Fight Aging! Newsletter, December 11th 2023

Biopharma Dealmakers - a Nature Research publication - brings together life scientists, biotech and pharmaceutical professionals, and investors from across the globe. Biopharma Dealmakers offers readers themed editorial features that provide insights into dealmaking and industry trends. Regular editorial content includes biopharma deal round-ups, financing news and a collection of 'business of science' articles from the Nature Research catalogue. Biopharma Dealmakers also includes profiles of companies looking to partner or seek investment that showcases their pipeline products, technologies, therapeutic focus and partnering strategies. In this issue: Top 20 biopharma deals of 2023. Live forever: approaches to reverse aging. What are the drivers behind CNS deal flow? Oligonucleotide therapies broaden their reach. Make way for gene editing.

Delaying aging, restoring youth, regenerative medicine... whatever term is used, research aiming to target fundamental mechanisms of aging to increase life expectancy and quality has flourished in recent years. Ten years ago, researchers wrote a review that described hallmarks of aging, including genomic instability, stem cell exhaustion, deregulated nutrient sensing, mitochondrial dysfunction, and cellular senescence. Among efforts to target these hallmarks with potential therapies, those focused on cellular senescence have been at the forefront of industry activity, with more than 20 companies established in the past decade. In this piece, we highlight some of the progress and challenges for a selection of these companies.

Cholesterol is largely manufactured in the liver and transported throughout the body via a system of carrier molecules such as low-density lipoprotein (LDL) particles. Inside cells, cholesterol is esterified to provide protection from the toxicity of free cholesterol. Local excesses can overwhelm this protective mechanism and cells have no internal mechanism for degrading cholesterol. "When your system of transport breaks down, which happens in obesity and aging, localized excesses of cholesterol form. Our data show that the consequent toxicity is an important cause of downstream damage and disease." No current therapeutics directly target free cholesterol. While lifestyle changes, statins, or PCSK9 inhibitors can dramatically reduce LDL cholesterol levels to lower risk of atherosclerosis and slow its progression, they do not significantly impact free-cholesterol excess or reverse the damage caused by free cholesterol. "Getting rid of excess free cholesterol was impossible until our approach to effectively target it."

Established therapies focused on lowering LDL cholesterol cannot meaningfully remove established plaques, but Repair's animal studies have shown a sizeable reversal of plaques following gene therapy mediated clearance of free cholesterol. The company is now finalizing its formulation and preclinical studies. Repair is also developing a therapy for NASH, which affects 3% to 6% of the US population, being more prevalent in patients with metabolic disease and obesity. It progresses from inflammation and fibrosis to cirrhosis in approximately 20% of cases and is associated with increased overall mortality. There is no US Food and Drug Administration (FDA)-approved therapy for NASH, and, like atherosclerosis, its progressive pathology is largely irreversible. Repair's gene therapy reduced liver-tissue free cholesterol in mouse models significantly after only a few days, rapidly reducing key serum markers of liver damage. Moreover, hallmarks of NASH pathology including liver inflammation, insulin resistance and, most importantly, liver fibrosis were all significantly reduced following an 8-week therapy.

Researchers discovered that a subtype of cells that sit between the innate and adaptive immune system were dramatically dysfunctional where senescent cells were accumulating. They m showed in two different mouse models of disease that the number and function of these invariant natural killer T (iNKT) cells was significantly reduced in tissues with high levels of senescent cells. Initial work showed that a tool compound, alpha-galactosylceramide (αGalCer) could be used to activate iNKT cells and reduce senescent cells in adipose tissue, leading to durable improvements in blood glucose levels, insulin resistance and HbA1c levels in diet-induced obese mice.

Subsequently, to demonstrate the widespread utility of immune-based senolysis, the company applied the approach to a severe model of pulmonary fibrosis. In this study, a single treatment at the peak of disease resulted in the ablation of senescent cells in the lung and attenuation of key fibrotic and inflammatory markers, which ultimately resolved fibrosis. Deciduous Therapeutics has used computational assisted design to synthesise a suite of proprietary therapies that could be used in the clinic to re-activate tissue-resident iNKT cells. To date, the company's lead program has shown single-dose efficacy in resolving both metabolic and fibrotic diseases along with a favorable safety profile at doses significantly higher than the efficacious dose.

With the global population aging, the number of people with multiple chronic health conditions has been rising because medicine still focuses on treatment rather than prevention. It is estimated that one in three people in the world lives with two or more chronic diseases. One way to prevent and even reverse chronic diseases is through lifestyle changes through health promotion and education. This also helps delay the onset of geriatric syndrome (frailty, cognitive decline, and reduced performance in the activities of daily living scale). This is why a new discipline of medicine has emerged to specifically address this issue: lifestyle medicine.

The American College of Lifestyle Medicine (ACLM) promotes a science-based approach that integrates lifestyle factors to prevent and treat chronic conditions. There are six pillars of lifestyle medicine: nutrition, physical activity, stress management, restorative sleep, social connection, and avoidance of risky substances. The goal of this discipline is not only to prolong the lifespan but to increase the healthspan by reducing the morbidity span. A study estimated that adherence to four or five low-risk lifestyle factors (diet, physical activity, alcohol intake, etc.) at age 50 could extend life expectancy free of major chronic diseases (cancer, cardiovascular disease, or diabetes) by 7.6 years in men and 10.6 years in women when compared to people with no low-risk lifestyle factors

Healthspan is defined as longevity without diseases and is often associated with a higher quality of life. Healthy longevity is a World Health Organization (WHO) priority. Chronological age, the number of years a person has been alive, is a great predictor of disease prevalence and mortality risk but is unchangeable. On the other hand, biological age is variable and measures the accumulation of physiological damage in individuals, meaning that two individuals of the same chronological age can have different biological ages. Thus, a biological marker providing a quantifiable overall insight into the patient's current health status would be of great use.

A few longevity markers do currently exist, such as PhenoAge (algorithms to improve chronological age by adding 9 biomarkers found in routine blood tests) or GrimAge, which is an epigenetic clock that can evaluate the biological age of an individual using DNA methylation-based markers. These tests are reliable for determining biological age, but there is little literature linking them to healthspan potential and even less to each of the pillars of lifestyle medicine. A new biomarker, the longevity protein klotho, might become a game-changing tool for measuring metabolic health and predicting the potential for healthy longevity. This review introduces the klotho protein as a potential novel, cost-effective biomarker and integrative tool to quantify and monitor the health status of individuals adopting lifestyle behavioral changes and summarizes current knowledge on the extent of klotho regulation across the six pillars of lifestyle medicine.

Based on this narrative analysis, klotho is a very promising marker candidate for lifestyle medicine due to its potential involvement in the six pillars of lifestyle medicine. Although we have identified knowledge gaps that warrant further study (randomized trials) to better understand the use of klotho in monitoring the effect of a lifestyle change intervention, it has enormous potential to enable objective, quantitative, and rapid monitoring of the overall health and the healthspan of patients. Klotho could be used as a marker in clinical studies where it is difficult to control the entire patient environment. Klotho is easy to quantify and, in the case of age-related diseases, would be an excellent marker to follow, as some diseases show no perceptible symptoms for a long period of time.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder that affects over 50 million people worldwide. A key pathological hallmark of the disease is the accumulation of amyloid-beta (Aβ) plaques in the brain, which leads to progressive decline in cognitive function. Microglia, resident immune cells of the brain, are thought to play a vital role in the clearance of Aβ plaques, a function that is impaired in AD.

The research team sought to investigate how microglia control Aβ clearance and how they become dysfunctional in AD. Through their elegant study, the team discovered that VCAM1, a cell surface protein on microglia, mediates microglial migration towards Aβ and promotes microglial clearance of Aβ. The team also discovered that another protein found in Aβ plaques, APOE, acts in conjunction with VCAM1 to mobilize microglia to Aβ plaques. The team further found that stimulating the "VCAM1-APOE" pathway reduced AD pathology in a mouse model of AD. These findings suggest that proper VCAM1 functioning is critical for microglial migration and clearance of Aβ.

The team also examined VCAM1-expressing microglia in the brain tissue of AD patients. Interestingly, AD patients exhibited elevated levels of soluble VCAM1 in the cerebrospinal fluid, which suggested dysregulated VCAM1-APOE signaling. This observation correlates with reduced clearance of Aβ by microglia. Collectively, the findings of the study implicate VCAM1-APOE signaling in the pathogenesis of AD and identify VCAM1 as a promising target for AD therapy.

In Alzheimer's disease (AD), sensome receptor dysfunction impairs microglial damage-associated molecular pattern (DAMP) clearance and exacerbates disease pathology. Although extrinsic signals, including interleukin-33 (IL-33), can restore microglial DAMP clearance, it remains largely unclear how the sensome receptor is regulated and interacts with DAMP during phagocytic clearance. Here, we show that IL-33 induces VCAM1 in microglia, which promotes microglial chemotaxis toward amyloid-beta (Aβ) plaque-associated ApoE, and leads to Aβ clearance. We show that IL-33 stimulates a chemotactic state in microglia, characterized by Aβ-directed migration.

Functional screening identified that VCAM1 directs microglial Aβ chemotaxis by sensing Aβ plaque-associated ApoE. Moreover, we found that disrupting VCAM1-ApoE interaction abolishes microglial Aβ chemotaxis, resulting in decreased microglial clearance of Aβ. In patients with AD, higher cerebrospinal fluid levels of soluble VCAM1 were correlated with impaired microglial Aβ chemotaxis. Together, our findings demonstrate that promoting VCAM1-ApoE-dependent microglial functions ameliorates AD pathology.

Lifespan has nearly doubled over the recent seven decades, but the final years of life come often with aging-associated diseases, most prominently cardiovascular disease (CVD) featured by progressive deterioration of cardiovascular structure and function. Aging imposes extensive changes on cardiovascular tissues that lead them toward a pathological state including hypertrophy, left ventricular dysfunction, arterial stiffness, and vascular dysfunction. Extrinsic factors, such as environment and lifestyle, and intrinsic processes, such as oxidative stress and inflammation, exacerbate DNA damage response, metabolic remodeling, and epigenetic drift, and thereby promote cellular aging in the cardiovascular system. These irreversible changes progressively impair the ability of cells to proliferate, which is critical to replace damaged cells that naturally accumulate in aged cardiac and vascular tissues.

During the recent decade, it is increasingly understood that the accumulation of the non-proliferating cells, so-called "senescent cells," declines mammalian tissues and organ function. According to the emerging "adult stem cell senescence theory of aging," stem cells and/or progenitor cells harboring in the heart and blood vessels or circulating progenitor cells, which replenish either preexisting senescent stem cells or specialized cardiomyocytes (CMs) and endothelial cells (ECs), become exhausted and lose their stemness during aging. The aging/senescence milieu suppresses endogenous regenerative and reparative mechanisms in the adult stem cells and progenitor cells, and also limits the success of cell-based regenerative therapies that aimed at repairing injured and dysfunctional tissues and restoring a youthful phenotype in the cardiovascular system. In a middle-size human study involving 119 humans with cardiovascular disease (32-86 years), more than 50% of tissue-specific cardiac progenitor cells (CPCs) exhibited the senescence phenotype.

Reactive oxygen species (ROS) have been viewed as pathological molecules that undermine normal cellular pathways by increasing oxidative stress. The cardiovascular system is principally vulnerable to reactive oxygen species (ROS) induced oxidative damage due to its high metabolic demand and low antioxidant defense capacity in aging. Single-cell RNA-Seq analysis of mouse aged cardiovascular ECs reveals transcriptomic reprogramming, including upregulation of ROS metabolic process in these cells. Not only in aged arterial ECs, single-nucleus RNA-Seq verify that oxidative responses are enriched in aged CMs in both primate and human hearts. These studies and beyond have demonstrated that these aged cardiac and arterial tissues exhibit a higher level of senescence-associated β-galactosidase staining and expression of pro-senescence genes including IL1β, IL17, and Type-I interferon (IFN-α). The relentless ROS production can also cause oxidative stress in cellular components, leading to cardiovascular stem/progenitor cell senescence and impaired proliferation and differentiation.

A mounting body of evidence underscores the significance of targeting redox machinery to restore stem cell self-renewal and enhance their differentiation potential into youthful cardiovascular lineages. Hence, the redox machinery holds promise as a target for optimizing cardiovascular regenerative therapies. In this context, we delve into the current understanding of redox homeostasis in regulating stem cell function and reprogramming processes that impact the regenerative potential of the cardiovascular system. Furthermore, we offer insights into the recent translational and clinical implications of redox-targeting compounds aimed at enhancing current regenerative therapies for aging cardiovascular tissues.

Loyal was only a few months old and about five people when we decided to begin by targeting the abnormally short lifespan of large breed dogs with a drug program we code-named LOY-001. LOY-001 extends lifespan in part by reducing IGF-1 to levels seen in smaller-breed dogs. The IGF-1 axis is one of the most well-studied longevity pathways. In model organisms from C. elegans to mice, reducing IGF-1 extends healthy lifespan, and increasing IGF-1 shortens healthy lifespan. In humans, certain centenarians have been shown to have genetically lower levels of IGF-1.

Today, I'm so proud to announce that Loyal has earned what we believe to be the FDA's first-ever formal acceptance that a drug can be developed and approved to extend lifespan. In regulatory parlance, we have completed the technical effectiveness portion of our conditional approval application for LOY-001's use in large dog lifespan extension. As there was no established regulatory path for a lifespan extension drug, we had to design from scratch a scientifically strong and logistically feasible way to demonstrate efficacy of an aging drug. This process took more than four years, resulting in the 2,300+ page technical section now approved by the FDA. It included interventional studies of LOY-001 in an FDA-accepted model of canine aging and an observational (no-drug) study of 451 dogs.

Our interventional studies with LOY-001 showed that the drug improved clinically-relevant aging parameters. We assessed these in laboratory studies using a dog model that represents accelerated aging. We then correlated those results with quality of life scores in the observational study, as independently measured by dog owners, and health outcomes as measured by veterinarians. This was key to show that the biological benefits of the drug are linked to clinically relevant outcomes. From our data, the FDA believes LOY-001 is likely to be effective for large dog lifespan extension in the real world. Once we satisfactorily complete safety and manufacturing sections and other requirements, vets will be able to prescribe LOY-001 to extend the lifespan of large dogs while we complete the confirmatory pivotal lifespan extension study in parallel.

Epigenetic drift or "disorder" increases across the mouse lifespan and is suggested to underlie epigenetic clock signals. While the role of epigenetic drift in determining maximum lifespan across species has been debated, robust tests of this hypothesis are lacking. Here, we test if epigenetic disorder at various levels of genomic resolution explains maximum lifespan across four mammal species. We show that epigenetic disorder increases with age in all species and at all levels of genomic resolution tested. The rate of disorder accumulation occurs faster in shorter lived species and corresponds to species adjusted maximum lifespan.

While the density of cytosine-phosphate-guanine dinucleotides ("CpGs") is negatively associated with the rate of age-associated disorder accumulation, it does not fully explain differences across species. Our findings support the hypothesis that the rate of epigenetic drift explains maximum lifespan and provide partial support for the hypothesis that CpG density buffers against epigenetic drift.

Earlier this year, scientists discovered that excessive brain inflammation is critical for disease initiation and can predict whether cognitively unimpaired elderly are at a higher risk of developing Alzheimer's symptoms. This earlier research hinted at the importance of neuroinflammation in the pathological cascade involving other key players in Alzheimer's pathology including amyloid beta and tau. Now new findings provide the first strong evidence that brain inflammation is also a direct cause of neuropsychiatric symptoms that often accompany Alzheimer's-associated dementias.

In the new study, the researchers worked with 109 elderly individuals, the majority of whom had no cognitive impairments. Most of those individuals were, however, positive for amyloid and tau. By measuring levels of neuroinflammation, amyloid beta, and tau via brain imaging and comparing the results with clinical assessments of neuropsychiatric symptom severity, the scientists discovered that microglial activation was strongly associated with a variety of neuropsychiatric symptoms, including disturbed sleep and agitation. While levels of amyloid and tau alone were predictive of neuropsychiatric symptoms, neuroinflammation seemed to have an added effect.

Neuroinflammation was most strongly associated with caregivers or family members reporting their loved one's rapid mood swings from calm to tears or anger, one of the common symptoms of the disease. Individuals whose caregivers showed higher levels of distress when caring for them had greater levels of brain inflammation. Taken together, the study adds to the growing evidence of the role of brain inflammation in the early stages of the disease progression, when symptoms like excess irritability tend to emerge. It also suggests that clinical trials targeting neuroinflammation as a preventive therapy for Alzheimer's could track neuropsychiatric symptoms as one way of measuring the treatment's effectiveness. Conversely, drugs specifically targeting neuroinflammation could potentially help reduce neuropsychiatric symptom severity and alleviate some of the psychological burden experienced by caregivers, thus improving patient support.

Aging is accompanied by the gradual decline in cellular and organismal fitness. At the macromolecular level, impaired protein homeostasis (proteostasis) and genome integrity are key features of aging. The age-dependent deteriorative changes are interconnected with each other to decrease the lifespan and increase the incidence of age-associated diseases, which eventually lead to death. Similar to other species, C. elegans exhibits age-associated changes such as the reduction in genome stability, proteostasis, lipid homeostasis, and immunity. Recent studies have indicated that RNA quality also declines during aging in C. elegans.

Eukaryotes are equipped with homeostatic systems that are crucial for the maintenance of mRNA quality, which is regulated by diverse surveillance pathways. Misprocessed mRNAs need to be eliminated by these RNA surveillance pathways. Nonsense-mediated mRNA decay (NMD), no-go decay, nonstop decay, and ribosome-associated quality control (RQC) are crucial for mRNA and protein quality control. mRNA splicing, which is a major pre-mRNA processing event in eukaryotes, selects and joins exons that are separated by introns, thus enabling diverse gene expression. Changes in splicing occur during aging and may reflect the deteriorated transcriptome quality. Abnormal mRNA splicing underlies the generation of aberrant transcripts that disrupts the proteostasis by producing truncated proteins and causing ribosome stalling, followed by ribosome collision.

Here we review recent studies that report on the key functions of various factors that regulate mRNA surveillance and splicing in the longevity and aging of C. elegans. Our review provides crucial information regarding the conserved functions of mRNA quality control in aging, which may be potentially utilized as therapeutic targets of aging and age-associated diseases in humans.

Over the last decade, growing evidence has suggested that the periphery contributes to the etiology of age-associated neurodegenerative diseases. Manipulation of skeletal muscle protein quality control pathways protects against the accumulation of aggregation-prone disease proteins in the invertebrate brain and retina. The mechanisms responsible for these benefits remain poorly understood, some of these effects are mediated by secreted factors that communicate metabolic and inflammatory signals between tissues. Although the source and identity of these neuroprotective circulating cytokines are unclear, several are known to be secreted from skeletal muscle, an unconventional endocrine organ that secretes a myriad of bioactive factors that induce metabolic changes in distant tissues such as liver, adipose tissue, and the central nervous system (CNS).

Skeletal muscle metabolism is regulated in part by transcription factor E-B (TFEB), a master regulator of the lysosomal-to-nucleus signaling that integrates cellular metabolism and lysosomal function. TFEB expression and function are strongly induced in skeletal muscle in response to interventions with neuroprotective effects against aging and neurodegenerative disease, including low nutrient conditions and exercise. TFEB controls muscle metabolic flexibility during exercise, inducing the expression of genes involved in mitochondrial biogenesis, fatty acid oxidation, and oxidative phosphorylation.

Here, we report the generation of a transgenic mouse with enhanced muscle metabolism via lifelong overexpression of TFEB. The resulting enhanced TFEB signaling protects against the onset of age-associated mitochondrial dysfunction in aging skeletal muscle. Overexpression of TFEB in skeletal muscle significantly reduces hippocampal accumulation of neuropathological hallmarks and reduces neuroinflammation in a mouse model of tauopathy, despite no exogenous activation of the transgene in the CNS. Muscle TFEB overexpression ameliorates proteotoxicity, reduces neuroinflammation, and promotes transcriptional remodeling of the "healthy" aged CNS, preserving cognitive performance in aging mice. Our results implicate maintenance of skeletal muscle function in regulating mammalian CNS health, and suggest that skeletal muscle-originating factors may act as therapeutic targets against age-associated neurodegenerative diseases.

Mitochondrial dysfunction is a common occurrence in the aging process and is observed in diseases such as age-related macular degeneration (AMD). Increased levels of reactive oxygen species lead to damaged mitochondrial DNA (mtDNA), resulting in dysfunctional mitochondria, and, consequently, mtDNA causes further harm in the retinal tissue. However, it is unclear whether the effects are locally restricted to the high-energy-demanding retinal pigment epithelium or are also systematically present. Therefore, we measured mtDNA copy number (mtDNA-CN) in peripheral blood using a qPCR approach in elderly participants with and without AMD from the AugUR study (n = 2,262).

We found significantly lower mtDNA-CN in the blood of participants with early (n = 453) and late (n = 170) AMD compared to AMD-free participants (n = 1630). In regression analyses, we found lower mtDNA-CN to be associated with late AMD when compared with AMD-free participants. Each reduction of mtDNA-CN by one standard deviation increased the risk for late AMD by 24%. This association was most pronounced in geographic atrophy (odds ratio = 1.76), which has limited treatment options. These findings provide new insights into the relationship between mtDNA-CN in blood and AMD, suggesting that it may serve as a more accessible biomarker than mtDNA-CN in the retina.

Sarcopenia is a challenging disease for drug development, and there is currently no clinically approved therapeutic. Outcomes in clinical trials depend on functional gains in muscle performance, rather than just increases in mass, while also being well tolerated with low side effects. Sarcopenia is also a complex multifactorial disorder, and the underlying mechanisms are not fully understood. This review focused on pre-clinical drug development for sarcopenia. Due to the lack of approved therapeutics and a large projected market value, there are a large number and variety of different compounds and target pathways/cellular mechanisms under investigation.

A large proportion of current research is focusing on natural compounds and extracts, due to their characterized biological activity and advantages for further drug development. Much research effort is also focusing on the role of non-coding RNAs in sarcopenia progression, which can provide targets for small molecules currently under development for inhibiting non-coding RNA biogenesis. A number of type 2 diabetes drugs, such as SGLT2 inhibitors, DPP-IV inhibitors, and GLP-1 analogs, are also being investigated for their effects on skeletal muscle mass in type 2 diabetes patients and animal models. It will be important to consider whether these drugs can also be effective in the context of pre-diabetes or normoglycemia.

Mitochondria have a pivotal role in maintaining muscle function and are known to become dysfunctional in aging. Mitochondria-targeting drugs also hold great promise for treating sarcopenia and may utilize recent advances in mitochondria drug delivery systems. Drug repositioning strategies are also providing clinically validated candidates with known pharmacokinetics in humans. These previously characterized drugs can also provide new insights into the molecular pathways regulating skeletal muscle atrophy. A wider adoption of cell-based screening systems, based on known master regulatory genes, such as PGC-1α, could accelerate throughput and increase the number of hits for further analysis. Overall, much effort is being focused on identifying drug candidates with promising pre-clinical therapeutic activity in sarcopenia models, which raises the probability of successful drug development for this debilitating and increasingly prevalent disease.

The peripheral nervous system is made up of all the nerves that branch out from the brain and spinal cord to give us sensation throughout our bodies. There are many cell types in peripheral nerves, here researchers focus on understanding neurons, which transmit information throughout the nervous system, and Schwann cells, which protect healthy neurons and repair damaged ones. The peripheral nervous system's ability to repair damage is remarkable considering that the central nervous system - made up of the brain and spinal cord - is not able to repair damage. Yet, the mechanisms that orchestrate this feat have remained poorly understood.

To unravel how Schwann cells differentiate to begin repairing peripheral nerve damage, the researchers looked at mouse models of Charcot Marie Tooth disease (CMT), a type of hereditary neuropathy. In mice with CMT, the researchers noticed that the Schwann cells completing repairs had high levels of Mitf in their nuclei - where the genetic instructions for how to be a Schwann cell and how to conduct repairs are stored. Upon investigation of this relationship between Mitf and Schwann cells, they found that Mitf was in the cytoplasm of Schwann cells until sensing neuronal damage. Damage then prompted Mitf to relocate from the cytoplasm of the cell to the nucleus, where it would direct the Schwann cell to make repairs.

To validate the importance of Mitf in creating repair Schwann cells, the researchers removed Mitf altogether. In cases of both trauma and CMT, nerve repair was arrested in the absence of Mitf - demonstrating that Mitf is required for peripheral nerve repair and regeneration. "Harnessing Schwann cell repair programs has great potential in treating chronic diseases. It's possible that with targeted therapeutics, we can prompt more Schwann cells to repair peripheral nerve damage and push those repairs to completion in chronic cases. Furthermore, now that we have a better grasp on the repair mechanisms, we can see if it's possible to initiate repairs in the brain stem and spinal cord, too."

Pulmonary fibrosis (PF) is a chronic, progressive, devastating, and irreversible interstitial lung disease, with a median survival of 2 to 3 years after diagnosis. The present comprehension of the pathogenesis of PF entails the repetitive injury of alveolar epithelial cells (AECs) due to various risk factors, such as environmental exposure, viral infections, genetic predisposition, oxidative stress, and immunological factors. This injury subsequently results in the abnormal activation of AECs and dysregulated epithelial repair processes. The dysregulated epithelial cell secretes multiple cytokines and growth factors and interacts with endothelial, mesenchymal, and immune cells via multiple signaling mechanisms to trigger fibroblast and myofibroblast activation and promote extracellular matrix deposition, ultimately leading to the destruction of lung function, diminished exercise tolerance, and a decreased quality of life.

The existing epidemiological data from various data sources indicate that the average age of patients with PF is estimated to be over 65 years, and the incidence increases with age. Furthermore, individuals aged 70 and above have a risk of developing PF that is seven times higher than those in their 40s. Therefore, PF is now considered an age-related lung disease. Among the hallmarks of aging, cellular senescence serves as the primary driver behind tissue and organ aging, as well as an independent risk factor for PF progression. Age-related disturbances were increasingly observed in epithelial cells and fibroblasts in PF lungs compared to age-matched cells in normal lungs. Physiologically, alveolar epithelial type II (ATII) cells, serving as progenitor cells of the alveoli, differentiate into alveolar type 1 (ATI) cells in response to injury. Utilizing organoid cultures, single-cell transcriptomics, and lineage tracing, it has been discovered that ATII cells differentiate into ATI cells and acquire a transitional state known as pre-alveolar type 1 cell during the process of maturation. This transitional state exhibits regulation by TP53 signaling, making it susceptible to DNA damage and undergoing transient senescence.

However, there are at least two harmful consequences of persistent senescence. On the one hand, telomere wear and mitochondrial dysfunction lead to permanent cell-cycle arrest, which in turn causes stem cell/progenitor cell-renewal dysfunction and the loss of self-repair and regeneration abilities. On the other hand, senescent cells produce pro-inflammatory, pro-fibrotic, and stroma-remodeling cytokines such as IL-6, TGF-β, and several matrix metalloproteinases collectively known as the senescence-associated secretory phenotype (SASP), which can activate myofibroblast and scar formation. In fact, some components of SASP appear to enhance the growth arrest of exposed adjacent cells in a paracrine manner, further driving senescence, leading to low-grade chronic inflammation, and increasing susceptibility to pulmonary fibrosis.

A comprehensive understanding of how senescence promotes the occurrence and progression of PF can provide new insights into the further treatment of age-related diseases. This review presents compelling recent evidence indicating that cellular senescence is a significant driving factor in age-related lung diseases such as PF. It systematically summarizes the causes of cellular senescence in PF and the signaling pathways regulating different types of cellular senescence and also provides potential therapeutic strategies for targeting cellular senescence to improve PF. These strategies include targeting the clearance of senescent cells, intervening in senescence-related signaling pathways, and inhibiting the secretion of SASP.

Although it's well-known that eating less meat improves cardiovascular health, diet studies are often hampered by factors such as genetic differences, upbringing and lifestyle choices. By studying identical twins, however, the researchers were able to control for genetics and limit the other factors, as the twins grew up in the same households and reported similar lifestyles. The trial, conducted from May to July 2022, consisted of 22 pairs of identical twins for a total of 44 participants. The study authors selected healthy participants without cardiovascular disease from the Stanford Twin Registry - a database of fraternal and identical twins who have agreed to participate in research studies - and matched one twin from each pair with either a vegan or omnivore diet.

The authors found the most improvement over the first four weeks of the diet change. The participants with a vegan diet had significantly lower low-density lipoprotein cholesterol (LDL-C) levels, insulin, and body weight - all of which are associated with improved cardiovascular health - than the omnivore participants. At three time points - at the beginning of the trial, at four weeks and at eight weeks - researchers weighed the participants and drew their blood. The average baseline LDL-C level for the vegans was 110.7 mg/dL and 118.5 mg/dL for the omnivore participants; it dropped to 95.5 for vegans and 116.1 for omnivores at the end of the study. The optimal healthy LDL-C level is less than 100.

Because the participants already had healthy LDL-C levels, there was less room for improvement. Researchers speculated that participants who had higher baseline levels would show greater change. The vegan participants also showed about a 20% drop in fasting insulin - higher insulin level is a risk factor for developing diabetes. The vegans also lost an average of 4.2 more pounds than the omnivores.

Researchers had previously developed tiny robots using clumps of embryonic frog cells. But the medical applications of these 'xenobots' were limited, because they weren't derived from human cells and because they had to be manually carved into the desired shape. The researchers have now developed self-assembling 'anthrobots' made of human cells and are investigating their therapeutic potential using human tissue grown in the laboratory.

The researchers grew spheroids of human tracheal skin cells in a gel for two weeks, before removing the clusters and growing them for one week in a less viscous solution. This caused tiny hairs on the cells called cilia to move to the outside of the spheroids instead of the inside. These cilia acted as oars, and the researchers found that the resulting anthrobots - each containing a few hundred cells - often swam in one of several patterns. Some swam in straight lines, others swam in circles or arcs, and some moved chaotically.

To test the anthrobots' therapeutic potential, researchers placed several into a small dish. There, the anthrobots fused together to form a 'superbot', which the researchers placed on a layer of neural tissue that had been scratched. Within three days, the sheet of neurons had completely healed under the superbot. This was surprising because the anthrobot cells were able to perform this repair function without requiring any genetic modification. Going forward, researchers think anthrobots made from a person's own tissue could be used to clear arteries, break up mucus or deliver drugs, with or without genetic engineering.