Fight Aging! Newsletter, January 28th 2019

Juvenescence has raised the first 46 million tranche of series B financing en route to an anticipated 100 million round. The investment, which values Juvenescence at 400 million, tees the anti-aging startup to advance the multiasset pipeline it has built over the past 18 months toward readouts. Jim Mellon, a British billionaire biotech investor, created Juvenescence with early Medivation backer Greg Bailey and three others in 2017. Since then, the founders have used their cash and contacts to turbocharge the growth of Juvenescence with 115 million in investment. Juvenescence expects that figure to rise in the coming months when it closes the next tranche of a forecast 100 million round.

The rapid fundraising, and mooted 2019 IPO, reflect Juvenescence's belief that it is in the early stages of a longevity land grab. By pulling in handfuls of money, Juvenescence has been able to pen a string of deals and position itself to support the programs through to important readouts. Juvenescence already has its fingers in lots of pies. Using its early funding, the startup licensed assets from the Buck Institute for Research on Aging, bought controlling stakes in AgeX Therapeutics and LyGenesis - a pair of regenerative medicine players - formed artificial intelligence joint ventures with Insilico Medicine and Netramark and invested 10 million in a small molecule senolytics program.

Life Biosciences will on Monday announce the completion of a 50M funding round - twice its original target - to invest in a range of approaches to extending healthy life. "We have undertaken a big land-grab of longevity-related intellectual property and we have pulled together a lot of the world's longevity scientists." Longevity is a rapidly expanding sector of the biotech industry, as scientists learn more about the way biological pathways fail in old age. Investors in Life Biosciences are mainly wealthy individuals and family trusts, reflecting a widespread view that ageing millionaires are keen to put some of their money into longevity research.

Life Biosciences had quietly raised 25M in an early financing round in 2017. It declined to disclose the company's current value but others familiar with the latest fundraising estimated the valuation at about 500M. "We are tackling all eight pathways of age-related decline." These include cellular senescence, stem cell exhaustion, and dysfunction in mitochondria (the energy-generating units in cells). Six "daughter companies" work semi-independently on different development projects. One such company, Senolytic Therapeutics, is developing compounds and technologies that target senescent cells. Researchers believe that destroying these "zombie" cells will counteract some of the adverse effects of ageing.

In multiple sclerosis (MS), a disease that strips away the sheaths that insulate nerve cells, the body's immune cells come to see the nervous system as an enemy. Some drugs try to slow the disease by keeping immune cells in check, or by keeping them away from the brain. But for decades, some researchers have been exploring an alternative: wiping out those immune cells and starting over. The approach, called hematopoietic stem cell transplantation (HSCT), has long been part of certain cancer treatments. A round of chemotherapy knocks out the immune system and an infusion of stem cells - either from a patient's own blood or, in some cases, that of a donor - rebuilds it. The procedure is already in use for MS and other autoimmune diseases at several clinical centers around the world, but it has serious risks and is far from routine. Now, new results from a randomized clinical trial suggest it can be more effective than some currently approved MS drugs.

Nearly 30 years ago, when hematologist Richard Burt saw how HSCT worked in patients with leukemia and lymphoma, he was struck by a curious effect: After those patients rebuilt their immune systems, their childhood vaccines no longer protected them. Without a new vaccination, the new immune cells wouldn't recognize viruses such as measles and mumps and launch a prompt counterattack. That suggested that in the case of an autoimmune disease, reseeding the immune system might help the body "forget" that its own cells were the enemy.

Burt and others have since used HSCT for a variety of autoimmune diseases, including rheumatoid arthritis and lupus. In the past few years, several teams have reported encouraging results in MS. But only one study - which evaluated just 17 patients - directly compared HSCT to other available drug treatments. In the new trial, Burt and his colleagues recruited 110 people with the most common form of MS, known as relapsing-remitting. In that form of the disease, patients can go long periods without symptoms - which include muscle weakness and vision problems - before inflammation flares up. Trial participants had at least two such relapses in the previous year, despite being on one of several approved MS drugs.

Half the participants continued with drug treatment but switched from a drug that wasn't working for them to a drug of a different class. The other half underwent HSCT. First, the researchers collected their blood to reinfuse later. Then, they gave patients a combination of drugs to kill most of their immune cells. In this trial, the patients would have regenerated their own immune systems with stem cells in bone marrow that were spared annihilation. But they received the reinfusion of their own stem cell-rich blood to help speed recovery by several days. A year later, the researchers evaluated how far the disease had progressed in each of the patients. According to a zero-to-10 scale of disability that includes measures of strength, coordination, and speech, roughly 25% of those in the drug treatment group showed at least a one-point worsening in their score, compared with just 2% of those in the transplant group. MRI scans also revealed less extensive brain lesions in the transplant group and improvements in a patient survey about quality of life. Five years after treatment, about 15% of people in the transplant group had had a relapse, versus about 85% of the control group.

T cell therapies, including CAR T-cell therapy, have shown great promise for treating certain types of cancer. Current approaches involve collecting T cells from a patient, genetically engineering the T cells with a receptor that helps them recognize and destroy cancer cells, and then infusing the cells back into the patient. But engineered T cells do not always function well, treatment is expensive because it is tailored to each patient, and some people with cancer don't have enough T cells to undergo the therapy. Therefore, a technique that produces T cells without relying on collecting them from patients is an important step toward making T cell therapies more accessible, affordable and effective.

Other researchers have been only partially successful in their attempts to generate T cells using methods that involve combining pluripotent stem cells with a layer of supporting cells. But the T cells produced in those previous studies did not mature to become fully functional T cells. However, it was demonstrated that the 3D structure of an artificial thymic organoid allowed mature T cells to develop from adult blood stem cells. A new study now demonstrates the use of such organoids to coax pluripotent stem cells - which can give rise to every cell type in the body and which can be grown indefinitely in the lab - into becoming mature T cells capable of killing tumor cells.

The research demonstrated that artificial thymic organoids can efficiently make mature T cells from both kinds of pluripotent stem cells currently used in research: embryonic stem cells, which originate from donated embryos, and induced pluripotent stem cells, which are created by reprogramming adult skin or blood cells back to an embryonic-like state. The researchers also showed they could genetically engineer pluripotent stem cells to express a cancer-targeting T cell receptor and, using artificial thymic organoids, generate T cells capable of targeting and killing tumor cells in mice.

Engineered T cell therapies hold promise for the effective treatment of cancer and chronic viral infections. The ability to generate T cells on demand from self-renewing human pluripotent stem cells (PSC) may substantially advance the cell therapy field by permitting production of universal-donor T cells from stably gene-modified PSC lines. Although protocols to differentiate PSC into essentially any non-hematopoietic or hematopoietic lineage have been extensively reported, generation of fully functional mature T cells that resemble their adult counterparts has been more problematic. Differentiation of T cells from human PSCs has been limited on two fronts: the ability to specify hematopoietic progenitor cells with T-lineage potential, and the capacity of existing methods to support the positive selection and maturation of T-lineage committed precursors to conventional, naive T cells.

We recently reported that a three-dimensional (3D) artificial thymic organoid (ATO) culture system permits in vitro differentiation of human HSPCs to functional, mature T cells using a standardized Notch ligand-expressing stromal cell line in serum-free conditions. Notably, we observed that both the medium and the 3D structure were critical. We report here that a modified ATO system (PSC-ATO) permits the differentiation of human embryonic stem cell (ESC) and induced pluripotent stem cell (iPSC)-derived human embryonic mesodermal progenitors (hEMPs) to mature, conventional T cells in vitro.

Longevity Escape Velocity (LEV) is the minimum rate of medical progress such that individual life expectancy is raised by at least one year per year if medical interventions are used. This does not refer to life expectancy at birth; it refers to life expectancy calculated from a person's statistical risk of dying at any given time. This is equivalent to saying that a person's expected future lifetime remains constant despite the passing years. It's possible, given sufficient ongoing improvement of medicine and its democratisation, that nearly everyone on the planet, at a certain date in the future, will benefit from therapies that allow Longevity Escape Velocity to be attained, at least until aging is eradicated completely.

If a given intervention "saves a life", this usually means that it averts 30 to 80 Disability-Adjusted Life Years (DALYs). This figure comes up from the remaining life expectancy of the recipients of the intervention. In order to evaluate the impact of aging research, one could be tempted to try to estimate how many end-of-life DALYs that a possible intervention resulting from the research could save and adjust the number using the probability of success of the research.

This line of reasoning is part of the impact, and it has to be factored in, but it doesn't consider where the largest impact of aging research is: making the date of Longevity Escape Velocity come closer. This would have the effect of saving many lives from death due to age-related decline and disease, but here, "a life" means, more or less, 1000 Quality-Adjusted Life Years (QALYs). The average lifespan of a person who reached LEV will be around 1000 years, mostly without disability, as 1/1000 is more or less the current risk of death of someone between 20 and 30 years old.

We are highly uncertain about, and do not have internal consensus regarding, the potential extension in healthy lifespan that might result if one or two of the present major objectives in anti-aging research were accomplished. Some of us see several years of healthy life extension as the plausible potential upside and others see larger possible gains, but all of us involved in creating this report expect that any increase in healthy lifespan would keep average lifespan within the range of natural lifespans observed in humans today (barring a historically exceptional increase in the rate of scientific progress).

We think the best case for this cause involves the prospect of healthy life extension within the range that some humans currently live. In contrast, some people who are interested in the mechanisms of aging have promoted the idea of "curing" aging entirely. Our default view is that death and impairment from "normal aging" are undesirable. However, we would have some concerns about indefinite life extension, mainly related to entrenchment of power and culture. We don't have internal consensus on whether, and to what extent, such indefinite life extension would be desirable, and don't consider it highly relevant to this write-up. We don't see promising life science research that would result in indefinite life extension in the next few decades, barring a historically exceptional increase in the rate of scientific progress.

Our program officer offers the following forecast to make the above more precise/accountable: By January 1, 2067, there will be no collection of medical interventions for adults that are healthy apart from normal aging, which, according to conventional wisdom in the medical community, have been shown to increase the average lifespan of such adults by at least 25 years, compared with not taking the interventions.

A simple blood test reliably detects signs of brain damage in people on the path to developing Alzheimer's disease - even before they show signs of confusion and memory loss. The test detects neurofilament light chain, a structural protein that forms part of the internal skeleton of neurons. When brain neurons are damaged or dying, the protein leaks out into the cerebrospinal fluid that bathes the brain and spinal cord and from there, into the bloodstream.

Finding high levels of the protein in a person's cerebrospinal fluid has been shown to provide strong evidence that some of their brain cells have been damaged. But obtaining cerebrospinal fluid requires a spinal tap, which many people are reluctant to undergo. Here, researchers studied whether levels of the protein in blood also reflect neurological damage. To find out whether protein blood levels could be used to predict cognitive decline, the researchers collected data on 39 people with disease-causing variants when they returned to the clinic an average of two years after their last visit. The researchers found that people whose blood protein levels had previously risen rapidly were most likely to show signs of brain atrophy and diminished cognitive abilities when they revisited the clinic. "It will be important to confirm our findings in late-onset Alzheimer´s disease and to define the time period over which neurofilament changes have to be assessed for optimal clinical predictability."

A new study shows that harmful single tau molecules take different shapes that each correlates to a distinct type of larger assembly that will form and self-replicate across the brain. Researchers had already established that the structure of larger tau assemblies determines which type of dementia will occur - which regions of the brain will be affected and how quickly the disease will spread. But it was unknown what specified these larger structures. The new research reveals how a single tau molecule that changes shape at the beginning of the disease process contains the information that determines the configuration of the larger, toxic assemblies. This finding suggests that characterization of the conformation of single tau molecules could predict what incipient disease is occurring - Alzheimer's or other types of dementia.

The team is trying to translate these findings into clinical tests that examine a patient's blood or spinal fluid to detect the first biological signs of the abnormal tau, before the symptoms of memory loss and cognitive decline become apparent. The researchers are also working to develop treatments to stabilize shape-shifting tau molecules, prevent them from assembling, or promote their clearance from the brain.

The blood-brain barrier is a filtration system, letting in good things (glucose, amino acids) and keeping out bad things (viruses, bacteria, blood). It's mostly comprised of endothelial cells lining the 400 miles of arteries, veins, and capillaries that feed our brains. Some evidence indicates that leaks in the blood-brain barrier may allow a protein called amyloid into the brain where it sticks to neurons. This triggers the accumulation of more amyloid, which eventually overwhelms and kills brain cells.

"Cognitive impairment, and accumulation in the brain of the abnormal proteins amyloid and tau, are what we currently rely upon to diagnose Alzheimer's disease, but blood-brain barrier breakdown and cerebral blood flow changes can be seen much earlier. This shows why healthy blood vessels are so important for normal brain functioning." Blood-brain barrier leaks can be detected with an intravenously administered contrast substance in concert with magnetic resonance imaging. Brain microbleeds, another sign of leakage, also can be picked up with MRI. A slowdown in the brain's uptake of glucose, visible via PET scan, can be a another result of blood-brain barrier breakdown.

Researchers examined saliva samples from three sets of patients, those with Alzheimer's disease, those with mild cognitive impairment, and those with normal cognition. Using a powerful mass spectrometer, they examined more than 6,000 metabolites - compounds that are part of our body's metabolic processes - to identify any changes or signatures between groups. "In this analysis, we found three metabolites that can be used to differentiate between these three groups. This is preliminary work, because we've used a very small sample size. But the results are very promising. If we can use a larger set of samples, we can validate our findings and develop a saliva test of Alzheimer's disease. So far, no disease-altering interventions for Alzheimer's disease have been successful. For this reason, researchers are aiming to discover the earliest signals of the disease so that prevention protocols can be implemented."

The human gut harbors trillions of bacteria (known as the gut microbiota), which play important roles in health and diseases. Several recent studies have characterized the human gut microbiome in the elderly. Gut microbial diversity generally decreases when people age, which is likely due to changes in physiology, diet, medication, and lifestyles. Decreased diversity, considered an indicator of an unhealthy microbiome, has been linked to different chronic conditions such as obesity and type 2 diabetes. In addition to decreased diversity, the changes of the gut microbiome composition to an imbalanced state, i.e. dysbiosis, also correlates with frailty, inflammation, and neurodegenerative disorders.

Given the fact that most of the elderly experience gut associated comorbidities, it is extremely challenging to define a healthy gut microbiome in this population. Changes in the gut environment such as inflammation, leaky gut, production of reactive oxygen species and application of medications can all affect the gut microbiome. In that regard, centenarians have been used as a model of healthy aging because of their capability to delay or avoid chronic diseases. Therefore, the gut microbiome in this cohort might be used to define a healthy gut microbiome. The genetics, and recently epigenetics, of the centenarians have been extensively investigated, but relatively little is known about their gut microbiotas until now.

Researchers examined the gut microbiome of a cohort of healthy, long-living Chinese individuals including nonagenarians (90-99 years old) and centenarians (older than 100). They found that this cohort of long-living people possesses a more diverse gut microbiota than younger adults, contradictory to conventional views. They also found that a group of bacteria, members of which are known short-chain fatty acid (SCFA) producers such as Clostridium cluster XIVa, are enriched in the long-living Chinese. To verify their discovery, they analyzed an independent Italian data set. Consistently, the long-living Italians also had more diverse gut microbiotas than the younger group. When they combined the Italian and the Chinese data sets, they found that although the gut microbiota structures are significantly different, probably due to the differences in diet, genetics, and environment, 11 of the top 50 bacterial features that differentiate the long-living individuals from the younger group were shared.

These studies clearly revealed that more diverse and balanced gut microbiotas are present in healthy, long-living people, whereas disturbed gut microbiotas with dysbiosis are observed in the elderly who suffer from different comorbidities. We thus hypothesize that modulation of the gut microbiome to maintain a healthy gut microbiome will promote healthy aging. One rationale behind this hypothesis is inflammaging, i.e. increased chronic, low-grade inflammation in the elderly, which is associated with different chronic diseases. SCFAs are important in maintaining gut homeostasis. SCFAs provide the primary energy for colon epithelial cells and possess anti-inflammation properties. The enrichment of these SCFA producers in long-living individuals suggests that these bacteria might reduce inflammation and its resulting damage in this cohort, which likely contributed to their healthy aging.

The adult brain can generate new neurons from neural stem cells. The process of neurogenesis occurs throughout life primarily in the dentate gyrus of the hippocampus and the subventricular zone (SVZ). This process is highly regulated, and although the signals that control neurogenesis are not yet fully understood, it is known that neurogenesis declines with age, suggesting that the neurogenic signals are susceptible to age-related deficits observed elsewhere in the brain.

Calorie restriction is one mechanism by which age-related deficits may be reduced in aged animals. Calorie restriction can markedly increase mean and maximum lifespan and improve physiologic markers of health, including insulin sensitivity, body mass index, and plasma markers of cardiovascular disease. Calorie restriction has beneficial effects in blood and muscle stem cell function, and can protect against neuronal damage in neurodegenerative models. In the hippocampus, calorie restriction enhances proliferation of progenitor cells, although whether these newly born cells survive and mature into neurons is not clear.

Chronic inflammation is a known factor in aging, suggesting that inflammatory cells likely contribute to the development of deficits in the aging brain. Cellular senescence is a phenomenon by which cellular division ceases in the aged organism, and is modifiable in laboratory models. Inflammation is associated with senescence in in vitro models because senescent cells secrete pro-inflammatory cytokines.

In this study, we show that calorie restriction is protective against age-related increases in senescence and microglia activation and pro-inflammatory cytokine expression in an animal model of aging. Further, these protective effects mitigated age-related decline in neuroblast and neuronal production, and enhanced olfactory memory performance, a behavioral index of neurogenesis in the SVZ. Our results support the concept that calorie restriction might be an effective anti-aging intervention in the context of healthy brain aging.

Older adults who move more than average, either in the form of daily exercise or just routine physical activity such as housework, may maintain more of their memory and thinking skills than people who are less active than average, even if they have brain lesions or biomarkers linked to dementia. "We measured levels of physical activity in study participants an average of two years prior to their deaths, and then examined their donated brain tissue after death, and found that a more active lifestyle may have a protective effect on the brain. People who moved more had better thinking and memory skills compared to those who were more sedentary and did not move much at all."

The study assessed 454 older adults; 191 had dementia and 263 did not. All participants were given physical exams and thinking and memory tests every year for 20 years. The participants agreed to donate their brains for research upon their deaths. The average age at death was 91 years. At an average of two years before death, researchers gave each participant an activity monitor called an accelerometer. The wrist-worn device monitored physical activity around the clock, including everything from small movements such as walking around the house to more vigorous activity like exercise routines. Researchers collected and evaluated seven days of movement data for each participant and calculated an average daily activity score. The results were measured in counts per day, with an overall average of 160,000 counts per day.

People without dementia had an average of 180,000 counts per day, and people with dementia had an average of 130,000 counts per day. Researchers found that higher levels of daily movement were linked to better thinking and memory skills. The study also found that people who had better motor skills - skills that help with movement and coordination - also had better thinking and memory skills. For every increase in physical activity by one standard deviation, participants were 31 percent less likely to develop dementia. For every increase in motor ability by one standard deviation, participants were 55 percent less likely to develop dementia.

Pathologically, Alzheimer's disease (AD) brains harbor amyloid plaques that contain extracellularly deposited amyloid β (Aβ) from cleaved amyloid precursor protein, and neurofibrillary tangles formed by intracellular accumulation of hyperphosphorylated and misfolded tau protein. These characteristic entities inspired a leading theory that centers on the loss of proteostasis within the brain, which instigates the pathogenic course of AD. The Amyloid Cascade Hypothesis has guided numerous studies in the past two decades, which helped reveal insights of the neuronal properties and pathological events initiated by Aβ and subsequently by tau aggregation.

However, it is clear that late-onset Alzheimer's disease (LOAD) is collectively modified by numerous genetic factors that govern diverse cellular and molecular pathways, including many genes involved in the immune responses. Consequently, the Neuroinflammation Hypothesis emphasizes the dysregulation of central nervous system (CNS) immune response as a key factor in the etiology of neurodegenerative diseases. In recent years, neuroinflammation is increasingly recognized as an integral and critical contributor in AD pathogenesis.

The role played by the immune system in AD pathogenesis is prominent but is by no means limited to the brain. Copious evidence from clinical and experimental research suggests an influential, yet largely underappreciated, force in AD pathogenesis: systemic immune signals originating outside the brain. Despite genetic evidence implicating adaptive immunity in AD, it remains ill-defined how adaptive immune cells with limited presence inside the parenchyma exert their effects on AD pathologies and cognitive functions. Nevertheless, T cells have been shown to participate in other neurodegenerative diseases, such as Parkinson's disease and amyotrophic lateral sclerosis.

Many inconsistent results have been reported on the impacts of T cell subsets on CNS pathogenesis in Aβ-based experimental models. Noticeably missing at this time is the examination of tau-specific T cells and the possible involvement of Treg cells in tau pathology, a major gap in understanding the participation of the adaptive immune arm in AD pathogenesis. Despite the technical challenge to study rare cells, new technologies such as high-dimensional single-cell analysis should significantly improve the quantification and classification of diverse immune cell populations in the AD brain. Whether T cells and B cells, self-reactive or bystanders, afford protective immune surveillance or pathogenic immune attack requires thorough delineation.

Cellular senescence refers to a process induced by various types of stress that causes irreversible cell cycle arrest and distinct cellular alterations, including profound changes in gene expression, metabolism, and chromatin organization as well as activation/reinforcement of anti-apoptotic pathways and development of a pro-inflammatory secretome or senescence-associated secretory phenotype (SASP). However, because of challenges and technical limitations in identifying and characterizing senescent cells in living organisms, only recently have some of the diverse in vivo roles of these unique cells been discovered.

New findings indicate that senescent cells and their SASP can have acute beneficial functions, such as in tissue regeneration and wound healing. However, in contrast, when senescent cells accumulate in excess chronically at sites of pathology or in old tissues they drive multiple age-associated chronic diseases. Senotherapeutics that selectively eliminate senescent cells ("senolytics") or inhibit their detrimental SASP ("senomorphics") have been developed and tested in aged preclinical models. These studies have established that targeting senescence is a powerful anti-aging strategy to improve "healthspan" - i.e., the healthy period of life free of chronic disease.

The roles of senescence in mediating age-related bone loss have been a recent focus of rigorous investigation. Studies in mice and humans demonstrate that with aging, at least a subset of most cell types in the bone microenvironment become senescent and develop a heterogeneous SASP. Furthermore, age-related bone loss can be alleviated in old mice, with apparent advantages over anti-resorptive therapy, by reducing the senescent cell burden genetically or pharmacologically with the first class of senolytics or a senomorphic. Collectively, these findings point to targeting senescence as a transformational strategy to extend healthspan, therefore providing strong rationale for identifying and optimizing senotherapeutics to alleviate multiple chronic diseases of aging, including osteoporosis, and set the stage for translating senotherapeutics to humans, with clinical trials currently ongoing.

The death rate from cancer in the US has declined steadily over the past 25 years. As of 2016, the cancer death rate for men and women combined had fallen 27% from its peak in 1991. This decline translates to about 1.5% per year and more than 2.6 million deaths avoided between 1991 and 2016. The drop in cancer mortality is mostly due to steady reductions in smoking and advances in early detection and treatment. A total of 1,762,450 new cancer cases and 606,880 deaths from cancer are expected to occur in the US in 2019. During the most recent decade of available data (2006 - 2015), the rate of new cancer diagnoses decreased by about 2% per year in men and stayed about the same in women. The cancer death rate (2007 - 2016) declined by 1.4% per year in women and 1.8% per year in men.

The most common cancers diagnosed in men are prostate, lung, and colorectal cancers. Together, they account for 42% of all cases in men, with prostate cancer alone accounting for nearly 1 in 5 new cases. For women, the 3 most common cancers are breast, lung, and colorectal. Together, they account for one-half of all cases, with breast cancer alone accounting for 30% of new cases. These cancers also account for the greatest numbers of cancer deaths. One-quarter of all cancer deaths are due to lung cancer.

Lung cancer death rates declined 48% from 1990 to 2016 among men and 23% from 2002 to 2016 among women. From 2011 to 2015, the rates of new lung cancer cases dropped by 3% per year in men and 1.5% per year in women. The differences reflect historical patterns in tobacco use. Breast cancer death rates declined 40% from 1989 to 2016 among women. The progress is attributed to improvements in early detection. Colorectal cancer death rates declined 53% from 1970 to 2016 among men and women because of increased screening and improvements in treatment.

Adults ages 85 and older represent the fastest-growing population group in the US. The group's numbers are expected to nearly triple from 6.4 million in 2016 to 19 million by 2060. Cancer risk increases with age, and the rapidly growing older population will increase demand for cancer care. People ages 85 and older represent 8% of all new cancer diagnoses, translating to about 140,690 cases in 2019. Cancer is the second-leading cause of death in the oldest old, following heart disease. 103,250 cancer deaths among this age group are expected in 2019, accounting for 17% of all cancer deaths. As of January 1, 2019, an estimated 1,944,280 people ages 85 and older were cancer survivors, representing 1/3 of all the men and 1/4 of all the women in this age group. They are the fastest-growing group of cancer survivors. Among adults age 85 with no history of cancer, the risk of a cancer diagnosis in their remaining lifetime is 16.4% for men and 12.8% for women.

Macrophages are immune cells just like T cells and B cells, but differ in that they can eat cells that are not supposed to be in the body. In fact, they are the most prominent immune cell found in cancer, but unfortunately, most are often convinced to help cancer grow and spread. Cancer cells frequently stop macrophages from attacking them by expressing CD47, a "don't eat me" signal. Researchers now say that merely blocking inhibitory signals like CD47 is not always sufficient to convince macrophages to attack cancer. Instead, two signals are required. First, they need a signal to activate them - such as a toll-like receptor agonist. After that, a second signal - such as a CD47 inhibitor - can lower the threshold needed to wage battle on the cancer.

The team used this approach by activating macrophages with CpG, a toll-like receptor agonist that sends the first signal, and found that it rapidly induced shrinkage of tumors and prolonged survival of mice even without the requirement of T cells. Unexpectedly, they also found that the activated macrophages were able to eat cancer cells even in the presence of high levels of CD47.

To understand the molecular basis of this phenomenon, the team traced the metabolic activity of macrophages and determined that activated macrophages began to utilize both glutamine and glucose as fuel to support the energy requirements needed for them to eat cancer cells. This rewiring of the macrophages metabolism was necessary for CpG to be effective, and the researchers say these findings point to the importance of macrophage metabolism in determining the outcome of an immune response. "It is the metabolism that ultimately allows macrophages to override signals telling them not to do their job."

Comparative genomic analyses leverage the mechanisms of natural selection to find genes and biochemical pathways related to complex traits and processes. Multiple works have used these techniques with the genomes of long-lived mammals to shed light on the signalling and metabolic networks that might play a role in regulating age-related conditions. Similar studies on unrelated longevous organisms might unveil novel evolutionary strategies and genetic determinants of ageing in different environments. In this regard, giant tortoises constitute one of the few groups of vertebrates with an exceptional longevity: in excess of 100 years according to some estimates.

In this manuscript, we report the genomic sequencing and comparative genomic analysis of two long-lived giant tortoises: Lonesome George - the last representative of Chelonoidis abingdonii, endemic to the island of Pinta (Galapagos Islands, Ecuador) - and an individual of Aldabrachelys gigantea, endemic to the Aldabra Atoll and the only extant species of giant tortoises in the Indian Ocean. Comparison of these genomes with those of related species, using both unsupervised and supervised analyses, led us to detect lineage-specific variants affecting DNA repair genes, inflammatory mediators, and genes related to cancer development. Our study also hints at specific evolutionary strategies linked to increased lifespan, and expands our understanding of the genomic determinants of ageing.

This analysis singled out 43 genes with evidence of giant-tortoise-specific positive selection. This list includes genes with known roles in the dynamics of the tubulin cytoskeleton (TUBE1 and TUBG1) and intracellular vesicle trafficking (VPS35). Importantly, the analysis of genes showing evidence of positive selection also includes AHSG and FGF19, whose expression levels have been linked to successful ageing in humans. The list of genes with signatures of positive selection also features TDO2, whose inhibition has been proposed to protect against age-related diseases through regulation of tryptophan-mediated proteostasis. In addition, we found evidence for positive selection affecting several genes involved in immune system modulation, such as MVK, IRAK1BP1, and IL1R2. Taken together, these results identify proteostasis, metabolism regulation and immune response as key processes during the evolution of giant tortoises via effects on longevity and resistance to infection.

An important trait of large, long-lived vertebrates is their need for tighter cancer protection mechanisms, as illustrated by Peto's paradox. Therefore, we analysed more than 400 genes classified in a well-established census of cancer genes as oncogenes and tumour suppressors. We found that several putative tumour suppressors are expanded in turtles compared with other vertebrates. In addition, expansion of PRF1, together with the tortoise-specific duplication of PRDM1, suggests that immunosurveillance may be enhanced in turtles. Taken together, these results suggest that multiple gene copy-number alterations may have influenced the mechanisms of spontaneous tumour growth. Nevertheless, further studies are needed to evaluate the genomic determinants of putative giant-tortoise-specific cancer mechanisms.

Although infectious agents have been implicated in the development and progression of Alzheimer's disease (AD), the evidence of causation hasn't been convincing. In a new study in animal models, oral Porphyromonas gingivalis (Pg) infection led to brain colonization and increased production of amyloid beta (Aβ), a component of the amyloid plaques commonly associated with AD. The study team also found the organism's toxic enzymes, or gingipains, in the neurons of patients with AD. Gingipains are secreted and transported to outer bacterial membrane surfaces and have been shown to mediate the toxicity of Pg in a variety of cells. The team correlated the gingipain levels with pathology related to two markers: tau, a protein needed for normal neuronal function, and ubiquitin, a small protein tag that marks damaged proteins.

Seeking to block Pg-driven neurotoxicity, Cortexyme set out to design a series of small molecule therapies targeting Pg gingipains. In preclinical experiments, researchers demonstrated that by inhibiting the compound COR388, there was reduced bacterial load of an established Pg brain infection, blocked Aβ42 production, reduced neuroinflammation, and protected neurons in the hippocampus - the part of the brain that mediates memory and frequently atrophies early in the development of AD. In October 2018, Cortexyme announced results from its Phase 1b clinical trial of COR388. COR388 showed positive trends across several cognitive tests in patients suffering from AD, and Cortexyme plans to initiate a Phase 2 and 3 clinical trial of COR388 in mild to moderate AD in 2019.

Previous research has looked at the associations between weight (BMI, body mass index), physical activity, and reaching old age, but most studies have combined both sexes, or focused exclusively on men. Women and men's lifespans differ, which may be influenced by factors such as hormones, genes, and/or lifestyle. To explore these differences further, the researchers analysed data from the Netherlands Cohort Study (NLCS), which included more than 120,000 men and women aged between 55 and 69 when it began in 1986. They wanted to see if there were any links between height, weight, leisure time physical activity, and the likelihood of reaching the age of 90, and if there were any differences between men and women.

Some 7807 participants (3646 men and 4161 women aged between 68 and 70) provided detailed information in 1986 on their current weight, height, weight when aged 20, and their leisure time physical activity. This included activities such as gardening, dog walking, DIY (home improvements), walking or cycling to work, and recreational sports, which were grouped into categories of daily quotas: less than 30 minutes; 30 to 60 minutes; and 90 minutes or more.Participants were then monitored until death or the age of 90, whichever came first.

Some 433 men (16.7%) and 944 women (34.4%) survived to the age of 90. Women who were still alive by this age were, on average taller, had weighed less at the start of the study, and had put on less weight since the age of 20 than those who were shorter and heavier. What's more, women who were more than 175 cm (5 feet 9 inches) in height were 31 per cent more likely to reach 90 than women less than 160 cm ( 5 feet 3 inches). No such associations were seen among the men.

When it came to physical activity levels, men who clocked up over 90 minutes a day were 39 per cent more likely to reach 90 than those who did less than 30 minutes. And every extra 30 minutes of daily physical activity they racked up was associated with a 5 per cent increase in their chances of turning 90. But this wasn't the case for women. Those who chalked up more than 30-60 minutes a day were 21 per cent more likely to reach 90 than those managing 30 minutes or less. But there seemed to be an optimal threshold for women: around 60 minutes a day was associated with the best chance of their celebrating a 90th birthday.