Fight Aging! Newsletter, August 26th 2019

Every living organism lives in a permanent struggle with extrinsic and intrinsic agents that can damage it. Without its own repair mechanisms, life of living creatures would be extremely short, since the accumulation of harmful substances would damage the cellular elements, their function, which would ultimately result in damage to the various tissues and accelerated aging of the entire organism. Most of the aging definition involves a gradual, heterogeneous impair in the structure, function, and maintenance of repair systems of various organs and an increased inclination to various diseases. One could say that the age/aging phases are easy to recognize, but the mechanisms responsible for the aging process are difficult to define and harder to prove. Technological progress has established various methodological approaches to detect some cellular and molecular mechanisms associated with aging. Among others, scientists have focused recently on senescence (cellular aging, biological aging) mechanisms as one of the key factor in a complex aging process.

Aging is an intrinsic feature of all living beings. The complex process of biological aging is the result of genetic and, to a greater extent, environmental factors and time. It occurs heterogeneously across multiple cells and tissues. As the rate of aging is not the same in all humans, the biological age does not have to be in accordance with the chronological age. Many age-associated changes and hallmarks are evident in the human body. In the background of all the changes that occur during aging are three key factors - inflammation, immune aging, and senescence.

In order to examine why and how people become old with different rate, it is necessary to define the primary indicators/biomarkers of the healthy aging process. Only in this way it will be possible to distinguish the phenomenon of aging due to the processes caused by various diseases that are commonly associated with the aging process. In this sense, the scientific community is continually investing great efforts in discovering such biomarkers.

According to the American Federation for Aging Research recommendations, aging biomarkers should meet several criteria. They have to: 1. predict the rate of aging (correlate with aging); 2. monitor a basic process that underlies the aging process (determine "healthy aging", not the effects of disease); 3. be able to be tested repeatedly without harming the person; 4. be applicable to humans and animals. However, currently, there is no biomarker that would meet all of these criteria. Currently, due to the stated fact that many of the hallmarks of aging do not meet biomarker definition criteria, it may be better to use terms a) hallmarks of senescent cells or hallmarks of aging or b) possible biomarkers of senescence.

Thus in summary, there are currently no standardized biomarkers of cellular aging process or the healthy aging of the organism. Biomarkers described in literature do not meet all criteria of an ideal aging biomarker and actually represent various hallmarks of the aging process. Most biomarkers currently being examined as senescence or aging biomarkers are related to age-related illnesses rather than the process of healthy aging. As the effector mechanisms of senescence are neither necessarily specific to senescence nor present in all forms of senescence (the rate of senescence is not the same for all types of cells), the interpretation of existing biomarkers of senescence (for now the hallmarks or possible biomarkers) should be context dependent. Additionally, a combination of multiple biomarkers should be used.

Detection of biomarkers, in particular their quantification and validation, are necessary for understanding the senescence processes (diagnostic biomarkers), monitoring of the rate of senescence (prognostic and predictive biomarkers) and the possible use of appropriate therapy intervention (pharmacodynamic biomarkers). The discovery and selection of reliable biomarkers, and the use of reproducible methods could help to better understanding of complex web of senescence and aging processes, but it will also open some new questions. Despite new findings at the cellular and molecular level the understanding the aging process is still limited.

A growing number of scientists are questioning our basic conception of aging. What if you could challenge your death - or even prevent it altogether? What if the panoply of diseases that strike us in old age are symptoms, not causes? What would change if we classified aging itself as the disease? David Sinclair, a geneticist at Harvard Medical School, is one of those on the front line of this movement. Medicine, he argues, should view aging not as a natural consequence of growing older, but as a condition in and of itself. Old age, in his view, is simply a pathology - and, like all pathologies, can be successfully treated. If we labeled aging differently, it would give us a far greater ability to tackle it in itself, rather than just treating the diseases that accompany it.

It is a subtle shift, but one with big implications. How disease is classified and viewed by public health groups such as the World Health Organization (WHO) helps set priorities for governments and those who control funds. Regulators, including the US Food and Drug Administration (FDA), have strict rules that guide what conditions a drug can be licensed to act on, and so what conditions it can be prescribed and sold for. Today aging isn't on the list. Sinclair says it should be, because otherwise the massive investment needed to find ways to fend it off won't appear.

Reprogramming is a way to reset the body's so-called epigenetic marks: chemical switches in a cell that determine which of its genes are turned on and which are off. Erase these marks and a cell can forget if it was ever a skin or a bone cell, and revert to a much more primitive, embryonic state. The technique is frequently used by laboratories to manufacture stem cells. But Izpisúa Belmonte is in a vanguard of scientists who want to apply reprogramming to whole animals and, if they can control it precisely, to human bodies. Izpisúa Belmonte believes epigenetic reprogramming may prove to be an "elixir of life" that will extend human life span significantly.

James Clement, 63, is a spry man with a shaved head and clear eyes, who spends his days gulping vitamins and trying to figure out how to make people live longer, including himself, his parents, and even me. From a home and several outbuildings in Gainesville, Florida, Clement runs BetterHumans, which he calls the world's "first transhumanist research organization." With funds from wealthy elderly men he knows, he is independently exploring drugs known to extend the healthy life span of rodents. Using a calculator, he extrapolates what a suitable human dose might be, and then finds people who will take them.

Who wouldn't want to reach 110, if not 500? Unlike mere armchair futurists, the life extensionists are prepared to experiment on themselves, and others, using vitamins and prescription cancer drugs, as well as compounds available only by finagling them from chemical suppliers. Lately the idea of living longer, maybe a lot longer, seems more realistic. As biologists uncover the fundamental facts of life, even ivory-tower academics now claim they know what the molecular "hallmarks" of aging are. In their lab animals, at least - roundworms and white mice - they can regularly increase life spans by 20% or 30% and sometimes more.

Given these clues, Clement has financed and supervised four small studies, in volunteers, of treatments found to extend the healthy lives of rodents - the immune drug rapamycin, supplements that increase NAD+ levels, a combination of compounds that kill off senescent cells, and injections of plasma concentrated from umbilical cords. His aim is "to do as many small trials as possible" to generate and publish basic information on safety and possible benefits. With that, he says, people interested in life extension "can decide to take the risk."

The Decade of Healthy Ageing (2020-2030) is an opportunity to bring together governments, civil society, international agencies, professionals, academia, the media, and the private sector for ten years of concerted, catalytic and collaborative action to improve the lives of older people, their families, and the communities in which they live. Healthy ageing is the process of developing and maintaining the functional ability that enables wellbeing in older age. Functional ability is about having the capabilities that enable all people to be and do what they have reason to value.

Populations around the world are ageing at a faster pace than in the past and this demographic transition will have an impact on almost all aspects of society. The world has united around the 2030 Agenda for Sustainable Development: all countries and all stakeholders pledged that no one will be left behind and determined to ensure that every human being can fulfill their potential in dignity and equality and in a healthy environment. A decade of concerted global action on healthy ageing is urgently needed. Already, there are more than 1 billion people aged 60 years or older, with most living in low- and middle-income countries. Many do not have access to even the basic resources necessary for a life of meaning and of dignity. Many others confront multiple barriers that prevent their full participation in society.

The extent of the beneficial opportunities that arise from increasing longevity will depend heavily on one key factor: health. If people are experiencing these extra years of life in good health, their ability to do the things they value will be little different from that of a younger person. If these added years are dominated by poor health, the implications for older people and for society are much more negative.

Poor health does not need to dominate older age. Most health problems confronting older people are associated with chronic conditions, particularly noncommunicable diseases. Many can be prevented or delayed by engaging in healthy behaviours such as not smoking and drinking, eating well and undertaking regular physical activity. Even for people with declines in capacity, supportive environments can ensure that they live lives of dignity and continued personal growth. Healthy ageing can be a reality for all.

We certainly welcome WHO's vision of the world in which all people can live longer and healthier lives. However, the Zero draft does not address sufficiently "Strategic objective 5: Improving measurement, monitoring and research on Healthy Ageing" of the WHO's Global strategy and action plan on ageing and health. Regarding the Zero draft for the Decade of Healthy Ageing from June 12, 2019, its section 4.4 "Fostering research and innovation" should be significantly strengthened with biomedical and clinical research agenda. In fact, a separate section should be developed on biomedical research and innovation on ageing.

Research and development in the areas of biological ageing and ageing-related disease is the major long-term strategy to improve health and the quality of life in older ages. Therefore, the work and cooperation in the area of biomedical and clinical research in ageing and ageing-related diseases by the WHO, the WHO parties, and non-governmental stakeholders' should be explicitly stated as an agenda item for the Decade of Healthy Ageing. There is a growing body of consensus about the need to include research and development for healthy longevity as a part of the global WHO agenda. Aging health and R&D for healthy longevity must be included into the WHO Work Program.

Senolytics, NAD+ restoration, lipid replacement, decalcification, mTOR modulation, geroprotectors ... - the first generation of human rejuvenation therapies is available today. However, the field is still very young and the information often spotty. New therapies are emerging, and existing ones are updated or replaced. Many of us can not or do not want to wait for decades until we have all the knowledge, perfect therapies and a lifetime of experience on how to implement such therapies. To take advantage of this exciting development right now, we need to navigate this time of transition and make very personal decisions about which treatments to apply and when. Arming ourselves with the best knowledge about therapeutic options is vital.

To rise to this challenge, we have created our Rejuvenation Now initiative to: (a) continuously identify potential new rejuvenation therapies; (b) systematically evaluate new and existing therapies on their benefits, risks, procedures and potential application; (c) evaluate providers for specialized therapies (such as stem cell treatments); (d) freely share our evaluations, protocols, and learnings. The initiative is set up as an international collaboration of scientists and doctors in combination with the team we are building at our foundation's headquarters.

This analysis of NAD+ restoration therapy is part of Forever Healthy's Rejuvenation Now initiative that seeks to continuously identify new therapies and systematically evaluate them on their risks, benefits, procedures and potential application. NAD+ is a pyridine nucleotide found in all living cells. It plays an important role in energy metabolism and is a substrate for several enzymes (including those involved in DNA repair). NAD+ levels may decline markedly with age and restoring those levels to a youthful state is believed to have beneficial effects on health and longevity.

Restoration of NAD+ levels has been shown to have beneficial effects on several organ systems and diseases with an excellent acute toxicity profile. The main benefits are in diseases or conditions that threaten the energetic status of the cell such as ischemic stroke, heart failure/infarction, and mitochondrial diseases. The highest level of evidence for NAD+ restoration therapy in humans is for skin diseases. There is a multitude of potential benefits for which the evidence level is still quite low because of the lack of clinical trials.

The major risks are related to tumorigenesis, the buildup of metabolites with undesirable effects, and an increase in the proinflammatory senescence-associated secretory phenotype of senescent cells. These have not appeared in clinical trials to date but have been identified during mammalian preclinical trials. More clinical trials are necessary to adequately assess the risk of long term NAD+ supplementation. Short and medium-term supplementation (up to twelve weeks) with NR elevates NAD+ levels safely and effectively but there is a lack of studies examining the potential adverse health effects of chronic, year-long NAD+ supplementation.

In 2012, a paper entitled "Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity" turned everything upside down. Data were misinterpreted to indicate rapamycin causes diabetes. Because the paper was published in a high profile journal, basic researchers believe that rapamycin is harmful and causes diabetes, which prompted calls for development of rapamycin-like drugs without rapamycin effects. In fact, however, this paper does not show that rapamycin causes type 2 diabetes; it shows that prolonged treatment with rapamycin causes glucose intolerance and insulin resistance in mice, which is in agreement with earlier studies. Furthermore, the study showed that these metabolic alterations were associated with increased longevity, indicating better health.

In humans, diagnosis of diabetes depends on the arbitrary choice of a threshold for fasting blood glucose: it was 140 mg/dl before 1997 and 126 mg/dl after 1997. But what is the arbitrary diagnostic threshold in mice? It is not defined. Is the slight increase in fasting glucose sufficient for a "diagnosis" of diabetes in mice? Does such hyperglycemia decrease life span or cause nephropathy? It does not. As we will discuss next, similar glucose intolerance and insulin resistance can also be caused by prolonged fasting and extreme very low calorie diet (VLCD). Prolonged fasting and starvation cause a condition well known in the past but unknown to modern researchers: starvation pseudo-diabetes.

During starvation or prolonged fasting, glucose utilization by nonbrain tissues is inhibited in order to feed the brain. Prolonged fasting is characterized by low insulin levels, gluconeogenesis, lipolysis, ketogenesis, and ketosis (ketone bodies in the blood), glucose intolerance, and hepatic resistance to insulin. When a starved animal is fed with glucose, it cannot utilize the glucose (glucose intolerance), leading to transient glycosuria (glucose in the urine) and polyuria (high urine volume).

Given that rapamycin is a starvation- or CR-mimetic, its metabolic effects can be viewed as "starvation-mimicking side effects." I advance the hypothesis that in animals (and humans) rapamycin can cause a reversible and benevolent condition, identical to starvation pseudo-diabetes. If so, this condition may, in theory, prevent development of genuine type 2 diabetes and its complications. For example, rapamycin prevents diabetic nephropathy. The results of recent studies are consistent with the idea that rapamycin-induced metabolic alterations are reversible and beneficial in nature. Hyperglycemia may be a marker of beneficial processes, given that rapamycin ameliorates nephropathy, despite elevating blood glucose levels in a mouse model of type 2 diabetes.

The notion of benevolent insulin resistance also resolves the insulin resistance paradox; that is, insulin resistance is associated with both decreased or increased life span. Insulin resistance due to activation of mTOR shortens life span, whereas insulin resistance due to inhibition of mTOR increases life span. Simply stated, insulin resistance associated with TOR overactivation is bad, but insulin resistance associated with inactive TOR is good. This is the mTOR-centric view on glucose metabolism. Detrimental metabolic alterations should have detrimental consequences, such as diabetic complications, but there is no evidence that rapamycin-induced glucose intolerance is detrimental. On the contrary, rapamycin improves nephropathy in diabetic mice, despite increasing blood glucose levels.

Researchers examined 317 participants enrolled in the Wisconsin Registry for Alzheimer's Prevention, an ongoing observational study of more than 1,500 people with a history of parents with probable Alzheimer's dementia. Registrants were cognitively healthy and between the ages of 40 and 65 years at the time of enrollment. Participation in the registry included an initial assessment of biological, health and lifestyle factors associated with the disease and follow-up assessments every two to four years.

All participants completed a questionnaire about their physical activity and underwent neuropsychological testing and brain scans to measure several biomarkers associated with Alzheimer's disease. The researchers compared data from individuals younger than 60 years with older adults and found a decrease in cognitive abilities as well as an increase in biomarkers associated with the disease in the older individuals. However, the effects were significantly weaker in older adults who reported engaging in the equivalent of at least 30 minutes of moderate exercise five days a week.

In another study, researchers studied 95 people, also from the registry, who were given scores called polygenic risk scores, based on whether they possessed certain genetic variants associated with Alzheimer's. Similar to the previous research, the researchers also looked at how biomarkers changed with genetic risk and what role, if any, aerobic fitness might play. Not surprisingly, people with higher risk scores also showed increased biomarkers for the disease. Again, the researchers found that the effect was weaker in people with greater aerobic fitness, a score incorporating age, sex, body mass index, resting heart rate, and self-reported physical activity.

A third study examined MRIs from 107 individuals from the registry who were asked to run on a treadmill to determine their oxygen uptake efficiency slope, a measure of aerobic fitness. In line with previous studies, the researchers again found that an indicator of Alzheimer's disease, known as white matter hyperintensities, significantly increased in the brain with age, but not so much in participants with high levels of aerobic fitness.

Human average life expectancy in developed countries has increased dramatically in the last century, a phenomenon which is potentially accompanied by a significant rise in multi-morbidity and frailty among older individuals. Nevertheless, some individuals appear someway resistant to causes of death, such as cancer and heart disease, compared with the rest of the population, and are able to reach very old ages in good clinical conditions, while others are not. Thus, during the last two decades we have witnessed an increase in the number of studies on biological and molecular factors associated with the variation in healthy aging and longevity.

Several lines of evidence support the genetic basis of longevity: from the species-specific maximum lifespan to the genetically determined premature aging syndromes. Studies in human twins, that aimed to distinguish the genetic from the environmental component, highlighted a heritability of life span close to 25%. In centenarians' families, the offspring of long-lived individuals not only exhibit a survival advantage compared to their peers, but also have a lower incidence of age-related diseases. On the other hand, population studies found that genetic factors influence longevity in age- and sex-specific ways, with a most pronounced effect at advanced age and possibly in men compared to women. All this evidence indicates that a genetic influence on longevity exists, laying the foundation for the search for the genetic components of extreme long life.

Consequently, over the past three decades, there has been a surge in genetic research, due in part to advances in molecular technologies, starting as studies of single genetic variants in candidate genes and pathways, moving on to array-based genome-wide association studies (GWAS) and subsequently to next generation sequencing (NGS). However, despite a plethora of studies, only few variants (in the APOE, FOXO3A, and 5q33.3 loci) have been successfully replicated in different ethnic groups and the emerging picture is complex.

For instance, it is an understatement to think that long-lived people harbor only favorable variants, completely avoiding risk alleles for major age-related diseases; indeed, there is evidence that many disease alleles are present in long-lived people. It is more probable that the longevity phenotype is the result of a particular combination of pro-longevity variants and risk alleles for pathologies, likely interacting in networks in a sex- and age-specific way. Finally, characteristics of aging are extremely heterogeneous, even among long-lived individuals, due to the complex interaction among genetic factors, environment, lifestyle, culture and resiliency. Population and study specificity, lack of statistical power for such a rather rare phenotype and missing heritability represent further hard obstacles to overcome in genotype-phenotype association studies. Thus, many challenges remain to be addressed in the search for the genetic components of human longevity.

Juvenescence, a life sciences company utilising expert drug developers and artificial intelligence experts to create therapeutics and technologies to treat diseases of aging and to increase human longevity, is pleased to announce the successful closure of its 100 million Series B round, including a total of 10 million from its founders and a further 10 million each from four cornerstone investors, including Grok Ventures, the investment company of Mike Cannon-Brookes (Atlassian cofounder), and Michael Spencer's private investment company, IPGL. This brings the total to 165 million that Juvenescence has raised in 18 months and speaks to the extraordinary opportunity as well as interest in developing therapeutics with the capacity to modify aging.

Juvenescence is creating a longevity ecosystem, with world class scientists, seasoned drug developers, machine learning experts and a strong team with financial acumen to navigate this emerging new biotech growth sector and to develop 12 therapeutic candidates within the field of healthy aging. "This has been such an exciting six months for Juvenescence. We have been able to add extraordinary people to the Juvenescence team who will bring our age modifying therapeutics to market. We have also augmented our team working on using machine learning for drug discovery and for drug development: culminating with closing on this 100 million Series B financing which provides us with sufficient working capital to progress many of our programs to their initial inflection points".

Amyloid-β plaques, the protein aggregates that form in the brains of Alzheimer's patients, disrupt many brain functions and can kill neurons. They can also damage the blood-brain barrier - the normally tight border that prevents harmful molecules in the bloodstream from entering the brain. Researchers have now developed a tissue model that mimics the effects of amyloid-β on the blood-brain barrier, and used it to show that this damage can lead molecules such as thrombin, a clotting factor normally found in the bloodstream, to enter the brain and cause additional damage to Alzheimer's neurons. "We were able to show clearly in this model that the amyloid-β secreted by Alzheimer's disease cells can actually impair barrier function, and once that is impaired, factors are secreted into the brain tissue that can have adverse effects on neuron health."

The blood vessel cells that make up the blood-brain barrier have many specialized proteins that help them to form tight junctions - cellular structures that act as a strong seal between cells. Alzheimer's patients often experience damage to brain blood vessels caused by amyloid-β proteins, an effect known as cerebral amyloid angiopathy (CAA). It is believed that this damage allows harmful molecules to get into the brain more easily.

Researchers decided to study this phenomenon, and its role in Alzheimer's, by modeling brain and blood vessel tissue on a microfluidic chip. They engineered neurons to produce large amounts of amyloid-β proteins, just like the brain cells of Alzheimer's patients. The researchers then devised a way to grow these cells in a microfluidic channel, where they produce and secrete amyloid-β protein. On the same chip, in a parallel channel, the researchers grew brain endothelial cells, which are the cells that form the blood-brain barrier. An empty channel separated the two channels while each tissue type developed.

After 10 days of cell growth, the researchers added collagen to the central channel separating the two tissue types, which allowed molecules to diffuse from one channel to the other. They found that within three to six days, amyloid-β proteins secreted by the neurons began to accumulate in the endothelial tissue, which led the cells to become leakier. These cells also showed a decline in proteins that form tight junctions, and an increase in enzymes that break down the extracellular matrix that normally surrounds and supports blood vessels. As a result of this breakdown in the blood-brain barrier, thrombin was able to pass from blood flowing through the leaky vessels into the Alzheimer's neurons. Excessive levels of thrombin can harm neurons and lead to cell death.

Throughout history, humankind has been preoccupied with longevity, death, and immortality, as evidenced by the first known epic, describing Gilgamesh's futile quest for immortality. Death due to old age, however, appears to be rather rare in nature, as most species are confronted with various extrinsic sources of mortality, including predation, malnutrition, and life-threatening temperatures, all of which can limit the life span of individuals in their natural habitats. The vastly different life spans among closely related species were selected mainly via pressure exerted by extrinsic mortality risks that had to be balanced with the need for successful offspring generation. Some trees may persist thousands of years, whereas some insect species live for only a few days and other species, such as the small freshwater animal hydra, are thought to live indefinitely.

Over the past three decades, environmental and metabolic factors as well as evolutionarily conserved pathways that influence life span have been identified. Examples include several stress factors that, in excess, can negatively affect life span but that, in moderation, can trigger protective responses that lead to life span extension in a process called hormesis. For example, DNA damage is thought to accumulate in tissues during aging. DNA damage drives the aging process via mechanisms ranging from interference with replication and transcription to the DNA damage response (DDR) that triggers apoptosis and cellular senescence. A similar relationship can be observed regarding the nutritional state of animals, as severe nutrient and energy limitation can lead to death; however, calorie restriction (CR) or intermittent fasting has positive effects on life span in several model organisms, and modulation of metabolic parameters in a 2-year human trial showed potential benefits.

The immune system is an important regulator that not only profoundly influences life span directly by preventing premature death due to infections but also protects organisms via cancer surveillance and removal of senescent cells. While the prowess of the immune system fades during aging through a process called immunosenescence, nuclear DNA damage, accumulating extranuclear DNA, and senescent cells fuel inflammation. Targeting senescent cells has shown positive effects on immune function in mice and therefore appears to be a promising field of research to improve tissue aging in the elderly, including attempts to re-establish a balanced output of aging HSCs to regenerate lymphopoiesis during aging. In contrast, the senescence program might protect cells from transforming into cancer cells and has been implicated in tissue regeneration after skin injury. Together, these observations indicate that senescent cells serve dual roles in influencing life span: pro-longevity tumor suppression and tissue repair versus involvement in pro-aging inflammatory reactions.

Plaques and tangles have so far been the focus of attention in Alzheimer's disease. Plaques, deposits of a protein fragment called beta-amyloid, look like clumps in the spaces between neurons. Tangles, twisted fibers of tau, another protein, look like bundles of fibers that build up inside cells. "The dominant theory based on beta-amyloid buildup has been around for decades, and dozens of clinical trials based on that theory have been attempted, but all have failed. In addition to plaques, lysosomal storage is observed in brains of people who have Alzheimer's disease. Neurons - fragile cells that do not undergo cell division - are susceptible to lysosomal problems, specifically, lysosomal storage, which we report is a likely cause of Alzheimer's disease."

An organelle within the cell, the lysosome serves as the cell's trashcan. Old proteins and lipids get sent to the lysosome to be broken down to their building blocks, which are then shipped back out to the cell to be built into new proteins and lipids. To maintain functionality, the synthesis of proteins is balanced by the degradation of proteins. The lysosome, however, has a weakness: If what enters does not get broken down into little pieces, then those pieces also can't leave the lysosome. The cell decides the lysosome is not working and "stores" it, meaning the cell pushes the lysosome to the side and proceeds to make a new one. If the new lysosome also fails, the process is repeated, resulting in lysosome storage.

"The brains of people who have lysosomal storage disorder, another well-studied disease, and the brains of people who have Alzheimer's disease are similar in terms of lysosomal storage. But lysosomal storage disorder symptoms show up within a few weeks after birth and are often fatal within a couple of years. Alzheimer's disease occurs much later in life. The time frames are, therefore, very different." Researchers posit that long-lived proteins, including beta-amyloid and tau, can undergo spontaneous modifications that can make them undigestible by the lysosomes. The changes occur in the fundamental structure of the amino acids that make up the proteins and are the equivalent of flipping the handedness of the amino acids, with amino acids spontaneously acquiring the mirror images of their original structures.

"Enzymes that ordinarily break down the protein are then not able to do so because they are unable to latch onto the protein. It's like trying to fit a left-handed glove on your right hand. We show in our paper that this structural modification can happen in beta-amyloid and tau, proteins relevant to Alzheimer's disease. These proteins undergo this chemistry that is almost invisible, which may explain why researchers have not paid attention to it. It's been long known that these modifications happen in long-lived proteins, but no one has ever looked at whether these modifications could prevent the lysosomes from being able to break down the proteins. One way to prevent this would be to recycle the proteins so that they are not sitting around long enough to go through these chemical modifications."

It is commonly accepted that neurons of the central nervous system shut down their ability to grow when they no longer need it; this occurs normally after they have found their target cells and established synapses. However, recent findings show that old nerve cells have the potential to regrow and to repair damage similar to young neurons. "Actually, this is quite surprising. It is by no means a matter of course that young and adult nerve cells share the same mechanisms. Neurons show vigorous growth during embryonic development. Mature nerve cells, on the other hand, usually do not grow and fail to regenerate. Our study now reveals that although the ability to grow is inhibited in adult cells, the neurons keep the disposition for growth and regeneration."

Neurons only show their growth talent during embryonic development. At this stage, they form long projections called axons in order to connect and thus transmit signals. However, the ability to grow and thus regrow after injury dwindles when the nervous system reaches the adult stage. Only neurons of the periphery, e. g. those in the arms and legs, retain a pronounced potential for mending damaged connections. However, if axons in the spinal cord are severed, they do not regrow. Consequently, the pathway for nerve impulses remains disturbed.

In recent years scientists identified various factors that influence the growth of neurons. Certain proteins - those of the cofilin/ADF family - proved to play a pivotal role. During embryonic development, these molecules control the formation of cell protuberances that ultimately evolve into axons. The scientists found that the growth and regrowth of neurons is fueled by the turnover of actin filaments. These string shaped molecules belong to the molecular scaffold that gives the cell its form and stability. The proteins of the cofilin/ADF family partially dissolve this corset. It is only through this breakup that the structure of the cell can change - and thus the neuron can grow and regenerate. "In our recent study, we found that it is precisely these proteins that drive growth and regeneration, also in adult neurons. An approach for future regenerative interventions could be to target actin."

In a study that spanned two and a half decades and looked at data from more than 4,700 participants, researchers have added to evidence that abnormal blood pressure in midlife persisting into late life increases the likelihood of developing dementia. Although not designed to show cause and effect, the study suggests that maintaining a healthy blood pressure throughout life may be one way to help decrease one's risk of losing brain function. In their study, they found that those people with the high blood pressure condition hypertension during middle age and during late life were 49% more likely to develop dementia than those with normal blood pressure at both times. But, putting one at even greater risk was having hypertension in middle age and then having low blood pressure in late life, which increased one's dementia risk by 62%.

High blood pressure was considered any measurement more than 140/90 millimeters of mercury, whereas low blood pressure was defined as less than 90/60 millimeters of mercury. A cognitive exam, caregiver reports, hospitalization discharge codes, and death certificates were used to classify participant brain function and determine cognitive impairment. High blood pressure can be genetic, but can also be the result of not enough exercise and poor diet. As people age, the top blood pressure number (systolic) oftentimes increases while the bottom number (diastolic) can decrease due to structural changes in the blood vessels. Dementia itself may lead to a lowering of blood pressure, as it may disrupt the brain's autonomic nervous system. Further, stiffening of the arteries from disease and physical frailty can also lead to low blood pressure in late life.

In 2006, researchers reported for the first time the reprogramming of induced pluripotent stem cells (iPSC) from mouse somatic cells by forced expression of the transcription factors Oct4, Sox2, Klf4, and c-Myc, now termed Yamanaka factors. Subsequently, the Yamanaka factors, or other combinations of factors were successfully used to reprogram a wide range of mouse or human somatic cells into iPSC. iPSC achieve a high degree of dedifferentiation and acquire properties similar to those of embryonic stem cells (ESC). Indeed, iPSC and ESC are morphologically indistinguishable, and in vitro these cells have the potential to differentiate into cells of the three germ layers (ectoderm, endoderm, and mesoderm) and to originate virtually all cells of adult organisms.

Work by many researchers worldwide has led to the understanding of the molecular bases and to the improvement of the cell reprogramming process, bringing iPSC closer to safe clinical applications. However, the full translational potential of iPSC is still hampered by flaws, such as the inefficiency and the frequent incomplete reprogramming of the cells, and de novo mutations occurring during the reprogramming process and during the cultivation of generated iPSC. The efficiency to reprogram somatic cells into iPSC remains low (often much less than 1%), and likely further decline in aged cells or in cells with a high number of divisions.

An interesting concept of cell-aging reversion in vivo