Fight Aging! Newsletter, October 31st 2016

Imagine a future where people can enjoy their 80s in the same way they enjoyed their 20s. A future where people no longer suffer from age-related diseases. A future where we all are given more time to spend with our loved ones. We are working to make this future your future. CellAge is a dynamic startup aiming to increase human healthspan and reduce the incidence of age-related diseases by helping human body destroy aged cells. Our breakthrough technology concept harvests the promises from synthetic biology and recent findings in ageing research to deliver novel products and therapies. Our products will help to advance ageing research even further and help people live healthier lives.

Our society as a whole is getting older and as a consequence incidences of age-related diseases, such as cancer, cardiovascular diseases and osteoarthritis, are increasing at an alarming rate. Furthermore, detrimental effects of aging not only decreases the quality of life in old age but is an ever-expanding and unsustainable drain on private and national resources for health and social care. Despite these enormous problems, there are very few effective products which address these and related challenges. Recently, a new target, which could help tackle many of the mentioned problems, has been validated by a number of in vivo and in vitro studies. It has been shown that senescent cells (cells which have ceased to replicate due to stress or replicative capacity exhaustion) are linked to a number of diseases and their removal increases mouse healthspan (period of life free of serious diseases). The concept of our technology is to increase patient's health span and life expectancy by removing aged cells, also known as senescent cells, by use of combinatorially targeted senolytic gene therapy. Large number of biomarkers used in our targeting will not only allow removal of significant proportions of senescent cells but also has low off-target effects, sparing other healthy cells which sometimes closely resemble aged cells.

Aging is the main risk factor for many degenerative diseases and declining health. Senescent cells are part of the underlying mechanism for time-dependent tissue dysfunction. These cells can negatively affect neighbouring cells through an altered secretory phenotype: the senescence-associated secretory phenotype (SASP). The SASP induces senescence in healthy cells, promotes tumour formation and progression, and contributes to other age-related diseases such as atherosclerosis, immune-senescence and neurodegeneration. Removal of senescent cells was recently demonstrated to delay age-related degeneration and extend lifespan.

To better understand cell aging and to reap the benefits of senescent cell removal, it is necessary to have a reliable biomarker to identify these cells. Following an introduction to cellular senescence, we discuss several classes of biomarkers in the context of their utility in identifying and/or removing senescent cells from tissues. Although senescence can be induced by a variety of stimuli, senescent cells share some characteristics that enable their identification both in vitro and in vivo. Nevertheless, it may prove difficult to identify a single biomarker capable of distinguishing senescence in all cell types. Therefore, this will not be a comprehensive review of all senescence biomarkers but rather an outlook on technologies and markers that are most suitable to identify and isolate senescent cells.

Diabetic retinopathy is the most prominent complication of diabetes and the leading cause of blindness in working age individuals. The ability to control and cure this disease has been limited so far. But a study sheds new understanding on the mechanisms of the disease as it uncovered a program of accelerated aging of the neurons, blood vessels and immune cells of the retina in areas where blood vessels had been damaged. Researchers found that cells of the retina that are cut off from their main source of oxygen and nutrients during disease are resilient and do not die. Instead, they enter a state of cellular senescence where they are dormant yet start producing a series of factors that contribute the blinding disease.

The exciting work lead to the successful mapping and identification of the molecules that are activated during this process of premature aging. Interfering with the early cellular aging process occurring in mouse models of retinopathy with currently available and novel drugs resulted in improved regeneration of blood vessels within the retina and reduced retinal damage. "Currently available treatments for diabetic retinopathy are either invasive or present adverse side effects when used for long term regimens. Our study does not identify a cure, but by mapping out the events that lead to premature senescence in retinopathy, we are now able to consider novel therapeutic interventions to slow down the disease process and preserve vision."

Pathological angiogenesis is the hallmark of diseases such as cancer and retinopathies. Although tissue hypoxia and inflammation are recognized as central drivers of vessel growth, relatively little is known about the process that bridges the two. In a mouse model of ischemic retinopathy, we found that hypoxic regions of the retina showed only modest rates of apoptosis despite severely compromised metabolic supply. Using transcriptomic analysis and inducible loss-of-function genetics, we demonstrated that ischemic retinal cells instead engage the endoplasmic reticulum stress inositol-requiring enzyme 1α (IRE1α) pathway that, through its endoribonuclease activity, induces a state of senescence in which cells adopt a senescence-associated secretory phenotype (SASP).

We also detected SASP-associated cytokines (plasminogen activator inhibitor 1, interleukin-6, interleukin-8, and vascular endothelial growth factor) in the vitreous humor of patients suffering from proliferative diabetic retinopathy. Therapeutic inhibition of the SASP through intravitreal delivery of metformin or interference with effectors of senescence (semaphorin 3A or IRE1α) in mice reduced destructive retinal neovascularization in vivo. We conclude that the SASP contributes to pathological vessel growth, with ischemic retinal cells becoming prematurely senescent and secreting inflammatory cytokines that drive paracrine senescence, exacerbate destructive angiogenesis, and hinder reparative vascular regeneration. Reversal of this process may be therapeutically beneficial.

UNITY Biotechnology, Inc. ("UNITY"), a privately held biotechnology company creating therapeutics that prevent, halt, or reverse numerous diseases of aging, today announced the closing of a 116 million Series B financing. The UNITY Series B financing ranks among the largest private financings in biotech history and features new investments from longtime life science investors ARCH Venture Partners, Baillie Gifford, Fidelity Management and Research Company, Partner Fund Management, and Venrock. Other investors include Bezos Expeditions (the investment vehicle of Jeff Bezos) and existing investors WuXi PharmaTech and Mayo Clinic Ventures. Proceeds from this financing will be used to expand ongoing research programs in cellular senescence and advance the first preclinical programs into human trials.

The financing announcement follows the publication of research that further demonstrates the central role of senescent cells in disease. The paper, written by UNITY co-founders Judith Campisi and Jan van Deursen and published today, describes the central role of senescent cells in atherosclerotic disease and demonstrates that the selective elimination of senescent cells holds the promise of treating atherosclerosis in humans. In animal models of both early and late disease, the authors show that selective elimination of senescent cells inhibits the growth of atherosclerotic plaque, reduces inflammation, and alters the structural characteristics of plaque such that higher-risk "unstable" lesions take on the structural features of lower-risk "stable" lesions. "This newly published work adds to the growing body of evidence supporting the role of cellular senescence in aging and demonstrates that the selective elimination of senescent cells is a promising therapeutic paradigm to treat diseases of aging and extend healthspan. We believe that we have line of sight to slow, halt, or even reverse numerous diseases of aging, and we look forward to starting clinical trials with our first drug candidates in the near future."

Researchers, it is hoped, will one day find a miracle cure for all kinds of diseases. Yet over and over again it has been shown that even if it takes a little more effort than swallowing a little pill, exercise is an excellent preventive and curative treatment for many diseases. A new study shows that even low physical fitness, up to 20% below the average for healthy people, is sufficient to produce a preventive effect on most of the risk factors that affect people with cardiovascular disease. To measure the impact of physical fitness on heart disease risk factors, the researchers selected 205 men and 44 women with heart disease, including coronary artery disease, stroke, congestive heart failure, and heart valve disease, and had them undergo a stationary bike stress test to determine their fitness level. The results showed that normal physical fitness, even up to 20% below the population average, is sufficient to have a preventive effect on five of the eight risk factors affecting people with cardiovascular disease - abdominal circumference, diabetes, hypertension, obesity, and excess weight. Normal physical fitness means having the physical fitness of a person of the same weight, height, sex, and age, and who is disease-free. The easiest way to achieve this is to follow the recommendations of the World Health Organization - 150 minutes per week of moderate exercise or 75 minutes of vigorous exercise.

More and more studies confirm that sitting is bad for our health. It increases the likelihood of developing cardiovascular disease and other lifestyle-related illnesses such as diabetes. Some studies have estimated that being sedentary kills as many people as smoking. The average adult in the Western world sits between 9 and 11 hours a day, a number that only increases as we age. In fact, in a study in older adults just published researchers found that the least sedentary third of their study participants still spent between 12 and 13 hours in sedentary behavior, while the most sedentary of the elders in the study were sedentary for up to 15 hours a day.

But how does being fit affect the health risk associated with a sedentary lifestyle, especially in older adults, who are the most likely to be sedentary? The researchers found that older women and men in the most sedentary group were correspondingly 83% and 63% more likely to have risk factors for cardiovascular disease compared to women and men who were least sedentary. But when the researchers took fitness into account, they found that having high age-specific fitness (in this case, being among the fittest 40%) reduced the likelihood of having cardiovascular risks factors posed by extended time spent being sedentary. However, no such effect was found in those who were physically active without being fit. "Our Western lifestyles necessarily involve a lot of sitting, and we spend more and more time sitting on average as we age. But our findings show that being fit plays an important part in successful ageing and may lend protection against the negative health effects of being sedentary."

Mild Cognitive Impairment (MCI) defines people who have noticeably reduced cognitive abilities such as reduced memory but are still able to live independently, and is a precursor to Alzheimer's disease. Findings from the Study of Mental and Resistance Training (SMART) trial show, for the first time, a positive causal link between muscle adaptations to progressive resistance training and the functioning of the brain among those over 55 with MCI. "What we found in this follow up study is that the improvement in cognition function was related to their muscle strength gains. The stronger people became, the greater the benefit for their brain." SMART was a randomised, double-blind trial involving 100 community-dwelling adults with MCI, aged between 55 and 86. These new findings reinforce research from the SMART trial, whereby MRI scans showed an increase in the size of specific areas of the brain among those who took part in the weight training program. These brain changes were linked to the cognitive improvements after weight lifting.

To assess the efficacy of a progressive aerobic exercise training program on cognitive and everyday function among adults with mild subcortical ischemic vascular cognitive impairment (SIVCI), this was a proof-of-concept trial comparing a 6-month, thrice-weekly, progressive aerobic exercise training program (AT) with usual care plus education on cognitive and everyday function with a follow-up assessment 6 months after the formal cessation of aerobic exercise training. Seventy adults randomized to aerobic exercise training or usual care were included in intention-to-treat analyses. At the end of the intervention, the aerobic exercise training group had significantly improved Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-Cog) performance compared with the usual care plus education group (-1.71 point difference); however, this difference was not significant at the 6-month follow-up (-0.63 point difference). There were no significant between-group differences at intervention completion and at the 6-month follow-up in EXIT-25 or ADCS-ADL performance. Examination of secondary measures showed between-group differences at intervention completion favoring the AT group in 6-minute walk distance (30.35 meter difference) and in diastolic blood pressure (-6.89 mm Hg difference). This study provides preliminary evidence for the efficacy of 6 months of thrice-weekly progressive aerobic training in community-dwelling adults with mild SIVCI, relative to usual care plus education.

Articular cartilage is the tissue on the end of a bone that cushions the surface of the joint and is vital for painless movement. Because the tissue doesn't have its own blood supply, it has limited capacity to repair itself once damaged, leading to degenerative joint conditions like osteoarthritis. Traditional methods to prevent or delay onset of cartilage degeneration following traumatic events like microfracture surgery don't create the healthy cartilage needed to endure the forces of everyday movement. Even novel medical advances using patients' own articular cartilage cells (chondrocytes) have been unable to predictably restore cartilage structure and function in the long term.

Researchers investigated an alternative approach using engineered cartilage tissue grown from patients' own cartilage cells from the nasal septum which have a unique capacity to grow and form new cartilage tissue. This phase 1 study included 10 patients with full-thickness cartilage lesions of the knee. The researchers extracted a small biopsy specimen (6mm in diameter) from the nasal septum under local anaesthetic using a minimally invasive procedure. The harvested cells were multiplied by exposing them to growth factors for 2 weeks. The expanded cells were then seeded onto collagen membranes and cultured for 2 additional weeks, generating a 30 x 40mm cartilage graft. The engineered graft was then cut into the right shape and used to replace damaged cartilage that was surgically removed from the recipient's knee. Despite variable degrees of defect filling, MRI scans at 2 years revealed the development of new tissue with similar compositional properties of native cartilage. Moreover, nine recipients (one was excluded because of several independent sports injuries) reported substantial improvements in the use of their knee and in the amount of pain compared to before surgery. No adverse reactions were reported.

The researchers say that the small number of participants and the relatively short follow-up time will mean further studies will be needed. Similar to other early phase surgical studies, the trial did not involve a control group, so other studies will be needed to establish a comparison in effectiveness with currently available treatments, and to assess the possible bias of a placebo effect. "Our findings confirm the safety and feasibility of cartilage grafts engineered from nasal cells to repair damaged knee cartilage. But use of this procedure in everyday clinical practice is still a long way off as it requires rigorous assessment of efficacy in larger groups of patients and the development of manufacturing strategies to ensure cost effectiveness. Moreover, in order to extend the potential use of this technique to older people or those with degenerative cartilage pathologies like osteoarthritis, a lot more fundamental and pre-clinical research work needs to be done."

Extremely interesting for aging research are those individuals able to reach older ages still with functions similar to those of younger counterparts. We examined liver samples from ad libitum-fed old (28-month-old, AL-28) and ad libitum-fed very old (32-month-old, AL-32) rats for a number of markers, relevant for mitochondrial functionality and mitochondrial DNA (mtDNA) content. As for the mtDNA content and the protein amounts of the citrate synthase and the antioxidant peroxiredoxin III there were no significant changes in the AL-32 animals. No significant longevity-related change was found for TFAM amount, but a 50% reduction in the amount of the Lon protease, responsible for turnover of TFAM inside mitochondria, characterized the AL-32 rats. No longevity-related change was observed also for the amounts of the mtDNA repair enzymes OGG1 and APE1, whereas the intra-mitochondrial amount of the cytochrome c protein showed a 50% increase in the AL-32 rats, indicating a likely reduced initiation of the intrinsic apoptotic pathway.

Totally unexpected was the doubling of two proteins, very relevant for mitochondrial dynamics, namely MFN2 and DRP1, in the AL-32 rats. This prompted us to the calculation of all individual mitochondrial fusion indexes that grouped together in the AL-32 rats, while in the AL-28 animals were very different. We found a strong positive correlation between the fusion indexes and the respective mtDNA contents in two AL-28 and four AL-32 rats. This supports the idea that the limited prevalence of fusion above a still active mitochondrion fission should have ensured a functional mitochondrial network and should have led to a quite narrow range of high mtDNA contents, likely the best-suitable for extended longevity. Our findings strongly suggest that, among the multiple causes leading to the longevity of the AL-32 rats, the maintenance of an adult-like balance of mitochondrial dynamics seems to be very relevant for the regulation of mtDNA content and functionality.

Cognitive decline is a highly prevalent condition among the aging population that causes significant morbidity in the elderly and results in rising expense for the healthcare system. Although aging is a major risk factor for cognitive impairment, some individuals with exceptional longevity demonstrate delayed onset of dementia by as much as 13 years, with many not manifesting it at all. The fact that individuals with exceptional longevity possess factors that allow them to delay or avoid age related diseases make them a particularly attractive model for the study of healthy aging. One of the features identified in individuals with exceptional longevity was partial resistance to insulin-like growth factor-1 (IGF-I) resulting from a mutation in the IGF-I receptor gene. Subsequent studies have shown that lower IGF-I and IGF-I/IGF binding protein-3 (IGFBP-3) ratio are associated with extended survival in nonagenarians and better performance at activities of daily living.

Despite evidence from humans and experimental models that reduced circulating IGF-I may promote longevity and healthy lifespan, the role of peripheral IGF-I in cognition and muscle function remains unresolved. Several cross-sectional and prospective studies linked lower IGF-I to poorer cognitive function, as well as higher risk for mild cognitive impairment and Alzheimer's disease. On the other hand, a recent prospective study in older men associated IGF-I levels in the lowest quintile with less cognitive decline. Adding to this debate are the differences observed between the sexes. For example, in the Rancho-Bernardo cohort higher IGF-I was associated with better cognitive function only among men, but not women. With the understanding that healthspan extension is an important determinant of healthy aging, we set out to test the hypothesis that individuals with exceptional longevity and low circulating IGF-I levels not only exhibit extended survival, but are also healthier in cognitive and muscle function domains. Furthermore, given our prior findings that low IGF-I benefited females preferentially, we tested whether this association is sex-specific in relation to these other clinical outcomes.

IGF-I levels and cognitive assessment were available for 203 participants, 163 female and 40 male, median age 97.2 years and 97.5 years, respectively. Measured levels of IGF-I were not found to be significantly different between males and females; however, the IGF-I/IGFBP-3 ratio was significantly lower in females compared to males. Lower serum IGF-I levels were found to be associated with better cognitive function in females with exceptional longevity, but not in males. Furthermore, no detriment to muscle mass or function was observed in this cohort among women or men with IGF-I levels within the lowest tertile of IGF-I compared to individuals with IGF-I in the upper two tertiles. Our study is the first to demonstrate a gender specific negative association between IGF-I and cognition in the extremely elderly. This supports previous data showing that lower IGF-I may have protective effects in aging that may be gender specific. No association was found between tertiles of circulating IGF-I and muscle mass or muscle function in our cohorts. These results suggest that circulating IGF-I plays a minimal role in maintaining muscle mass or strength in individuals with exceptional longevity.

The contribution of metabolic factors on the severity of osteoarthritis (OA) is not fully appreciated. This study aimed to define the effects of hypercholesterolemia on the progression of OA. Apolipoprotein E-deficient (ApoE-/-) mice and diet-induced hypercholesterolemic (DIHC) rats were used to explore the effects of hypercholesterolemia on the progression of OA. Both models exhibited OA-like changes, characterized primarily by a loss of proteoglycans, collagen and aggrecan degradation, osteophyte formation, changes to subchondral bone architecture, and cartilage degradation. Surgical destabilization of the knees resulted in a dramatic increase of degradative OA symptoms in animals fed a high-cholesterol diet compared with controls. Clinically relevant doses of free cholesterol resulted in mitochondrial dysfunction, overproduction of reactive oxygen species (ROS), and increased expression of degenerative and hypertrophic markers in chondrocytes and breakdown of the cartilage extracellular matrix.

We showed that the severity of diet-induced OA changes could be attenuated by treatment with both atorvastatin and a mitochondrial targeting antioxidant. The protective effects of the mitochondrial targeting antioxidant were associated with suppression of oxidative damage to chondrocytes and restoration of extracellular matrix homeostasis of the articular chondrocytes. In summary, our data show that hypercholesterolemia precipitates OA progression by mitochondrial dysfunction in chondrocytes, in part by increasing ROS production and apoptosis. By addressing the mitochondrial dysfunction using antioxidants, we were able attenuate the OA progression in our animal models. This approach may form the basis for novel treatment options for this OA risk group in humans.

Vitamin D has much wider effects regulating calcium absorption and promoting bone growth - at least in the nematode worm, C. elegans. Research shows that vitamin D works through genes known to influence longevity and impacts processes associated with many human age-related diseases. The study may explain why vitamin D deficiency has been linked to breast, colon and prostate cancer, as well as obesity, heart disease and depression. "Vitamin D engaged with known longevity genes - it extended median lifespan by 33 percent and slowed the aging-related misfolding of hundreds of proteins in the worm. Our findings provide a real connection between aging and disease and give clinicians and other researchers an opportunity to look at vitamin D in a much larger context."

The study shines a light on protein homeostasis, the ability of proteins to maintain their shape and function over time. It's a balancing act that goes haywire with normal aging - often resulting in the accumulation of toxic insoluble protein aggregates implicated in a number of conditions, including Alzheimer's, Parkinson's and Huntington's diseases, as well as type 2 diabetes and some forms of heart disease. "Vitamin D3, which is converted into the active form of vitamin D, suppressed protein insolubility in the worm and prevented the toxicity caused by human beta-amyloid which is associated with Alzheimer's disease. Given that aging processes are thought to be similar between the worm and mammals, including humans, it makes sense that the action of vitamin D would be conserved across species as well. Vitamin D3 reduced the age-dependent formation of insoluble proteins across a wide range of predicted functions and cellular compartments, supporting our hypothesis that decreasing protein insolubility can prolong lifespan. We've been looking for a disease to associate with vitamin D other than rickets for many years and we haven't come up with any strong evidence. But if it's a more global marker of health or longevity as this paper suggests, that's a paradigm shift. Now we're talking about something very different and exciting."

Given adequate funding, researchers plan to test vitamin D in mice to measure and determine how it affects aging, disease and function - and hope that clinical trials in humans will go after the same measurements. "Maybe if you're deficient in vitamin D, you're aging faster. Maybe that's why you're more susceptible to cancer or Alzheimer's. Given that we had responses to vitamin D in an organism that has no bone suggests that there are other key roles, not related to bone, that it plays in living organisms."

While one currently available treatment - injections of a fragment of parathyroid hormone (PTH) - can stimulate bone formation, it also stimulates the resorption of bone. "We wanted to understand how PTH signaling affects gene expression within bone cells, particularly in osteocytes, which are buried deep within bone itself. By identifying an essential step in that signaling cascade - turning off an enzyme called SIK2 - our findings shed light on a new mechanism of PTH signaling in bone and identify a potential new treatment for osteoporosis."

Most currently available osteoporosis drugs work by slowing down the destruction of bone, but their effectiveness is limited and long-term use can occasionally have side effects. The PTH-based drug teriparatide increases bone density; but in addition to its also accelerating bone resorption, the fact that teriparatide must be administered by daily injection discourages many patients from using it to treat a symptom-free condition. To better understand the mechanisms underlying the effects of PTH on osteocytes, the research team focused on a gene called SOST, which inhibits bone formation and is known to be suppressed by PTH. The team's experiments first showed that PTH suppressed SOST expression by means of transcription-regulating enzymes called HDACs - specifically HDAC4 and HDAC5 - activation of which previous research had indicated was regulated by enzymes called SIKs. The researchers confirmed that PTH signaling turns off the activity of the SIK2 enzyme.

A series of experiments with small-molecule SIK inhibitors revealed that they regulated not only the expression of SOST but also of other PTH target genes such as RANKL, a molecule that stimulates bone resorption. The research team then showed that an SIK2-specific inhibitor called YKL-05-093 mimicked the effects of PTH on gene expression both in cells and in mice. Since repeat dosing with YKL-05-093 had adverse effects on mice, the researchers tested a closely related compound YKL-05-099 and found that daily doses safely stimulated bone formation in male mice. The team was surprised to find that YKL-05-099 also reduced levels of osteoclasts - cells responsible for the breakdown of bone - indicating that it had the desired dual effect of stimulating bone formation and suppressing bone resorption. "We don't completely understand why YKL-05-099 reduces osteoclasts, but we think the combination could be very useful therapeutically. In addition to concentrating on understanding how this compound inhibits osteoclasts - which may lead us to develop even more specific SIK2 inhibitors - we also need to see if it increases bone mass in an animal model of postmenopausal osteoporosis, such as older female mice that have had their ovaries removed."

Dietary restriction (DR), defined as a regime of limited protein intake without malnutrition, leads to increased lifespan and health span in all tested model organisms. One of the conserved fundamental adaptations to DR, or to other low-nutrient conditions such as fasting, involves a metabolic shift toward increased triglyceride (TG) utilization. DR increases the conversion of dietary carbohydrates into lipids, elevates fat storage, and accelerates lipid turnover in flies, which appears to have a profound positive impact on longevity. Drosophila has emerged as an excellent model organism to explore the mechanisms driving diet- and/or age-related changes in lipid metabolism. Importantly, Drosophila provides critical technical advantages that allow characterizing tissue-tissue coordination during metabolic adaptation. While lipids are stored in the fat body and transferred to oenocytes for mobilization, the Drosophila intestine also contributes to lipid synthesis and cholesterol homeostasis. The Drosophila intestine plays a key role in modulating health span by modulation of immune responses, metabolic homeostasis, and stress signaling.

The adult intestine is regenerated by intestinal stem cells (ISCs), which divide to replace functional enterocytes (ECs) and enteroendocrine cells when needed. The intestine is also central to longevity in Drosophila, as gut function rapidly declines in aging flies. Furthermore, in old flies, the ability of the intestine to generate and store lipids is severely compromised, and restoring the adequate metabolic function of this tissue increases health span. The age-related decline in intestinal function in flies is a consequence of complex inflammatory conditions that are associated with increased protein misfolding. How endoplasmic reticulum (ER) stress and ER stress response pathways influence diet- and/or age-related metabolic function of the intestinal epithelium remains unclear.

The ER stress transducer IRE1 triggers one of the three signaling pathways engaged by ER stress. Interestingly, IRE1 also influences lipid homeostasis. IRE1 is also required for S6K- and HIF-1-mediated lifespan extension under DR in C. elegans, though the mechanisms mediating this effect remain unclear. During ER stress, IRE1 dimerizes and splices the mRNA of XBP1, leading to translation of a functional transcription factor that induces genes involved in ER biogenesis, protein folding, and degradation to restore ER homeostasis. The role of IRE1/XBP1 in the regulation of lipid homeostasis has not been explored in the context of a DR intervention or during conditions of obligatory lipid recruitment, such as prolonged fasting/starvation. Here, we identify IRE1 as a player in DR-induced lifespan extension in flies. Our data suggest that IRE1 is required for the metabolic shift toward elevated TG turnover occurring during DR and that the absence of IRE1 is detrimental under this dietary intervention. Moreover, we identify the transcription factor Sugarbabe as a downstream target of the IRE1/XBP1 module that is required for increased lipid turnover under DR. Our results provide insights into physiological mechanisms that link tissue-specific metabolic adaptation to lifespan extension under DR conditions.

In this article we clarify mechanisms of genetic regulation of human aging and longevity traits. The objective of this article is to address the issues in previous research of not reaching a genome-wide level of statistical significance and lack of replication in the studies of independent populations. We performed a genome-wide association study (GWAS) of human life span using different subsets of data from the original Framingham Heart Study (FHS) cohort corresponding to different quality control procedures, and we used one subset of selected genetic variants for further analyses. We used a simulation study to show that this approach to combining data improves the quality of GWAS with FHS longitudinal data to compare average age trajectories of physiological variables in carriers and noncarriers of selected genetic variants.

We used a stochastic process model of human mortality and aging to investigate genetic influence on hidden biomarkers of aging and on dynamic interaction between aging and longevity. We investigated properties of genes related to selected variants and their roles in signaling and metabolic pathways and showed that the use of different quality control procedures results in different sets of genetic variants associated with life span. We selected 24 genetic variants negatively associated with life span and showed that the joint analyses of genetic data at the time of biospecimen collection and follow-up data substantially improved significance of associations of 24 selected single-nucleotide polymorphisms with life span. We also showed that aging-related changes in physiological variables and in hidden biomarkers of aging differ for the groups of carriers and noncarriers of selected variants.

The results of these analyses demonstrated benefits of using biodemographic models and methods in genetic association studies of these traits. Our findings showed that the absence of a large number of genetic variants with deleterious effects may make substantial contribution to exceptional longevity. These effects are dynamically mediated by a number of physiological variables and hidden biomarkers of aging. The results of these research demonstrated benefits of using integrative statistical models of mortality risks in genetic studies of human aging and longevity.

Cells enter a state of senescence in response to certain stresses. Studying mouse models, researchers examined the role of senescent lipid-loaded macrophages (so-called "foam cells") in the pathogenesis of atherosclerosis. At early stages of atherosclerosis, senescent foam cells promoted the expression of inflammatory cytokines. At later stages, they promoted the expression of matrix metalloproteases implicated in the rupture of atherosclerotic plaque, which can lead to blood clots. Experimental removal of the senescent cells had beneficial effects at both stages of the disease.

Advanced atherosclerotic lesions contain senescent cells, but the role of these cells in atherogenesis remains unclear. Using transgenic and pharmacological approaches to eliminate senescent cells in atherosclerosis-prone low-density lipoprotein receptor-deficient (Ldlr-/-) mice, we show that these cells are detrimental throughout disease pathogenesis. We find that foamy macrophages with senescence markers accumulate in the subendothelial space at the onset of atherosclerosis, where they drive pathology by increasing expression of key atherogenic and inflammatory cytokines and chemokines. In advanced lesions, senescent cells promote features of plaque instability, including elastic fiber degradation and fibrous cap thinning, by heightening metalloprotease production. Together, these results demonstrate that senescent cells are key drivers of atheroma formation and maturation and suggest that selective clearance of these cells by senolytic agents holds promise for the treatment of atherosclerosis.

Microbes that cause diseases like HIV, malaria, and hepatitis C exploit and often activate immune checkpoint pathways - cell surface receptors such as CTLA4 and PD-1 - to slow immune cells and prevent their elimination by the host. T cells that are supposed to clear an infection, instead, become "exhausted." The cell-surface receptors naturally act like brakes to tell the immune system to not react as strongly during normal situations and help the immune system avoid damaging healthy tissue or causing autoimmunity. Blocking PD-1 can reinvigorate exhausted T cells and improve control of chronic infections and cancer. However, whether blocking PD-1 can reprogram exhausted T cells into durable memory T cells is unclear. Researchers have now found that reinvigorating exhausted T cells in mice using a PD-L1 blockade caused very few T memory cells to develop. After the blockade, re-invigorated T cells became re-exhausted if antigen from the virus remained high, and failed to become memory T cells when the virus was cleared.

Epigenetics is the way chemical modifications to DNA and the proteins binding DNA determine which genes are expressed by a cell type. Epigenetic profiles can be highly stable and confer long-term identity to a cell. (In other words, the reason a liver cell stays a liver cell and doesn't become a lung cell is due largely to epigenetics since both liver and lung cells have the same genes.) "What these new findings on exhausted T cells tells us is that the unique epigenetic profile of exhausted T cells causes these cells to express a different overall set of genes compared to memory or effector T cells." However, this epigenetic pattern was only minimally changed following the PD-L1 blockade. This prevented these exhausted T cells from changing into the more protective effector or memory cell types. "We were surprised that the exhausted T cell epigenetic profile was not reprogrammed. Instead, the benefit we see after PD-1 pathway blockade is caused by only transient changes in gene expression that is not durable, rather than permanent epigenetic reprogramming." These findings suggested that exhausted T cells are a distinct lineage of T cells in and of themselves instead of just being effector or memory T cells restrained by checkpoint pathways. "We predicted that exhausted T cells would not have a distinct epigenetic profile but have the molecular flexibility to obtain immune memory. But we found that exhausted T cells are quite set in their ways. We think this shows that epigenetic fate inflexibility may limit current immunotherapies based on PD-1 checkpoint inhibitors."