Autophagy is an evolutionarily conserved cellular process, through which damaged organelles and superfluous proteins are degraded, for maintaining the correct cellular balance during stress insult. It involves formation of double-membrane vesicles, named autophagosomes, that capture cytosolic cargo and deliver it to lysosomes, where the breakdown products are recycled back to cytoplasm. Dysregulation of autophagy can induce various disease manifestations, such as inflammation, aging, metabolic diseases, neurodegenerative disorders, and cancer. The understanding of the molecular mechanism that regulates the different phases of the autophagic process and the role in the development of diseases are only in an early stage. There are still questions that must be answered concerning the functions of the autophagy-related proteins.

Autophagy, Inflammation and Aging

Autophagy has been identified as main regulator of the inflammasome; a major innate immune pathway activated by exogenous stimuli, such as pathogenic microorganisms, or by endogenous mediators, such as reactive oxygen species (ROS), mitochondrial damage, and environmental irritants. Inflammasome activation involves formation and oligomerization of a protein complex, followed by release of proinflammatory cytokines, such as IL-1β and IL-18, from innate immune cells. In particular, when endogenous mediators induce massive inflammatory response, they can cause tissue damage and promote the onset of inflammatory diseases. Therefore, negative or positive regulation of inflammasome is essential to ensuring a good state of health.

As demonstrated by multiple studies, autophagy can negatively regulate inflammasome activation through different mechanisms, including by removing damaged organelles such as mitochondria, leading to reduced release of ROS and subsequent suppression of inflammasome activation. Autophagy deficiency causes inflammasome-related inflammatory diseases. Overall, data suggests that inflammasome and autophagy mutually regulate each other, favoring the balance between inflammatory response to defend itself from the host and prevention of excessive inflammatory response that can induce tissue damage and inflammatory disease. Recent studies have shown that the impaired autophagy activity that characterizes aging is due to accumulation of dysfunctional mitochondria, ROS, and NLRP3 inflammasome activation in macrophages. These factors predispose the cells to greater risk towards aging diseases, such as atherosclerosis and type 2 diabetes.

Autophagy and Neurodegenerative Disorders

The aggregation of misfolded proteins and some neuronal population losses are typical of the expression of pathological neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Autophagy has been reported to be involved in the occurrence of neurodegenerative disorders, being the main intracellular system for degrading damaged organelles and aggregated proteins. In neurodegenerative diseases, an alteration of the maturation mechanism of the autophagosome in the autophagolysosome has been found.

Moreover, autophagy plays an important role in the degradation of different proteins correlated with degenerative diseases, such as mutated α-synuclein in Parkinson's disease, mutant huntingtin in Huntington's disease, and the mutant TPD-43 in amyotrophic lateral sclerosis. In Alzheimer's disease, the presence of extracellular amyloid-β plaques and intracellular neurofibrillary tangles, composed of hyperphosphorylated tau proteins aggregates, has been revealed. In the healthy brain, the autophagosome vesicles are not very visible; instead, in the Alzheimer's disease brain, numerous autophagosomes are noticeable. Accumulation of autophagy vacuoles arises from impaired clearance rather than autophagy induction, suggesting the later stages of autophagy modulation as a possible therapeutic strategy for Alzheimer's disease.

The role of autophagy in Parkinson's disease has been demonstrated by the presence in neurons of lysosomal and autophagosomes alterations; to support this evidence, when the lysosome is functionally altered, the amount of α-synuclein is elevated, indicating an alteration of the autophagy pathway. TFEB has been identified as the factor that positively regulates genes related to formation of autophagosomes and the lysosome fusion, increasing the clearance of lysosomal exocytosis. Recently, it has been shown that its overexpression can reduce the lysosome damage and thus improve the neurological disorders related with α-synuclein.

Malfunctions in the cells' protein-disposal machinery can lead to the accumulation of misfolded proteins, which clog up the cell, interfere with its functions, and, over time, precipitate the development of diseases, including neurodegenerative conditions such as amyotrophic lateral sclerosis and Alzheimer's. The best-studied biochemical system used by cells to remove junk proteins is the ubiquitin-proteasome pathway. It involves tagging defective or unneeded proteins with ubiquitin molecules marking them for destruction by the cell's protein-disposal unit, known as 26S proteasome.

Past research has shown that this machinery can be activated by pharmacological agents that boost the levels of a molecule known as cAMP, the chemical trigger that initiates the cascade leading to protein degradation inside cells, which in turn switches on the enzyme protein kinase A. The lab's previous research found that cAMP-stimulating drugs enhanced the destruction of defective or toxic proteins, particularly mutant proteins that can lead to neurodegenerative conditions. The new findings, however, reveal that shifts in physiological states and corresponding changes in hormones can regulate this quality-control process independent of drugs.

The researchers analyzed the effects of exercise on cells obtained from the thigh muscles of four human volunteers before and after vigorous biking. Following exercise, the proteasomes of these cells showed dramatically more molecular marks of enhanced protein degradation, including greater levels of cAMP. The same changes were observed in the muscles of anesthetized rats whose hind legs were stimulated to contract repeatedly. Fasting - even for brief periods - produced a similar effect on the cells' protein-breakdown machinery. Fasting increased proteasome activity in the muscle and liver cells of mice deprived of food for 12 hours, the equivalent of an overnight fast.

Exposure to the fight-or-flight hormone epinephrine produced a similar effect. Epinephrine, also known as adrenaline, is responsible for stimulating the liver and muscle to mobilize energy reserves to boost heart rate and muscle strength during periods of physiologic stress. Liver cells treated with epinephrine showed marked increases in cAMP, as well as enhanced 26S proteasome activity and protein degradation. Taken together, these findings demonstrate that the rate of protein degradation can rise and fall swiftly in a variety of tissues in response to shifting conditions, and that such changes are mediated by fluctuations in hormone levels.

Most studies of proteolysis by the ubiquitin-proteasome pathway have focused on the regulation by ubiquitination. However, we showed that pharmacological agents that raise cAMP and activate protein kinase A by phosphorylating a proteasome subunit enhance proteasome activity and the cell's capacity to selectively degrade misfolded and regulatory proteins. We investigated whether similar adaptations occur in physiological conditions where cAMP rises. Proteasome activity increases by this mechanism in human muscles following intense exercise, in mouse muscles and liver after a brief fast, in hepatocytes after epinephrine or glucagon, and renal collecting duct cells within 5 minutes of antidiuretic hormone. Thus, hormones and conditions that raise cAMP rapidly enhance proteasome activity and the cells' capacity to eliminate damaged and preexistent regulatory proteins.

Scientists have identified a potential explanation for the mysterious death of specific brain cells seen in Alzheimer's, Parkinson's, and other neurodegenerative diseases. The new research suggests that the cells may die because of naturally occurring gene variation in brain cells that were, until recently, assumed to be genetically identical. This variation - called "somatic mosaicism" - could explain why neurons in the temporal lobe are the first to die in Alzheimer's, for example, and why dopaminergic neurons are the first to die in Parkinson's.

The finding emerged unexpectedly from investigations into schizophrenia. It was in that context that researchers first discovered the unexpected variation in the genetic makeup of individual brain cells. That discovery may help explain not just schizophrenia but depression, bipolar disorder, autism and other conditions. Researchers expected that this mosaicism would increase with age - that mutations would accumulate over time. What they found is exactly the opposite: younger people had the most mosaicism and older people had the least. Based on the finding, researchers believe that the neurons with significant genetic variation, known as CNV neurons, may be the most vulnerable to dying. And that could explain the idiosyncratic death of specific neurons in different neurodegenerative diseases. People with the most CNV neurons in the temporal lobe, for example, might be likely to develop Alzheimer's.

Neocortical neurons are among the most diverse and longest-lived mammalian cells. Every human neocortical neuron may contain private somatic variants. Single nucleotide variants (SNVs) are especially common, with hundreds per neuron reported, and with frequencies of more than 3,000 SNVs per neuron observed in aged individuals. Endogenous mobile elements such as retrotransposons are also active during brain development. Mobile element activity has been linked to the generation of copy-number variants (CNVs). By contrast to other somatic variants, large CNVs almost always affect multiple genes. A reanalysis of published data herein found an average of 63 genes affected per neuronal CNV.

The most salient feature of the brain CNV atlas that we have produced is an anti-correlation between the age of an individual and the percentage of CNV neurons in the frontal cortex of that individual. By contrast, the initial assessment of CNV location finds evidence for the enrichment of a subset of long genes and neurally associated gene ontology categories only in aged brains. Given the enrichment of these CNVs in aged, not young, neurons, CNVs affecting some genomic loci may be more compatible with neural survival than others. We found similar rates of CNV non-neurons at different ages; however, it will be interesting to determine whether other long-lived cells (e.g., cardiomyocytes) show a similar change in mosaic composition during aging.

We provide evidence that a functional consequence of CNV neurons may be selective vulnerability to aging-related cell death. Age-related cognitive decline is associated with notable decreases in cerebral cortical thickness, myelination, and synapse number accompanied by ex vacuo enlargement in ventricular volume. Although neuronal cell death is generally considered to be minimal in the healthy mature brain, rates of ∼10% cerebral cortical neuron loss during adulthood are consistent with stereological counts in neurotypical individuals. The decline in CNV neuron prevalence that we observe between individuals younger than 30 years old and individuals older than 70 years old is also strikingly consistent with selective CNV neuron loss during a person's adult lifetime. We conclude that the most parsimonious interpretation of these data is that many, but not all, CNV neurons are selectively vulnerable to aging-associated atrophy.

Skeletal muscle has remarkable regenerative capacity, relying on precise coordination between resident muscle stem cells (satellite cells) and the immune system. The age-related decline in skeletal muscle regenerative capacity contributes to the onset of sarcopenia, prolonged hospitalization, and loss of autonomy. Although several age-sensitive pathways have been identified, further investigation is needed to define targets of cellular dysfunction. Autophagy, a process of cellular catabolism, is emerging as a key regulator of muscle regeneration affecting stem cell, immune cell, and myofiber function.

The pharmacological induction of autophagy represents a promising strategy to improve stress resistance and regeneration of skeletal muscle. Spermidine and rapamycin are two examples of drugs that have been studied for their autophagy-inducing effects and lifespan extension in rodent models. While rapamycin acts directly on mTOR, spermidine's polyamine effects on histone acetylation status upregulates various autophagy-related transcripts and suppresses necrosis. The positive benefits of spermidine in muscle tissues of mice and rats have been shown by mitigating age-related muscular atrophy as well as functional myopathies that originate from autophagy failure.

Spermidine also modulates macrophage polarization in mice towards reduced inflammation, though some evidence suggests the autophagy inducing effects of rapamycin more directly target T lymphocytes. Taken together, these agents act as "caloric restriction mimetics" to induce autophagy and contribute to improvements in lifespan of mice. Specifically, the effects of autophagy induction show promise as it related to therapies targeting muscle stem cell myogenic capacity.

Muscle stem cells and monocytes/macrophages are essential for skeletal muscle homeostasis and regeneration. A common theme among these cell populations is the idea that autophagy is a key process that is altered in aged cells leading to functional decline. Autophagy is no longer an emerging regulator of cellular function but has consistently been shown to play a central and important role, especially in the context of aging. Stem cells, in particular, show dysfunctional autophagy during initial stages of activation while caloric restriction and physical activity allow a sensitization to autophagy with beneficial outcomes in cellular activation and function. The exact role for autophagy in muscle regeneration will be complex considering the temporal nature and diverse cell types contributing to the regenerative program. However, global induction of autophagy appears beneficial to the regenerative capacity in the aged muscle. Continuing to uncover the molecular events responsible for age-related perturbations in these pathways is critical for exposing pharmaceutical targets to combat the aging process and improve tissue regeneration in aged individuals.

Based on exercise stress testing performance, the researchers developed a formula to calculate how well people exercise - their "physiological age" - which they call A-BEST (Age Based on Exercise Stress Testing). The equation uses exercise capacity, how the heart responds to exercise (chronotropic competence), and how the heart rate recovers after exercise. "Telling a 45-year-old that their physiological age is 55 should be a wake-up call that they are losing years of life by being unfit. On the other hand, a 65-year-old with an A-BEST of 50 is likely to live longer than their peers."

The study included 126,356 patients referred between 1991 and 2015 for their first exercise stress test, a common examination for diagnosing heart problems. It involves walking on a treadmill, which gets progressively more difficult. During the test, exercise capacity, heart rate response to exercise, and heart rate recovery are all routinely measured. The data were used to calculate A-BEST, taking into account gender and use of medications that affect heart rate.

The average age of study participants was 53.5 years and 59% were men. More than half of patients aged 50-60 years - 55% of men and 57% of women - were physiologically younger according to A-BEST. After an average follow-up of 8.7 years, 9,929 (8%) participants had died. As expected, the individual components of A-BEST were each associated with mortality. Patients who died were ten years older than those who survived. But A-BEST was a significantly better predictor of survival than chronological age, even after adjusting for sex, smoking, body mass index, statin use, diabetes, hypertension, coronary artery disease, and end-stage kidney disease. This was true for the overall cohort and for both men and women when they were analysed separately.

Keeping physically and mentally active in middle age may be tied to a lower risk of developing dementia decades later. The study involved 800 Swedish women with an average age of 47 who were followed for 44 years. At the beginning of the study, participants were asked about their mental and physical activities. Mental activities included intellectual activities, such as reading and writing; artistic activities, such as going to a concert or singing in a choir; manual activities, such as needlework or gardening; club activities; and religious activity.

Participants were given scores in each of the five areas based on how often they participated in mental activities, with a score of zero for no or low activity, one for moderate activity and two for high activity. For example, moderate artistic activity was defined as attending a concert, play or art exhibit during the last six months, while high artistic activity was defined as more frequent visits, playing an instrument, singing in a choir or painting. The total score possible was 10.

Participants were divided into two groups. The low group, with 44 percent of participants, had scores of zero to two and the high group, with 56 percent of participants, had scores of three to 10. For physical activity, participants were divided into two groups, active and inactive. The active group ranged from light physical activity such as walking, gardening, bowling or biking for a minimum of four hours per week to regular intense exercise such as running or swimming several times a week or engaging in competitive sports. A total of 17 percent of the participants were in the inactive group and 82 percent were in the active group.

During the study, 194 women developed dementia. Of those, 102 had Alzheimer's disease, 27 had vascular dementia, and 41 had mixed dementia, which is when more than one type of dementia is present, such as the plaques and tangles of Alzheimer's disease along with the blood vessel changes seen in vascular dementia. The study found that women with a high level of mental activities were 46 percent less likely to develop Alzheimer's disease and 34 percent less likely to develop dementia overall than the women with the low level of mental activities. The women who were physically active were 52 percent less likely to develop dementia with cerebrovascular disease and 56 percent less likely to develop mixed dementia than the women who were inactive.

Soon after the attainment of peak bone mass, the balance between bone resorption and bone formation begins to progressively tilt in favor of the former, in both women and men. Age-related bone loss in mice is associated with an increase in the number of osteoclasts, the cells responsible for degrading the bone matrix. Nonetheless, a decline in bone formation is the seminal culprit of skeletal aging in both humans and rodents. A decrease in the number of osteoblasts, the cells that synthesize the bone matrix, underlies the loss of bone in aged mice. Osteoblasts differentiate from mesenchymal progenitors; the number of these osteoprogenitors declines with advancing age and this decline is associated with increased markers of cellular senescence.

Osteocytes, former osteoblasts buried in the bone matrix, are postmitotic and the most abundant cell type in bone. Osteocytes modulate bone resorption and formation. Earlier findings have elucidated that, like other postmitotic cells, osteocytes in the bone of aged female and male mice show markers of senescence. Several, but not all, senescent cell types exhibit high levels of the cyclin inhibitor p16. For example, senescent osteocytes have increased levels of p16, while senescent osteoblast progenitors have elevated levels of p21, but not p16.

Selective elimination of cells expressing p16 in mouse models increases life- and healthspan. Currently, two of such models have been described: the INK-ATTAC and the p16-3MR mice. Using the p16-3MR model, we have effectively depleted senescent cells in the skin, lungs, muscle, and bone marrow, including senescent hematopoietic and muscle stem cells, and suppressed the senescence-associated secretory phenotype (SASP) in aged mice. It has been found that elimination of p16-expressing cells in 20-month-old mice for a 4-month period, using the INK-ATTAC transgene, increases bone mass. These findings support the notion that senescent cells contribute to age-related bone loss.

However, the identity of the senescent cells that are responsible for skeletal aging remains unknown. Likewise, the extent to which elimination of p16-expressing cells rescues skeletal aging is unknown. Here, we investigated the skeletal effects of long-term ablation of senescent cells using p16-3MR mice - an alternative to the INK-ATTAC model of p16-expressing cell elimination. The key objectives of this work were two: first, to eliminate p16 senescent cells from 12 to 24 months of age, the time period during which C57BL/6 mice experience a dramatic age-related loss of bone mass, and determine whether the experimental maneuver could prevent the loss of bone. And second, to eliminate p16 senescent cells from 20 to 26 months of age in order to determine whether this intervention could restore bone mass in mice that had already lost it.

The activation of the p16-3MR transgene greatly diminished p16 levels in the brain, liver, and osteoclast progenitors from the bone marrow. The age-related increase in osteoclastogenic potential of myeloid cells was also abrogated. However, this did not alter p16 levels in osteocytes - the most abundant cell type in bone - and had no effect on the skeletal aging of p16-3MR mice. These findings indicate that the p16-3MR transgene does not eliminate senescent osteocytes but it does eliminate senescent osteoclast progenitors and senescent cells in other tissues. Elimination of senescent osteoclast progenitors, in and of itself, has no effect on the age-related loss of bone mass. Hence, other senescent cell types, such as osteocytes, must be the seminal culprits.

While there is a lot of talk about the growing income inequality and the increasing gap between the rich and the poor, the difference in overall utility one can get in this life is rapidly decreasing. The rich can get a slightly better package but the net gain in utility will be marginal. One does not fly business class to arrive earlier. The arbitrary separation of classes, ethnic groups, races, and nations is only drawing our attention away from the most important and unsolved challenge - aging. Regardless of how much money you have, you cannot live substantially longer or better. Aging does not discriminate and death comes to us all. Life does not provide a path for continuous improvement. Aging is a universal equalizer.

Effective altruism is the idea that doing good and donating money to worthy causes is really just the start. It is suggested that we use research and reason to make sure our help reaches the most people and has the most impact on their lives. One of the keys to effective altruism, therefore, is to work on the right problems. Imagine for a second that you are a character and life was a video game. How would you know if you're winning? Does your wealth really indicate whether you're good at the game, or just lucky? Can it tell you whether you're even enjoying the game? Would that score say anything about how you improved the game itself, or whether you improved the game for your fellow players?

A better way to check your score at life is a metric called QALY, or quality-adjusted life year. QALY can serve as a universal score because QALY measures both how long you live and how well you live. QALY represents a year of life lived in an optimal healthy state. QALY can also be shared and distributed. For each year that we remain healthy, our acts and our contributions - anything from giving birth to paying taxes to work on scientific advances - could raise their QALY of other people all around the world. We call this optimizing global QALY.

The traditional approach to altruism is to donate accumulated wealth to charities and worthy causes. However, a far more effective way to maximize global QALY is to stay healthy, live longer, direct your wealth intelligently and keep contributing to the world in all the other ways money can't count. So, that means the best way - in fact, the only way - to generate effective altruism and maximize global QALY is to focus on aging and longevity research.

For those of you who are driven to find the most effective way to maximize QALY on a global scale, becoming part of the growing movement to help people live longer and healthier lives is an obvious option. Personally engaging in longevity research, understanding the key concepts, and distributing the resources into longevity and aging projects that maximize global QALY may very well be the most altruistic endeavor you can embark on. The longevity biotechnology is rapidly emerging as an industry with the new funding sources, credible business models, and early successes. There are new ways to measure the rate of aging and new tools to understand the driving mechanisms behind the many debilitating processes will soon emerge as more experimental data becomes available.

Scientists speculate that biologic age may be tied to environmental exposures. If so, it may be a useful indicator of disease risk. They used three different measures, called epigenetic clocks, to estimate biologic age. These clocks measure methylation found at specific locations in DNA. Researchers use these clocks to estimate biologic age, which can then be compared to chronologic age. The researchers used DNA from blood samples provided by women enrolled in the Sister Study, a group of more than 50,000 women in the U.S. and Puerto Rico. The study was specifically designed to identify environmental and genetic risk factors for breast cancer. The research team measured methylation in a subset of 2,764 women, all of whom were cancer-free at the time of blood collection.

"We found that if your biologic age is older than your chronologic age, your breast cancer risk is increased. The converse was also true. If your biologic age is younger than your chronologic age, you may have decreased risk of developing breast cancer. However, we don't yet know how exposures and lifestyle factors may affect biologic age or whether this process can be reversed. If you look at a group of people who are all the same age, some may be perfectly healthy while others are not. That variability in health may be better captured by biologic age than chronologic age."

Alleged certainty: this fallacy consists of concluding something is true because "everybody knows" it is. "Everybody knows" that there are too many people on this planet and therefore rejuvenation is a bad idea; "everybody knows" that life-saving treatments, such as rejuvenation, will always be only for the rich; and so on. Whether or not everybody actually knows these things doesn't matter; what does matter is the evidence used to back them up. For example, overpopulation is not at all a black-and-white issue; whether we're overpopulated depends on the metrics that are taken into account. The best way to counter this fallacy may be simply asking for evidence and pointing out that simply claiming that everyone knows something isn't sufficient proof, especially if the topic is not at all uncontroversial.

Appeal to anger: this fallacy attempts to justify an argument based solely on negative emotions. In the context of life extension, this fallacy is rarely committed alone; it usually hinges on other fallacies or weak arguments that are used as premises. For example, someone might be outraged that you worry about life extension when, allegedly, there are much worse problems than aging in the world, and he might use the supposed outrageousness of life extension to gloss over the fact that aging is a problem, whether or not worse problems than it exist. If someone commits this fallacy, you should kindly point out that the way he feels about a statement or an idea is not what makes it true or false. Whether we're outraged by something doesn't mean that we can discount it.

Appeal to authority: the infamous appeal to authority involves believing a claim solely because the person who made it is in a position of authority or prestige. When discussing rejuvenation, the appeal to authority fallacy is sometimes observed when people say that rejuvenation isn't possible or that some possible negative consequences of it are certain because an expert said so. The expert in question might well be right, but in order to establish it, his evidence must be examined to make sure that he isn't genuinely mistaken or doesn't have some other reason to make an unsubstantiated claim. Explain that everyone can make a mistake, no matter how smart, authoritative, or knowledgeable he may be. You don't take for granted what Albert Einstein said because he was one of the greatest physicists of all time; his claims, too, need proof, and until said proof is presented and verified, you can't say whether the claim is true or false.

Appeal to motive: this fallacy consists of dismissing an idea on the grounds of the motives of its proponent. A typical life extension-related example is that of patient-funded clinical trials. At such an early stage, experimental rejuvenation therapies are indeed expensive, and governments may not be willing to pay for what seems like a moon shot. Thus, wealthy people willing to pay to try the therapies are effectively making it easier to test them. Some people may argue that wealthy people are doing this not to help the research but for their own benefit; consequently, they feel outraged and despise the idea of patient-funded trials entirely, deeming it nothing but proof that rejuvenation is only for the rich. Explain that anyone's motives for endorsing an idea are irrelevant when assessing whether the idea is good or not. It may help if you explain that you too disagree with the motives of people who push life extension only for their own interest but that life extension is a worthy goal per se.

Appeal to nature: the appeal to nature fallacy consists of implying that everything that is natural is better than everything that is not natural. In the context of life extension, you can expect to encounter this fallacy as the most classical of objections, the one and only "but aging is natural, while rejuvenation is not!" This fallacy is why people infer that aging is better or more desirable than using rejuvenative therapies to avoid it-which is not unlike saying that having cancer is better than using immunotherapy to cure it. The appeal to nature fallacy is easily countered with examples of undesirable yet perfectly natural things that we suffer from and desirable yet unnatural things that we use every day. Depending on how entrenched someone is, you can expect that person to resort to a double standard right after - "yes, but with aging, it's different." It is not. The bottom line is that naturalness is not a sufficient criterion to judge whether or not is something is good or desirable, regardless of what that thing may be.

A phase 3 trial of GenSight Biologics' Leber hereditary optic neuropathy (LHON) gene therapy has missed its primary endpoint. The AAV gene therapy was no better than placebo at improving vision at 48 weeks, leading GenSight to look to future updates to salvage the study. GenSight designed GS010 to improve the vision of patients with a particular mutation in the mitochondrial ND4 gene and moved the gene therapy into a pair of phase 3 trials in 2016. One trial enrolled patients who had suffered vision loss for 6 to 12 months. The other recruited people whose vision loss began less than six months ago. Both trials missed their primary endpoints.

The latest clinical setback involves LHON patients with six months or less of vision loss enrolled in the RESCUE trial. As in the other study, GenSight set out to link GS010 to a 15-letter improvement over placebo on a vision test. Each subject received GS010 in one eye and a sham injection in the other. This time around, the eyes treated with GS010 deteriorated by 19 letters over the first 48 weeks of the trial, compared to a 20-letter decline in the control cohort. The top-line figures hide a trend that shows vision in both arms of the trial declined before improving. Eyes treated with GS010 improved by 13 letters from their low point, while the placebo group recorded an 11-point improvement.

The trial failed to show GS010 is statistically superior to placebo against secondary endpoints, too. After 48 weeks, GS010 statistically had no more effect on the temporal retinal nerve fiber layer, papillomacular bundle thickness and ganglion cell volume than placebo. While GS010 outperformed the sham treatment on some other measures, the overall data set offers little encouragement that the gene therapy is effective at 48 weeks. The question is whether it will become effective as more weeks pass. GenSight thinks it will, in part because of its experience with the other phase 3 trial.

One reason behind many unsuccessful cancer treatments is the cancers' ability to hijack the immune system to support its own growth. This is assisted by the so-called tumour-associated macrophages that can be educated by cancer cells to dampen anti-tumour immune responses. Macrophages are phagocytes that form the first line of defence towards invading pathogens and they have a crucial role in maintaining tissue homeostasis. Macrophages have a large repertoire of functions in immune activation and resolving inflammation.

Researchers investigated the possibility to utilise tumour-associated macrophages to increase the immunological detection and killing of cancer cells. Previously, it was observed that Clever-1 controls leukocyte trafficking between tissues. A new study found that blocking Clever-1 function on macrophages activated the immune system and was highly effective in inhibiting cancer progression. By inhibiting Clever-1 functions, tumour-associated macrophages that normally impair adaptive immune cell activation, such as cancer cell killing by cytotoxic T cells, were managed to be re-educated so that they had increased ability to present antigen and secrete pro-inflammatory cytokines leading to increased activation of killer T cells.

The antibody therapy targeting Clever-1 worked in the studied tumour mouse models as efficiently as the PD-1 antibody therapy that is in clinical use. The PD-1 antibody maintains the functionality of the killer T cells. It is notable that the Clever-1 antibody therapy targeting macrophages also increased the activity of the killer T cells efficiently. In certain mouse models of cancer, a combination of anti-Clever-1 and anti-PD-1 therapies prevented tumour growth and formation of metastases more effectively than either treatment alone.

Aging is related to progressive deterioration of central nervous system function and contributes to the pathogenesis of neurodegenerative disease. Previous studies have implicated alterations in the molecular mechanisms of aging with changes in the brain environment such as abnormal aggregation of proteins, neuronal loss, neuroinflammation, and cognitive deficits. The dysfunctions in aging could lead to neurodegenerative disease including mild cognitive impairment, cerebrovascular disease, Parkinson's disease, and Alzheimer's disease. In particular, disruption of the blood-brain barrier (BBB) is one of several major pathological features of these age-related neurodegenerative diseases. Moreover, many studies have demonstrated that BBB dysfunction may be a cause or consequence of neurodegeneration.

Acid sphingomyelinase (ASM), encoded by the Smpd1 gene, plays an important housekeeping role in sphingolipid metabolism and is known to regulate cell apoptosis, proliferation, and differentiation. Although ASM is expressed in virtually all cell types under normal conditions, ASM secreted from endothelial cells (ECs) is significantly associated with numerous diseases. ECs are the major cell type forming the BBB, along with pericytes and astrocytes, and the interaction between ECs and other neuronal cells is critical for the maintenance of neurological health in the brain. Previous studies have suggested that an increase in ASM activity may contribute to age-related brain damage. Nevertheless, the specific role of ASM in maintaining the integrity of the BBB and/or age-related neurodegeneration remains unclear.

In a recent study, we for the first time demonstrated that ASM derived from ECs plays a central role in aging-induced BBB disruption and neurodegeneration. Higher ASM activity was detected in plasma from older individuals (65-90 years) compared with plasma from their younger counterparts (24-45 years). We also confirmed similar results in plasma derived from old mice (20-months). The robust elevation in ASM levels in the brains of old mice was associated with microvessels, and ECs derived from microvessels were the main contributors for elevated ASM activity. These results indicated that ASM activity increased in aged plasma and brain ECs, and could affect brain dysfunction in the process of aging.

Old Smpd1 +/- mice, in which ASM is genetically inhibited, exhibited a significant reduction in ASM activity in the plasma and brain ECs. In addition, capillary density in the brains of older mice was decreased by EC death, while old Smpd1 +/- mice exhibited higher capillary density. BBB permeability was also increased in the brains of old mice. In contrast, a substantial decrease in permeability in old Smpd1 +/- mice was observed. Moreover, the leakiest vessels in the brain did not exhibit an apoptotic signal in both old mice and old Smpd1 +/- mice, indicating that the death of ECs caused by ASM was not the main cause of BBB disruption in aging.

In conclusion, our findings suggest a central role for ASM as a regulator of BBB integrity and neuronal function in aging, as well as highlight the potential of ASM as a drug target for anti-aging. To date, few inhibitors that can directly inhibit ASM have been found; nevertheless, highly potent and selective ASM inhibitors are anticipated to be developed in the future. Therefore, further studies investigating the development of functional ASM inhibitors may be highly valuable for understanding the anti-aging process and for the treatment of various age-related neurodegenerative diseases.

Aging is characterized by a progressive loss of physiological integrity and function over time. Being the largest risk factor for the incidence of cancer, cardiovascular, and neurological diseases, it results from several interconnected molecular processes that decline with advancing age and that are commonly categorized in nine "aging hallmarks". Among these hallmarks, which are nevertheless interdependent, epigenetic alterations and cellular senescence have gained increased relevance, as they have been modulated by the current mainstream anti-aging therapies.

Although a single universal marker for cellular senescence is still to be unveiled, senescent cells present several distinguishing features in vitro, such as flattened morphology and enlarged nuclear size, and increased senescence-associated β-galactosidase (SA-β-Gal) activity. Moreover, cellular senescence is accompanied by the development of a senescence-associated secretory phenotype (SASP), a distinctive cell-specific secretome. There has been intensive research examining the regulatory mechanisms behind cellular senescence and SASP. It is now clear that this occurs on two fronts; while p53 and pRB are responsible for halting cell cycle progression during cell senescence, the regulation of the secretory component seems to be mainly mediated by the NF-κB signaling pathway.

For several decades, many observations have demonstrated an incidence of aneuploidy along human chronological aging. Aneuploidy is defined as an abnormal chromosome number resultant from chromosome mis-segregation during cell division, in both gametes and somatic cells. The molecular mechanisms behind the age-associated aneuploidy globally point to alterations in the expression levels of genes that are involved in the cell cycle and in the mitotic apparatus. Interestingly, genomic instability, telomere erosion, epigenetic drift, and defective proteostasis, which are the primary hallmarks of aging acting as initiating triggers leading to secondary hallmarks, have all been reported to induce mitotic defects and aneuploidization. Moreover, aneuploidy resulting from lagging chromosomes/weakened mitotic checkpoint has been associated with cellular senescence and premature aging.

While we are left to learn more what a truly senescent cell is, if there is the need of long- or short-term clearance from the organism, and, more importantly, if we can rescue the still proliferative "pre-senescent" cells. In this context, a new candidate hallmark for aging arises, aneuploidy, an abnormal chromosomal number that results from mis-segregation events during mitosis, which has been linked to normative aging and age-associated diseases, with the underlying mechanisms being poorly understood. Recently, aneuploidy was shown to increase with advancing age due to an overall dysfunction of the mitotic machinery. Furthermore, several reports have uncovered the impact of aneuploidy on cellular fitness and proliferative capacity, with several characteristics of aneuploid cells overlapping with those that are found in aged cells.

Our latest work provided insight as to how senescent cells arise, by demonstrating that elderly proliferative cells, primed with the expression of a senescence core gene signature, evolved into permanent cell cycle arrest (full senescence) following passage through a faulty mitosis. This further supports that improving mitotic fitness may be used as a potential anti-aging strategy, thereby counteracting the SASP-induced inflammatory microenvironment and helping to protect stem cell and parenchymal cell functions.