Fight Aging!

Microglia are innate immune cells of the central nervous system, analogous to macrophages elsewhere in the body. Like macrophages, microglia are involved in tissue maintenance and repair, as well as in clearance of molecular waste and destruction of pathogens. Interestingly, microglia are one of the classes of immune cell that, similarly to B cells, will repopulate quite rapidly following selective destruction. That destruction is now routinely achieved in animal models using small molecule CSF1R inhibitors.

When this destruction and replacement is performed in old animals, the new microglia lack many of the undesirable features characteristic of microglia in old tissues, and behave in a more youthful fashion. Senescent microglia are removed, but there are likely other beneficial differences before and after.

This has attracted some interest in that part of the research community involved in finding ways to address the aging of the brain. As shown in today's open access research, when this microglial replacement is accomplished prior to brain injury, it can reduce the normal, unhelpful, inflammatory reaction to that trauma. Lasting inflammation and disruption of brain tissue function are reduced. This is perhaps a measure of the degree to which aged microglia are biased towards harmful inflammation.

Microglial replacement in the aged brain restricts neuroinflammation following intracerebral hemorrhage

Inflammation is a critical aggravator of neural injury following brain insults. In the aged brain, microglia exhibit an exaggerated and uncontrolled inflammatory phenotype in response to brain insults or immune stimulation. Rather than an enhanced immune response at baseline level, aged microglia possess a primed profile that is demonstrated by augmented production of inflammatory factors such as interleukin (IL)-1β and reactive oxygen species following stimulus. Although evidence suggests a link between the primed profile of the aged microglia and vulnerability of the old brain to inflammation-related secondary injury following acute insult, it remains poorly understood to what extent the aged microglia with a primed profile can impact the neuroinflammation and the outcome of acute brain injury.

The survival of microglia critically depends on signaling through the colony-stimulating factor 1 receptor (CSF1R). Administration of CSF1R inhibitor PLX3397 eliminates microglia in the whole brain that continues when CSF1R inhibition is present. Moreover, removal of CSF1R inhibition stimulates the rapid repopulation of the entire brain with new microglial cells, leading to effective replacement of the entire microglia population, a process takes approximately 2-3 weeks to complete.

Recent evidence suggests that withdrawal of CSF1R inhibitors in the old mice leads to complete repopulation of new microglia with characteristics resembling young microglia. Therefore, withdrawal of CSF1R inhibitors in the old brain resets the primed microglia and provides an opportunity to determine the impact of aged microglia on neural injury upon brain insults. In this study, we investigated the impact of microglial replacement in the aged brain on neural injury using a mouse model of intracerebral hemorrhage (ICH) induced by collagenase injection.

We found that replacement of microglia in the aged brain reduced neurological deficits and brain edema after ICH. Microglial replacement-induced attenuation of ICH injury was accompanied with alleviated blood-brain barrier disruption and leukocyte infiltration. Notably, newly repopulated microglia had reduced expression of IL-1β, TNF-α, and CD86, and upregulation of CD206 in response to ICH. Our findings suggest that replacement of microglia in the aged brain restricts neuroinflammation and brain injury following ICH.

This popular science article takes an approach that seems useful when presenting the argument for treating aging as a medical condition to people who are entirely unfamiliar with the concept. At present the practice of medicine treats the symptoms of aging only, addressing each symptom - each age-related condition - separately. But most old people have numerous conditions, stemming from the same underlying causes, the causative mechanisms of aging. It only makes sense to address age-related conditions more efficiently, and the path to that goal is to target these deeper causes of aging, thereby treating numerous age-related conditions with one intervention.

Over half of UK adults over the age of 65 live with two or more long-term health conditions - commonly known as multimorbidity. Crucially, over half of GP consultations and hospital appointments involve patients with multimorbidity. In the UK, care for people with multimorbidity is also estimated to take up to 70% of health and social care expenditure.

Multimorbidity is currently managed by treating each disease separately. This means people will need to take multiple medications at the same time (known as polypharmacy), and will also have to attend multiple medical appointments for each condition. Not only can this put a strain on the NHS, polypharmacy can also put patients at increased risk of negative drug interactions and unintended harm. There's a clear need to improve the way multimorbidity is treated. But research shows that to do this, we need to instead start looking at targeting the key causes of multimorbidity when searching for treatments.

Although multimorbidity differs for each person, we know that patients tend to suffer from the same groups of diseases - known as "clusters". This suggests that each cluster may share a common underlying cause. For example, a person with multimorbidity may suffer from heart problems (such as heart disease and high blood pressure) and diabetes, which may all stem from the same cause - such as obesity. Identifying and treating the cause of a patient's disease clusters would allow us to more effectively combat several - or even all - of the diseases a patient has using a single treatment.

Such an approach has not yet been taken, in large part because medical research and drug discovery tends to focus on treating a single disease. Importantly one of the biggest risk factors for developing multimorbidity is getting older. This is why researchers think targeting the biological causes of ageing could be one way of treating multimorbidity, by preventing clusters of diseases from developing in the first place.

For example, we become less able to remove senescent cells from our body as we get older, causing them to accumulate and increase our risk of disease. Researchers think that if we could prevent these cells from building up, we may be better able to prevent multimorbidity from happening to begin with. Drugs which can kill senescent cells (called senolytics) already exist, and are currently used to treat certain types of leukaemia, and are now being trialled on patients with the chronic lung condition idiopathic pulmonary fibrosis. Given that senolytics are already in clinical use, this means they could quickly be repurposed for use in patients with multimorbidity if proven to be effective on other conditions too.

Link: https://theconversation.com/tackling-ageing-may-be-best-way-to-prevent-multiple-chronic-conditions-from-developing-in-older-people-174645

Nicotinamide adenine dinucleotide (NAD) is an important part of the mechanisms by which mitochondria produce chemical energy store molecules to power cellular processes. NAD levels fall with age, concurrent with growing mitochondrial dysfunction. There is some enthusiasm for approaches - such as supplementation with vitamin B3 derivatives - that might compensate for this issue and thereby improve mitochondrial function in later life.

Researchers here suggest that in fact the quality and quantity of evidence for NAD+ levels to decline with age doesn't rise to the level that the scientific community should by using as a basis to proceed towards the development of interventions. I think it most likely that more rigorous work will confirm the existing evidence. More pertinent objections to sizable investment in NAD upregulation are that (a) exercise increases NAD levels to a greater degree than any of the other approaches assessed to date, and (b) the results of clinical trials of NAD upregulation are decidedly mediocre.

Nicotinamide adenine dinucleotide (NAD+) is an essential molecule involved in various metabolic reactions, acting as an electron donor in the electron transport chain and as a co-factor for NAD+-dependent enzymes. In the early 2000s, reports that NAD+ declines with aging introduced the notion that NAD+ metabolism is globally and progressively impaired with age. Since then, NAD+ became an attractive target for potential pharmacological therapies aiming to increase NAD+ levels to promote vitality and protect against age-related diseases.

This review summarizes and discusses a collection of studies that report the levels of NAD+ with aging in different species (i.e., yeast, C. elegans, rat, mouse, monkey, and human), to determine whether the notion that overall NAD+ levels decrease with aging stands true. We find that, despite systematic claims of overall changes in NAD+ levels with aging, the evidence to support such claims is very limited and often restricted to a single tissue or cell type. This is particularly true in humans, where the development of NAD+ levels during aging is still poorly characterized. There is a need for much larger, preferably longitudinal, studies to assess how NAD+ levels develop with aging in various tissues. This will strengthen our conclusions on NAD metabolism during aging and should provide a foundation for better pharmacological targeting of relevant tissues.

Link: https://doi.org/10.3390/nu14010101

Chronic inflammatory signaling is an important issue in aging, both generally throughout the body, and in localized hot spots such as atherosclerotic lesions in blood vessel walls. Macrophage cells responsible for clearing out molecular waste and repairing damage in blood vessels are made less effective by inflammatory signaling. The feedback loop of ineffective macrophages becoming incapacitated by the toxic lesion environment, while inflammation draws in more macrophages, is at the center of the progression of atherosclerosis. Ultimately these fatty lesions grow to the point of rupture, and the result is a heart attack or stroke.

In today's research materials, scientists report on a less well studied component of inflammation, in that macrophages express olfactory receptors also found in cells in the nose, and can identify aldehydes in the bloodstream. The cells react with raised inflammatory signaling. The presence of such compounds increases with age, and this contributes to the growing dysfunction of macrophage cells that should be working to keep blood vessel walls free from metabolic waste and damage.

A cautionary note on this front is that past efforts to treat atherosclerosis by suppression of inflammatory signaling did not produce exceptional results. The outcomes looked little better than therapies that lower LDL cholesterol in the bloodstream, producing only a minor reduction in the size of existing lesions. Since mortality risk scales with the size and number of lesions, the great unmet need here is a way to rapidly and safely remove lesions. Present strategies can only slow the condition, and do little for the high risk groups in which patients already exhibit sizeable lesions.

Immune cells can sniff out octanal in blood, triggering dangerous inflammation and atherosclerosis

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.

Olfactory receptor 2 in vascular macrophages drives atherosclerosis by NLRP3-dependent IL-1 production

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.

In recent years, researchers have investigated retrotransposon activity in the context of aging. Retrotransposons, a class of transposable element, are sequences in the genome capable of replication, perhaps archeological debris from the ancient interactions of cells and viruses, co-opted by evolution. Transposable elements are largely suppressed in youth, but the suppression mechanisms become less effective in later life, one of countless cellular mechanisms that runs awry for reasons that are far from fully understood. It is a challenge to connect specific changes in gene expression to specific underlying causes of aging; a cell is a system in which everything interacts with everything else. Cellular metabolism is far from fully mapped at the detail level, even before considering the ways in which metabolism - and the surrounding microenvironment that a cell reacts to - accrues damage and shifts with age.

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.

Link: https://doi.org/10.3389/fnagi.2021.786897

A charitable view of the FDA is that it is populated by well-meaning people who happen to believe that (a) any cost in lives, time, and funds is worth it in order to prevent harm by commission, and (b) zero risk is a possible goal in medicine. The Hippocratic Oath Enforcement Agency, if you like. There are much less charitable views, given the present state of regulatory capture that dramatically raises costs and slows development, as well as the invisible graveyard of countless lives lost to the absence of medical technologies that would otherwise exist and be widely available at reasonable prices.

There is no established regulatory path to approval for treatments that target aging. So at present biotech and pharma companies working on therapies that target mechanisms of aging pick a single age-related disease in order to gain regulatory approval. It is assumed that there will be widespread off-label use thereafter. There are efforts underway to pave a better road, but this will take a good long time at the usual glacial pace of large regulatory agencies.

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.

Link: https://www.longevity.technology/kitalys-institute-breaking-down-the-barriers-to-longevity-clinical-trials/

Senescent cells are play a role in the onset and progression of near every age-related condition. Cells become senescent constantly throughout the body and throughout life, most because they have reached the Hayflick limit to replication. In youth, senescent cells are efficiently removed, either through programmed cell death or by the immune system. With age, the immune system declines in effectiveness. Senescent cells begin to linger and grow in number. These errant cells secrete a mix of pro-growth, pro-inflammation signals that, when present over the long term, disrupt cell and tissue function.

Today's open access review takes a look at senescent cells in the aging liver, and their contribution to liver disease. While human trials have yet to be undertaken for liver conditions, it is plausible that selectively destroying senescent cells using senolytic therapies will prove to be beneficial to patients. This is true of so many different age-related conditions that the research and development community has started in on clinical trials for only a small fraction of them.

Thus there is a role for philanthropy here, to take presently available, low-cost senolytic therapies such as the dasatinib and quercetin combination and run low-cost, rapid trials of efficacy for dozens of age-related conditions. With proof that this can help patients with specific issues, more physicians will be open to prescribing senolytic therapies off-label, and we may see many more aged people benefit sooner than would be the case if the field is left to established institutions.

Biliary Epithelial Senescence in Liver Disease: There Will Be SASP

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.

Sustained psychological stress is shown to accelerate the progression of atherosclerosis. The most plausible biological explanations involve the effects of stress on (a) the immune system, resulting in raised inflammatory signaling, and on (b) blood pressure. Raised blood pressure can accelerate atherosclerosis, as well as raise the risk of rupture of atherosclerotic lesions. The relationship between stress and atherosclerosis may well have as much to do with the lifestyle effects of stress and their downstream effects on cardiovascular health over the long term, however.

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.

Link: https://doi.org/10.3389/fcvm.2021.738654

FOXO3 is one of the few genes in which variants correlate with human longevity in multiple study populations. Effect sizes are still small of course, meaning a modest adjustment to the odds of reaching very old age, but one can at least look into the role of FOXO3 and say something about processes likely to be important in human late life mortality. Evidence suggests that FOXO3, while influencing very general cell behaviors such as stress responses, is involved in vascular aging. Cardiovascular disease is the largest cause of human mortality. That said, it seems unlikely that there is any basis for effective therapy in a deeper examination of FOXO3; the effect of variants on human longevity just isn't large enough.

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.

Link: https://doi.org/10.3389/fcvm.2021.778674

Altos Labs was formed to develop in vivo reprogramming into a viable class of therapies to treat aging. Reprogramming occurs during embryonic development, and the discovery of the Yamanaka factors allows this process to be enacted in any cell. To date this has largely been used in the development of induced pluripotent stem cells, a source of cells for research and therapy. The other effects of reprogramming are coming to be just as interesting, however: a resetting of the epigenetic marks characteristic of cells in old tissues, and a restoration of mitochondrial function. Studies in mice show that partial reprogramming, reversing epigenetic aging while not converting cells into stem cells, produces benefits. Can this be made safe enough for use in humans? Therein lies the question.

As the launch announcement indicates, Altos Labs is shaping up to be a sizable project, populated by luminaries from academia and industry. It may have more committed funding at this point than the whole of the rest of the nascent longevity industry. It is likely an interesting story, yet to be told, as to how exactly in vivo reprogramming, of all of the possible approaches to the treatment of aging, gained so much support among high net worth individuals interested in aging as a field of development. If these funds are spent well, the next decade will see all of the immediate questions answered regarding the use of in vivo reprogramming as a therapy.

The present big picture understanding of reprogramming is an interesting one. It may be the case that cycles of DNA damage and repair lead, via the usual indirect routes of cellular biochemistry, to much of the characteristic epigenetic change that occurs with age. In which case resetting those epigenetic marks is indeed a form of repair and rejuvenation, of a similar scope as senolytic therapies that remove senescent cells and their negative impact on metabolism. Reprogramming cannot repair DNA damage, it cannot do much for accumulations of metabolic waste that even young cells cannot break down, such persistent cross-links and lysosomal aggregates. But it may well achieve enough to be worth the effort to develop a safe implementation for human medicine.

Altos Labs launches with the goal to transform medicine through cellular rejuvenation programming

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 $3B 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."

Senolytic therapies to selectively destroy senescent cells in old tissues have produced rapid rejuvenation in mice, turning back many different age-related diseases in many different studies. Senescent cells actively maintain a disrupted, inflammatory state of tissue when not cleared effectively by the immune system. Initial human trials of the dasatinib and quercetin combination (readily available to self-experimenters as well, prescribed off-label) have produced promising results. But as the authors of this paper note, there is still far too little human data to satisfy the cautions of regulators. Many more trials should be underway, particularly for dasatinib and quercetin, to definitively establish that this is a path worth pursuing, and allow the physician community to prescribe senolytics widely in the aged population.

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.

Link: https://doi.org/10.1016/S2666-7568(21)00300-7

As a general rule, one should take with a grain of salt the results of any individual study on gene variants and correlations with longevity or disease risk. The results rarely replicate. Longevity in particular is a complex emergent phenomenon, and any one gene variant has only a small effect, highly dependent on interactions with environment and other genes. If anything, more rigorous studies of large genetic databases have been steadily decreasing the estimated contribution of genetic variants to variations in human life span. It is near all a matter of culture and lifestyle choice. That said, there are a few well defined gene variants that correlate with Alzheimer's disease risk, those examined in this paper. One should just be a little dubious as to whether the modest correlations with longevity will replicate in other study populations.

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.

Link: https://doi.org/10.3389/fgene.2021.748781

Today's open access paper provides an interesting view on the age-related reduction in cellular NAD+ levels, a topic of interest in the longevity community these past years. Nicotinamide adenine dinucleotide (NAD) is an important piece of molecular machinery in the function of the electron transport chain in mitochondria. The primary role of mitochondria is to generate the chemical energy store molecule adenosine triphosphate (ATP), used to power the cell. NAD cycles between NAD+ and NADH during this process, and lower levels of NAD imply a growing dysfunction in cellular energy metabolism.

Separately, researchers here show that lowered levels of NAD act to prime a cell for inflammatory activity. Mitochondrial dysfunction with age may affect levels of chronic inflammation in tissues via this mechanism. As we all know by now, chronic inflammation sustained over years provides a sizable contribution to degenerative aging, disrupting the normal processes of tissue maintenance, changing cell behavior for the worse, and accelerating many of the common age-related conditions.

Given this, it is interesting that fairly direct, compensatory restoration of NAD levels via the various approaches based on supplementation of vitamin B3 derivatives (niacin, nicotinamide riboside, nicotinamide mononucleotide, and so forth) perform so indifferently in clinical trials. They do not address deeper causes of this age-related decline, but do compensate in the production of more NAD. That said, exercise is better at restoring NAD levels in older people. Equally exercise produces numerous other beneficial effects on metabolism and cell function. The challenge in thinking about any newly considered mechanism of aging is, at the end of the day, whether or not it has a large effect size. The evidence for effect size is often indirect and dubious.

Intracellular NAD+ Depletion Confers a Priming Signal for NLRP3 Inflammasome Activation

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.

There is a growing enthusiasm for aging research and the development of interventions aimed at slowing or reversing aging. This has reached the point at which people with significant resources are becoming involved, and thus the more prominent projects in the research and development communities are gaining support that would have been hard to find just a few short years ago. This new funding for the Dog Aging Project is a good example of the growing level of support for work on aging, undertaken by people who have bought into the vision of a future in which medical technology allows for much longer, healthier lives for all.

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.

Link: https://newsroom.uw.edu/news/tech-entrepreneurs-pledge-25-million-dog-aging-project

One of the signs of investor enthusiasm for an industry is the existence of projects that raise significant funding at a very early stage of their development. We're seeing that happen for cellular reprogramming, but companies started by well-connected individuals in other parts of the longevity industry are now raising a great deal of funding in early preclinical stages of development. This suggests that we will continue to see a growing influx of capital into the development of ways to treat aging as a medical condition, pulling more research projects out of the constraints of academia and into an environment of greater funding and attention. We can hope that an acceleration of progress across the field will result from this.

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.

Link: https://techcrunch.com/2022/01/10/with-funding-from-top-investors-gameto-is-aiming-to-delay-even-eradicate-menopause/