Fight Aging! Newsletter, November 23rd 2020

Unity Biotechnology was one of the darlings of the nascent anti-aging biotech sector. In August, that idea took a hit when Unity announced that its lead drug candidate had failed to beat a placebo in reducing joint pain and stiffness, according to interim results from a trial of patients with osteoarthritis of the knee. The company's stock plunged more than 60% on the news, nearly one-third of Unity staff were laid off, and its experimental drug UBX0101 - the first novel 'senolytic' agent ever to enter clinical testing - was swiftly abandoned.

That setback threw a pall over the entire senolytic field. A research note cited "substantially greater risk to the senolytic hypothesis." However, other experts were more sanguine about a class effect, highlighting issues with trial design, study population and UBX0101 itself - a small-molecule inhibitor of MDM2 designed to boost the activity of the proapoptotic p53 protein - as possible explanations for study failure. In the meantime, more than two dozen other startups continue to pursue approaches to target senescent cells - strategies that range from cell destruction and containment to senescence prevention and even reversal. "There are lots of different ways to tackle this, and I think that the initial failure of Unity's first clinical trial shouldn't be a discouragement. The field is young, it's still early, and there's a lot left to be discovered and tried," says Tim Cash, CSO of Senolytic Therapeutics.

Like Unity, most of these startups drew inspiration from a 2011 paper and a follow-up report showing the promise of senescent cell clearance to protect against age-related organ deterioration in normal aging mice as well. "I refer to those mice as the mice that launched a thousand ships," says Matthew Scholz, cofounder and CEO of Oisín Biotechnologies, a senolytics-focused gene therapy company. When it comes to raising funds, many of those senolytic 'ships' have hit rocky waters in recent months. Because of the UBX0101 trial failure, some investors - already burned once by the hype that surrounded the ill-fated anti-aging company Sirtris Pharmaceuticals and fearing a repeat with companies such as Unity - have shied away from pouring additional money into the antisenescence drug market.

Yet industry insiders say the problem with Unity's trial had more to do with the specifics of that drug and its study protocol than with the strategy of senolysis writ large. "Of course, we've been anxiously following their progress through the clinic, and we're disappointed too," says Lewis Gruber, CEO and CSO of SIWA Therapeutics, a company developing an antibody drug directed against a type of advanced glycation end product found on the surface of senescent cells. "But the actual technical results are, at least so far, not of concern to us. We don't see it as a problem for senolytics in general."

For starters, MDM2 may not have been the best target for senescent cell destruction. The protein is one of the most important negative regulators of p53, responsible for the ubiquitination and degradation of the proapoptotic tumor suppressor. As such, inhibiting MDM2 risks unleashing indiscriminate cell killing in off-target, non-senescent tissues. To avoid that kind of toxicity, Unity relied on a local delivery strategy. But according to biomedical engineer Jennifer Elisseeff from Johns Hopkins University in Baltimore, Maryland, local injections of UBX0101 are not sufficient to improve knee function in old mice with osteoarthritis. In her lab, systemic administration of another senolytic agent, navitoclax, was needed to tamp down the general inflammation in the body that was hampering tissue repair.

Then there's the drug itself. Other senescence researchers say that, in their hands, MDM2 inhibitors such as nutlin-3a have only weak senolytic activity. And there's evidence from Judith Campisi's lab to suggest that the drug could also work through attenuation of the SASP. If that mechanism predominates over cell elimination, a single dose of UBX0101, as administered in the trial, might thus offer only temporary relief before the inflammatory secretome would come flaming back.

Yet the early success of dasatinib and quercetin in human trials at least shows that the concept of senolysis is possible in patients. And it gives anti-aging researchers hope that more pronounced benefits will be seen with therapeutics rationally designed to modulate senescence in some way. "It'll happen sooner or later. The technology is just too good."

We are on the cusp of a revolution in our understanding of the causes and consequences of aging. As aging research gathers pace, this panel discussion brings together some of the leading experts in the field of gerontology to discuss the cutting edge scientific work being done to advance the fight against aging.

The progress being made in extending life- and health-spans represents both a challenge and an opportunity. How can we ensure our investments see us comfortably through an extended life and how can we capitalise on the huge financial possibilities that successful treatments for aging would present? This panel brings together three of the leading investors in the field of Longevity to discuss the opportunities and potential pitfalls.

NAD+ (nicotinamide adenine dinucleotide), a key metabolite central to an efficient and healthy metabolism, declines with age. This previously unexplained phenomena is associated with numerous age-related diseases and has spawned the development of many nutritional supplements aimed at restoring NAD+ to more youthful levels. Researchers have now identified chronic inflammation as a driver of NAD+ decline. They show that an increasing burden of senescent cells, which is also implicated in the aging process, causes the degradation of NAD via the activation of CD38 (cyclic ADP ribose hydrolase) a protein that is found on the cell membranes both inside and on the surface of many immune cells.

Experiments were done in mice and involved metabolic tissue from visceral white fat and the liver which were examined during aging and acute responses to inflammation. The work was validated in primary human macrophages. "Our initial hypothesis was that CD38 activation would be driven by inflammation. But we found that in this case, the activation occurred with both acute and age-related inflammation. That was a surprise."

Senescent cells, which stop dividing in response to DNA damage, spew a multitude of pro-inflammatory proteins, called the senescence-associated secretory phenotype or SASP. Evolution selected cellular senescence as a protective measure against cancer; but as senescent cells accumulate in tissues over the course of a lifetime, the SASP drives low grade chronic inflammation which is associated with age-related disease, including late life cancer. "These inflammatory proteins in the SASP induce macrophages to proliferate, express CD38, and degrade NAD+. It's a maladaptive process. But drugs that target the SASP or CD38 may offer us another way to deal with the decline of NAD+."

Declining tissue nicotinamide adenine dinucleotide (NAD) levels are linked to ageing and its associated diseases. However, the mechanism for this decline is unclear. Here, we show that pro-inflammatory M1-like macrophages, but not naive or M2 macrophages, accumulate in metabolic tissues, including visceral white adipose tissue and liver, during ageing and acute responses to inflammation. These M1-like macrophages express high levels of the NAD-consuming enzyme CD38 and have enhanced CD38-dependent NADase activity, thereby reducing tissue NAD levels.

We also find that senescent cells progressively accumulate in visceral white adipose tissue and liver during ageing and that inflammatory cytokines secreted by senescent cells (the senescence-associated secretory phenotype, SASP) induce macrophages to proliferate and express CD38. These results uncover a new causal link among resident tissue macrophages, cellular senescence, and tissue NAD decline during ageing and offer novel therapeutic opportunities to maintain NAD levels during ageing.

Ezekiel Emanuel is best known for writing a controversial article in 2014, headlined "Why I Hope to Die at 75", in which he strongly rejects the desire to live beyond the age of 75 and expresses his opinion that continuing to live after such an age is meaningless. At age 63, he is getting closer to the age at which he thinks life is pointless, and I believe that a large reason why he is so pessimistic about life beyond 75, whether he realizes it or not, is based on the current state of medicine. This line of reasoning does not take into account how medicine, and in particular how we treat aging could change in the next decade or two.

Current medicine does a great job at keeping people alive for longer, but they often have to live with one or more chronic diseases. Given that, I am not surprised that Emanuel is not enamored with living a long life, especially as that could entail being disabled, bed-bound, or otherwise suffering a poor quality of life as the result of debilitating age-related diseases. However, things could be different in the not so distant future, and being 75 could see the majority of people far more fit, healthy, and vibrant than ever before in human history thanks to advances in aging research. Therapies that directly target aging could potentially make people biologically younger (in particular their immune systems) and much more able to withstand COVID-19 and other diseases.

The decline of the immune system is a key reason why the elderly are most susceptible to infectious diseases such as COVID-19, and there has been considerable interest in the rejuvenation of the immune system in recent years. Dr. Greg Fahy from Intervene Immune has had some early success with thymus rejuvenation in a small human pilot study and demonstrated that it is possible to cause the thymus, which shrinks and loses its capacity to produce T cells during aging, to regrow and resume production of those cells. Another example of immune rejuvenation is currently being developed by Samumed, a biotechnology company that is developing drugs that target the Wnt pathway to restore it to youthful function.

These are only some of the examples of why healthy life expectancy could rise significantly in the near future, and there are plenty of reasons to remain future positive. This is the future direction of medicine and healthcare, a world where being 75 does not mean you are thrown on the scrap heap and where people like Emanuel will no longer feel that life has no meaning. I am confident that in such a world, being 75 would not be the burden he thinks it will be, and this is why I hope to be alive at 75.

Hyperbaric oxygen therapy (HBOT) utilizes 100% oxygen in an environmental pressure higher than one absolute atmospheres (ATA) to enhance the amount of oxygen dissolved in body's tissues. Repeated intermittent hyperoxic exposures, using certain HBOT protocols, can induce physiological effects which normally occur during hypoxia in a hyperoxic environment, the so called hyperoxic-hypoxic paradox. In addition, it was recently demonstrated that HBOT can induce cognitive enhancements in healthy aging adults via mechanisms involving regional changes in cerebral blood flow. On the cellular level, it was demonstrated that HBOT can induce the expression of hypoxia induced factor (HIF), vascular endothelial growth factor (VEGF), and sirtuin (SIRT), stem cell proliferation, mitochondrial biogenesis, angiogenesis, and neurogenesis. However, no study to date has examined HBOT's effects on telomere length and senescent cell accumulation.

Thirty-five healthy independently living adults, aged 64 and older, were enrolled to receive 60 daily HBOT exposures. Whole blood samples were collected at baseline, at the 30th and 60th session, and 1-2 weeks following the last HBOT session. Peripheral blood mononuclear cells (PBMCs) telomeres length and senescence were assessed. Telomeres length of T helper, T cytotoxic, natural killer and B cells increased significantly by over 20% following HBOT. The most significant change was noticed in B cells. There was a significant decrease in the number of senescent T helpers by -37.30% post-HBOT. T-cytotoxic senescent cell percentages decreased significantly by -10.96% post-HBOT.

In conclusion, the study indicates that HBOT may induce significant senolytic effects that include significantly increasing telomere length and clearance of senescent cells in the aging populations.

A substantial minority of participants from the Framingham Heart Study, (nearly nine percent), had potentially clinically significant liver fibrosis (scarring). This the first study of this size and scale done in the United States. More than 3,000 middle-aged Framingham Heart Study participants (over a three-year period) underwent a test or vibration-controlled transient elastography that quantifies how much fat is in the liver and also measures the stiffness of the liver. Liver stiffness correlates with the degree of liver scarring. "We found that liver fibrosis was associated with more adverse cardiometabolic risk factors, even after accounting for liver fat which is a known risk factor for cardiometabolic disease. In particular, we observed that approximately one-quarter of the participants with diabetes had evidence of possibly clinically significant liver fibrosis."

These findings support the consideration of screening for liver fibrosis in high-risk groups, though additional studies are needed to determine the benefits/costs of screening. "Liver biopsy is the gold standard for diagnosing liver fibrosis; however, new non-invasive tests exist that can quickly and painlessly help doctors determine if you are at risk for having clinically significant liver fibrosis." If liver fibrosis is identified early, before cirrhosis is established, it is treatable. Greater recognition of and awareness of liver fibrosis as a consequence of nonalcoholic fatty liver disease will hopefully allow more patients to receive treatment to prevent complications of advanced liver disease.

We are working on a broad-spectrum antiviral drug. You can help us achieve a future free of the suffering caused by viruses. SARS-CoV-2 is just the tip of the iceberg. We also plan to tackle HIV, Hepatitis B, Influenza, Herpes, CMV, EBV, the common cold, and others. Viruses infect animals, too, both pets and livestock. Today, almost a hundred years after the discovery of penicillin and sulfa, although we have a few antivirals, none of the current commercial products have a breadth of activity that even slightly measures up to the spectrum of those first antibiotics. In fact, new antivirals currently have to be customized for each different virus. For example, Tamiflu only works for the flu, not SARS-CoV-2, and viruses are already developing resistance.

However, a few years ago, researchers at MIT's Lincoln Lab came up with an antiviral protein that works much differently from conventional antiviral drugs. Their published research showed this compound to be effective against 15 different viruses, including Influenza H1N1, Rhinovirus (the common cold), Dengue, Adenovirus, and others - a true broad-spectrum antiviral. With the advent of Covid-19, as well as with the significant human, animal and financial burden of many other viruses, and the ongoing risk of the appearance of new ones, the time is right to pick up where Lincoln Lab left off, and complete the commercial development of this compound. We believe this protein is non-toxic and that it should also be effective against SARS-CoV-2. Based on the way it works, there is good reason to believe it could be effective against a very wide range of viruses.

The next step is funding for fabrication and testing, including against SARS-CoV-2. We've already done the legwork of identifying the suppliers we will need, and the costs and associated regulations. Most or all of this work can be contracted-out, so we don't even need a laboratory of our own yet. We are anticipating the need to fine-tune our fabrication process a bit, followed by additional testing in the lab, and then quickly moving on to in vivo testing. Once successful in lab animals, we plan to progress to safety trials in people. We want to make this drug safe and available for use in humans as soon as we practically can.

This compound's effectiveness has already been replicated and published by two other labs. In one, they tested against PRRSV. In the other, against Influenza. Previous lab testing shows that the compound has been effective against every virus tested, including a wide-cross section of virus types. However, unknowns do remain. This is why we need your help. In addition to confirming effectiveness, we want to look at things like dosing. As with most drugs, there may also end up being certain contraindications or limitations, which we will need to identify, and work around if we can.

An observational study suggests that among people who have not had a previous cardiovascular event, those aged 70 to 100 years may gain the most benefit from taking medications that lower cholesterol compared to younger age groups, in terms of the number of heart attacks and cardiovascular events that could potentially be prevented per person treated. The study, involving more than 90,000 people living in Copenhagen, Denmark, including 13,779 people aged between 70 and 100 years, concluded that people aged over 70 years had the highest incidence of heart attack and cardiovascular disease of any age group. Heart attacks per 1,000 people per year irrespective of LDL cholesterol levels: Age 80-100, 8.5; age 70-79, 5.2; age 60-69, 2.5; age 50-59, 1.8; age 20-49, 0.8 - i.e. in people aged 80-100 years, there were 8.5 heart attacks per 1,000 people each year.

The study also estimates that the number of older people who need to receive a moderate-intensity statin therapy to prevent one heart attack in five years is fewer than for younger age groups. One heart attack will be prevented for every 80 people aged 80 to 100 years treated. In people aged 50 to 59 years, 439 need to be treated to prevent one incidence of heart attack, the researchers estimate.

In a separate systematic review and meta-analysis, researchers show that cholesterol-lowering therapies are as effective at reducing cardiovascular events in people aged 75 years or older as they are in younger people. The study, which included data from more than 21,000 people aged 75 years or older from 29 randomised controlled trials, found that cholesterol-lowering medications reduced the relative risk of major vascular events in older patients by 26% per 1mmol/L reduction in LDL cholesterol, which is comparable to the risk reduction in patients younger than 75 years (15% per 1mmol/L reduction in LDL cholesterol).

Together, the findings strengthen evidence that cholesterol-lowering medications can benefit older adults, who have historically been underrepresented in clinical trials of these therapies, and could help reduce the burden of cardiovascular disease in an aging population.

Physical activity has been suggested to prevent the conversion of mild cognitive impairment (MCI) to dementia in patients. We investigated the association between the continuance and regularity of physical activity and the risk of developing dementia in patients with MCI. We analyzed 6-year followed up data for 247,149 individuals in the National Health Insurance Service (NHIS) cohort of Korea who were enrolled between January 1, 2009, and December 31, 2015.

The patients were divided into four groups: those who did not engage in physical activity consistently (Never-PA group), those who initiated physical activity (Initiation-PA group), those who ceased physical activity (Withdrawal-PA group), and those who performed physical activity consistently (Maintenance-PA group). We also divided the patients into two groups: those who engaged in physical activity irregularly (Irregular-PA) and those who undertook physical activity regularly (Regular-PA).

Our analysis shows that continued physical activity in patients with MCI is associated with a lower risk of dementia of the Alzheimer type (DAT). It appears that the decision to start physical activity leads to a lower risk of DAT, while ceasing physical activity may cause the risk of DAT to increase again. In addition, a higher frequency of physical activity appears to prevent conversion from MCI to DAT (moderate-intensity physical activity more than 5 days per week or vigorous-intensity physical activity more than 3 days per week).

We observed that the Maintenance-PA group had 18% fewer dementia conversions than the Never-PA group, while the Initiation-PA group had 11% less dementia conversion than the Never-PA group. We interpret this to indicate that continuing physical activity occurring at both time points was more effective than initiating a new physical activity between the two time points. Evidence suggests that the longer the duration of physical activity, the greater the effect of physical activity on cognitive function. The findings for the Initiation-PA group may therefore reflect the shorter duration of physical activity compared to the Maintenance-PA group.

There are at least two major mechanisms by which continuous physical activity may prevent the conversion from mild cognitive impairment to dementia. Physical activity increases the expression of neurotrophic factors such as brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-1), and vascular endothelial growth factor (VEGF). BDNF is important for maintaining neuronal development and for exercise-related improvements in cognitive function. IGF-1 and VFGF play important roles in neurogenesis and angiogenesis and influence the induction of hippocampal BDNF.

Physical activity also increases cerebral blood flow (CBF). After 12 weeks of physical activity, CBF has been shown to increase in the anterior cingulate cortex and hippocampal CBF increased in elderly patients with subjective memory complaints after 16 weeks of physical activity. CBF is thought to maintain cerebral perfusion to help maintain brain volume.

The blood-brain barrier (BBB) plays a crucial role in maintaining the specialized microenvironment of the central nervous system (CNS). In aging, the stability of the BBB declines and the permeability increases. The list of CNS pathologies involving BBB dysfunction is growing. The opening of the BBB and subsequent infiltration of serum components to the brain can lead to a host of processes resulting in progressive synaptic, neuronal dysfunction, and detrimental neuroinflammatory changes. Such processes have been implicated in different diseases, including vascular dementia, stroke, Alzheimer's disease (AD), Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, hypoxia, ischemia, and diabetes mellitus.

The BBB damage is also observed in tauopathies that lack amyloid-β overproduction, suggesting a role for tau in BBB damage. Tauopathies represent a heterogeneous group of around 20 different neurodegenerative diseases characterized by abnormal deposition of microtubule-associated protein tau (MAPT) in cells of the nervous system. Neuropathology of tauopathies is defined as intracellular accumulation of neurofibrillary tangles (NFTs) consisting of aggregated hyper- and abnormal phosphorylation of tau protein and neuroinflammation.

Disruption of the BBB found in tauopathies is driven by chronic neuroinflammation. Production of pro-inflammatory signaling molecules such as cytokines, chemokines, and adhesion molecules by glial cells, neurons, and endothelial cells determine the integrity of the BBB and migration of immune cells into the brain. The inflammatory processes promote structural changes in capillaries such as fragmentation, thickening, atrophy of pericytes, accumulation of laminin in the basement membrane, and increased permeability of blood vessels to plasma proteins. Here, we summarize the knowledge about the role of tau protein in BBB structural and functional changes.

Hematopoietic stem cells (HSCs) maintain balanced blood cell production in a process called hematopoiesis. As humans age, their HSCs acquire mutations that allow some HSCs to disproportionately contribute to normal blood production. This process, known as age-related clonal hematopoiesis, predisposes certain individuals to cancer, cardiovascular, and pulmonary pathologies. There is a growing body of evidence suggesting that factors outside cells, such as extracellular vesicles (EVs), contribute to the disruption of stem cell homeostasis during aging.

The present study demonstrates that healthy individuals maintain circulating EVs consistent in terms of size, particle concentration, and total protein per particle between 20-85 years of age. In contrast, blood EV protein profile composition changes over time in humans, and our in silico analyses, suggests that certain organs or cell types may be responsible for this change, by altering EV production and releasing EVs into the bloodstream. Most strikingly, the blood circulating EVs produced from middle and older-aged individuals stimulate HSC colony-forming ability in contrast to younger individuals and untreated controls.

This work highlights that blood EVs impart important extracellular signals to HSCs as humans age. We posit that EVs may provide a compensatory stimulus that counter-balances a decrease in HSC functionality in individuals approaching middle-age. Current work is investigating how these activation signals, provided by the EVs, may impact the trajectory of expansion of mutations via clonal hematopoiesis, which may have profound implications in the development of hematological-based malignancies later in life. We demonstrate, for the first time a fundamental age-specific difference in blood EVs that specifically affects HSCs in individuals after 40 years of age, prior to the detection of classically defined clonal hematopoiesis.

The genome in every human cell is damaged on a daily basis, for example in the skin by UV radiation from the sun. Damage to the DNA causes diseases such as cancer, influences development, and accelerates aging. Congenital malfunctions in DNA repair can lead to extremely accelerated aging in rare hereditary diseases. Therefore, preservation and reconstruction processes are particularly important to ensure development and to maintain tissue function. DNA is rolled up into structures called chromatin, wound around the histone packaging proteins like cables on cable drums. This packaging is regulated by methyl groups. Various proteins are responsible for placing methyl groups on histones or removing them. The number of groups on the packaging proteins affects the activity of genes and thus the protein production of the cell.

In experiments with nematodes, the research team showed that after repairing damaged DNA, two methyl groups were increasingly found on the DNA packages. Furthermore, they found that errors in placing these two methyl groups on the histones (H3K4me2) accelerated the damage-induced aging process, while increased position of this histone alteration prolongs the lifespan after DNA damage. By controlling the proteins that either set or remove these methyl groups, the resistance to DNA damage - and thus the aging process of the animals - could be influenced.

Further analysis of the role of these two methyl groups showed that the enrichment of H3K4 after genome damage with two methyl groups supports the cells in restoring the balance after DNA damage. "Now that we know the exact changes in chromatin, we can use this to precisely limit the consequences of DNA damage. I hope that these findings will enable us to develop therapies for hereditary diseases characterized by developmental disorders and premature aging. Due to the fundamental importance of DNA damage in the aging process, such approaches could also counteract normal aging and prevent age-related diseases."

Alzheimer's disease is the most common form of dementia with more than 40 million affected people worldwide. To this day, there are no existing therapies for the effective prevention or treatment of the disease. Many recently identified Alzheimer's disease-associated risk genes are expressed preferentially or exclusively in microglia, the immune cells of the brain. A recent study investigated the role of the microglia-specific Plcg2-P522R genetic variant in Alzheimer's disease and found that it enhances several immune cell-specific functions.

A genome-wide association study from 2017, which included a Finnish cohort of Alzheimer's disease patients and healthy controls, identified Alzheimer's disease-associated risk loci in three genes, TREM2, ABI3, and PLCG2, which are mainly expressed in microglia. Several genetic variants of the TREM2 gene have been found to increase the risk for Alzheimer's disease. These TREM2 variants lead to a partial loss of function of the receptor and impair the activation of microglia. Consequently, the removal of β-amyloid, which accumulates in the brain during Alzheimer´s disease, is reduced. Recently, it has been shown that the phospholipase C gamma 2 (PLCγ2) enzyme is involved in the signaling pathway initiated by TREM2. The PLCG2-P522R variant reduces the risk of developing Alzheimer's disease, but its effects on immune cell functions have not been previously described.

"It is interesting how several Alzheimer's disease-associated risk genes affect microglial cell functions through the same signaling pathway. It shows that targeting this pathway and the cellular functions it regulates may have significant therapeutic potential in the future."

A research team says it has identified a key marker that will help speed effective vaccine designs for cytomegalovirus (CMV), the most common congenital infection worldwide. The researchers describe an immune surrogate that demonstrates when a vaccine has elicited the necessary antibodies that protect against CMV infection. The finding is already being applied to screen potential vaccines.

"Despite the high global burden of disease, vaccine development to prevent infection remains hampered by challenges in generating protective immunity. The most efficacious CMV vaccine candidate tested to date is a soluble glycoprotein B (gB) subunit vaccine with MF59 adjuvant (gB/MF59), which achieved 50% protection in multiple phase 2 clinical trials. The vaccine-elicited immune responses that conferred this protection have remained unclear. We investigated the humoral immune correlates of protection from CMV acquisition in populations of CMV-seronegative adolescent and postpartum women who received the gB/MF59 vaccine. We found that gB/MF59 immunization elicited distinct CMV-specific immunoglobulin G (IgG)-binding profiles and IgG-mediated functional responses in adolescent and postpartum vaccinees, with heterologous CMV strain neutralization observed primarily in adolescent vaccinees."

"We determined that protection against primary CMV infection in both cohorts was associated with serum IgG binding to gB present on a cell surface but not binding to the soluble vaccine antigen, suggesting that IgG binding to cell-associated gB is an immune correlate of vaccine efficacy. Supporting this, we identified gB-specific monoclonal antibodies that differentially recognized soluble or cell-associated gB, revealing that there are structural differences in cell-associated and soluble gB are relevant to the generation of protective immunity."

"Our results highlight the importance of the native, cell-associated gB conformation in future CMV vaccine design. CMV has been recognized as a top priority for vaccine development for more than 20 years, yet we remain without an approved vaccine. This work provides a way to assure that current and future vaccine candidates stimulate an effective immune response."

Olfactory dysfunction is common in aging and associated with dementia and mortality. However, longitudinal studies tracking change in olfactory ability are scarce. We sought to identify predictors of interindividual differences in rate of olfactory identification change in aging. Participants were 1780 individuals, without dementia at baseline and with at least 2 olfactory assessments over 12 years of follow-up (mean age = 70.5 years; 61.9% female), from the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K). Odor identification was assessed with the Sniffin' Sticks. We estimated the impact of demographic, health, and genetic factors on rate of olfactory change with linear mixed effect models.

Advancing age, manufacturing profession, history of cerebrovascular disease, higher cardiovascular disease burden, diabetes, slower walking speed, higher number of medications, and the APOE ε4 allele were associated with accelerated odor identification decline. Multi-adjusted analyses showed unique associations of age, diabetes, and ε4 to olfactory decline. In 1531 participants who remained free of dementia during follow-up, age, cardiovascular disease burden, and diabetes were associated with accelerated decline. Of these, age and diabetes remained statistically significant in the multi-adjusted model.

In conclusion, demographic, vascular, and genetic factors are linked to rate of decline in odor identification in aging. Although some olfactory loss may be an inevitable part of aging, our results highlight the importance of vascular factors for the integrity of the olfactory system, even in the absence of dementia.