Fight Aging! Newsletter, August 14th 2017

Researchers have discovered that defects in the transport of lysosomes within neurons promote the buildup of protein aggregates in the brains of mice with Alzheimer's disease. The study suggests that developing ways to restore lysosome transport could represent a new therapeutic approach to treating the neurodegenerative disorder. A characteristic feature of Alzheimer's disease is the formation of amyloid plaques inside the brain. The plaques consist of extracellular aggregates of a toxic protein fragment called β-amyloid surrounded by numerous swollen axons, the parts of neurons that conduct electric impulses to other nerve cells.

These axonal swellings are packed with lysosomes, cellular garbage disposal units that degrade old or damaged components of the cell. In neurons, lysosomes are thought to "mature" as they are transported from the ends of axons to the neuronal cell body, gradually acquiring the ability to degrade their cargo. The lysosomes that get stuck and accumulate inside the axonal swellings associated with amyloid plaques fail to properly mature, but how these lysosomes contribute to the development of Alzheimer's disease is unclear. One possibility is that they promote the buildup of β-amyloid because some of the enzymes that generate β-amyloid by cleaving a protein called amyloid precursor protein (APP) accumulate in the swellings with the immature lysosomes.

Researchers investigated this possibility by impeding the transport of lysosomes in mouse neurons. The researchers found that neurons lacking a protein called JIP3 failed to transport lysosomes from axons to the cell body, leading to the accumulation of lysosomes in axonal swellings similar to those seen in Alzheimer's disease patients. The swellings also accumulated APP and two enzymes - called BACE1 and presenilin 2 - that cleave it to generate β-amyloid. Neurons lacking JIP3 therefore generated increased amounts of β-amyloid. The researchers then removed one copy of the gene encoding JIP3 - halving the amount of JIP3 protein - from mice that were already prone to developing Alzheimer's disease. These animals produced more β-amyloid and formed larger amyloid plaques, surrounded by an increased number of swollen axons. "Collectively, our results indicate that the axonal accumulations of lysosomes at amyloid plaques are not innocent bystanders but rather are important contributors to APP processing and amyloid plaque growth."

Amyloid plaques, a defining feature of Alzheimer's disease (AD) brain pathology, have long been recognized to contain an extracellular aggregate of the β-amyloid peptide that is surrounded by microglia and an abundance of swollen axons. These axons contain a massive accumulation of organelles that resemble lysosomes and/or hybrid organelles arising from the fusion of lysosomes with late endosomes and autophagosomes (subsequently referred to as lysosomes for simplicity). Despite their long-known and robust occurrence, the disease relevance of these lysosome-filled axonal swellings has not been established.

The high abundance of lysosomes within axonal swellings at amyloid plaques and their potential role as sites of APP processing raise questions concerning the fundamental mechanisms that govern axonal lysosome abundance. Multiple studies have identified late endosomes and autophagosomes within distal regions of axons that likely play key housekeeping functions by sequestering old or damaged proteins and organelles. However, to degrade and recycle their contents, these organelles must acquire lysosomal properties such as hydrolytic enzymes and a highly acidic lumen. To this end, these organelles are thought to undergo a maturation process within axons that is coupled with their retrograde axonal transport toward the neuronal cell body.

To test the contribution of axonal lysosomes to amyloid plaque pathology, we first sought to develop a genetic strategy to perturb axonal lysosome abundance. To this end, we identified an important role for mouse JNK-interacting protein 3 (JIP3) in regulating the abundance and maturation state of axonal lysosomes. Of particular interest, immature lysosomes accumulated in the axons of JIP3 knockout (KO) neurons in a manner that recapitulated the key molecular and morphological properties of plaque-proximal axonal lysosomes in AD, including the buildup of APP-processing machinery. Such changes in the abundance and/or localization of APP-processing proteins were accompanied by increased β-amyloid peptide production. We then tested the in vivo effect of depleting JIP3 in a mouse model of AD and found a dramatic worsening in the severity of amyloid plaque pathology. These observations support a model wherein the accumulation of lysosomes within local axonal swellings at plaques actively contributes to APP processing and plaque development and suggest that restoration of normal axonal lysosome transport and maturation could help to suppress the development and progression of AD brain pathology.

Researchers have discovered that a protein called cardiotrophin 1 (CT1) can trick the heart into growing in a healthy way and pumping more blood. They show that this good kind of heart growth is very different from the harmful enlargement of the heart that occurs during heart failure. They also show that CT1 can repair heart damage and improve blood flow in animal models of heart failure. "When part of the heart dies, the remaining muscles try to adapt by getting bigger, but this happens in a dysfunctional way and it doesn't actually help the heart pump more blood. We found that CT1 causes heart muscles to grow in a more healthy way and it also stimulates blood vessel growth in the heart. This actually increases the heart's ability to pump blood, just like what you would see with exercise and pregnancy."

Heart muscle cells treated with CT-1 become longer, healthier fibres. CT-1 causes blood vessels to grow alongside the new heart muscle tissue and increases the heart's ability to pump blood. When CT-1 treatment stops, the heart goes back to its original condition, just like it does when exercise or pregnancy end. CT-1 dramatically improves heart function in two animal models of heart failure - one caused by a heart attack (affecting the left side of the heart) and one caused by high blood pressure in the lungs (pulmonary hypertension, affecting the right side of the heart). CT-1 stimulates heart muscle growth through a molecular pathway that has traditionally been associated with promoting cell suicide (apoptosis), but CT-1 has a better ability to control this pathway.

The researchers note that while exercise could theoretically have the same benefits as CT-1, people with heart failure are usually limited in their ability to exercise. The researchers have patents pending for the use of CT-1 to treat heart conditions and they hope to develop partnerships to test this protein in patients. If this testing is successful it will take a number of years for the treatment to become widely available.

Heart muscle growth, commonly referred to as cardiac hypertrophy, is a compensatory response that matches organ size to the systemic demands of the body. Hypertrophy can be a detrimental or beneficial adaptation, depending on the type of growth that occurs. In pathologic hypertrophy, heart muscle mass increases (wall thickness) without a corresponding improvement in function. Pathologic hypertrophy is generally irreversible and readily transitions to heart failure (HF), making this maladaptive process a leading cause of morbidity and mortality. Given the prominence in disease etiology, the biochemical and molecular characteristics of pathologic hypertrophy have been intensely studied and documented.

Physiologic cardiac hypertrophy is a form of beneficial remodeling, characterized by a modest increase in heart mass with improved contractile function that is reversible. Both pregnancy and endurance exercise provide well-documented means to engage this form of organ growth, a response that can also directly antagonize pathologic hypertrophy and the progression to heart failure. Akt- and MAPK-mediated signaling cascades appear to be consistent molecular signatures of physiologic hypertrophy, yet there is a paucity of definitive information regarding systemic factors that may initiate or propagate this healthy remodeling event. Insulin-like growth factor has been examined as a probable physiologic hypertrophy agonist, yet the pleiotrophic effects of this hormone may preclude its use as a bona fide cardiac restoration agent.

Cardiotrophin 1 (CT1) was originally identified as a promising hypertrophic agonist in vitro, however its expression has been more recently linked to myocardial pathology, systemic elevated blood pressure, and cardiac failure in both animals and humans. Despite these observational data implicating CT1 in certain cardiovascular diseases, this cytokine is known to bind and engage gp130 receptor complexes, a known pro-survival signal for cardiomyocytes. Therefore, we reasoned that elevated expression of CT1 in human cardiac pathologies may simply reflect a compensatory response, which attempts to curtail disease progression through the biologic remodeling activity of CT1.

Here, we demonstrate that human CT1 protein (hCT1) engages a fully reversible form of myocardial growth, and that hCT1 attenuates the ongoing pathology and loss-of-function in an aggressive and unremitting model of right heart failure (RHF). hCT1 promotes cardiomyocyte growth in part by inducing a limited activation of an otherwise pathologic hypertrophy signal, as mediated by the caspase 3 protease. In addition, hCT1 engages a cardiomyocyte-derived vascular growth signal to ensure that the modest heart muscle growth is temporally matched with a supporting angiogenic response. Moreover, two weeks administration of hCT1 in vivo produced cardiac remodeling that was similar to that induced by exercise and, in a model of progressive RHF due to severe pulmonary arterial hypertension, improved cardiac function and reversed right ventricle (RV) dilatation. These data suggest that hCT1 fulfills the criteria as a beneficial remodeling agent, with a capacity to curtail or limit an intractable form of HF.

From its initial discovery, it was postulated that senescence, on some level, was linked with organismal ageing. Modern forms of this hypothesis propose that senescent cells are produced gradually throughout life. These then begin to accumulate in mitotic tissues and act as causal agents of the ageing process through the disruption of tissue function. This conceptual model carries three underlying assumptions: firstly that senescent cells are present in vivo, secondly that they accumulate with age, and finally that an accumulation of senescent cells can have a negative impact. Each is worthy of examination.

A steady production of senescent cells is quite plausible if the kinetics whereby populations of normal cells become senescent in vitro are assumed to be similar in vivo. Many early reports evaluated findings with the mistaken underlying assumption that cell cultures become senescent because all of the cells divide synchronously for a fixed number of times and then stop. In fact, it has been known since the early 1970s that each time a cell goes through the cell cycle (i) it has a finite chance of entering the senescent state and (ii) this chance increases with each subsequent division. Thus, senescent cells appear early on if a cell population is required to divide. Indirect demonstrations that senescent cells occur in vivo, accumulate with ageing, and do so at reduced rates in organisms where ageing is slowed (for example, by dietary restriction) were occasionally published from the 1970s onwards. However, they were technically difficult to perform and correspondingly hard to interpret.

Senescence triggers changes in gene expression. A central component of this shift is the secretion of biologically active proteins (for example, growth factors, proteases, and cytokines) that have potent autocrine and paracrine activities, a process termed the senescence-associated secretory phenotype (SASP). This results in cells that overproduce a wide variety of pro-inflammatory cytokines, typically through the induction of nuclear factor kappa B (NF-κB) and matrix-degrading proteins such as collagenase. Other radical phenotypic changes, such as calcification, have also been shown to occur in some cell types with the onset of replicative senescence. The individual components of the SASP vary from tissue to tissue and, within a given cell type, can differ depending upon the stimulus used to induce senescence (for example, in fibroblasts rendered senescent by oncogene activation compared with telomere attrition or mitochondrial dysfunction). Such studies demonstrated that senescent cells could, at least potentially, produce significant and diverse degenerative pathology.

However, the observation that something can produce pathology does not mean that it must produce pathology, and a historic weakness of the cell senescence literature was that the in vivo studies essential to testing the causal relationship between ageing and cellular senescence (induced by any mechanism) were lacking. However, the production of transgenic mouse models in which it was possible to eliminate senescent cells has finally made such tests experimentally feasible. Initial studies demonstrated first that senescent cells appeared to play a causal role in a variety of age-associated pathologies in the BubR1 mutant mouse and subsequently that either life-long removal of senescent cells or their clearance late in life significantly attenuated the development of such pathologies in these progeroid animals. This clearly demonstrated that senescent cells can have significant, deleterious effects in vivo. Interestingly, the removal of senescent cells in this system was not associated with increased lifespan (an observation that demonstrated that it is possible to achieve classic 'compression of morbidity' by deleting senescent cells). However, on more conventional genetic backgrounds, attenuated age-related organ deterioration was accompanied by increases in lifespan of the order of 25%.

A justifiable claim can be made to consider these studies 'landmarks' in the field in that (i) they demonstrate a causal relationship between senescent cells and 'ageing' and (ii) the same mechanism can cause changes associated with 'ageing' as well as those associated with 'age-related disease'. These results have unusually profound philosophical implications for a scientific paper and challenge a fundamental ontological distinction that has been drawn for almost two thousand years between 'natural' ageing and 'unnatural' disease.

Whether an enhanced emphasis on basic human studies is a useful parallel-track approach to the pioneering work now taking place in rodent models or an essential next step is a matter of perspective. Many fundamental mechanisms of ageing are conserved between species, but there are often important species-specific differences. Those inclined to stress the cross-species similarities will be inclined to deprioritise human studies and vice versa. Regardless of the species of origin, the extent of variation in the phenotype of senescent cells derived from the same tissue in different individuals is not well characterised. It would be surprising if important intra-individual variation did not exist within the general population as well as 'outliers' (for example, centenarians and those with accelerated ageing diseases such as Werner's syndrome). Although data on differential SASP profiles in response to a senescence stimulus are beginning to enter the literature, they remain fragmentary concerning the senescent cell phenotype in different tissues.

Despite these gaps, progress is being made towards the development of 'senolytic' drugs that can destroy senescent cells - with the goal of duplicating the effects of the transgenic mouse models first in normal animals and eventually in human patients. Initial results seem promising.

Researchers have created a small molecule that prevents or impedes tooth cavities in a preclinical model. The inhibitor blocks the function of a key virulence enzyme in an oral bacterium, a molecular sabotage that is akin to throwing a monkey wrench into machinery to jam the gears. In the presence of the molecule, Streptococcus mutans - the prime bacterial cause of the tooth decay called dental caries - is unable to make the protective and sticky biofilm that allows it to glue to the tooth surface, where it eats away tooth enamel by producing lactic acid. This selective inhibition of the sticky biofilm appears to act specifically against S. mutans, and the inhibitor drastically reduced dental caries in rats fed a caries-promoting diet. "Our compound is drug-like, non-bactericidal and easy to synthesize, and it exhibits very potent efficacy in vivo. It is an excellent candidate that can be developed into therapeutic drugs that prevent and treat dental caries."

The glucan biofilm is made by three S. mutans glucosyltransferase, or Gtf, enzymes. The crystal structure of the GtfC glucosyltransferase is known, and the researchers used that structure to screen - via computer simulations - 500,000 drug-like compounds for binding at the enzyme's active site. Ninety compounds with diverse scaffolds showing promise in the computer screening were tested for their ability to block biofilm formation by S. mutans in culture. Seven showed potent inhibition and one, #G43, was tested more extensively. #G43 inhibited the activity of enzymes GtfB and GtfC. #G43 did not inhibit the expression of the gtfC gene, and it did not affect growth or viability of S. mutans and several other oral bacteria tested. Also, #G43 did not inhibit biofilm production by several other oral streptococcal species. In the rat-model of dental caries, animals on a low-sucrose diet were infected with S. mutans and their teeth were treated topically with #G43 twice a day for four weeks. The #G43 treatment caused very significant reductions in enamel and dentinal caries.

Dental caries is a multifactorial disease of bacterial origin, which is characterized by the localized destruction of dental hard tissues. Though the oral cavity harbors over 700 different bacterial species, Streptococcus mutans initiates the cariogenic process and remains as the key etiological agent. Using key matrix producing enzymes, glucosyltransferases (Gtfs), S. mutans produces sticky glucosyl glucan polymers, which facilitate the attachment of the bacteria to the tooth surface. The glucans is a major component of the biofilm matrix that shields the microbial community from host defenses. Furthermore, copious amounts of lactic acid are produced as a byproduct of bacterial consumption of dietary sugars within the mature biofilm community, which ultimately leads to demineralization of the tooth surface, ensuing cariogenesis.

Selectively targeting cariogenic pathogens such as S. mutans has been explored previously, however it was found that the antimicrobial peptide also alters the overall microbiota. Our increasing understanding of bacterial virulence mechanisms provides new opportunities to target and interfere with crucial virulence factors such as Gtfs. This approach has the added advantages of not only being selective, but may also help to preserve the natural microbial flora of the mouth, which may avoid to exert the strong pressure to promote the development of antibiotic resistance, overcoming a major public health issue in the antibiotic era. It is well established that glucans produced by S. mutans Gtfs contribute significantly to the cariogenicity of dental biofilms. Therefore, the inhibition of the Gtf activity and the consequential glucan synthesis would impair the S. mutans virulence, which could offer an alternative strategy to prevent and treat biofilm-related diseases.

S. mutans harbors three Gtfs: GtfB, GtfC, and GtfD. Previous studies have demonstrated that glucans produced by GtfB and GtfC are essential for the assembly of the S. mutans biofilms. We conducted an in silico screening of 500,000 drug-like small molecule compounds targeting GtfC and identified top scored scaffolds for in vitro biofilm assays. Seven potent biofilm inhibitors emerged from this study, the lead compound #G43 was further characterized and shown to have anti-biofilm activity through the binding to GtfBC and the inhibition of the activity of GtfBC. The lead compound drastically reduced bacterial virulence in a rat model of dental caries.

"Societies are not aware of frailty as an avoidable health problem and most people usually resign themselves to this condition. Fortunately, by proper lifestyle and adequate physical, mental, and social activities, one may prevent or delay the frailty state." Frailty encompasses a range of symptoms that many people assume are just an inescapable part of aging. These include fatigue, muscle weakness, slower movements, and unintentional weight loss. Frailty also manifests as psychological and cognitive symptoms such as isolation, depression, and trouble thinking as quickly and clearly as patients could in their younger years. These symptoms decrease patients' self-sufficiency and frail patients are more likely to suffer falls, disability, infections, and hospitalization, all of which can contribute to an earlier death.

There is ample evidence that the prevalence and impact of frailty can be reduced, at least in part, with a few straightforward measures. Unsurprisingly, age-appropriate exercise has been shown to be one of the most effective interventions for helping the elderly stay fit. Careful monitoring of body weight and diet are also key to ensuring that older patients are not suffering from malnutrition, which often contributes to frailty. "Social campaigns should inform societies about age related frailty and suggest proper lifestyles to avoid or delay these conditions. People should realize that they may change their unfavorable trajectories to senility and this change in mentality is critical to preparing communities for greater longevity."

Frailty is a geriatric syndrome caused by a multisystem decrease in reserve capability and is associated with a high risk for various adverse outcomes. Frailty is not synonymous with either comorbidity or disability, but comorbidity is a risk factor for frailty, and disability is an outcome of frailty. Pre-frailty is a condition predisposing and directly preceding frailty. The frailty state is associated with a variety of adverse consequences, such as falls, cognitive decline, infections, hospitalization, disability, institutionalization, and death. Frail patients present much worse prognoses than non-frail patients, particularly in cardiovascular diseases. Moreover, frailty impairs the effects of invasive treatments in these disorders, e.g., percutaneous coronary interventions, transcatheter aortic valve implantations or coronary artery bypass grafting. Frailty also imposes a significant financial burden on health systems, particularly because frailty appears to have an incremental effect on ambulatory health expenditures.

Awareness of these facts may afford us an opportunity to develop cost-effective care for this group of people, resulting in improvement in long-term care and its outcomes. However, despite numerous studies addressing this condition in recent years, frailty as an entity is not commonly recognized in the general population or even by some medical societies, and there are no consistent preventative and therapeutic strategies dedicated to this disorder. Because population aging is associated with a higher prevalence of frailty and pre-frailty, it is necessary to familiarize societies with these states. Moreover, if we want to improve the quality of life of elderly persons and reduce expenses for their care in the future, we should take preventative measures against frailty now. Therefore, it is time to begin treating frailty like other population-affecting diseases such as obesity, diabetes or hypertension. Appropriate prospective studies are needed to define which preventative lifestyle interventions should be implemented to ensure good physical and mental conditions in senility. Social campaigns could draw societies' attention to proper life habits that may be effective to avoid not only diabetes and cardiovascular diseases but also age-related frailty.

Learning capacity is known to decline with age, and similar effects are also associated with several neurodegenerative diseases. Regulation of insulin signaling by dietary restriction (DR) modulates lifespan in many organisms, and it has been also shown to enhance learning and memory. However, the underlying mechanisms of these processes are largely unknown due to the difficulty in disentangling the systemic effects of DR from any potentially brain-specific effects. Here, we have analyzed the molecular effects of dietary restriction in C. elegans and show that associative learning is enhanced by reducing production of the tryptophan metabolite kynurenic acid (KYNA).

KYNA is an antagonist of glutamatergic signaling in neurons, and we find that its depletion in the nervous system upon DR allows for increased activation of an interneuron that is both necessary and sufficient to mediate learning. We investigated the effects of reductions in either insulin or mTOR signaling pathways, as well as the effects of pharmacological and genetic interventions that lead to activations of AMPK and autophagy. We show that DR and these DR mimetics each result in learning enhancements. Despite their wide-ranging cellular and organismal effects, we find that the beneficial effects of each of these interventions on learning are fully dependent on reductions in KYNA.

Finally, we demonstrate that KYNA levels have no effect on organismal lifespan, indicating that the effects of this KYNA-mediated response to dietary restriction is truly specific to brain function and not a secondary consequence of improved health or longevity. As altered KYNA levels are associated with neurodegenerative and psychiatric diseases, our results suggest that this component may be an important modulator of learning and memory in humans as well.

During the last decades of the 20th century, a remarkable phenomenon became apparent. Contrary to general expectation, the increase in human life expectancy - a measure of average length of life within the population - that had been occurring steadily in developed countries for almost two centuries failed to hit its predicted ceiling and has carried on at the same rate as before. To appreciate why the continuing increase in life expectancy was unexpected, it is necessary to examine what had been driving its earlier increase: cleaner drinking water, better sanitation and improvements in housing, education and nutrition all contributed, aided latterly by the development and widespread application of vaccines, antibiotics and other advances in preventive and therapeutic medicine. As the last quarter of the 20th century began, the residual levels of early- and mid-life mortality had fallen so low that any further reductions could have had only a modest effect on further increasing life expectancy.

As it was assumed that the ageing process itself was essentially immutable - a biological given - it was expected that populations would simply contain greater numbers of older people. These would die at the same ages as the oldest of their predecessors, who had been fewer in number but aged just the same. What has changed, however, is that it is now the death rates of those of advanced age - 80 and older - that are falling fastest. Put simply, it seems that the nature of old age is undergoing a significant change. Old people are, as a rule, reaching more advanced ages in better and better condition, and this is reflected in the continuing increase in life expectancy. What is likely to happen to human longevity in the future? What factors influence our individual trajectories of health into old age? How feasible is it to think of discovering new ways to extend further the duration of healthy life free of disability and disease?

The evolution of ageing is now generally understood to have occurred not through programming of ageing as an adaptive benefit in its own right, but because the force of natural selection falls off strongly across the course of the lifespan. The different longevities of different species can be explained because the exposure to accidents varies from one species to another, and consequently, selection will favour a higher investment in somatic maintenance in a species better adapted to survive the hazards of its ecological niche than in a species subject to a higher extrinsic level of risk. Comparative studies of ageing consistently reveal that cell maintenance is greater in longer-lived organisms.

A striking feature of ageing is its variability. That ageing is malleable is evident from the falling death rates in old age. The more hygienic conditions of modern life in high-income countries, with fewer sources of physical stress and earlier interventions to maintain health, most probably explain why people now reach old age physically 'younger' than their parents and grandparents. Malleability is also evident through the social gradient in health and life expectancy, whereby those of lower socio-economic status have shorter life expectancy.

Recent progress in research on ageing has generated considerable interest in the potential for science to extend the human health span, i.e. the period free of significant disease or disability, beyond the improvements that are occurring already. These include the possibilities of the following: (i) drugs targeting molecular pathways found to be involved in the regulation of lifespan, such as rapamycin and resveratrol, or enzymes such as telomerase; (ii) control of food intake through dietary restriction or intermittent fasting, to mimic longstanding observations on the life-extending effects of caloric restriction in rodents; (iii) so-called 'senolytic' strategies selectively to remove senescent cells from aged tissues and organs; (iv) transfer of plasma or serum from young to old individuals, based on pioneering studies using pairs of young and old rodents whose circulatory systems were connected; (v) repurposing of existing drugs, such as metformin, previously licensed for treatment of diabetes and now of interest for potential anti-ageing properties.

Despite the exciting potential for progress, it is important to reflect briefly on the main challenges confronting the attempts to extend the health span. The regulatory framework within which new interventions to extend health span can be developed raises particularly interesting challenges. When targeting illness, especially if it is painful and life limiting, the barriers against accepting possible side-effects are lower. Thus, anti-ageing interventions will most easily gain approval if they target late-stage diseases. However, these are not the interventions that will most effectively extend the health span. The latter interventions are ones that would need to be introduced before or as soon as possible after the earliest signs of age-related health deficits become apparent. They will therefore also be candidates for application across the population at large.

It is as yet uncertain to what extent and when science will deliver improvements in health span. Given what we know already about the general nature of the ageing process and of its malleability, it seems entirely reasonable, indeed probable, that improvements of this kind will occur. It would be wise, however, not to promise or expect too much too soon. However, the same science is likely to provide further evidence to support and encourage the kinds of changes in nutrition and lifestyle that are already known to be effective, and here it is reasonable to expect benefits to occur faster.

Researchers have developed a new technology, tissue nanotransfection (TNT), that can generate any cell type of interest for treatment within the patient's own body. This technology may be used to repair injured tissue or restore function of aging tissue, including organs, blood vessels and nerve cells. "By using our novel nanochip technology, injured or compromised organs can be replaced. We have shown that skin is a fertile land where we can grow the elements of any organ that is declining."

Researchers studied mice and pigs in these experiments. In the study, researchers were able to reprogram skin cells to become vascular cells in badly injured legs that lacked blood flow. Within one week, active blood vessels appeared in the injured leg, and by the second week, the leg was saved. In lab tests, this technology was also shown to reprogram skin cells in the live body into nerve cells that were injected into brain-injured mice to help them recover from stroke. "This is difficult to imagine, but it is achievable, successfully working about 98 percent of the time. With this technology, we can convert skin cells into elements of any organ with just one touch. This process only takes less than a second and is non-invasive, and then you're off. The chip does not stay with you after the reprogramming of the cell starts. Our technology keeps the cells in the body under immune surveillance, so immune suppression is not necessary."

TNT technology has two major components: First is a nanotechnology-based chip designed to deliver cargo to adult cells in the live body. Second is the design of specific biological cargo for cell conversion. This cargo, when delivered using the chip, converts an adult cell from one type to another. TNT doesn't require any laboratory-based procedures and may be implemented at the point of care. The procedure is also non-invasive. The cargo is delivered by zapping the device with a small electrical charge that's barely felt by the patient. "The concept is very simple. As a matter of fact, we were even surprised that it worked so well. In my lab, we have ongoing research trying to understand the mechanism and do even better. So, this is the beginning, more to come."

In a recent study, researchers focused on a regenerative type of heart muscle cell called a mononuclear diploid cardiomyocyte (MNDCM). Zebrafish and newborn mammals, including mice and humans, have large numbers of MNDCMs and a relatively robust ability to regenerate heart muscle. However, adult mammals have few MNDCMs and a correspondingly limited capacity for regeneration after an injury such as a heart attack. Even so, the situation for adult mammals is not uniformly dire: the researchers observed a surprising amount of variation in the number of MNDCMs among different strains of adult mice. In some strains, MNDCMs accounted for only 1.9 percent of heart muscle cells. In others, a full 10 percent were MNDCMs. As expected, the higher the percentage of MNDCMs, the better the mice fared in regenerating their heart muscle after injury.

"This was an exciting finding. It suggests that not all individuals are destined to permanent heart muscle loss after a heart attack, but rather some can naturally recover both heart muscle mass and function. If we can identify the genes that make some individuals better at it than others, then perhaps we can stimulate regeneration across the board." Using an approach called a genome-wide association study, the researchers indeed identified one of the key genes underlying this variation: Tnni3k. By blocking this gene in mice, the researchers produced higher percentages of MNDCMs and enhanced heart regeneration. In contrast, activating this gene in zebrafish decreased MNDCMs and impaired heart regeneration. "The activity of this gene, Tnni3k, can be modulated by small molecules, which could be developed into prescription drugs in the future. These small molecules could change the composition of the heart over time to contain more of these regenerative cells. This could improve the potential for regeneration in adult hearts, as a preventative strategy for those who may be at risk for heart failure."

α-Klotho (klotho) is a pleiotropic protein that circulates as a hormone following cleavage from its transmembrane form. It regulates insulin, Wnt, and fibroblast growth factor (FGF) signaling. Overexpression of klotho extends life in organisms, whereas lowering klotho shortens it. Elevated klotho levels in humans, resulting from genetic variation, also associate with lifespan in some populations. In model organisms and humans, levels of klotho decline with age, chronic stress, cognitive aging, neurodegenerative disease, and models of neurodegenerative disease.

We previously discovered that life-long, genetic overexpression of klotho causally enhances normal cognition and neural resilience independent of age and when broadly expressed in the mouse body and brain. It does so, at least in part, by directly or indirectly optimizing synaptic functions through NMDA receptor (NMDAR)-dependent mechanisms. Importantly, genetic, lifelong, and widespread klotho elevation also contributes to neural resilience in a human amyloid precursor protein (hAPP) model of neurodegenerative disease related to AD; that is, it effectively counters cognitive and synaptic deficits despite high levels of pathogenic proteins, including Aβ, tau, and phospho-tau. The relevance of klotho to brain health in humans is supported by the findings that elevated serum klotho, related to variation in the gene, are associated with better measures, including cognition, structural reserve of the prefrontal cortex in normal aging, connectivity between cortical regions, and physical performance in aging, and that diminished klotho levels are associated with worse brain measures.

Whether acute klotho elevation represents a strategy that can rapidly enhance cognition, motor functions, and/or induce brain resilience is a gap in our knowledge of its therapeutic potential. Here we show that αKL-F, a fragment of the α-klotho protein similar to its secreted form, can acutely improve cognitive and motor functions following peripheral administration. It does so despite apparent impermeability to the blood-brain barrier in mice. Further investigation of αKL-F-mediated molecular mechanisms revealed activation of glutamatergic signaling and enhancement of synaptic plasticity. Our findings highlight a role for αKL-F in promoting optimal synaptic functions in the normal brain and to boost "synaptic health" in aging and disease-states. Because synaptic health may confer resilience against the effects of aging and a myriad of aging-and non-aging related neurologic and psychiatric diseases, the potential to enhance it may be relevant to the human condition.

Like much of the rest of the body, the brain loses flexibility with age, impacting the ability to learn, remember, and adapt. Now, scientists report they can rejuvenate the plasticity of the mouse brain, specifically in the visual cortex, increasing its ability to change in response to experience. Manipulating a single gene triggers the shift, revealing it as a potential target for new treatments that could recover the brain's youthful potential. Additional research will need to be done to determine whether plasticity in humans and mice is regulated in the same way.

The dramatic way in which the brain changes over time has long captured the imagination of scientists. A "critical window" of brain plasticity explains why certain eye conditions such as lazy eye can be corrected during early childhood but not later in life. The phenomenon has raised the questions: What ordinarily keeps the window open? And, once it's shut, can plasticity be restored? Earlier work showed that the critical window never opens in mice lacking a gene called Arc. Temporarily closing a single eye of a young mouse for a few days deprives the visual cortex of normal input, and the neurons' electrophysiological response to visual experience changes. By contrast, young mice without Arc cannot adapt to the new experience in the same way.

If there is no visual plasticity without Arc, the thinking goes, then perhaps the gene plays a role in keeping the "critical window" open. In support of the idea, the new investigation finds that in the mouse visual cortex, Arc rises and falls in parallel with visual plasticity. The two peak in teen mice and fall sharply by middle-age, suggesting they are linked. The researchers probed the connection further in two more ways. First they tested mice that have a strong supply of Arc throughout life. At middle-age, these mice responded to visual deprivation as robustly as their juvenile counterparts. By prolonging Arc's availability, the window of plasticity remained open for longer. In the second set of experiments, viruses were used to deliver Arc to middle age mice, after the critical window had closed. Following the intervention, these older mice responded to visual deprivation as a youngster would. In this case even though the window had already shut, Arc enabled it to open once again.

The prevailing notion of how plasticity declines is that as the brain develops, inhibitory neurons mature and become stronger. Increased inhibition in the brain makes it harder to express activity-dependent genes, like Arc, in response to experience or learning. That leads to decreased brain plasticity. Normally, Arc is rapidly activated in response to stimuli and is involved in shuttling neurotransmitter receptors out of synapses that neurons use to communicate with one another. Additional research will need to be done to understand precisely how manipulating Arc boosts plasticity.

Pathological cardiac hypertrophy is the cellular response to biomechanical or neurohumoral stimuli. The defining features of hypertrophy are increased cardiomyocyte size, enhanced protein synthesis and reinduction of the so-called fetal gene program. Although hypertrophy has traditionally been considered as an adaptive response required to sustain cardiac output, in the long term, hypertrophy predisposes individuals to heart failure, arrhythmia and sudden death. Despite the recent advances in understanding the molecular and cellular processes that contribute to cardiac hypertrophy, there remains the need for further investigation.

Cellular senescence describes the permanent form of cellular proliferative arrest. Senescent cells are characterized by phenotypic changes; for example, increased cell size, enhanced senescence-associated β-galactosidase (SA-β-gal) activity and high levels of cyclin-dependent kinase inhibitors (CDKIs) which block the cell cycle. The mammalian heart has long been considered a quiescent organ. Although there are a few studies suggesting that cardiomyocytes can divide at a low rate under certain conditions, it is widely believed that the majority of cardiomyocytes, if not all of them, are out of cell cycle shortly after birth. Therefore, the question that has been raised is whether cardiomyocytes can undergo senescence. Previous studies have revealed that cardiomyocytes from old mice show certain senescence-associated properties, including high SA-β-gal activity, increased CDKIs expression, accumulated lipofuscin and decreased telomerase activity. Based on the fact that cardiac senescence and hypertrophy share defining features and signaling pathways, the aim of our study is to find out whether cardiac senescence is involved in the process of pathological cardiac hypertrophy and what could be the specific biomarkers for evaluating cardiac aging.

Our present results show for the first time that a cardiac senescence phenotype occurs in isoproterenol-induced pathological cardiac hypertrophy by analysis of a wide range of senescence markers. Similar results were also reported in an angiotensin II-induced cardiac hypertrophy model, and dilated cardiomyopathy caused by cardiac-specific Bmi1 deletion manifested by the increased ratio of SA-β-gal positive cells. It suggested that not only does cardiac senescence exist in the heart but also that it is involved in multiple hypertrophy models.

In addition to average performance level, there is an increasing focus in ageing research on intraindividual variability or inconsistency in cognitive performance. Such variability in performance is often measured by the trial-to-trial within-person variation in reaction times (RT) on a single cognitive task and is known as intraindividual reaction time variability (IIVRT). IIVRT has received considerable attention as a useful indicator of neurobiological disturbance. Consistent with this, several studies indicate that IIVRT is greater in older age and in a variety of neuropathological conditions of old age. Associations have been found with measures of brain integrity, including white matter hyperintensities, brain connectivity, and dopaminergic neuromodulation.

Our present interest is whether this measure can predict mortality in old age. It is possible that neurobiogical changes that are related to eventual mortality are captured by variability measures and are present many years in advance. A few studies have reported that increased variability predicts mortality up to 19 years before eventual death in older populations but it is unknown whether this association is independent of general age-related cognitive decline, an established risk factor for mortality. Moreover, the potential influence of incipient dementia on this relationship has not been addressed adequately in previous studies.

Hence, IIVRT warrants investigation as a specific predictor of impending death in older age independently of global cognitive level and other mortality risk factors. Therefore, the aim of this study was to investigate the association of IIVRT with mortality over 8 years in a large, well-characterised population-based cohort of older adults aged 70 years and over. In this large community-based old age cohort, greater variability in RT performance but not slower mean RT predicted all-cause mortality while adjusting for conventional mortality risk factors of age, sex, cardiovascular risk and APOE ɛ4 status and important potential confounders. Our findings broadly support and extend the small extant literature by providing further support for a strong association between IIVRT and all-cause mortality. The findings supports the view of IIVRT as a behavioural marker of neurobiological integrity.

Researchers have identified the early neuropathic mechanism of polyglutamine brain disease, one of the representative degenerative brain diseases, and suggested a way to restore it. It is expected to accelerate the development of the early neuropathy treatment for a variety of degenerative brain diseases. The research teams have verified for the first time in the world that dendritic-specific Golgi, one of the cellular organelles in neurons, plays a key role in early neuropathy of degenerative brain disease.

In a model of degenerative brain diseases such as Huntington's chorea and spinal cord cerebellar degeneration that are caused by polyglutamine toxic protein, the research teams identified that deformation or abnormality of dendritic-specific Golgi, which plays a key role in supplying the cell membrane of brain cells, is the major cause of degenerative brain disease as it leads morphological transformation of neuronal cells.

In these morphologically modified brain cells, the study has demonstrated that the early neuropathy of diseased brain cells can be restored by inducing overexpression of the CrebA gene, the newly discovered key factor in pathology. In addition, by identifying the transcription factors involved in the early neuropathy caused by toxic proteins such as CrebA and high-level factor CREB-binding protein, the researchers have suggested that they could be new subjects to develop therapeutic agents for degenerative brain diseases.

It is widely believed that, with the passage of time, stem cells cease to differentiate between day and night cycles, in other words they lose their circadian rhythm, and that this loss promotes ageing. However, this has been found not to be the case. Two recent studies reject this hypothesis. During ageing, stem cells continue to show rhythmic activity but reprogram their circadian functions. "Aged stem cells conserve circadian rhythm but now perform another set of functions to tackle the problems that arise with age. The problem is that as they age, stem cells lose the rhythmic functions necessary for tissue protection and maintenance, which become replaced by functions aimed at coping with stress. Loss of the previous circadian functions of stem cells during natural ageing contributes in some way to greater damage and greater ageing".

In both studies, researchers compared stem cells from young mice (three months old) with those of aged mice (between 18 and 22 months old) in three kinds of tissue, namely skin, muscle and liver, every four hours over one day. It is known that a low-calorie diet delays the signs of ageing in primates and mice. In another set of experiments, researchers gave mice a low-calorie diet for six months and compared them with counterparts on a normal diet. The animals on the low-calorie diet conserved most of the rhythmic functions of their youth. According to the researchers, this would explain why a calorie restriction diet slows down ageing. What is not clear is whether low-calorie diets would keep ageing at bay in humans. In this regard, it is important to further examine why metabolism has such a dominant effect on the stem cell ageing process and, once the link that promotes or delays ageing has been identified, to develop treatments that can regulate this link.

"Although ageing always involves circadian reprogramming, an interesting aspect of our results is that such reprogramming is specific and distinct for each type of tissue studied. This observation implies that although the entire organism is ageing, each tissue goes through this process in a different way. So to address the slowing down of ageing, it will be necessary to study each tissue separately. Keeping the rhythm of stem cells "young" is important because in the end these cells serve to renew and preserve very pronounced day-night cycles in tissues."