Intracellular nicotinamide adenine dinucleotide (NAD+) levels steadily decline with age in both rodents and humans. NAD+ is an essential electron acceptor in several redox reactions that maintain intracellular homeostasis. NAD+ also functions as a cofactor for non-redox NAD+-consuming enzymes, such as poly-ADP-ribose polymerases (PARPs) and sirtuins (SIRTs).

NAD+ is synthesized either from tryptophan in the de novo pathway or by recycling nicotinamide (NAM) in the salvage pathway. In mammals, the salvage pathway is the predominant source of NAD+ biosynthesis due to its high adaptability. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme for NAD+ biosynthesis in the salvage pathway, converts NAM to nicotinamide mononucleotide (NMN), which is subsequently converted into NAD+ by NMN adenyltransferase. Reduced NAMPT expression at both mRNA and protein levels has been observed in multiple tissues during aging and is primarily responsible for the aging-associated NAD+ decline.

NAD+ decline is implicated in the pathophysiology of various diseases, including metabolic, cardiovascular, and neurodegenerative diseases. The supplementation of NAD+ using NAD+ pathway intermediates attenuates these degenerative disorders. Thus, NAD+ biosynthesis can be a potent therapeutic target for many aging-associated diseases. However, it is unclear whether NAD+ depletion can trigger or promote chronic proinflammatory responses that are closely associated with increased susceptibility to aging-associated diseases. Of note, a previous study showed that NAD+ depletion inhibits lipopolysaccharide (LPS)-induced Toll-like receptor (TLR) signaling in human monocytes. Similarly, inhibition of NAMPT (using FK866, a NAMPT-specific inhibitor) modulated the proinflammatory responses in macrophages.

In this context, we assessed whether FK866-induced NAD+ decline can modulate pattern-recognition receptor (PRR)-mediated responses in myeloid cells. Consequently, we propose that NAD+ depletion can trigger NLRP3 activation in macrophages and induce in vitro and in vivo inflammasome activation in the presence of NLRP3-activating stimuli.

Altos Labs (Altos) launched today as a new biotechnology company dedicated to unraveling the deep biology of cellular rejuvenation programming. Altos' mission is to restore cell health and resilience to reverse disease, injury, and the disabilities that can occur throughout life. The company launches with a community of leading scientists, clinicians, and leaders from both academia and industry working together towards this common mission. Altos launches with 3 billion fully committed from renowned company builders and investors.

The Altos executive team will be composed of Hal Barron, MD (incoming CEO), Rick Klausner, MD (Chief Scientist and Founder), Hans Bishop (President and Founder), and Ann Lee-Karlon, PhD (Chief Operating Officer). Hal Barron is currently President of R&D and Chief Scientific Officer at GSK and will join Altos as CEO and Board co-chair effective August 1, 2022. Klausner was former director of the National Cancer Institute and entrepreneur, Bishop was former CEO of GRAIL and Juno Therapeutics, and Lee-Karlon was former Senior Vice President at Genentech.

Altos will be initially based in the US in the San Francisco Bay Area and San Diego, and in the UK in Cambridge. The company will also have significant collaborations in Japan. Set within these geographies, activity will be organized across the Institutes of Science and the Institute of Medicine. The Altos Institutes of Science will pursue deep scientific questions and integrate their findings into one collaborative research effort. The Altos Institute of Medicine will capture knowledge generated about cell health and programming to develop transformative medicines.

"Altos seeks to decipher the pathways of cellular rejuvenation programming to create a completely new approach to medicine, one based on the emerging concepts of cellular health. Remarkable work over the last few years beginning to quantify cellular health and the mechanisms behind that, coupled with the ability to effectively and safely reprogram cells and tissues via rejuvenation pathways, opens this new vista into the medicine of the future. Altos begins with many of the leading scientists who are creating this new science. Together, we are building a company where many of the world's best scientists can collaborate internally and externally and develop their research with the speed, mission, and focus of private enterprise. Our success will depend upon a culture of intense collaboration, enthusiasm, and openness."

Cellular senescence is a pathophysiological phenomenon in which proliferative cells enter cell cycle arrest following DNA damage and other stress signals. Natural, permanent DNA damage can occur after repetitive cell division; however, acute stress or other injuries can push cells into premature senescence and eventually a senescence-associated secretory phenotype (SASP). In recent years, there has been increased evidence for the role of premature senescence in disease progression including diabetes, cardiac diseases, and end-stage liver diseases including cholestasis. Liver size and function change with aging, and presumably with increasing cellular senescence, so it is important to understand the mechanisms by which cellular senescence affects the functional nature of the liver in health and disease.

Cholangiocytes, which are morphologically heterogenous, polarized cells lining the biliary epithelium, have high absorptive/secretory functions and play a role in the 1) modification of canalicular bile, 2) paracrine communication with portal cells, and 3) regulation of immune cell infiltration. Cholangiocytes are the target of various liver diseases such as fatty liver diseases: non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic liver disease (ALD), and chronic cholestatic liver diseases including primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), biliary atresia, and cholangiocarcinoma. Biliary secretory functions regulate liver inflammation and fibrosis (by both autocrine and paracrine pathways) through secretion of cytokines and other factors which may contribute to liver damage. Cellular senescence increases in cholangiocytes of PSC patients, likely contributing to disease progression.

Everyone has a small amount of octanal in their blood, but scientists have shown that people with markers of cardiovascular disease, such as high LDL cholesterol, also have higher levels of octanal. This extra octanal can end up in blood due to diet or a phenomenon in cells called oxidative stress. The human nose is already good at smelling octanal. A 2019 study was the first to show that macrophages in blood vessel walls also have some of the olfactory receptors needed to "smell" molecules. These macrophages can sense octanal, thanks to an olfactory receptor called OR6A2. The new study is the first to show precisely how sniffing out octanal can boost inflammation in the arteries.

Researchers tested the effects of injecting octanal into wild type mice and into mice where the gene for the mouse macrophage receptor Olfr2 (which corresponds to OR6A2 in humans) was deleted. By comparing these mouse groups, researchers found that inflammation gets much worse as the Olfr2 receptor senses octanal. Over time, the arteries even begin to develop the lesions seen in atherosclerosis. The researchers then used a molecule called citral (which has a lemon-like odor), known to block this mouse olfactory receptor, and saw that inflammation went down. By making macrophages blind to octanal, they reversed the disease progression.

Atherosclerosis is an inflammatory disease of the artery walls and involves immune cells such as macrophages. Olfactory receptors (OLFRs) are G protein-coupled chemoreceptors that have a central role in detecting odorants and the sense of smell. We found that mouse vascular macrophages express the olfactory receptor Olfr2 and all associated trafficking and signaling molecules. Olfr2 detects the compound octanal, which activates the NLRP3 inflammasome and induces interleukin-1β secretion in human and mouse macrophages.

We found that human and mouse blood plasma contains octanal, a product of lipid peroxidation, at concentrations sufficient to activate Olfr2 and the human ortholog olfactory receptor 6A2 (OR6A2). Boosting octanal levels exacerbated atherosclerosis, whereas genetic targeting of Olfr2 in mice significantly reduced atherosclerotic plaques. Our findings suggest that inhibiting OR6A2 may provide a promising strategy to prevent and treat atherosclerosis.

Crocodiles are flourishing large-bodied ectotherms in a world dominated by endotherms. They survived the Cretaceous extinction event, that eradicated the dinosaurs who are thought to be their ancestral hosts. Crocodiles reside in polluted environments; and often inhabit water which contains heavy metals; frequent exposure to radiation; feed on rotten meat and considered as one of the hardy species that has successfully survived on this planet for millions of years. Another capability that crocodiles possess is their longevity. Crocodiles live much longer than similar-sized land mammals, sometimes living up to 100 years. But how do they withstand such harsh conditions that are detrimental to Homo sapiens?

Given the importance of the gut microbiome on its' host physiology, we postulate that the crocodile gut microbiome and/or its metabolites produce substances contributing to their hardiness and longevity. Thus, we conducted a literature search on this topic and herein, we discuss the composition of the crocodile gut microbiome, longevity, and cellular senescence in crocodiles, their resistance to infectious diseases and cancer, and our current knowledge of the genome and epigenome of these remarkable species. Furthermore, preliminary studies that demonstrate the remarkable properties of crocodile gut microbial flora are discussed.

Given the profound role of the gut microbiome in the health of its' host, it is likely that the crocodile gut microbiome and its' metabolites may be contributing to their extended life expectancy and elucidating the underlying mechanisms and properties of these metabolites may hold clues to developing new treatments for age-related diseases for the benefit of Homo sapiens.

Researchers have demonstrated a new approach with an mRNA preparation that reprograms T cells to attack heart fibroblast cells. Heart failure is often driven in part by these fibroblast cells, which respond to heart injury and inflammation by chronically overproducing fibrous material that stiffens the heart muscle, impairing heart function - a condition called fibrosis. In experiments in mice that model heart failure, the reduction in cardiac fibroblasts caused by the reprogrammed T cells led to a dramatic reversal of fibrosis.

The new technique is based on chimeric antigen receptor (CAR) T cell technology, which, until now, has required the harvesting of a patient's T cells and their genetic reprogramming in the lab to recognize markers on specific cell types in the body. These specially targeted T cells can then be multiplied using cell culture techniques and re-infused into the patient to attack a specific cell type. However, this standard CAR T cell strategy would be problematic when directed against heart failure or other fibrotic diseases in humans. Fibroblasts have a normal and important function in the body, especially in wound healing. CAR T cells that are reprogrammed genetically to attack fibroblasts could survive in the body for months or even years, suppressing the fibroblast population and impairing wound healing for all that time.

Therefore, in the new study, researchers devised a technique for a more temporary and controllable, and procedurally much simpler, type of CAR T cell therapy. They designed mRNA that encodes a T-cell receptor targeting activated fibroblasts and encapsulated the mRNA within tiny, bubble-like lipid nanoparticles (LNPs) that are themselves covered in molecules that home in on T cells. Injected into mice, the encapsulated mRNA molecules are taken up by T cells and act as templates for the production of the fibroblast-targeting receptor, effectively reprogramming the T cells to attack activated fibroblasts. This reprogramming is very temporary, however. The mRNAs are not integrated into T-cell DNA and survive within T cells for only a few days - after which the T cells revert to normal and no longer target fibroblasts.

A small but growing group is also beginning to focus on menopause, which impacts half the population and whose onset is associated with a long list of health conditions, from higher blood pressure, LDL cholesterol and triglycerides, which is a form of fat in the blood, to, even more frighteningly, a greater risk of breast cancer, heart disease, and osteoporosis.

The newest outfit focused on the cause is Gameto, which says it wants to solve the problem of "accelerated" ovarian aging to change the trajectory of women's health and equality. Ovaries age up to five times faster than any organ in the sense that they stop working far earlier than, say, the liver, or brain, or even skin. While women are born with a certain number of ovocytes - an immature female sex cell that later gives rise to a fully mature ovum or egg cell - they eventually run out of these, at which point their ovaries stop functioning as an organ and stop producing the hormones that control women's physiology.

One-year-old Gameto wants to help delay that process, or even push it off forever if a woman chooses, by developing a platform for ovarian therapeutics that will initially be used to improve the process of assisted fertility but hopefully, eventually, be used, too, to identify cell therapies that can prevent the medical burden of menopause. How exactly? It's still early days and the Gameto principals are loath to dive into specifics, but the young company has already begun testing whether ovarian supporting cells could help mature eggs and reduce the number of IVF cycles that women often endure currently. Some notable investors are willing to bet on that early evidence. New York-based Gameto just raised 20 million in funding led by Future Ventures. Other participants include Bold Capital Partners, Lux Capital, Plum Alley, TA Ventures, Overwater Ventures, Arch Venture Partners co-founder Robert Nelsen and 23andMe CEO Anne Wojcicki.

The Dog Aging Project, a scientific initiative to help companion dogs and people live longer, healthier lives together, has received a 2.5 million pledge from a consortium of tech entrepreneurs. The Dog Aging Project brings together a community of dogs, owners, veterinarians, researchers, and volunteers to carry out the largest canine health study in the world. The donation will expand this research into longevity science. The donors include Brian Armstrong, Coinbase founder and CEO; Peter Attia, physician; Juan Benet, Protocol Labs founder and CEO; Fred Erhsam, co-founder of Paradigm and Coinbase; Adam Fisher of Bessemer Venture Partners; author Tim Ferriss and the Saisei Foundation; Jed McCaleb, Stellar co-founder and CTO and founder of the Astera Institute; and food author Darya Rose and internet entrepreneur Kevin Rose.

The Dog Aging Project has two fundamental goals: first, to understand how genes, lifestyle, and environment influence aging; and second, to intervene to increase healthspan, the period of life spent free from disease. Discoveries made by the Dog Aging Project could be translatable to people. More than 32,000 companion dogs and their owners are already part of the Dog Aging Project. All the dogs live and play at home with their families. Most of these dogs participate in the observational Longitudinal Study of Aging. Each dog owner completes extensive surveys about the health and life experience of their dog through a secure research portal. This information is paired with comprehensive environmental, genetic, and biochemical data to yield insights about aging.

In addition, the Dog Aging Project is conducting a double-blind, placebo controlled, veterinary clinical trial of the medicine rapamycin, which at low doses has been shown to extend lifespan in laboratory animals. The trial is called TRIAD, an acronym for Test of Rapamycin in Aging Dogs. The 2.5 million in new funding provided by the consortium of donors will go directly to scientific research. This support will allow the Dog Aging Project to expand the TRIAD Trial to include more study locations and to increase the number of dogs enrolled in TRIAD.

Human longevity is influenced by the genetic risk of age-related diseases. As Alzheimer's disease (AD) represents a common condition at old age, an interplay between genetic factors affecting AD and longevity is expected. We explored this interplay by studying the prevalence of AD-associated single nucleotide polymorphisms (SNPs) in cognitively healthy centenarians, and replicated findings in a parental-longevity genome-wide association study (GWAS).

We found that 28 of 38 SNPs that increased AD-risk also associated with lower odds of longevity. For each SNP, we express the imbalance between AD- and longevity-risk as an effect-size distribution. Based on these distributions, we grouped the SNPs in three groups: 17 SNPs increased AD-risk more than they decreased longevity-risk, and were enriched for β-amyloid metabolism and immune signaling; 11 variants reported a larger longevity-effect compared to their AD-effect, were enriched for endocytosis/immune-signaling, and were previously associated with other age-related diseases. Unexpectedly, 10 variants associated with an increased risk of AD and higher odds of longevity.

Altogether, we show that different AD-associated SNPs have different effects on longevity. Most AD-associated variants that increase the risk of the disease are associated with lower odds of longevity. We identified a subset of variants with a larger effect on longevity than on AD, that were previously associated as risk-factors for other age-related diseases, and that are selectively enriched for endocytosis and immune signaling functions, and expressed in microglia and endothelial cells.

Over the past decade, it has become clear that tissue ageing is caused by the accumulation of senescent cells, which alters the physiological responses in the surrounding microenvironment in an autocrine and paracrine fashion through the senescence-associated secretory phenotype (SASP). The body of evidence showing that elimination of senescent cells seemed to be largely beneficial led to huge research efforts to identify novel agents that eliminate senescent cells in humans. However, the repurposing of existing drugs and the use of new senotherapeutics are associated with various side-effects; incomplete functional characterisation of peripheral tissues at systemic administration; an absence of standardised guidelines for timing, dose, and route of administration; and a paucity of efficacy and safety data from clinical trials. Therefore, the full potential of senotherapeutics has been hampered in clinical applications.

It is likely that the best senotherapeutic against age-associated diseases and malignancies is yet to be discovered. Dasatinib, quercetin, and other senolytics were discovered using a mechanism-based approach. High throughput screening technology, which allows for automated testing of thousands of molecules present in chemical compound libraries in in-vitro senescence models, could assist with the discovery of new effective senolytics. To date, high throughput screening of commercial chemical compound libraries has led to the discovery of new families of senolytics: HSP90 inhibitors,the BET family protein degraders, and cardiac glycosides.

Furthermore, the safety and potency of existing senolytics can be improved by molecular engineering and drug delivery approaches. For example, the use of ABT263 is limited due to dose-limiting platelet toxicity. Researchers devised a proteolysis-targeting chimera technology to reduce the platelet toxicity of ABT263 by converting it into PZ15227. Compared with ABT263, PZ15227 was shown to be less toxic to platelets, but was a more potent senolytic in vitro and in vivo. Similar strategies might be useful to improve the efficacy and the safety profile of other toxic or repurposed senolytic agents.

In conclusion, senolytic drugs have shown promising results in the elimination of senescent cells and in alleviating various diseases in animal models. However, in patients, there is a paucity in data on the efficacy and safety of senotherapeutics from clinical trials, including systemic effects and side-effects. In this regard it is important to assess the specificity of senolytics in killing targeted senescent cells and their cytotoxic effects, to identify reliable markers for intervention responses, to elucidate interactions with comorbidities and other drugs, and to standardise administration protocols.

Forkhead box O3 (FOXO3) has been proposed as a homeostasis regulator, capable of integrating multiple upstream signaling pathways that are sensitive to environmental changes and counteracting their adverse effects due to external changes, such as oxidative stress, metabolic stress, and growth factor deprivation. FOXO3 polymorphisms are associated with extreme human longevity. Intriguingly, longevity-associated single nucleotide polymorphisms (SNPs) in human FOXO3 correlate with lower-than-average morbidity from cardiovascular diseases in long-lived people.

Healthy aging is critical for addressing the increasing severity of global population aging. The unique role of FOXO3 in the vasculature provides promising avenues for therapeutics against aging-related vascular diseases. Post-translational modifications that regulate FOXO3 activity may be potential therapeutic targets. It is expected that research into strategies for delaying the occurrence and development of vascular aging by targeting the FOXO3 will uncover novel perspectives for the development of new drugs.

Despite advances in our understanding of FOXO3's function in retarding vascular senescence, the particular processes remain poorly known, and other issues remain unresolved. For instance, FOXO3 activation promotes vascular smooth muscle cell apoptosis, which may result in atherosclerotic plaque instability and rupture, causing myocardial infarction, and cerebral infarction. In some cases, FOXO3 promotes extracellular matrix degradation which may accelerate the progression of atherosclerosis. While therapies targeting FOXO3 seem appealing, we need to understand all the details to maximize its effectiveness. Despite these challenges, in-depth research into FOXO3 functions may pave the way for future therapeutic approaches.

Although the specific biological mechanisms by which chronic stress increases cardiovascular disease risk remain unclear, chronic low-grade inflammatory load appears as a possible link. Chronic stress exacerbates this load and leads to early progression of atherosclerosis and thrombotic complications. Inflammation plays a key role in the overall atherosclerotic step, involving the accumulation of foam cells, the formation of fatty stripe tissue and fibrous plaques, the rupture of acute plaques, and the formation of thrombus. Persistence of inflammation is necessary for plaque development and instability, and plays a decisive role in the pathogenesis and progression of coronary artery disease.

Studies have shown that chronic stress-induced hyperlipidemia and oxidative damage can contribute to the development of atherosclerosis. Although atherosclerosis is a chronic inflammatory disease, hyperlipidemia is a major risk factor for changes in intimal and media thickness during atherosclerosis. Experiments have found that compared with the control group, the high concentrations of serum total cholesterol, triglyceride, low density lipoprotein cholesterol (LDLC), and very low density lipoprotein cholesterol (VLDLC) could increase the atherosclerosis index in the chronic stress group, while the concentration of high density lipoprotein cholesterol did not change significantly.

Chronic stress plays a very important role in the development of hypertension, and its mechanisms are known to involve long-term abnormal neurological and endocrine activity, such as significantly elevated levels of corticosteroids, cortisol, epinephrine, norepinephrine, and angiotensin. Initially, the sympathetic nerve-adrenal medulla system is an important factor in the development of hypertension. Under chronic stress, plasma adrenaline, norepinephrine, and dopamine increase rapidly. It is now clear that in hypertension, the sympathetic nervous system activity is increased, and sympathetic excitation causes small arteriovenous contractions, leading to an increase in diastolic/systolic blood pressure.

An endocrinologist by training, Kitalys Institute founder Alexander Fleming is well qualified to take on the regulators. He spent more than a decade at the FDA, where he led the medical reviews that resulted in approval of drugs including metformin, as well as the first statin, insulin analog, and PPAR agonist. Getting approved longevity and geroscience therapies into the public domain is what Kitalys and its conferences and initiatives are all about. No easy task, as Fleming is all too aware. "I think we have some unique challenges in the geroscience domain, in particular the kind of evidence that will be required for regulatory approval. It's going to take a much longer clinical trial to get the evidence to show that the product is working, and not just on the typical endpoint that would be used to approve a drug."

One of the key challenges in geroscience and interventions that target aging is that, unless an intervention truly reverses a disability or something that people already are experiencing, then it will require very long studies to show the benefit. The first such longevity trial, the TAME trial on metformin, is about to commence, led by Nir Barzilai. "Nir and his colleagues are about to embark on a trial that could run three to five years to show an effect across multiple chronic diseases. But here's the thing - we can't expect metformin to produce more than very small effects in slowing the onset of each chronic disease. The premise of the TAME trial is that putting these small effects together in a composite endpoint will show that metformin is doing something sooner than it would be possible to demonstrate an effect on the individual diseases. Still, these effects, even when summed will never be noticed by the individual. But that is what we need - we need that data. So, that's really what we're striving to do - to create an environment that will produce that data. Part of that is having clear regulatory pathways that define the goal posts."

Kitalys is already engaged in what he considers to be two major educational projects. "One is to the regulatory authorities themselves. It's not that they are antagonistic to the development of geroscience products. They are enthralled by the science, but they're scratching their heads as to what they're being asked to do. So, we want to help them on that front. The other educational project involves the people on the other side, particularly those either in the lab or trying to do translational work, and who feel that the regulators are part of the problem. And that's not really true - the regulators are simply reflecting the reality that it takes a long time to get evidence to justify approval of products that may require decades of individual use to provide full benefit." Fleming believes that both sides need to understand each other's predicament and challenges.

The etiology of aging-associated neurodegenerative diseases (NDs), such as Parkinson's disease (PD) and Alzheimer's disease (AD), still remains elusive and no curative treatment is available. Age is the major risk factor for PD and AD, but the molecular link between aging and neurodegeneration is not fully understood. Aging is defined by several hallmarks, some of which partially overlap with pathways implicated in NDs. Recent evidence suggests that aging-associated epigenetic alterations can lead to the derepression of the LINE-1 (Long Interspersed Element-1) family of transposable elements (TEs) and that this derepression might have important implications in the pathogenesis of NDs.

Almost half of the human DNA is composed of repetitive sequences derived from TEs and TE mobility participated in shaping the mammalian genomes during evolution. Although most TEs are mutated and no longer mobile, more than 100 LINE-1 elements have retained their full coding potential in humans and are thus retrotransposition competent. Uncontrolled activation of TEs has now been reported in various models of neurodegeneration and in diseased human brain tissues. We will discuss in this review the potential contribution of LINE-1 elements in inducing DNA damage and genomic instability, which are emerging pathological features in NDs. TEs might represent an important molecular link between aging and neurodegeneration, and a potential target for urgently needed novel therapeutic disease-modifying interventions.