Today, I'm excited to introduce Arda Therapeutics. Arda is taking aim at chronic diseases and aging by eliminating the pathological cells that drive these conditions. Our approach starts by using single-cell data to identify pathological cells and specific markers to target them. We then design therapies to eliminate these - and only these - cells. We are initially focused on treating chronic diseases, with the long-term goal of extending healthy lifespan.

The idea of eliminating - or "targeting" - bad cells is not new; most cancer treatments are based on this strategy. Yet when it comes to other diseases, rather than removing harmful cells, most therapeutics modulate the activity of individual proteins with the goal of modifying cell behavior. However, cell behavior is a consequence of complex regulatory networks: multiple pathways contribute, often with redundancy, making cell behavior difficult to change via single targets. We believe that in many cases the better strategy is to eliminate the entire pathological network - that is, the entire cell.

Our team combines expertise in pathological cell clearance with a rare blend of computational and drug development know-how. Still, there is no guarantee of success. Ten years from now, I believe there will be dozens of cell targeting therapeutics for chronic diseases. I hope many of them are Arda's. But if we fail at making successful drugs, we will at least succeed in mapping part of this new territory, making it a bit easier for others to take the next step. Ultimately, we are running the same relay race, and the trophy is more quality time for all of us.

Cellular senescence is a state of permanent cell cycle arrest accompanied by a hyper-secretory phenotype (Senescence-Associate Secretory Phenotype, or SASP), and is associated with both injury and aging-related pathologies within affected organs. Removal of senescent cells is beneficial to both organ function and organism survival. Severe acute injury of any large organ is associated with systemic effects including multi-organ failure, of which acute liver failure (ALF) is a paradigm. ALF is itself associated with senescence induction and subsequent regenerative failure. Studies both in vitro and in vivo have shown that senescence can be transmitted in a paracrine manner within affected organs, however whether senescence can spread systemically to more distant organs remains unknown.

Here we use acute liver senescence as an exemplar model, independent of systemic aging, to test whether senescence can be transmitted between organs in an endocrine manner. The SASP is a central mediator of the non-autonomous effects of senescent cells. We present evidence that senescence can be transmitted to and affect the function of distant organs in a systemic manner. In the context of acute injury, senescence has often been described as part of a finely-tuned mechanism with overall beneficial effects for wound healing. As described by others, SASP factors are able to induce reprogramming in neighbouring cells, facilitating tissue regeneration. However, following severe injury, this mechanism may have the opposite effect, through excessive SASP production, including senescence- and reprogramming-inducing factors. This excess of SASP factors may enter the circulation and induce widespread senescence and reprogramming to distant organs. In turn, this excessive stimulus for senescence, re-programming and regeneration can compromise organ function.

Systemic transmission of senescence may be relevant to several diseases. Here we use a model of hepatocyte-specific senescence to model an acute senescence phenotype, such as the one observed during ALF. ALF is itself characterised by sequential multi-organ failure typically beginning with the kidney and also involving the brain and lung in addition to other organs. This clinical progression may, at least in part, be underpinned by the systemic transmission of senescence. The observation that TGFβ signalling is a central driver of systemic transmission of senescence paves the way for new therapeutic approaches in diseases where this phenomenon occurs. This is in line with the beneficial effects of senolytics and senomorphics that have been elegantly demonstrated on numerous pathologies.

People have been cured in the clinic of advanced melanoma through treatment with their own immune cells that were harvested out of tumor tissue. The problem is, because of the way the cells are harvested, it only works in a very small number of patients. The cells of interest, called tumor-infiltrating lymphocytes (TILs), are natural immune cells that invade tumor tissue. In cell therapies used in clinics today a mixture of "exhausted" and "naïve" cells is used to treat tumors. After they are extracted from tissue, cells are grown in labs far away from the patients they were harvested from. By the time they've multiplied and are ready to be placed back in the body, many of the cells are exhausted and unable to fight, having been in the tumor for too long.

Using a new technology called microfluidic affinity targeting of infiltrating cells (MATIC), researchers can pinpoint which cells are most active through cell sorting techniques enabled with nanotechnology. Scientists used MATIC to find what the authors called the "Goldilocks population" of cells, producing dramatic results for the mice population they were looking at. Tumors in mice shrank dramatically - and in some mice disappeared completely - producing a large improvement in survival rates compared to more traditional methods of TIL recovery.

Adoptive cell therapies require the recovery and expansion of highly potent tumour-infiltrating lymphocytes (TILs). However, TILs in tumours are rare and difficult to isolate efficiently, which hinders the optimization of therapeutic potency and dose. Here we show that a configurable microfluidic device can efficiently recover potent TILs from solid tumours by leveraging specific expression levels of target cell-surface markers. The device, which is sandwiched by permanent magnets, balances magnetic forces and fluidic drag forces to sort cells labelled with magnetic nanoparticles conjugated with antibodies for the target markers.

Compared with conventional cell sorting, immunomagnetic cell sorting recovered up to 30-fold higher numbers of TILs, and the higher levels and diversity of the recovered TILs accelerated TIL expansion and enhanced their therapeutic potency. Immunomagnetic cell sorting also allowed us to identify and isolate potent TIL subpopulations, in particular TILs with moderate levels of CD39 (a marker of T-cell reactivity to tumours and T-cell exhaustion), which we found are tumour-specific, self-renewable and essential for the long-term success of adoptive cell therapies.

A view of the animal world suggests that because reproduction and maintenance are both costly, animals simply can't maximize both. So the more energy and nutrients an individual invests in producing offspring, the faster it will probably age, and the shorter its life will be. Yet in social insects such as termites, ants, bees, and wasps, the queens appear to have found a way to have their cake and eat it. In many colonies, queens that lay hundreds of eggs every day can stay alive for years or even decades, while workers that never lay a single egg in their life will die after a few months.

Differences in the genetic code can't explain the unusual longevity of queens compared to workers. All workers are daughters of the queen and, in many cases, any of those daughters could have grown up to become queens themselves had they received the appropriate royal treatment when they were larvae. Since the queen is the only one in a colony laying eggs, colonies with long-lived queens are likely to grow larger and send forth more young queens to start new nests, as well as males to fertilize them. In other words, many scientists reason, there must have been strong selective pressure to keep the queen alive for as long as possible by evolving delayed aging.

To try to learn more about what enables the long life of queens in social insects, a team of researchers decided to compare the activity levels of various genes in termites, ants and bees - two species of each. In all, they studied 157 individuals, including insects of different ages as well as different castes. Unsurprisingly, the team found that genes that are known to play crucial roles in reproduction showed different activity patterns in queens than they did in sterile workers. Some of these genes, which carry instructions for making proteins called vitellogenins, were active in queens of all species.

The main role of vitellogenins is to support the production of yolk for the eggs. But some scientists suspect that vitellogenins may be doing more than that: In honeybees, at least, research has found that vitellogenins also function as antioxidants. If vitellogenins do the same thing in other social insects, they might contribute to the resistance of queens to oxidation. The team also found differences in the activity of genes involved in the prevention of oxidative damage or the repair of such damage, between queens and egg-laying workers compared with sterile workers. But the precise genes involved differed strongly from one species to another. Apparently, each species has evolved its own way of keeping its queens alive longer.

This somewhat bewildering variety across species reveals an important lesson about the nature of aging: There isn't one button or switch that allows a species to invest more, or less, in maintenance or reproduction, but a whole dashboard of them that is set up slightly differently in each species.

The exceptional longevity of social insect queens despite their lifelong high fecundity remains poorly understood in ageing biology. To gain insights into the mechanisms that might underlie ageing in social insects, we compared gene expression patterns between young and old castes (both queens and workers) across different lineages of social insects (two termite, two bee and two ant species). After global analyses, we paid particular attention to genes of the insulin/insulin-like growth factor 1 signalling (IIS)/target of rapamycin (TOR)/juvenile hormone (JH) network, which is well known to regulate lifespan and the trade-off between reproduction and somatic maintenance in solitary insects.

Our results reveal a major role of the downstream components and target genes of this network (e.g. JH signalling, vitellogenins, major royal jelly proteins and immune genes) in affecting ageing and the caste-specific physiology of social insects, but an apparently lesser role of the upstream IIS/TOR signalling components. Together with a growing appreciation of the importance of such downstream targets, this leads us to propose the TI-J-LiFe (TOR/IIS-JH-Lifespan and Fecundity) network as a conceptual framework for understanding the mechanisms of ageing and fecundity in social insects and beyond.

ISRIB has restored memory formation in mice months after traumatic brain injuries and shown potential in treating neurodegenerative diseases, including Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis (ALS). It also seems to reduce age-related cognitive decline. Researchers believe that the reason the molecule can do so much is that it plays an essential role in how the brain handles stress from physical injuries or neurological diseases. Under siege from such problems, the brain, in essence, shuts down cognitive functions like memory formation to protect itself. The new molecule reverses that.

Will ISRIB work to reverse cognitive decline in people? We still don't know. So far most of the work has been done in mice or human cells in a petri dish. But we will soon know more: in 2015 the molecule was licensed by Calico Labs, the Silicon Valley biotech established by the founders of Google to find drugs based on the biology of aging. It aims to transform the molecule into a treatment for a wide array of disorders, including ALS and Parkinson's disease, as well as the damage from traumatic brain injury. In 2021, Calico announced that human safety trials had begun on the first drug candidate for neurodegenerative diseases it had developed based on ISRIB, and that a study in ALS patients was slated to begin later in the year.

An aging research initiative called Altos Labs recently launched with 3 billion in initial financing from backers. This is the latest in a recent surge of investment in ventures seeking to build anti-aging interventions on the back of basic research into epigenetic reprogramming. In December, NewLimit was founded, an aging-focused biotech backed by an initial 105 million investment.

The discovery of the 'Yamanaka factors' - four transcription factors (Oct3/4, Sox2, c-Myc, and Klf4) that can reprogram a differentiated somatic cell into a pluripotent embryonic-like state - transformed stem cell research by providing a new source of embryonic stem cell (ESC)-like cells, induced pluripotent stem cells (iPSCs), that do not require human embryos for their derivation. But in recent years, Yamanaka factors have also become the focus for another burgeoning area: aging research.

So-called partial reprogramming consists in applying Yamanaka factors to cells for long enough to roll back cellular aging and repair tissues but without returning to pluripotency. Several groups have shown that partial reprogramming can dramatically reverse age-related phenotypes in the eye, muscle, and other tissues in cultured mammalian cells and even rodent models by countering epigenetic changes associated with aging. These results have spurred interest in translating insights from animal models into anti-aging interventions.

Even though Life Biosciences and several other startups are investigating Yamanaka factors with a view to reversing human aging, the biology of rejuvenation by reprogramming remains enigmatic and opaque, at best. "These first papers make some astonishing observations. But much more research is needed to dig into the molecular and mechanistic processes that are occurring." Given that fully reprogrammed iPSCs readily form tumors known as teratomas, scientists must determine whether the cellular clock can be wound back safely in humans - which means the race to the clinic will likely be a marathon rather than a sprint.

Previous studies suggest that a substantial number of deaths could be prevented annually by increasing population levels of physical activity. However, previous estimates have relied on convenience samples, used self-reported physical activity data, and assumed relatively large increases in activity levels (e.g., more than 30 minutes per day). The potential public health benefit of changing daily physical activity by a manageable amount is not yet known. In this study, we used accelerometer measurements (1) to examine the association of physical activity and mortality in a population-based sample of US adults and (2) to estimate the number of deaths prevented annually with modest increases in moderate-to-vigorous physical activity (MVPA) intensity.

This analysis included 4,840 participants. Increasing MVPA by 10, 20, or 30 minutes per day was associated with a 6.9%, 13.0%, and 16.9% decrease in the number of deaths per year, respectively. We estimated that approximately 110,000 deaths per year could be prevented if US adults aged 40 to 85 years or older increased their MVPA by a small amount (ie, 10 minutes per day). To our knowledge, this is the first study to estimate the number of preventable deaths through physical activity using accelerometer-based measurements among US adults while recognizing that increasing activity may not be possible for everyone. These findings support implementing evidence-based strategies to improve physical activity for adults and potentially reduce deaths in the US.

Of the 150,000 deaths that occur on Earth every day, over two thirds of them are due to ageing. This is because, biologically, the ageing process is the cause of our biggest killers, like cancer, heart disease, and dementia. Though diet, lifestyle, and other factors can make these more or less likely, their effect is dwarfed by the biological consequences of getting older. Every so often, a study proposes a 'limit' on human lifespan, either by looking at demographic trends, or analysing aspects of human biology. However, these 'limits' have repeatedly been smashed historically, as life expectancy in the leading country has increased by three months per year, every year for almost two centuries.

Scientists have found dozens of ways to intervene in the ageing process in the lab. A lot of people imagine that living longer would mean extending the frail years at the end of life, dragging out our decrepitude. But this understandable worry gets things backwards from a biological perspective: as we treat ageing, we'd increase healthspan by deferring the age-related changes that cause disease, and this would cause people would live longer. Exceptionally long-lived humans don't just live longer, but spend a greater fraction of their lives in good health.

In spite of big-money bets from billionaires, it's not clear how long it will be before we can expect to see the first anti-ageing medicines in hospitals, or the local pharmacy. Moving from an idea that works in mice in the lab to human treatments is a notoriously difficult process. However, it seems likely that they will arrive in time for most people alive today. Front-runners, like senolytic drugs that remove aged, senescent cells from the body have proved their mettle in mice and are already undergoing human trials, so it's quite possible they could be in use before the decade is out. More speculative ideas, like the cellular reprogramming being explored by Altos Labs, might be decades away - but, if you're middle-aged or younger today, or a little older but live longer thanks to the first generation of anti-ageing drugs, a few decades is still soon enough to matter.

Slow gait and mobility decline are common in older age and are associated with adverse outcomes such as mobility disability, reduced quality of life, loss of autonomy in daily life activities, and mortality. Such a decline may arise from impairments in the central nervous system (CNS), musculoskeletal system, and metabolic systems. Previous findings suggest that age-related decline of mitochondrial function may contribute to loss of mobility. Compared to young adults, older adults have lower skeletal muscle oxidative capacity and higher metabolic cost of walking.

Proposed mechanisms underlying the relationship between mitochondrial dysfunction and mobility decline include impairments in energy production and energy utilization. Energy production can be impaired due to age-related decline of mitochondrial function, possibly through a combination of lack of energy, increased oxidative stress, oxidative damage to mitochondrial DNA and the complexes of the electron transport chain, and altered gene expression.

We examined 380 cognitively normal participants aged 60 and older who were well-functioning (gait speed ≥ 1.0 m/s) and free of Parkinson's disease and stroke at baseline and had data on baseline skeletal muscle oxidative capacity and one or more mobility assessments during an average 2.5 years. Muscle oxidative capacity was measured by phosphorus magnetic resonance spectroscopy as the post-exercise recovery rate of phosphocreatine (kPCr). Mobility was measured by four walking tests.

Lower baseline kPCr was associated with greater decline in all four mobility measures. Thus among initially well-functioning older adults, worse muscle mitochondrial function predicts mobility decline, and part of this longitudinal association is explained by decline in muscle strength and mass. Our findings suggest that worse mitochondrial function contributes to mobility decline with aging. The longitudinal relationship between skeletal muscle mitochondrial function and mobility decline appeared to be mediated by the change in thigh muscle strength, lean mass, and fat mass.

Researchers have discovered that a protein naturally present in the gut acts on the microbiota and causes the formation of molecules that exacerbate the symptoms of these diseases. The protein in question, phospholipase A2-IIA, was discovered several years ago in the fluid that surrounds the joints of people with arthritis. The protein was subsequently detected elsewhere in the body, notably in the gut where it is produced in abundance. "It took a long time before we realized that it exhibits antibacterial activity. The protein interacts little with the membrane of human cells, but it has high affinity for bacterial membranes. It binds to these membranes and splits them, releasing small molecules such as fatty acids."

To study the effect of this protein on gut microbiota, researchers used a line of transgenic mice. These mice have the human gene that codes for phospholipase A2-IIA. As they age, they spontaneously develop manifestations of chronic systemic inflammation. Experiments on these mice revealed that phospholipase alters the profile of bacterial lipids that end up in the gut. By releasing fatty acids from the bacterial membranes, the protein produces proinflammatory lipids that exacerbate chronic inflammation and increase the severity of arthritis symptoms in these mice.

These breakthroughs could have therapeutic implications, he says. "The work of both teams suggests that local inhibition of phospholipase may alleviate the inflammatory process that exacerbates certain diseases. It also suggests that blocking the bacterial proinflammatory lipids produced in the gut by this protein could reduce symptoms in people with systemic inflammatory diseases. The next step in our work is to test these ideas in patients with arthritis."

Limb regeneration is a frontier in biomedical science. Identifying triggers of innate morphogenetic responses in vivo to induce the growth of healthy patterned tissue would address the needs of millions of patients, from diabetics to victims of trauma. Organisms such as the African clawed frog (Xenopus laevis) - whose limited regenerative capacities in adulthood mirror those of humans - are important models with which to test interventions that can restore form and function.

Here, we demonstrate long-term (18 months) regrowth, marked tissue repatterning, and functional restoration of an amputated Xenopus laevis hindlimb following a 24-hour exposure to a multidrug, pro-regenerative treatment delivered by a wearable bioreactor. The treatment used 1,4-dihydrophenonthrolin-4-one-3carboxylic acid (1,4-DPCA), brain-derived neurotrophic factor (BDNF), growth hormone (GH), resolvin D5 (RD5), and retinoic acid (RA).

Regenerated tissues composed of skin, bone, vasculature, and nerves significantly exceeded the complexity and sensorimotor capacities of untreated and control animals' regeneration. RNA sequencing of early tissue buds revealed activation of developmental pathways such as Wnt/β-catenin, TGF-β, hedgehog, and Notch. These data demonstrate the successful "kickstarting" of endogenous regenerative pathways in a vertebrate model.

Almost all mature cells that undergo apoptosis in an age-dependent or an accidental manner are completely recovered in tissue-specific microenvironments without any physiological changes. After peripheral blood leukocytes are released into the local region, fibroblast cells and new blood vessels commonly proliferate during wound healing. Inducible repair tools mainly supplied from blood vessels are cleared by peripheral blood phagocytic macrophages. Finally, hematopoietic stem cell (HSC)-derived precursor cells migrate from bone marrow (BM) to the microenvironment to rebuild damaged tissues.

In this review, we question how to control inflammation and fibrosis in older patients with lifestyle-related diseases, including NASH. We now propose the alternative inflammation and fibrosis pathway in CD40+ endothelial cells in hepatic sinusoids (HSECs) other than the main fibrosis pathway in HSCs. We suggest that HSCs are activated by bone marrow derived macrophages following the cell-cell interaction between senescent hepatocytes and senescent HSECs. However, the physiological condition of HSCs in a NASH-specific environment with chronic inflammation is still unclear. Therefore, it is very difficult to obtain a direct strategy for treating HSCs. Conversely, we hypothesized that senescent CD40+ HSECs are activated by CD154 on infiltrating senescent Th2 cells. This activation is enhanced by the cell-cell interaction among senescent hepatocytes, senescent HSECs, and senescent Küpffer cells.

Recently, the removal of senescent cells (senolysis) has been proposed for the treatment of lifestyle-related diseases. Kidney-type glutaminase (KGA) expression is increased according to low pH by lysosomal membrane damage. This induces an enhancement of the glutaminase 1 (GLS1) gene to maintain senescent cells. Senolysis induced by a GLS1 inhibitor rescues inflammation in lifestyle-related diseases. Therefore, we propose an alternative fibrosis pathway involving the cell-cell interaction of senescent cells in a NASH-specific environment with chronic inflammation at old age. Further examination is needed to determine how to control inflammation and fibrosis in older patients with lifestyle-related diseases, including NASH.

The first person to receive a transplanted heart from a genetically modified pig is doing well after the procedure. Physicians and scientists worldwide have for decades been pursuing the goal of transplanting animal organs into people, known as xenotransplantation. Last week's procedure marks the first time that a pig organ has been transplanted into a human who has a chance to survive and recover. In 2021, surgeons transplanted kidneys from the same line of genetically modified pigs into two legally dead people with no discernible brain function. The organs were not rejected, and functioned normally while the recipient bodies were sustained on ventilators.

Xenotransplantation has seen significant advances in recent years with the advent of CRISPR-Cas9 genome editing, which made it easier to create pig organs that are less likely to be attacked by human immune systems. The latest transplant used organs from pigs with ten genetic modifications. The researchers had applied to the US Food and Drug Administration (FDA) to do a clinical trial of the pig hearts in people, but were turned down. The agency was concerned about ensuring that the pigs came from a medical-grade facility and wanted the researchers to transplant the hearts into ten baboons before moving on to people.

But a 57-year-old patient team a chance to jump straight to a human transplant. The patient had been on cardiac support for almost two months and couldn't receive a mechanical heart pump because of an irregular heart beat. Neither could he receive a human transplant, because he had a history of not complying with doctors' treatment instructions. Given that he otherwise faced certain death, the researchers got permission from the FDA to give the patient a pig heart.

For now, transplantation is limited by the supply of pigs as well as regulatory hurdles. There is currently just one company - Revivicor, owned by United Therapeutics - that has suitable facilities and clinical-grade pigs. To make the pig heart used in the transplant, the company knocked out three pig genes that trigger attacks from the human immune system, and added six human genes that help the body to accept the organ. A final modification aims to prevent the heart from responding to growth hormones, ensuring that organs from the 400-kilogram animals remain human-sized.

Hepatocyte transplantation holds great promise as an alternative approach to whole-organ transplantation. Intraportal and intrasplenic cell infusions are primary hepatocyte transplantation delivery routes for this procedure. However, patients with severe liver diseases often have disrupted liver and spleen architectures, which introduce risks in the engraftment process. We previously demonstrated intraperitoneal injection of hepatocytes as an alternative route of delivery that could benefit this subpopulation of patients, particularly if less invasive and low-risk procedures are required; and we have established that lymph nodes may serve as extrahepatic sites for hepatocyte engraftment. However, whether other niches in the abdominal cavity support the survival and proliferation of the transplanted hepatocytes remains unclear.

Here, we showed that hepatocytes transplanted by intraperitoneal injection engraft and generate ectopic liver tissues in fat-associated lymphoid clusters (FALCs), which are adipose tissue-embedded, tertiary lymphoid structures that are localized throughout the peritoneal cavity. The FALC-engrafted hepatocytes formed functional ectopic livers that rescued tyrosinemic mice from liver failure. Consistently, analyses of ectopic and native liver transcriptomes revealed a selective ectopic compensatory gene expression of hepatic function-controlling genes in ectopic livers, implying a regulated functional integration between the two livers. Thus abdominal FALCs are essential extrahepatic sites for hepatocyte engraftment after transplantation and, as such, represent an easy-to-access and expandable niche for ectopic liver regeneration when adequate growth stimulus is present.