Fight Aging! Newsletter, March 1st 2021

Chemokines are chemotactic cytokines that orchestrate cell trafficking and behavior in homeostasis and disease. Chemokines are pivotal players in various inflammatory diseases, including atherosclerosis. Therapeutic anti-cytokine approaches are successfully used in several inflammatory diseases and the positive results obtained with an interleukin-1β (IL-1β)-blocking antibody in the CANTOS trial have validated the inflammatory paradigm of atherosclerosis in humans and demonstrated the potential utility of anti-inflammatory drugs in patients with atherosclerotic disease. However, CANTOS also highlighted the need for molecular strategies with improved selectivity and less side effects.

While anti-chemokine strategies such as antibodies or small molecule drugs (SMDs) have been established, targeting a specific chemokine/receptor axis remains challenging due to the promiscuity in the chemokine network. In addition to antibodies and SMDs, soluble receptor-based approaches have proven as a powerful anti-cytokine strategy in inflammatory/immune diseases. For example, soluble tumor necrosis factor-receptor-1 (TNFR1)-based drugs are in clinical use for rheumatoid arthritis. However, soluble receptor-based approaches are not established for chemokine receptors.

Macrophage migration-inhibitory factor (MIF) is an evolutionarily conserved, multi-functional inflammatory mediator that is structurally distinct from other cytokines. We reasoned that designing CXCR4 ectodomain-derived peptides mimicking its interaction surface with MIF might be a promising approach to develop receptor-selective MIF inhibitors. Moreover, as the CXCL12/CXCR4 pathway exhibits critical homeostatic functions in resident arterial endothelial and smooth muscle cells and has a critical atheroprotective role, we aimed to generate CXCR4 mimics specific for MIF/CXCR4, while sparing CXCL12 pathways. Such mimics would be soluble chemokine receptor ectodomain-based inhibitors with receptor- and agonist-selective targeting properties. This approach would address current gaps in tailored chemokine-selective targeting strategies and receptor-specific MIF therapeutics in inflammatory and cardiovascular diseases.

We here report on engineered CXCR4 ectodomain-derived peptide mimics that selectively bind to the atypical chemokine MIF but not to CXCL12. Signaling experiments, chemotaxis, foam cell formation, and leukocyte recruitment studies in vitro and in the atherosclerotic vasculature demonstrate that such mimics can act as agonist-specific anti-atherogenic compounds, blocking CXCR4-mediated atherogenic MIF activities, while sparing CXCL12 and protective MIF/CD74-dependent signaling in cardiomyocytes. We show that our CXCR4 mimic is not only enriched in atherosclerotic plaque tissue in a MIF-specific manner in mouse and human lesions, but functionally protects from lesion development and atherosclerotic inflammation in an atherogenic Apolipoprotein e-deficient (Apoe-/-) model in vivo.

Within the last few years, senescence has been increasingly recognized as a central component of tumor biology and the response to anti-cancer therapies. In its simplest form, senescence is a stress response that occurs subsequent to replicative-, oxidative-, oncogene-, and therapy-induced insults. Senescent cells undergo a prolonged growth arrest, yet remain metabolically viable, and can be identified by an array of phenotypes. Senescence is also almost universally accompanied by the secretion of various soluble and insoluble factors, termed the senescence associated secretory phenotype (SASP). However, despite these hallmark features, it is important to understand that the senescent phenotype can be highly variable, based on cell type and senescence-inducing stimulus.

Premalignant and malignant (tumor) cells, although typically undergoing rapid replication, can also enter a senescent cell state, characterized by a stable growth arrest and the presence of multiple senescence hallmarks. During malignant transformation, for example, senescence can serve to delay or subvert the progression to tumorigenesis of premalignant cells, thereby acting as a tumor suppressive mechanism. In established malignancies undergoing treatment, a plethora of anti-cancer drugs with variable mechanisms of action have been shown to promote a form of therapy-induced senescence (TIS) both in vitro and in vivo. For example, conventional therapies such as etoposide, doxorubicin, and cisplatin are established inducers of TIS.

While TIS has long been established in the cancer field, a full understanding of how senescence may impact patient outcome has been evolving and is far from complete. The long-held traditional paradigm argued that senescence was an irreversible cell fate, and as such, TIS was purported to be a beneficial outcome of therapy in that it could lead to permanent abrogation of established tumor growth. However, in recent years, multiple reports have been generated in support of the premise that cells that have entered into TIS can, in fact, escape the senescent growth arrest. Furthermore, tumor cells that escape senescence have been reported to develop more aggressive phenotypes associated with increased stemness and drug resistance.

In addition, TIS in non-tumor cells has been linked with several untoward effects of cancer therapy, including cancer relapse, and more importantly, senescent tumor cells themselves have been demonstrated to directly account for the emergence of recurrent cancer phenotypes. Therefore, while the senescent growth arrest may confer short-term advantages with regards to tumor progression, these beneficial effects may only be short-lived, and may be permissive for the development of more pernicious cancer phenotypes over an extended period of time.

There is little question that senolytic agents constitute a promising addition to conventional and possibly also targeted cancer therapies that promote tumor cell senescence. It is now largely accepted that senescence is likely to be an undesirable outcome of cancer therapy in terms of the detrimental effects of the secretions from senescent cells as well as the potential of senescent tumor cells to escape from arrest and regenerate the disease. However, there is limited information available as to whether senescence is actually a central response to therapy in the clinic, either in the primary tumor or in residual surviving tumor cells, despite extensive evidence for this outcome in preclinical experimental model systems.

Other issues that remain to be resolved include the lack of uniformity in the action of senolytics against aging related pathologies and tumor cell senescence, durability of the response, the development of resistance and toxicity to normal tissue. Nevertheless, there do appear to be a variety of strategies available for circumventing issues of toxicity, including structural modifications and drug delivery systems. Consequently, it is likely that a more in-depth understanding of the factors that determine which "types" of senescence are susceptible to the senolytics will ultimately result in these agents being incorporated into standard of care, at least for certain types of cancers and in combination with select antitumor drugs.

Every country around the world is set to see an increase in the share of its population aged over 65. That leads to concerns about the negative macroeconomic consequences of an ageing society. However, at the same time life expectancy trends mean we are living longer and are on average in good health for longer. That should be good news for the economy. Future economic growth depends on exploiting the opportunities a longevity dividend brings and minimising the costs of an ageing society. In 2020 the ESRC awarded Professor Andrew Scott a £1 million grant to investigate an economic longevity dividend. The research program is both empirical and theoretical and is aimed at identifying the magnitude of a longevity dividend, the channels through which it operates and the policies that can be used to maximise its impact.

Life expectancy has increased dramatically over the last 150 years. These developments pose a number of important questions: Is it preferable to make lives healthier by compressing morbidity or longer by extending life? What are the gains from targeting aging itself, with its potential to make lives both healthier and longer? How does the value of treating aging compare to eradicating specific diseases? How will these gains evolve over time and be affected by demographic trends? We take an economic rather than biological perspective to answer these questions. Specifically, we use the Value of Statistical Life (VSL) approach to place a monetary value on the economic gains from longer life,better health, and changes in the rate at which we age.

VSL models have two distinct advantages for our purposes. Firstly, they are already used by a variety of government agencies to evaluate different policy measures and treatments. Secondly, by modeling how economic decisions interact with changes in health and longevity, we can analyze not just the current gains to targeting aging but how these gains will evolve in the future. The results reveal a distinctive feature of age-targeting treatments. Interactions between health, longevity, economic decisions and demographics create a virtuous circle, such that the more successful society is in improving how we age the greater the economic value of further improvements.

The study revealed that a compression of morbidity that improves health is more valuable than further increases in life expectancy. However, in order to raise economic gains, longevity has to improve too. Slowing down aging reduces the rate at which biological damage occurs and improves both health and mortality. The authors calculated a slowdown in aging that increases life expectancy by one year is worth $38 trillion, and for ten years $367 trillion!

With an advisory board packed with longevity firepower (including Aubrey de Grey of the SENS Research Foundation, James Clement of Betterhumans and Gary Hudson of Oisín Biotechnologies), IntraClear Biologics is on a bioengineering longevity mission to "help humanity win the war against age-related diseases." IntraClear is based in Tallinn, a city often dubbed the European Silicon Valley due to Estonia's Government's innovative policies and education initiatives and the fact that it has one of the highest start-ups per capita rates in the world. With a research programme that includes developing a therapy for the removal of intracellular junk from the human body and developing a comprehensive panel of primary aging biomarkers, we were keen to talk to their Chief Science Officer, Ariel Feinerman, to find out more.

Feinerman attributes IntraClear's origin to three influences: Dr Aubrey de Grey who really sparked his interest in longevity, physician Alexander Morozov from Belarus, who drew his attention to lipofuscin and Yevgen Haletskyi from Kiev, Ukraine who listened to Feinerman and Morozov's lectures and became interested in their programme. Haletskyi offered support and angel investment and IntraClear, with Haletskyi as its CEO, was born.

IntraClear is built around lipofuscin, common intracellular junk which is a fluorescent complex mixture of highly oxidised cross-linked macromolecules like lipids, sugars, proteins, and heavy metals ions. "Even though lipofuscin has been known since 1912, researchers don't fully know its composition and structure. Lipofuscin accumulates in all cells of the body, especially in the skin, brain and muscles, it inhibits proteasome and has cytotoxic effects. The accumulation of lipofuscin is associated with many aging pathologies, like neurodegenerative, neuromuscular, inflammatory, etc, and it heavily causes skin aging. Our idea is simple but powerful. Our gene therapy will have two parts: mRNA from which cells can synthesise lipofuscin-breaking enzyme and a fusogenic liposome as a vehicle." IntraClear is considering licensing the liposome vehicle tech Fusogenix from Entos Pharmaceuticals, but is also considering developing its own vehicle to ensure passage across the blood-brain barrier.

"It is particularly interesting how we will obtain the enzymes. Firstly we will isolate lipofuscin from human tissues. Because lipofuscin is likely specific in each tissue we focus on the skin, muscles, and brain, but if we cannot isolate lipofuscin using current technology, we will use physical methods like nanoscale NMR to investigate lipofuscin in vivo. This is avery promising, although emerging technology, so we need to improve it ourselves. After we investigate the structure of lipofuscin using a variety of methods, we will use metagenomic analysis to search for bacteria which have lipofuscin-breaking enzymes."

As a result of normal metabolism, many by-products are formed in our body. Normally, almost all such products are removed using various repair mechanisms. However, some of them cannot be removed from the cells and extracellular space. Over time, they accumulate and lead to disruption of the normal function of cells and tissues, impair the metabolism and cause various diseases. Currently, our group is conducting a histological study of skin tissues, muscles (including heart), brain, and liver. We study lipofuscin granules in the materials. Based on the results of this stage, a histological atlas (virtual/physical) of lipofuscin content in different tissues in people of different ages/sex/with different chronic diseases will be released.

The number of tendon stem cells (TSCs) and their self-renewal potentials is reduced in elderly tendinopathy patients compared to young patients, leading to a possible role of impaired stem cell potential and differentiation in the tendon structure during aging. The correlation of cellular senescence and age-associated tissue dysfunction has been hypothesized. TSCs from aged/degenerated human Achilles tendon biopsies exhibit proliferation and clonogenicity deficits accompanied by premature entry into cellular senescence by upregulation of p16Ink4a. The stem cells become exhausted during tendon aging and degeneration, in terms of size and functional fitness. Sufficient healthy stem cells are essential for tendon tissue regeneration. Our study links the reversal of tendon stem cell senescence to rapamycin, potentially through induction of autophagy. This study may have important implications for preventing cell senescence and aging-induced tendinopathy, as well as for the selection of novel therapeutic targets of chronic tendon diseases.

Our results showed that the treatment of bleomycin, a DNA damaging agent, induced rat patellar TSC (PTSC) cellular senescence. The senescence was characterized by an increase in the senescence-associated β-galactosidase activity, as well as senescence-associated changes in cell morphology. On the other hand, rapamycin could extend lifespan in multiple species, including yeast, fruit flies, and mice, by decelerating DNA damage accumulation and cellular senescence. As an inhibitor of mTOR, rapamycin is a prospect of pharmacological rejuvenation of aging stem cells. Our findings show that rapamycin partially decreases the senescence-associated β-gal activity and morphological alterations, which indicate that rapamycin reverses senescence in rat PTSCs at both molecular and cellular levels.

Autophagy is a major mechanism for maintaining cellular homeostasis via autophagic cell death. Studies have shown that the activity of autophagy is constitutively high in mesenchymal, hematopoietic, dermal, and epidermal stem cells. Autophagy plays a key role in the control of self-renewal and the stemness of stem cells, and growing evidences have linked autophagy and the mTOR signaling pathway. Some proposed underlying antiaging mechanisms by rapamycin include downregulated translation, increased autophagy, altered metabolism, and increased stress resistance. In this study, we have demonstrated that bleomycin treatment increases the p62 expression, while decreases LC3 II/LC3 I ratio, and rapamycin treatment reverses these molecular changes induced by bleomycin, thus reroutes the senescent TSCs to autophagic signaling. These findings support the idea that the beneficial effects of rapamycin for the TSC senescence might be through the mechanism of autophagy induction.

Heart disease. Cancer. Diabetes. Dementia. Researchers spend billions of dollars every year trying to eradicate these medical scourges. Yet even if we discover cures to these and all other chronic conditions, it won't change our ultimate prognosis: death. "That's because you haven't stopped aging," says Jay Olshansky, PhD, a professor of epidemiology and biostatistics. But what if we could? What if we are trying to extend longevity in the wrong way? Instead of focusing on diseases, should we take aim at aging itself? Some scientists think so. Fueled in part by a billion dollars of investor money, they are attempting to reverse-engineer your molecular biological clock. Their goal? To eliminate not merely diseases that kill people, but to prevent death itself.

Aubrey de Grey, PhD, a biomedical gerontologist, has drawn wide attention for his belief that the first person who will live to be 1,000 years old is already among us. He believes there's no cap on how long we can live, depending on what medicines we develop in the future. "The whole idea is that there would not be a limit on how long we can keep people healthy," de Grey says. He's the chief science officer and co-founder of the SENS Research Foundation, which funds research on how to put the brakes on aging. De Grey's view, in theory, isn't so far-fetched.

The medical term for growing old is senescence. Buffeted by DNA damage and stresses, your cells deteriorate and eventually stop multiplying, but don't die. That slowdown may have big consequences for your health. Your genes become more likely to get mutations, which can pave the way for cancer. Mitochondria, which produce energy in the cell, struggle to fuel your body. That can damage cells and cause chronic inflammation, which plays a part in diabetes, arthritis, ulcerative colitis, and many other diseases.

One major hallmark of aging is the growing stockpile of these senescent cells. Damaged cells become deactivated as a way to protect your body from harmful or uncontrolled cell division. But like the rotten apple that spoils the whole bunch, senescent cells encourage their neighbors to turn dysfunctional, too. They also emit proteins that trigger inflammation. Your body naturally removes these dormant cells. But older immune systems have a harder time cleaning up, so the senescent cells are more likely to hang around. Flushing out this accumulated debris may be one way to avert aging, some experts say.

Fibrotic disorders span across multiple organ systems. A consistent pathological finding in these disorders is the accumulation of activated myofibroblasts and deposition of mature extracellular matrix in association with impaired capacity for epithelial cell regeneration. In most species and across organs in humans, regeneration and fibrosis are antagonistically and inversely related. While impaired regeneration leads to fibrosis, a skewing of the tissue repair response to fibrosis may reciprocally dampen latent regenerative capacity. Aging is known to be associated with impaired regenerative capacity, and it is also an established risk factor for human fibrotic disorders.

The biology of aging has advanced in recent years and, in addition to the identification of molecular and cellular hallmarks, several genes have been linked to life span. Multiple studies have implicated two genes, sirtuin 3 (SIRT3) and the forkhead box (FOX) transcription factor FOXO3A, with longevity. SIRT3 is localized to mitochondri1. SIRT3 ablation leads to accelerated aging, cancer, and age-related neurodegenerative disease.

We propose that aging biology can be leveraged to develop novel therapeutic strategies that target cellular plasticity and fate in established fibrosis. In this study, we report that SIRT3 is downregulated in fibroblasts from individuals with idiopathic pulmonary fibrosis and following bleomycin-induced injury in the lungs of aged mice with persistent, non-resolving fibrosis; restoring SIRT3 expression in late reparative phases reverses established lung fibrosis. Furthermore, this study reveals that the pro-resolution effect of SIRT3 is mediated by macrophage-derived paracrine signaling that activates FOXO3A in fibroblasts, upregulates pro-apoptotic BCL2 family proteins and induces apoptotic cell death essential for fibrosis resolution.

Pregnancy-associated plasma protein-A (PAPP-A) is a secreted metalloprotease that increases insulin-like growth factor (IGF) availability by cleaving IGF-binding proteins. Reduced IGF signaling extends longevity in multiple species, and consistent with this, PAPP-A deletion extends lifespan and healthspan; however, the mechanism remains unclear.

To clarify PAPP-A's role, we developed a PAPP-A neutralizing antibody and treated adult mice with it. Transcriptomic profiling across tissues showed that anti-PAPP-A reduced IGF signaling and extracellular matrix (ECM) gene expression system wide. The greatest reduction in IGF signaling occurred in the bone marrow, where we found reduced bone, marrow adiposity, and myelopoiesis. These diverse effects led us to search for unifying mechanisms.

We identified mesenchymal stromal cells (MSCs) as the source of PAPP-A in bone marrow and primary responders to PAPP-A inhibition. Mice treated with anti-PAPP-A had reduced IGF signaling in MSCs and dramatically decreased MSC number. As MSCs are (1) a major source of ECM and the progenitors of ECM-producing fibroblasts, (2) the originating source of adult bone, (3) regulators of marrow adiposity, and (4) an essential component of the hematopoietic niche, our data suggest that PAPP-A modulates bone marrow homeostasis by potentiating the number and activity of MSCs.

We found that MSC-like cells are the major source of PAPP-A in other tissues also, suggesting that reduced MSC-like cell activity drives the system-wide reduction in ECM gene expression due to PAPP-A inhibition. Dysregulated ECM production is associated with aging and drives age-related diseases, and thus, this may be a mechanism by which PAPP-A deficiency enhances longevity.

Altered gut microbial ecosystems have been associated with increased risk of metabolic and immune disorders. Aging is associated with chronic inflammation, a risk for age-associated pathologies such as atherosclerosis, insulin resistance, diabetes, as well as Alzheimer's disease. Emerging evidence reveals aging-associated changes in the composition, diversity, and function of gut microbiota increases gut permeability and activates innate immune responses. Therefore, microbiome-based interventions against aging-associated health issues should provoke attention.

The microbiota-targeted interventions slow down aging process through preventing insulin resistance, improving immunity, suppressing chronic inflammation, as well as regulating metabolism. Additionally, fecal microbiota transplantation (FMT) extends mouse lifespan. Moreover, donor metabolic characteristics drive the effects of FMT on recipient insulin sensitivity in male adult. Furthermore, feces from lean donors can transiently improve the insulin sensitivity in some obese male patients with metabolic syndrome, and the improvement is driven by baseline intestinal microbiota composition of the recipients. These findings suggested the importance of donor as well as recipient in dictating the transplantation outcomes. Additional studies are needed to understand the sex effect.

Women and men differ substantially regarding the degree of insulin sensitivity, body composition, energy balance, and the incidence of metabolic diseases. Others' and our studies show sex differences in microbiota may account for sex dissimilarity in metabolism and metabolic diseases. However, whether the sex of donor and recipient affect FMT efficacy in metabolism has not been examined.

In the current study, we tested a hypothesis that aging-associated metabolic issues such as insulin resistance may be due to aging-induced structural and functional changes of the gut microbiome in a sex-dependent manner. Thus, we analyzed aging-associated gut microbiota and metabolome on inflammatory signaling and metabolism in both sexes. Our novel data revealed that aging differentially affects metabolic signaling and metabolome in males and females. Additionally, sex difference in insulin sensitivity narrowed as mice age. Because aged male mice were the most insulin resistant group, whereas young female mice were the most insulin sensitive group, FMT were performed by using aged male feces (AFMT) and young female feces (YFMT).

Our data showed that AFMT lead to insulin resistance only in females, which abolished sex difference in insulin sensitivity and colon metabolome. Moreover, YFMT reduced body weight and fasting blood glucose in males and improved insulin sensitivity in females, leading to greater sex differences in insulin sensitivity and colon metabolome. Together, FMT effects on metabolic changes are sex specific.

Calico Life Sciences and AbbVie today announced clinical-stage programs in two areas - immuno-oncology and neurodegeneration, currently in Phase I studies. In addition, the companies are advancing a strong pipeline of novel targets that includes more than 20 active programs in discovery or preclinical development in age-related diseases. The lead Calico immuno-oncology program is focused on PTPN2 inhibitors which act at multiple steps in the cancer immunity cycle. There are two molecules currently in Phase I development, ABBV-CLS-579 and ABBV-CLS-484, both of which are novel, orally bioavailable PTPN2 inhibitors. The two molecules are being developed by Calico in collaboration with AbbVie.

The lead Calico neurodegeneration molecule (ABBV-CLS-7262) is an eIF2B activator which targets a key regulator of the highly conserved integrated stress response pathway. Inhibition of this pathway has therapeutic potential in a number of neurodegenerative diseases, such as ALS, Parkinson's disease, and traumatic brain injury. ABBV-CLS-7262 is currently in Phase I studies with plans to begin a study later this year in patients with ALS. "We believe that at the root of every great advance in medicine is a deep understanding of the biology that underlies a specific disease pathway. The quest for this depth of understanding has been our primary focus at Calico in the areas of aging and age-related diseases. Our approach requires patience, perseverance and great collaboration both internally and with external partners such as AbbVie and the Broad Institute, who not only share the same philosophy, but are able to execute upon it."

Researchers analyzed gut microbiome, phenotypic, and clinical data from over 9,000 people - between the ages of 18 and 101 years old - across three independent cohorts. The team focused, in particular, on longitudinal data from a cohort of over 900 community-dwelling older individuals (78-98 years old), allowing them to track health and survival outcomes. The data showed that gut microbiomes became increasingly unique (i.e. increasingly divergent from others) as individuals aged, starting in mid-to-late adulthood, which corresponded with a steady decline in the abundance of core bacterial genera (e.g. Bacteroides) that tend to be shared across humans.

Strikingly, while microbiomes became increasingly unique to each individual in healthy aging, the metabolic functions the microbiomes were carrying out shared common traits. This gut uniqueness signature was highly correlated with several microbially-derived metabolites in blood plasma, including one - tryptophan-derived indole - that has previously been shown to extend lifespan in mice. Blood levels of another metabolite - phenylacetylglutamine - showed the strongest association with uniqueness, and prior work has shown that this metabolite is indeed highly elevated in the blood of centenarians.

"Interestingly, this uniqueness pattern appears to start in mid-life - 40-50 years old - and is associated with a clear blood metabolomic signature, suggesting that these microbiome changes may not simply be diagnostic of healthy aging, but that they may also contribute directly to health as we age. For example, indoles are known to reduce inflammation in the gut, and chronic inflammation is thought to be a major driver in the progression of aging-related morbidities. Prior results in microbiome-aging research appear inconsistent, with some reports showing a decline in core gut genera in centenarian populations, while others show relative stability of the microbiome up until the onset of aging-related declines in health. Our work, which is the first to incorporate a detailed analysis of health and survival, may resolve these inconsistencies. Specifically, we show two distinct aging trajectories: 1) a decline in core microbes and an accompanying rise in uniqueness in healthier individuals, consistent with prior results in community-dwelling centenarians, and 2) the maintenance of core microbes in less healthy individuals."

This analysis highlights the fact that the adult gut microbiome continues to develop with advanced age in healthy individuals, but not in unhealthy ones, and that microbiome compositions associated with health in early-to-mid adulthood may not be compatible with health in late adulthood.

Bile ducts act as the liver's waste disposal system, and malfunctioning bile ducts are behind a third of adult and 70 per cent of children's liver transplantations, with no alternative treatments. There is currently a shortage of liver donors. Approaches to increase organ availability or provide an alternative to whole organ transplantation are urgently needed. Cell-based therapies could provide an advantageous alternative. However, the development of these new therapies is often impaired and delayed by the lack of an appropriate model to test their safety and efficacy in humans before embarking in clinical trials.

Now, scientists have developed a new approach that takes advantage of a recent perfusion system that can be used to maintain donated organs outside the body. Using the techniques of single-cell RNA sequencing and organoid culture, the researchers discovered that, although duct cells differ, biliary cells from the gallbladder, which is usually spared by the disease, could be converted to the cells of the bile ducts usually destroyed in disease and vice versa using a component of bile known as bile acid. This means that the patient's own cells from disease-spared areas could be used to repair destroyed ducts.

To test this hypothesis, the researchers grew gallbladder cells as organoids in the lab. Organoids are clusters of cells that can grow and proliferate in culture, taking on a 3D structure that has the same tissue architecture, function, and gene expression as the part of the organ being studied. They then grafted these gallbladder organoids into mice and found that they were indeed able to repair damaged ducts, opening up avenues for regenerative medicine applications in the context of diseases affecting the biliary system.

The team used the technique on human donor livers taking advantage of the perfusion system. They injected the gallbladder organoids into the human liver and showed for the first time that the transplanted organoids repaired the organ's ducts and restored their function. This study therefore confirmed that their cell-based therapy could be used to repair damaged livers.

Longevity is understood by many as the extension of average healthy lifespan - or healthspan. Short of the camp Hollywood fantasy of "living forever", the longevity industry has its sights set on a world without age-related disease, rather than a world without mortality per se. Longevity businesses are therefore biotech companies that target specific age-related processes, enabling the eventual end-user to live an optimal life.

Remy Gross, vice president of business development at the Buck Institute for Research on Aging, one of the world's foremost research centres on ageing and age-related diseases, says that the goal to reach 120 years of age is logical. Mammals typically live roughly six times the length of birth to maturity, he says; if you argue that humans mature at 20, that puts us on track for a 120-year lifespan. Established in 1999, the institute comprises researchers-turned-companies that look at the underlying fundamental mechanisms of ageing or biochemical pathways that accelerate dysfunction, whether that be cancer, heart disease, metabolism, or cellular senescence.

"In the past five years, in particular, there has been a sea change," Mr Gross says, attributing it to the rise of Buck spin-out Unity Biotechnology, a company focused on cellular senescence, and Google's moonshot secretive ageing company Calico. "A lot of people looked at Calico and said 'If these guys are buying into it, there's got to be something here'," he remarks, adding that in a short space of time, venture capitalists and entrepreneurs started to see potential for a tractable business model. Fast forward to today's COVID-19 pandemic, whose impact on the scientific community and the public perception of science has "emboldened" innovators and investors alike, he continues. "We should be able to get bigger answers out of better questions."

An unbalanced microbial ecosystem on the human skin is closely related to skin diseases and has been associated with inflammation and immune responses. However, little is known about the role of the skin microbiome on skin aging. Here, we report that the Streptococcus species improved the skin structure and barrier function, thereby contributing to anti-aging. Metagenomic analyses showed the abundance of Streptococcus in younger individuals or those having more elastic skin. Particularly, we isolated Streptococcus pneumoniae, Streptococcus infantis, and Streptococcus thermophilus from the faces of young individuals.

Treatment with secretions of S. pneumoniae and S. infantis induced the expression of genes associated with the formation of skin structure and the skin barrier function in human skin cells. The application of culture supernatant including Streptococcal secretions on human skin showed marked improvements on skin phenotypes such as elasticity, hydration, and desquamation. Gene Ontology analysis revealed overlaps in spermidine biosynthetic and glycogen biosynthetic processes. Streptococcus-secreted spermidine contributed to the recovery of skin structure and barrier function through the upregulation of collagen and lipid synthesis in aged cells. Overall, our data suggest the role of skin microbiome into anti-aging and clinical applications.

The adaptive immune system has the enormous challenge to protect the host through the generation and differentiation of pathogen-specific short-lived effector T cells while in parallel developing long-lived memory cells to control future encounters with the same pathogen. A complex regulatory network is needed to preserve a population of naïve cells over lifetime that exhibit sufficient diversity of antigen receptors to respond to new antigens, while also sustaining immune memory. In parallel, cells need to maintain their proliferative potential and the plasticity to differentiate into different functional lineages.

Initial signs of waning immune competence emerge after 50 years of age, with increasing clinical relevance in the 7th -10th decade of life. Morbidity and mortality from infections increase, as drastically exemplified by the current COVID-19 pandemic. Many vaccines, such as for the influenza virus, are poorly effective to generate protective immunity in older individuals. Age-associated changes occur at the level of the T cell population as well as the functionality of its cellular constituents. The system highly relies on the self-renewal of naïve and memory T cells, which is robust but eventually fails. Genetic and epigenetic modifications contribute to functional differences in responsiveness and differentiation potential.

To some extent, these changes arise from defective maintenance; to some, they represent successful, but not universally beneficial adaptations to the aging host. Interventions that can compensate for the age-related defects and improve immune responses in older adults are increasingly within reach.