenerumab and LY3002813, aka N3pG. It clinched the case that these antibodies can mop up brain amyloid, bringing many people with early symptomatic Alzheimer's disease (AD) below the threshold for amyloid positivity. At one to two years, this clearance took a long time. But still: researchers claimed that two years of treatment with high-dose gantenerumab essentially resets a person's trajectory of amyloid accumulation. "We are setting back the clock by 15 years."

To achieve these rates of clearance, researchers have had to greatly boost antibody dose, in many cases quadrupling the amounts used in earlier, unsuccessful trials. These high doses bring a greater risk of infusion site reactions and ARIA-E, the occurrence of leaky blood vessels causing edema in the brain. Scientists argued that these side effects are manageable with careful monitoring of patients. Moreover, ARIA-E can be lessened by gradually titrating up the antibody dose. However, clinicians noted that the jury is still out on how much this will help AD patients. "Several of the antibodies are looking good at removing amyloid, but the clinical efficacy still needs to be demonstrated."

The Blatant, Accepted Fraud of the "Anti-Aging" Marketplace Will Eventually Evaporate

The existence of actual, working rejuvenation therapies will eventually chase out the fraud and lies from the "anti-aging" marketplace, and what will be left is just plain old medicine - but much better, more advanced medicine than we have today. This will take years, however, and the established hucksters will continue to have a fine old time on their way out. They will continue to cherry-pick studies, cloak the junk that doesn't work in a thin veneer of science, mimicking the voices and marketing of legitimate ventures. The basic lie that is loudly propagated by the "anti-aging" business, that their products can make a difference, has been spoken for so long that is accepted as a part of the tapestry of society. Few people can bring themselves to be irate about it these days. It is another part of the ridiculous nonsense that we are subjected to on a daily basis.

This does mean, however, that anyone entering the realm of longevity science, whether wanting to improve their health or make a difference in the pace of progress, is faced with a much tougher uphill battle than should be the case. How to distinguish the lies of the "anti-aging" marketplace from the real science given no background in the field? How to pick out research projects and classes of therapy with a high expectation value from those that are good science that cannot possibly greatly influence the aging process? For every advocate who tries to help by presenting a realistic view of the field, there are twenty paid shills out there trying to persuade the world that blueberries hold back aging, or that apple stem cells are medically useful - or whatever the product they are selling today might be, regardless of the facts.

Now that we are starting to see the arrival of actual therapies aimed at targeting the processes of aging directly in order to prevent age-related diseases, it has become easier to separate two very distinct groups.

The first group consists of the snake oil salesmen peddling unproven supplements and therapies to whoever is foolish enough to buy and take things on faith without using the scientific method. The hucksters have long been a plague on our field, preying on the gullible and tainting legitimate science with their charlatanry and nonsense. One example is the "biotech company" that makes bold claims yet never delivers on those claims in practice, offering data based on poorly designed experiments and tiny cohorts that are statistically irrelevant; another example is the supplement peddler selling expensive supplement blends with flashy names, which, on inspection, turn out to be commonly available herbs and minerals mixed and sold at a high markup. These sorts of people have plagued our community and given the field a reputation of snake oil.

The second group are the credible scientists, researchers, and companies who have been working on therapies for years and sometimes more than a decade. Many of these therapies are following the damage repair approach advocated by Dr. Aubrey de Grey of the SENS Research Foundation over a decade ago. The basic idea is to take an engineering approach to the damage that aging does to the body and to periodically repair that damage in order to keep its level below that which causes pathology. These therapies are now starting to arrive, with some already in human trials right now, and this marks a milestone in our field: the credible science has finally outstripped the snake oil, and the focus can move from pseudoscience to real, evidence-based science.

While it will be some years yet before all therapies to end age-related diseases are here and available, and the hucksters are still peddling their wares, you can arm yourself with knowledge and protect yourself and our community from these people. Learn to evaluate science rather than taking things at face value, and avoid expensive scams and bad science.

Was the claim first announced through mass media or through scientific channels? Are the claimants transparent about their testing, and is there sufficient published data for reproduction? A properly developed technology will take years of development to reach release; is there a clear paper trail of studies and clinical trials supporting it? How good is the quality of data supporting the claim, and is it of statistical significance? Are the claimants reputable, and are they published in credible journals? The snake oil sellers will be with us for a few years yet, but by working together as a community and thinking critically about claims, we can help filter these people out and ultimately clean up the field for the benefit of legitimate scientists working on the real solutions to aging that will benefit us all.

A Review of the Effects of MitoQ on Biomarkers Related to Aging

If you have been following the development of mitochondrially targeted antioxidants as a potential therapy to modestly slow aging, you might find this open access paper interesting. MitoQ is one of the readily available compounds, with SkQ1 as the other. My impression from the papers is that SkQ1 and closely related plastoquinones have a larger effect size on life span in animal studies, but it still isn't more than a fraction of that produced by calorie restriction.

Mitochondrially targeted antioxidants appear to function by improving mitochondrial metabolism, but the most medically relevant effect observed so far is their ability to dampen the consequences of inflammation, particularly in inflammatory eye conditions. Inflammation and excessive levels of oxidative molecules go hand in hand. This same underlying mechanism may allow these compounds to reduce stiffness of blood vessels in older individuals, by reducing the impact of inflammation and the aged tissue environment on smooth muscle cells responsible for contraction and dilation. A human trial of MitoQ produced interesting data on this front. The paper here looks at a broader range of biomarkers and outcomes.

The postulated relationship between cellular decline and reactive oxygen species (ROS) has been well explored in the free radical theory of aging, which suggests that human lifespan and degenerative disease are tied to the adverse effects of ROS on cell structure and function. Once produced, ROS react with lipids, proteins, and nucleic acids causing oxidative damage to these macromolecules, over time contributing to the aging process.

Mitochondria are among the most metabolically active organelles in the body and are a primary source of energy production and oxidative phosphorylation. Oxidative phosphorylation, a process in energy production, results in the production of ROS. As both the major producer and primary target of ROS, mitochondria are thought to play an important role in aging.

Generally speaking, decreasing the concentration of ROS and thereby potential damaging capabilities, it is hypothesised that the aging process can be delayed. This concept has inspired a host of nutraceuticals aimed at alleviating oxidative damage, particularly in the mitochondria. To decrease mitochondrial oxidative damage, a number of mitochondria-targeted antioxidants have been developed. One such mitochondria-targeted antioxidant is MitoQ.

This review has examined the effect of MitoQ on oxidative stress markers related to the aging process. Our findings indicate that MitoQ has a statistically significant reduction in concentrations of 3-NT, a biomarker of protein oxidation produced upon the nitration of protein residues, which alters protein structure and function. This is of interest as nitration of protein residues has been shown to inhibit enzyme catalytics, and so MitoQ may promote efficiency of cellular processes as well as help decrease the concentration of reactive oxygen species.

Mitochondrial membrane potential has been shown to significantly increase upon administration of MitoQ, suggesting an upregulation in the functioning capacity of mitochondria with supplementation. Mitochondrial membrane potential is commonly used as an indication of functional status. While decreased membrane potential (depolarization) indicates damaged, dysfunctional mitochondria that cannot meet cellular energy demands, increased membrane potential (hyperpolarization) suggests increased functional capacity and work conducted.

Cell Reprogramming In Situ Generates Photoreceptor Cells to Treat Blindness in Mice

In situ cell reprogramming is an interesting approach to the treatment of degenerative blindness conditions in which photoreceptor cells are lost, but the retinal structure is otherwise largely intact. A number of demonstrations have been carried out in the past five years, in cell cultures and in mice. Here is the latest example of this line of work, in which preliminary evidence indicates that some degree of vision is restored. It is of course not all that easy to determine the quality of vision obtained in mice though any successful therapy for blindness; light sensitivity is one thing, but what exactly do they see in this scenario? Those quantifying efforts still lie ahead.

In vertebrates, Müller glia cells are the most common type of non-neuronal cells found in the retina and provide structural and functional stability for photoreceptor rods and cones. In cold-blooded vertebrates, such as zebrafish, Müller glia act as retinal stem cells, multiplying after retinal injury and reprogramming themselves as photoreceptor cells to replace damaged ones. In mammals, however, Müller glia cells do not spontaneously reprogram themselves into stem cells and then photoreceptor cells to replace damaged ones after injury.

Based on the data in zebrafish and other nonmammalian species, researchers have been looking for the correct cocktail of gene products to coax Müller glia to revert to a stem-cell-like state and then differentiate into retinal cells in mammals. In this study, researchers reprogrammed Müller glia cells into rod photoreceptors in the retinas of uninjured mice, both in wildtype mice and in two strains that serve as models of congenital blindness. The team developed a two-step technique, first injecting an adeno-associated virus with a gene that expresses β-catenin, a protein that helps the glia re-enter the cell cycle, into the retinas of the four-week-old mice. Two weeks later, the mice received a second injection of an adeno-associated virus with the genes that express the transcription factors Otx2, Crx, and Nrl - shown in past studies to aid in the development of rod photoreceptors.

After the second injection, when Müller glia divided, one daughter cell became a rod photoreceptor while the other remained a Müller glia cell. The new rods produced proteins characteristic of the light-sensing retinal cells. Recording light responses from retinal ganglion cells in the retinas of mutant mice that got the gene therapy showed that some of the cells responded, whereas none of the cells responded in mutant mice that did not receive the treatment. The team also detected light responses in the primary visual cortex of the brains of the treated mutant mice but not in the same brain region of untreated blind mice.


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