If We Could Efficiently Address the Causes of Aging, No-One Would Care About Social and Behavioral Factors in Aging

Aging is caused primarily by our biology, not by our choices. You can certainly cause yourself to age more rapidly by neglecting your health, but the only reason that we see any great level of concern regarding social and behavioral factors in aging is that rejuvenation therapies that have far larger beneficial results than exercise and diet are not yet in widespread use. So people can today look at effect sizes of a year gained here and a year lost there via lifestyle choices and think that this merits further investigation and funding, as it is on a par with what has been achieved via the poor past approaches to treating age-related disease.

In reality we should care very little about such small effects, and focus instead on medical research programs that can in principle add decades to healthy life spans by repairing the cell and tissue damage that causes aging. Bluntly, people who declare that breakthroughs in aging research must incorporate the study of social and behavioral factors are talking nonsense. It is the usual process of the social sciences fishing for funding in the wake of actually important work, combined with low expectations as to how much aging can be slowed or reversed in the decades ahead.

For breakthroughs in slowing aging, scientists must look beyond biolog

A trio of recent studies highlight the need to incorporate behavioral and social science alongside the study of biological mechanisms in order to slow aging. Exciting biological discoveries about rate of aging in non-human species are sometimes not applicable or lost when we apply them to humans. Including behavioral and social research can support translation of geroscience findings from animal models to benefit human. "The move from slowing fundamental processes of aging in laboratory animals to slowing aging in humans will not be as simple as prescribing a pill and watching it work. Compared to aging in laboratory animals, human aging has many behavioral/social in addition to cellular origins and influences. These influences include potential intervention targets that are uniquely human, and therefore are not easily investigated in animal research."

Several of these human factors have big impacts on health and mortality: stress and early life adversity, psychiatric history, personality traits, intelligence, loneliness and social connection, and purpose in life are connected to a variety of late-life health outcomes. These important factors need to be taken into account to get a meaningful prediction of human biological aging. "Geroscience can be augmented through collaboration with behavioral and social science to accomplish translation from animal models to humans, and improve the design of clinical trials of anti-aging therapies. It's vital that geroscience advances be delivered to everyone, not just the well-to-do, because individuals who experience low education, low incomes, adverse early-life experiences, and prejudice are the people who age fastest and die youngest."

"Social hallmarks of aging" can be strongly predictive of age-related health outcomes - in many cases, even more so than biological factors. While the aging field commonly discusses the biological hallmarks of aging, we don't tend to include the social and behavioral factors that lead to premature aging. Researchers have called the main five factors "the Social Hallmarks of aging" and poses that these should not be ignored in any sample of humans and the concepts should be incorporated where possible into non-human studies.

Researchers examined data that was collected in 2016 from the Health and Retirement Study, a large, nationally representative study of Americans over the age of 56 that incorporates both surveys regarding social factors and biological measurements, including a blood sample for genetic analysis. For the study, she focused the five social hallmarks for poor health outcomes: 1) low lifetime socioeconomic status, including lower levels of education, 2) adversity in childhood and adulthood, including trauma and other hardships, 3) being a member of a minority group, 4) adverse health behaviors, including smoking, obesity, and problem drinking, 5) adverse psychological states, such as depression, negative psychological outlook and chronic stress. The presence of these five factors were strongly associated with older adults having difficulty with activities of daily living, experiencing problems with cognition, and multimorbidity (having five or more diseases).

Pharmacology to Target the Mechanisms of Aging is a Going Concern

Traditional pharmacological drug development involves (a) identifying a protein or protein interaction of interest in the body, (b) screening the small molecule libraries for a compound that affects that target, and then (c) making a better version of that small molecule: more effective, less harmful. That remains the bulk of the medical research and development industry, despite the proliferation of other approaches, including cell therapies, gene therapies, recombinant proteins, monoclonal antibodies, and so forth. There are goals that cannot be achieved by small molecules, and, as techniques improve and costs fall, gene therapies of various sorts will ultimately replace a great many small molecule therapies.

That is yet to come, however, and thus much of the first wave of the longevity industry is focused on turning out small molecule drugs that can in some way influence mechanisms of aging. This can be very promising, as in the case of senolytic drugs that cause senescent cells to self-destruct, or it can be likely of only modest benefit, as in the case of mTOR inhibitors that provoke cells into greater stress response activity. All too much of the work taking place today is of the latter category, and will probably provide, at best, similar gains in long term health and life span to those that can be achieved by exercise or the practice of calorie restriction. If we want to truly change the shape of a human life, more than this is needed.

The number of compounds that have been shown to increase longevity in preclinical models is growing exponentially: it was approximately 300 in 2005, 1300 in 2015, and most recently to 2000 in 2020. Meanwhile, the discovery of longevity-associated genes has plateaued, following an exponential growth until approximately 2010 before transitioning to a slower growth over the last decade. There are probably many more longevity genes left, but the incentives for their discovery are reduced since most newly discovered genes now tend to eventually lead towards already known pathways.

The number of longevity companies has also doubtlessly increased dramatically, although this is harder to subjectively measure, as it is difficult to define what makes a company longevity-focused. Most of these companies deal with the hallmarks of aging, most notably oxidative stress and mitochondrial dysfunction, cellular senescence, and pathways implicated in caloric restriction, such as mTOR. The acquisition of longevity companies by big pharma, for example the purchase of Alkahest by Grifols, is also just beginning to occur. One concern is the lack of strategic diversity. It is possible that too much weight is being put on these areas despite the much broader range of potential strategies.

Recently, the field has also seen its first clinical failures, a notable rite of passage for all new fields of medicine. In 2019, ResTORbio's mTOR inhibitor RTB101 failed its Phase 3 trial for a lung disease, and Unity Biotechnology's senolytic UBX0101 failed to meet its endpoints in osteoarthritis just last year. A myriad of challenges can complicate translation, such as a lack of genetic diversity in preclinical models, pathways that are not conserved between species, and the selection of proper primary endpoints. However, the list of ongoing clinical trials is constantly growing, with active studies including COVID-19, macular degeneration, frailty, and neurodegenerative diseases. The TAME trial of metformin represents a pivotal proof-of-concept study, which may pave the way for future therapies aiming to broadly target longevity in their applications to the FDA rather than any specific disease. Interest has also been growing in off-label prescriptions and nutritional supplements.

There has also been a ramping up of computer-based methods being applied to the field of longevity. Bioinformatics, machine learning, and artificial intelligence, -omics approaches, and large public databases are just beginning to be fully utilized. These techniques may someday improve our abilities to predict the outcomes of clinical trials. They also aim to identify candidate drugs and biomarker and may eventually play a role in the application of personalized, precision medicine. When taken as a whole, these trends characterize a vibrant, growing longevity industry in its early maturation stage. There are many parallels to the early days of some fields of pharmacology that are now well established, such as cancer and heart disease.

Link: https://www.lifespan.io/news/longevity-pharmacology-comes-of-age/

Physical Exercise and the Resilience of the Brain to Aging

Being active and fit slows the impact of aging on the brain. A diverse set of mechanisms are involved, and, as is often the case in these matters, it is far from clear as to which of these mechanisms are the most important. Fitness helps to maintain the vascular system in a better shape, keep levels of chronic inflammation lower, causes mild stress that makes cells throughout the body undertake greater maintenance activities, ensures that the gut microbiome ages more slowly, better maintaining the production of metabolites that affect neurogenesis. And so forth - the list goes on.

Nowadays, we are constantly bombarded by media, physicians, and other health professionals to engage in physical/sports activities to reduce physical/psychological stress, improve our health, and reduce the risk of chronic disease. The literature has clearly demonstrated aerobic fitness as one of the best indicators of resilience. This is supported by evidence from a number of studies showing that physical fitness confers physiological and psychological benefits and protects against the development of stress-related disorders, as well as improves cognition and motor function that are a consequence of aging and of neurological disorders.

Although we have learned about neurobiological mechanisms of physical fitness from the neuroplasticity and neuroprotection that confer resilience, these effects and mechanisms are diverse and complex and need to be further explored. However, we can summarize that exercise modulates several mechanisms that may increase brain health and counteract brain disorders. Exercise positively influences neuronal reserve by increasing BDNF expression which promotes neurogenesis and synaptic plasticity, reduces oxidative stress and inflammation, and enhances cerebral and peripheral blood flow, which stimulates angiogenic factors that lead to positive changes in the structure and morphology of brain vasculature. All these changes shape brain activity and serve as a buffer against stress-related disorders.

While several models of physical activity or exercise may impact positively on brain resilience such yoga, dance, martial arts, etc., in this review we aimed to focus mainly on the effects of aerobic exercise of low and moderate intensity or resistance exercise. Thus, physiological markers including heart rate variability, blood pressure, and cortisol might be regularly used as indicator of stress to determine the impact of exercise on brain resilience. Some examples of stress systems are the immune-inflammatory system, the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nervous system. Disturbance of these systems could lead to hyperactivity of the HPA-axis, sympathetic activation, and systemic inflammation.

However, there are still unanswered questions concerning (1) whether physical exercise in early life can prevent or delay cognitive decline in later life, (2) the effectiveness of exercise programs for individuals across the life span and for those with neurological diseases, and (3) how much exercise is necessary to gain beneficial effects on cognitive health. This is a field of research that deserves more attention.

Link: https://doi.org/10.3389/fnbeh.2020.626769

Upregulation of Autophagy via mTOR Inhibition Reduces Tendon Stem Cell Senescence

One of the more interesting studies of cellular senescence in recent years was the demonstration that topical treatment with rapamycin, an inhibitor of mTOR signaling, over a period of months meaningfully reduced the burden of cellular senescence in the skin of aged individuals, leading to improvement in skin quality. It did not achieve this goal by directly destroying senescent cells, as rapamycin is not a senolytic drug. It acts instead to prevent some damaged cells from becoming senescent, or blunt the accumulation of damage in some vulnerable cells, or otherwise reduce the pace at which cells become senescent. That in turn means that senescent cell clearance must still be operational even in very old people: the aged immune system can destroy these cells, it is just falling behind.

It is an open question as to whether preventing cells from entering a senescent state is a good idea or not. This will likely depend on the details of the method used. Very selectively sabotaging the triggers of senescence would allow damaged cells to continue to undertake activity, which would likely raise the risk of cancer. We know that long term mTOR inhibition does not have this effect in mice, however; cancer risk is in fact reduced. So it is likely doing something to reduce the impact of the aged environment on the quality of cells. Given that we know that mTOR inhibition produces - in addition to a slowing of aging - greater cellular maintenance activities, such as greater autophagy to break down and recycle damaged proteins and structures in the cell, this seems a reasonable place to start looking.

Today's open access paper is an investigation of mTOR inhibition, upregulated autophagy, and cellular senescence in tendon stem cells, in order to better understand how mTOR inhibitors such as rapamycin can reduce the number of senescent cells following exposure to a toxic environment that induces DNA damage. For the reasons given above, it is good to know how it functions to produce this outcome. Is upregulation of autophagy over the long term universally a useful strategy to reduce senescent cell levels in older people, albeit taking six months to achieve what a senolytic drug would do in a few days?

Rapamycin Treatment of Tendon Stem/Progenitor Cells Reduces Cellular Senescence by Upregulating Autophagy

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.

On the Aging Adaptive Immune System

An interesting fact about the adaptive immune system: the number of T cells in the body remains much the same across the entire lifespan, even after the supply of new T cells all but ceases in middle age. T cells are created as thymocytes by hematopoietic cells in the bone marrow, and then mature in the thymus. The supply of new cells from the bone marrow is negatively affected by age, while the thymus atrophies, active tissue becoming replaced with fat. Lacking replacements, the T cell population in the body becomes increasingly exhausted, senescent, and otherwise damaged. Many T cells become inappropriately specialized to persistent viral infections such as cytomegalovirus, leaving too few naive T cells to tackle new threats. Harmful subpopulations of T cell arise, connected with chronic inflammation, autoimmunity, and tissue dysfunction. The aging of the immune system is an important component of age-related degeneration.

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.

Link: https://doi.org/10.1111/febs.15770

How Important is the Skin Microbiome in Skin Aging?

Changes in the gut microbiome have a role in aging, and the activities of microbial species (generation of beneficial metabolites, versus generation of harmful inflammation) may be as important as lifestyle choices such as exercise when it comes to the pace of aging. Certainly there is good evidence for rejuvenation of the gut microbiome via fecal microbiota transplantation to improve health and extend life in short-lived laboratory species. Is the skin microbiome similarly important to the physical manifestations of skin aging? There is much less evidence here, as work on this microbiome in the context of aging lags somewhat behind investigations of the gut microbiome. Nonetheless, intriguing results such as those noted here are presently being produced by researchers.

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.

Link: https://doi.org/10.1038/s42003-020-01619-4

Profiling IntraClear, Aiming to Break Down Lipofuscin in Aged Cells

The Russian and Eastern European longevity community is quite active, with a number of non-profit organizations such as the Science for Life Extension Foundation and Open Longevity. There is arguably a greater interest in engineering greater longevity in that part of the world than in the English-language regions. That said, I would say they are behind the US-centric longevity community in terms of translating patient advocacy and scientific programs into startup biotech companies. Their successes to date include the clinical development of mitochondrially targeted antioxidants, the small molecule discovery company Gero, as well as less directly relevant groups such as the Estonian Haut.AI. Today, I'll note another Estonian project, IntraClear Biologics, an early stage venture focused on clearance of lipofuscin and other forms of harmful metabolic waste.

Lipofuscin is a collection of persistent metabolic waste compounds, not completely categorized and understood, that builds up in the lysosomes of long-lived cells in older individuals. This negatively affects the function of lysosomes, a critical component in cellular maintenance, responsible for breaking down unwanted molecules and structures in the cell. Lipofuscin aggregation is a combination of age-related lysosomal dysfunction, coupled with the slow generation of persistent metabolic waste that cannot be effectively broken down even by functional lysosomes. One part of the SENS rejuvenation biotechnology agenda is clearance of lipofuscin in order to remove its damaging effects on cellular recycling and maintenance. So far not all that many groups are working on projects in this space, unfortunately.

I have seen more of the IntraClear materials than are discussed in the article here, and they have an ambitious program in mind, developing clinical assays to determine lipofuscin burden, while in parallel conducting drug discovery for therapies capable of degrading the persistent lipofuscin compounds that build up in old cells. The challenge is, as every, convincing someone to fund this approach to rejuvenation past the initial seed stage. Someone will have to: lipofuscin clearance is a broad topic, and it is clearly an important contribution to degenerative aging, particularly in the central nervous system where there are many long-lived cells. There are a lot of different problem molecules in the aggregated mess of metabolic byproducts given the name lipofuscin. This could keep a number of companies busy for quite some time. LysoClear, for example, is focused on clearing only the A2E found in retinal lipofuscin.

Bioengineering longevity: call for open source approach

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."

IntraClear Biologics

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.

Investment in the Longevity Industry is Growing

The longevity industry is focused on the production of therapies that target mechanisms of aging. The goal is to slow the progression of aging by making metabolism more resistant to the damage that is present in old tissues, or, better, to produce rejuvenation in the old by repairing that damage. The laboratory data of recent years, particularly animal studies of senolytic drugs capable of selectively destroying senescent cells, has convinced a great many people that this is a plausible near term goal. More than a hundred biotech startups are working on therapies that address mechanisms of aging. Not all will succeed, and not all of these projects are worth undertaking in the first place, given the small benefits that are the most likely outcome - but there are scores of important projects that may add significantly to the healthy human life span.

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."

Link: https://www.fdiintelligence.com/article/79406

Bile Duct Organoids as an Approach to Liver Repair

As Lygenesis is in the process of demonstrating, transplantation of functional liver tissue in the form of lab-grown organoids can restore enough lost liver function to make a meaningful difference to patients. Lygenesis transplants into lymph nodes, while the numerous other groups engaged in the production of liver organoids are focused on adding new liver tissue directly to the existing liver. The research here is an example of the type, including a clever proof of concept study using donor organs. A sizable number of such organs are too damaged for use in transplantation. For many lines of work in tissue engineering, enabling more donor organs to be used is an early possible application, prior to direct use in patients.

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.

Link: https://www.cam.ac.uk/research/news/lab-grown-mini-bile-ducts-used-to-repair-human-livers-in-regenerative-medicine-first

Economic Research on Treating Aging to Extend Healthy Longevity

In one sense, there is an enormous wealth of research on the economics of longer lives. This is a byproduct of the operations of sizable pensions and life insurance industries, dependent as they are on successfully predicting future trends in life span. On the other hand, outside this somewhat narrow scope, most concerned with the gain of a tenth of a year here and the loss of a tenth of a year there, there is comparatively little economic work that is directly tied to the research and advocacy communities engaged in trying to treat aging and greatly lengthen healthy human lifespan. That will change as the longevity industry both grows and succeeds in introducing age-slowing and rejuvenating therapies into the clinic.

The paper and commentary that I point out today might be taken as a sample of what lies ahead for the economics profession. At least some economists are at present managing to convince grant-awarding bodies in their field that, yes, there is real movement towards the treatment of aging, and perhaps someone should look into how that will likely play out in markets and societies. It should come as no great surprise to the audience here that even modest gains in slowing or reversing aging have vast economic benefits when they occur across an entire population. The cost of coping with aging is vast, the cost of incapacity and lost knowledge and death due to aging equally vast. It is by far the biggest and most pressing issue that faces humanity, and now we enter an era in which we can finally start to do something about it.

Investigating an Economic Longevity Dividend

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.

Paper All's Well That Ages Well: The Economic Value of Targeting Aging

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 trillion dollar upside to longevity

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!

The Gut Microbiome Becomes More Uniquely Dysfunctional with Age from Individual to Individual

The gut microbiome changes with age, and these changes are implicated in the progression of aging, such as via loss of beneficial metabolites produced by microbial species, or by chronic inflammation generated by harmful microbes when present in greater numbers. Researchers here add more data to what is known of the way in which the gut microbiome changes over the years, showing that the diversity of the microbiome increases across a population with increasing age. Resetting the gut microbiome to a more youthful configuration has been shown to be possible in animal studies via fecal microbiota transplantation from young individuals to old individuals. Given that fecal microbiota transplantation is already developed for use in human medicine, repurposing it for the treatment of old individuals should be an area of focus for the scientific and medical communities.

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.

Link: https://isbscience.org/news/2021/02/18/gut-microbiome-implicated-in-healthy-aging-and-longevity/

Calico, As Expected, is Working on Low Yield Projects in Aging

Calico represents a sizable investment in research and development related to aging and age-related disease. Unfortunately, all the signs have pointed towards this effort going into projects that cannot possibly do more than very modestly affect aging. The publicity materials here further confirm this view of their strategy. They are not targeting the underlying damage that causes aging, but rather manipulating stress response mechanisms in order to try to tinker the aged metabolism into a state that is slightly more resilient to that damage. Upregulation of stress responses, as illustrated by the practice of calorie restriction, can have interesting effects on life span in short-lived species, but does comparatively little for longevity in longer-lived species such as humans. This is not the path to meaningfully large outcomes. It will not change the world, the shape of a life, the late stages of decline, to a great enough degree to matter.

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."

Link: https://www.calicolabs.com/press/calico-and-abbvie-share-update-on-early-stage-clinical-programs

A Cautious View of Senolytics from the Cancer Research Community

Today's open access publication is an examination of therapy induced senescence in the treatment of cancers, and the role that senolytic therapies might play in cancer therapy. Senolytic therapies selectively destroy senescent cells, which accumulate with age, but are also created in sizable numbers by chemotherapy and radiotherapy. Senescent cells cease replication and begin to generate a potent mix of signals - the senescence-associated secretory phenotype (SASP) - that provoke chronic inflammation, disrupt tissue structure and function, and encourage other nearby cells to also become senescent. Cancer treatment shortens life expectancy, and it is thought that an increased burden of senescent cells is an important component of this outcome.

Many different senolytic approaches are presently under development for the treatment of age-related conditions, particularly those with a strong inflammatory component, given the effects of the SASP on the immune system. The results to date in aged animal models are very compelling, a reversal of age-related diseases that is far more reliable and impressive than that produced by any other method of treating aging. It is a short step to consider that these therapies should also be applied to cancer survivors, in order to remove the negative long-term consequences of therapy induced senescence. In effect, someone who has undergone chemotherapy or radiotherapy is more aged than his or her peers, and senolytics should reverse that additional aging in the same way as they should reverse the senescence burden of normal aging.

Beyond that, however, it is very unclear as to whether or not it is a good idea to apply senolytics during cancer treatment. The answer may vary from cancer to cancer and chemotherapeutic to chemotherapeutic. Senescent cells can have pro- and anti-cancer effects, and tip from one to the other as any given scenario of treatment and tumor growth progresses. A great deal more research must likely be undertaken in order to answer these questions.

Senolytics for Cancer Therapy: Is All That Glitters Really Gold?

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.

Data on the Effects of Fecal Microbiota Transplant Between Genders and Ages in Mice

The gut microbiome changes with age, losing populations that produce beneficial metabolites, and gaining populations that produce chronic inflammation and other harms. There are many possible contributions to this process of aging, but it is unclear as to which of them are important. It has been shown in animal studies that performing fecal microbiota transplantation from young to old individuals restores a more youthful gut microbiome for an extended period of time, improving health and extending life span. Researchers here add more data for the short term outcomes of fecal microbial transplantation in mice.

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 increased sex differences in insulin sensitivity and colon metabolome. Together, FMT effects on metabolic changes are sex specific.

Link: https://doi.org/10.21037/hbsn-20-671

Investigating the Mechanisms by which PAPP-A Inhibition Extends Life

Inhibition of PAPP-A is one of the many interventions capable of slowing aging in mice. Being able to slow aging and understanding how exactly that outcome is achieved are two very different things, however. Many of the age-slowing interventions demonstrated in animal studies remain quite poorly understood, insofar as identifying which of the many alterations in metabolism that they cause are important to the progression of aging. Obtaining that understanding is a slow, expensive undertaking, and this hurdle is a roadblock to any further development of these interventions. This challenge is one of the reasons why many of us think it better for the development of practical therapies to start at the other end of aging, at the known root causes, rather than working backwards from metabolic alterations shown to extend life.

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.

Link: https://doi.org/10.1111/acel.13313