Fight Aging!

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.

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

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

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.

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

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

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 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 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

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.

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

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

Chronic, unresolved inflammation is a feature of aging, and an important contributing cause of many age-related conditions. It is an inappropriate and damaging overactivation of the immune system, provoked by senescent cell signaling and various other forms of cell and tissue damage characteristic of aging. Why not just work to consistently suppress inflammation, then? The answer is that short-term inflammation is very important to health. It is needed in wound healing, destruction of potentially cancerous cells, and to fight off pathogens, and all of that remains true even in patients suffering from chronic inflammation throughout the body. Existing immunosuppressant therapies, such as the biologic drugs deployed to treat autoimmune conditions, have unpleasant long-term effects and make patients more vulnerable precisely because they have broad suppressive effects on the operation of the immune system.

Is it possible to be more selective, and only suppress the unwanted inflammatory signaling? In principle, yes. In practice, the immune system and its signaling is enormously complicated. That complexity is further quite different from tissue to tissue and situation to situation. Making inroads towards better immune suppression, more narrowly focused, with fewer side-effects, is very labor intensive. There are only so many researchers, only so much funding. Nonetheless, some progress is being made, as today's open access paper illustrates. The authors report on targeting inflammatory signaling that is more specifically associated with atherosclerosis than is the case for past attempts. This is an incremental advance, a narrowing of the target, and seems likely to still have some negative side-effects.

In atherosclerosis, fatty deposits called plaques form in blood vessel walls, narrowing and weakening the vessels. This occurs because the macrophage cells responsible for clearing up this sort of damage become overwhelmed. They try to clear out lipids from the plaques, become engorged, turn into foam cells, signal for other macrophages to come and help, and die, adding their mass to the plaque. Chronic inflammatory signaling is one aspect of the aging body that contributes to macrophage dysfunction, and it is that contribution that the approach described here seeks to remove.

Unfortunately, it seems likely that inflammatory signaling isn't the largest influence, in that reducing inflammation has been shown by other researchers to only have a small effect on existing plaque size. (This is while being possible, as shown here, to do better than this at reducing the development of plaques over time - but many approaches do quite well at prevention in mouse models. Reversal is the challenge). Reducing inflammation reverses existing plaques to about the same degree (less than 10%) that is produced by the use of statin drugs to lower blood cholesterol. The incapacity of macrophages appears more likely to be largely due to the presence of oxidized cholesterols or local excesses of cholesterol in the plaques.

A Repair Biotechnologies preclinical study reversed plaque size by nearly 50% via the approach of removing cholesterol directly from plaques, a considerably larger outcome than has been achieved by targeting either blood cholesterol or inflammation. Hopefully the Underdog Pharmaceuticals approach of sequestering 7-ketocholesterol from plaques will further prove the thesis by also doing well in vivo.

Designed CXCR4 mimic acts as a soluble chemokine receptor that blocks atherogenic inflammation by agonist-specific targeting

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.

Fibrosis is a malfunction of tissue maintenance in which excessive scar-like collagen deposits disrupt tissue structure and function. This may be one of the consequences of the chronic inflammation of aging, and senescent cell accumulation is implicated in the progression of fibrosis. Researchers here show that upregulation of SIRT3 can reverse some of the disruption of cell function that causes fibrosis, resulting in improvements to health in aged mice. The approach they take is to deliver SIRT3 plasmids into the airway, where they are taken up by macrophage cells. Altered macrophage behavior as a result of increased SIRT3 expression then produces further signaling and cell behavior changes that lead to a reduction in fibrosis.

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 the late reparative phase 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.

Link: https://doi.org/10.1038/s43587-021-00027-5

Work on treating aging as a medical condition, targeting the mechanisms that cause aging in order to slow or reverse its progression, has advanced to the point at which the popular science and medical resources of the world are writing overviews on the topic, seeking to better inform the public at large. We have come a long way in the past decade. The compelling animal data for approaches such as the targeted removal of senescent cells, showing rejuvenation in mice, is melting some of the skepticism that previously characterized attitudes towards the treatment of aging.

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.

Link: https://www.webmd.com/healthy-aging/story/is-there-a-cure-for-aging

Present trends in human life expectancy were established in an era in which little to nothing was being done to target the mechanisms of aging. As of fairly recently, this is changing. There is now a growing contingent of researchers, entrepreneurs, and clinicians attempting to treat aging as a medical condition. This introduces a shift from (a) trying - and largely failing - to address the symptoms of aging, to (b) trying to control the causes of aging. This will inevitably produce far greater gains in life expectancy than those achieved in the past, but the size and timing of those gains will be hard to predict.

This is worth thinking on, when reading papers such as the one I'll point out today, in which the authors project past trends into the future. Those past trends, a slow increase in life expectancy at birth, as well as remaining adult life expectancy at every age, year after year, will almost certainly not continue as-is. It will rather leap upward as the first rejuvenation therapies worthy of the name are widely deployed. But when and by how much will the numbers change?

It seems a fool's game to try to predict that outcome with any accuracy, but a great many of the world's institutions have come to depend upon good predictions of future life expectancy, perhaps lulled by the consistency of the trend to date. Consider the massive providers of life insurance, pensions, entitlement programs, and so forth, all of which calibrate their operations to a given level of mortality and survival in later life. There will thus be some upheaval attendant to the grand success of adding a few decades to the healthy human life span in the years ahead. A changing environment tends to shake out the dead wood from the competitive economic landscape. But at the end of the day, longer healthy life spans are always an economic good. More people will be productive for longer, with lower medical costs.

Demographic perspectives on the rise of longevity

This article reviews some key strands of demographic research on past trends in human longevity and explores possible future trends in life expectancy at birth. Demographic data on age-specific mortality are used to estimate life expectancy, and validated data on exceptional life spans are used to study the maximum length of life. In the countries doing best each year, life expectancy started to increase around 1840 at a pace of almost 2.5 years per decade. This trend has continued until the present. Contrary to classical evolutionary theories of senescence and contrary to the predictions of many experts, the frontier of survival is advancing to higher ages. Furthermore, individual life spans are becoming more equal, reducing inequalities, with octogenarians and nonagenarians accounting for most deaths in countries with the highest life expectancy.

If the current pace of progress in life expectancy continues, most children born this millennium will celebrate their 100th birthday. Considerable uncertainty, however, clouds forecasts: Life expectancy and maximum life span might increase very little if at all, or longevity might rise much faster than in the past. Substantial progress has been made over the past three decades in deepening understanding of how long humans have lived and how long they might live. The social, economic, health, cultural, and political consequences of further increases in longevity are so significant that the development of more powerful methods of forecasting is a priority.

The circadian clock operates at various levels, in cells, in tissues, and in the whole organism. In animals, aging disrupts the biochemistry of the circadian clock. Researchers here show that in individual cells, entering the state of senescence alters the circadian clock. As senescent cells accumulate with age, throughout the body, but particularly in tissues important to organism-level regulation of the circadian clock, is tempting to think that this might be a contributing factor in the disruption of the organism-level circadian clock in older individuals. One doesn't necessarily lead to the other, however. It is easy to suggest that any form of damage located regulatory tissues could have the same effect. Thus the data here is intriguing, and points the way to, for example, closely examining the behavior of the circadian clock following targeted removal of senescent cells in old animals, but it is not conclusive.

Senescent cells, which show the permanent growth arrest in response to various forms of stress, accumulate in the body with the progression of age, and are associated with aging and age-associated diseases. Although the senescent cells are growth arrested, they still demonstrate high metabolic rate and altered gene expression, indicating that senescent cells are still active. We recently showed that the circadian clock properties, namely phase and period of the cells, are altered with the establishment of replicative senescence. However, whether cellular senescence triggers the alteration of circadian clock properties in the cells is still unknown.

In this study we show that the oxidative stress-induced premature senescence induces the alterations of the circadian clock, similar to the phenotypes of the replicative senescent cells. We found that the oxidative stress-induced premature senescent cells display the prolonged period and delayed phases. In addition, the magnitude of these changes intensified over time, indicating that cellular senescence changes the circadian clock properties. Our current results corroborate with our previous findings and further confirm that cellular senescence induces altered circadian clock properties, irrespective of the replicative senescence or the stress-induced premature senescence.

Link: https://doi.org/10.3389/fnins.2021.638122

Researchers here find that a simple model of senescent cell accumulation, with thresholds at which disease occurs, can be made to match the observed variations in risk of most age-related diseases. It is interesting to ask just how much of degenerative aging is driven by this accumulation of senescent cells, and the senescence-associated secretory phenotype that causes inflammation and disrupts tissue function. Clearly not all of aging, but the results in animal studies suggest that senescent cells contribute a large enough fraction of the whole to be a compelling target for rejuvenation therapies. Models such as the one produced here help to flesh out the observed data from animal and human studies.

Recent work on senescent cell dynamics with age used these dynamics to explain the distribution of death times in mice and humans. It was shown that senescent cells are produced and removed with a half-life of days in young mice, but their removal rate slows down in old mice to a half-life of weeks. These data, together with longitudinal measurement of senescent cells in mice, were used to develop a stochastic model for senescent-cell production and removal, called the saturated-removal (SR) model. The SR model shows that senescent cells slow their own removal rate, which leads to wide variations between individuals in the number of senescent cells at old ages. Assuming that death occurs when senescent cells exceed a threshold, it was shown that the SR model explains the distribution of times of death.

Since senescent cells are implicated in many age-related diseases, and since a threshold-crossing event of senescent cells in the SR model has an exponentially rising probability with age, we asked whether age-related diseases can be modeled as a threshold-crossing phenomenon in which senescent cells exceed a disease-specific threshold. To explain the drop in incidence at very old ages, we add to this model the epidemiological notion of heterogeneity, in which some people are more susceptible to the disease than others. We show that the SR model with differential susceptibility provides a model with 2 or 3 free parameters that can explain a wide range of age-related incidence curves. This includes the incidence of many types of cancer, major fibrotic diseases, and hundreds of other age-related disease states obtained from a large-scale medical record database.

This conceptual picture explains why different diseases have similar exponential rise in incidence and a drop at very old ages, based on a shared biological process, the accumulation of senescent cells. It also can be used to optimize the frequency of treatments that eliminate senescent cells, showing that even infrequent treatment starting at old age can reduce the incidence of a wide range of diseases.

Link: https://doi.org/10.1111/acel.13314

Given the increased interest in the treatment of aging as a medical conditions, and the establishment of a longevity industry focused on building therapies that target the mechanisms of aging, it is now the case that more people are writing on the topic. Thankfully! There are many more and better introductions to aging research and its potential application to extending the healthy human life span than was the case a decade ago. Today's example is a good article, well worth keeping around and handing off to interested friends who want to know more about the exciting work that is presently taking place in academia and industry.

The Longevity FAQ

Inasmuch as one enjoys being alive, waiting longer until the signs of frailty and old age occur seems an appealing proposition, and so there is an entire field of research dedicated to understand the aging process. A recent summary for a popular audience is in David Sinclair's recent book Lifespan. But I wanted to provide a deeper and more concise explanation, plus communicating not only the results but also their robustness. There is also a previous Longevity FAQ from Laura Deming, but I thought something a bit longer that explains the field from the ground up should exist.

At first, reading about research regarding longevity can seem like magic: "We knocked out Sirt1 in mice, leading to reduced lifespan". That sentence is not only compressing a lot of information (What does it mean to knock out? What's Sirt1?) but also once we know that knocking out Sirt1 means to stop a gene from being expressed (i.e. stopping the cell from manufacturing the protein associated with that gene), we may want to know things like "Are there different ways of knocking out genes? How do different genes related in the genetics of aging relate to each other? If we do the same things in dogs, does it work?"

My goal here is to demystify what seems initially obscure, and to make available a summary of the current state of the art, the quality of the evidence available so far, and what promising avenues of research are being pursued at the moment.

Longevity research is an exciting area that has been making great progress in recent years. From the early discoveries that ageing can be modulated to the current advances in understanding how aging works, and how therapies could be developed to live longer, healthier lives. Progress seems easier on the "healthier" side of things, with many of studies showing that it is easier to prolong healthspan or expected lifespan and cure certain conditions that occur in the old age rather than the maximum lifespan of our species. Current research seems like it could enable most people to live past 100 years in reasonably healthy conditions, a feat that, to a lesser degree, is accomplished today by a tiny fraction of supercentenarians.

Researchers here provide epidemiological evidence to suggest that exercise, an active lifestyle, reduces the impact of heart attacks, making them less severe. We can hypothesize that this may be due to an increased generation of redundant blood vessels, perhaps, via upregulation of the processes of angiogenesis over the long term. Heart attacks are usually caused by blockage of an important blood vessel by fragments of a ruptured atherosclerotic plaque. If there are alternative paths for blood to flow into the affected tissue, then the immediate harms done are reduced.

Heart disease is the leading cause of death globally and prevention is a major public health priority. The beneficial impact of physical activity in stopping heart disease and sudden death on a population level is well documented. This study focused on the effect of an active versus sedentary lifestyle on the immediate course of a heart attack - an area with little information.

The researchers used data from 10 European observational cohorts including healthy participants with a baseline assessment of physical activity who had a heart attack during follow-up - a total of 28,140 individuals. Participants were categorised according to their weekly level of leisure-time physical activity as sedentary, low, moderate, or high. The association between activity level and the risk of death due to a heart attack (instantly and within 28 days) was analysed in each cohort separately and then the results were pooled.

A total of 4,976 (17.7%) participants died within 28 days of their heart attack - of these, 3,101 (62.3%) died instantly. Overall, a higher level of physical activity was associated with a lower risk of instant and 28-day fatal heart attack, seemingly in a dose-response-like manner. Patients who had engaged in moderate and high levels of leisure-time physical activity had a 33% and 45% lower risk of instant death compared to sedentary individuals. At 28 days these numbers were 36% and 28%, respectively. The relationship with low activity did not reach statistical significance.

Link: https://www.escardio.org/The-ESC/Press-Office/Press-releases/Instant-death-from-heart-attack-more-common-in-people-who-do-not-exercise

Cellular senescence is important in aging, as these cells disrupt tissue function and provoke chronic inflammation where they linger in old tissues. The phenomenon is found in cell types throughout the body, but researchers have shown that meaningful differences between cell types exist in the biochemistry of cellular senescence, and possibly between senescent states for the same cell type. A senolytic drug that can efficiently destroy one type of senescent cell may perform poorly for another type. This indicates that a diversity of development of senolytic therapies, and combinations of multiple therapies, will likely prove beneficial. Alternatively, approaches such as the suicide gene therapy developed by Oisin Biotechnologies may win out as p16 expression proves to be a more general characteristic of senescence than others.

There is a heterogeneity in markers expressed by senescent cells depending on both cell type and an insult used to induce senescence. However, there are several common features typical for the most types of senescent cells. The essential characteristic of senescence for any kind of dividing cells is the irreversible proliferation loss. The irreversibility of the cell cycle arrest is controlled by the cyclin-dependent kinase (CDK) inhibitors p16 and p21 and is often regulated by the tumor suppressor protein p53.

The other important features of senescent cells are the activation of a persistent DNA damage response; cell hypertrophy, which often arises as a result of impaired ribosomal biogenesis and protein synthesis; disturbance of lysosomal degradation and dysfunction of the rest degradation systems; increased activity of the specific lysosomal enzyme senescence-associated-β-galactosidase; various mitochondrial alterations; acquisition of the senescence-associated secretory phenotype.

Targeted elimination of senescent cells - senolysis - is one of the core trends in the anti-aging therapy. Cardiac glycosides were recently proved to be broad-spectrum senolytics. Here we tested senolytic properties of cardiac glycosides towards human mesenchymal stem cells (hMSCs). Cardiac glycosides had no senolytic ability towards senescent hMSCs of various origins. Using biological and bioinformatic approaches we compared senescence development in 'cardiac glycosides-sensitive' A549 cells and '-insensitive' hMSCs. The absence of senolysis was found to be mediated by the effective potassium import and increased apoptosis-resistance in senescent hMSCs.

We revealed that apoptosis-resistance, previously recognized as a common characteristic of senescence, in fact, is not a general feature of senescent cells. Moreover, only apoptosis-prone senescent cells are sensitive to cardiac glycosides-induced senolysis. Thus, we can speculate that the effectiveness of senolysis might depend on whether senescent cells indeed become apoptosis-resistant compared to their proliferating counterparts.

Link: https://doi.org/10.1101/2020.12.18.423449

An accumulation of lingering senescent cells takes place with advancing age. Senescent cells are created throughout life, entering the senescent state in response to reaching the Hayflick limit on replication, or DNA damage, or signaling from other senescent cells, or to a toxic environment. Senescent cells cease replication and instead generate a potent mix of inflammatory and pro-growth signals, the senescence-associated secretory phenotype (SASP). In youth near all senescent cells are rapidly destroyed, either by programmed cell death, or by the immune system. With advancing age, however, the processes of clearance slows down and the pace of creation picks up. The outcome is an increasing number of senescent cells in tissues throughout the body.

Senescent cells perform useful tasks in the short term. They help to coordinate regeneration following injury, and draw the attention of the immune system to damaged cells with a raised risk of becoming cancerous. When they linger for the long-term, however, their signaling produces chronic inflammation, changed behavior in neighboring cells, and disruption of tissue structure and function. In this way, senescent cells directly contribute to the onset and progression of numerous age-related conditions.

Targeted destruction of senescent cells via senolytic treatments has been shown to produce rejuvenation and extended life span in mice. Some of the earliest senolytic drugs target Bcl-xL, a protein that acts to hold back the onset of apoptosis and consequent cell death. Unlike normal cells, senescent cells are primed to enter apoptosis, and require significant activity of anti-apoptosis mechanisms in order to survive. Sabotaging these mechanisms thus selectively destroys senescent cells.

As noted in today's open access paper, Bcl-xL is upregulated in very long-lived humans in comparison to their shorter-lived peers. This Bcl-xL activity may assist in slowing aging modestly, raising the odds of surviving to an advanced age, via maintenance of a more functional immune system. That more functional immune system, more capable of destroying senescent cells, may counteract the downside of senescent cells being more able to resist apoptosis and self-destruction given higher Bcl-xL expression.

Bcl-xL as a Modulator of Senescence and Aging

Centenarians, the most aged individuals, should accumulate senescent cells and suffer from their deleterious effects, however, they enjoy a compression of morbidity. We have shown that they overexpress B-cell lymphoma-extra large (Bcl-xL). Bcl-xL could avoid an excessive burden of senescent cells through the regulation of intrinsic apoptosis, mitochondrial bioenergetics and oxidative stress. On the other hand, Bcl-xL maintains a fully functional immune system that ensures an efficient clearance of senescent cells. Moreover, there is a paradox, as inhibitors of Bcl-xL have been employed as senolytic agents, which have been shown to protect from aging in animal models.

Despite its well-documented anti-apoptotic role, Bcl-xL is also related to mitochondrial bioenergetics by modulating mitochondrial fusion and fission, increasing total mitochondrial biomass, and enhancing the efficiency of the ATP synthesis. As cellular senescence can be both beneficial and detrimental for the organism, accordingly, Bcl-xL might play a dual role on senescence.

A possible hypothesis could be that during acute senescence, Bcl-xL effects on mitochondria would help senescent cells to cover their metabolic demand to secrete the SASP to promote their clearance as part of the senescence-clearance-regeneration procedure. However, senescent cells are also characterized by dysfunctional mitochondria, due to an imbalance between mitochondrial fission and fusion, which is critical for the functionality of the mitochondrial network. In this scenario, Bcl-xL might avoid the accumulation of dysfunctional mitochondria in senescent cells, thus preventing their detrimental effect on tissue homeostasis.

Senescent cells mainly depend on the immune system to be cleared; thus, a dysfunctional immune system will lead to accumulation of senescent cells within tissues. To promote the depletion of senescent cells, senolytic drugs aim to eliminate senescent cells without affecting quiescent or proliferating cells. Since the expression of anti-apoptotic and pro-apoptotic genes is higher in senescent cells compared to healthy cells, inhibitors of Bcl-xL have been described as senolytic agents because they only induce apoptosis in senescent cells, both in vitro and in vivo. ABT737, ABT263 or Navitoclax, which targets the Bcl-2/Bcl-xL proteins, is a potent senolytic drug that selectively kills senescent cells, regardless of how they were induced.

Exercise is broadly beneficial to health, an effect in part mediated by the mild stress it inflicts on cells, causing increased cell maintenance activities in response, and in part by a vast and complex array of cell signaling that produces sweeping changes in cellular behavior. Some of that signaling is the result of the aforementioned mild stress, some of it not. Researchers here look one of these signals, the secretion of beta-hydroxybutyrate, and its beneficial effects on tissue function.

Recent studies have shown that exercise improves skeletal muscle and cognitive function by stimulating the secretion of numerous molecules. In particular, previous studies have suggested that exercise-induced beta-hydroxybutyrate (BHB) release might improve skeletal muscle and cognitive function, but to date these studies have been limited to cell models and animal models. Therefore, we aimed to determine how an exercise-induced increase in BHB affects skeletal muscle and cognitive function at a cellular level, in an animal model, and in humans. The effects of BHB on skeletal muscle and cognitive function were determined by treating muscle and glial cell lines with BHB, and by measuring the skeletal muscle and serum BHB concentrations in aged mice after endurance or resistance exercise. In addition, serum BHB concentration was measured before and after high-speed band exercise in elderly people, and its relationships with muscle and cognitive function were analyzed.

We found that BHB increased cell viability and brain-derived neurotrophic factor expression level in glial cells, and endurance exercise, but not resistance exercise, increased the muscle BHB concentration in aged mice. Furthermore, the BHB concentration was positively related to skeletal muscle and cognitive function. Exercise did not increase the serum BHB concentration in the elderly people and BHB did not correlate with cognitive function, but after excluding the five people with the highest preexisting serum concentrations of BHB, the BHB concentrations of the remaining participants were increased by exercise, and the concentration showed a tendency toward a positive correlation with cognitive function. Thus, the BHB released by skeletal muscle following endurance exercise may improve muscle and cognitive function in animals and humans.

Link: https://doi.org/10.14814/phy2.14497

The decline of cardiovascular disease in older people is the result of improved health practices, primarily less smoking, and a focus on lowering blood cholesterol via lifestyle change and drugs such as statins. The formation of fatty plaque in blood vessel walls occurs in later life, the condition known as atherosclerosis. The plaque narrows and weakens blood vessels throughout the body. The rupture of a vessel or disintegration of a plaque followed by a a downstream blockage is the mechanism that causes both stroke and heart attack. Atherosclerosis is a consequence of the mechanisms of aging and their downstream consequences, such as raised blood pressure, growing chronic inflammation, as well as oxidative stress that produces toxic oxidized forms of cholesterol. To the degree that this vascular aging has been slowed, or some of its consequences diminished, by the limited means available, cardiovascular disease and strokes will also decline in the older population.

A new study which examined the population of Denmark has found that people age 70 and older are having fewer strokes, and fewer people of all ages are dying from the disease. In older people, researchers found declines in both ischemic stroke, caused by a blockage of blood flow to the brain, and intracerebral hemorrhage, when a blood vessel bursts inside the brain. "Stroke is a leading cause of death and disability in the world. Recent research on the incidence of stroke has been mixed, and some studies have reported an increase among young people. However, our research found no increase in stroke among young people, and it also found the incidence of stroke declining among older people, which is encouraging."

For the study, researchers used national health care registries in Denmark to identify all people in the country hospitalized with a first-time stroke between 2005 and 2018. They identified 8,680 younger adults age 18 to 49 who had a stroke during that time, and 105,240 older adults age 50 and older. Researchers calculated yearly incidence rates for both ischemic and hemorrhagic stroke based on the Danish population. They also calculated incidence rates based on age.

Researchers found the incidence rate of stroke in people 49 and younger remained steady over the course of the study, with around 21 cases of ischemic stroke per 100,000 person-years at the start and end of the study. For intracerebral hemorrhage, the incidence rate in young people was around 2 cases per 100,000 person-years at the start and end of the study. The incidence rates of stroke declined in people 50 and older over the course of the study, with 372 cases of ischemic stroke per 100,000 person-years at the start of the study and 311 cases at the end. For intracerebral hemorrhage, there were 49 cases per 100,000 person-years at the start of the study and 38 cases at the end. However, stroke rates in people in their 50s were stable, with most of the decline in people age 70 and older.

"The improvements we found in survival rates are consistent with improvements in stroke care. We also examined stroke severity and found while mild strokes increased, the most severe cases declined. These changes could be related to improvements in stroke awareness in the general population as well as the care people receive for stroke, including in the ambulance and emergency department prior to hospitalization. Such care has led to faster and improved diagnostics, particularly regarding the mildest of cases."

Link: https://www.aan.com/PressRoom/Home/PressRelease/3856

The microvasculature of the body diminishes with age, and this is thought to be a major contributing factor in the progression of age-related loss of organ function, particularly in energy-hungry tissues such as muscles and the brain. Every tissue is densely packed with tiny blood vessels, hundreds of capillaries passing through every square millimeter in cross-section. This small-scale microvasculature is needed in order to efficiently deliver sufficient nutrients to all cells in a tissue. Absent capillaries, perfusion of nutrients is only useful over a very short distance indeed, and its effectiveness declines quickly as that limit is approached. Unfortunately, the density of capillary networks is lost with age.

The mechanisms regulating angiogenesis, the growth and maintenance of blood vessels, are very complex, but also quite well explored as a result of their relevance to many areas of medicine. Some approaches are demonstrated to produce usefully greater regrowth of blood vessels following injury in animal studies, such as mobilization of hematopoietic cells from the bone marrow. Many of the possible points of intervention via upregulation or interdiction of a single protein result in problematic growth, however. Blood vessels grow where they should not grow, or are poorly formed, or both. Excessive angiogenesis of leaky vessels in the eye, provoked by pro-growth signals secreted by senescent cells, is a feature of macular degeneration, for example.

Nonetheless, the evidence for loss of capillary density to be important in aging is compelling. This should be motivation enough to work on ways to safely invigorate the faltering mechanisms of angiogenesis, and thereby turn back this aspect of degenerative aging, improving tissue function throughout the body by no longer starving cells of required nutrients.

Microvascular Alterations in Alzheimer's Disease

Reduced capillary density with aging is attributed to diminished levels of angiogenic growth factors (such as VEGF), an imbalance between production of angiogenic and anti-angiogenic growth factors, and reduction of nitric oxide release and impaired vasodilation. The Neuroangiogenesis Hypothesis has been proposed, wherein a decline in growth factors and angiogenic cytokines leads to a reduction in vessel density and cognition. Restoration of vessel density through administration of growth factors, such as VEGF, is proposed as a treatment to prevent development of Alzheimer's disease (AD) symptoms. In addition to vessel loss, aging is linked to increased capillary tortuosity and a thickened basement membrane. Pericytes are lost or become dysfunctional, causing blood-brain barrier dysfunction and impaired flow regulation that decreases oxygen concentration in tissue.

Vascular risk factors are prominent in aged populations. This may be due to aging-induced inflammation and cytokine release, leading to endothelial dysfunction and arterial stiffening. Hypertension is associated with microvascular abnormalities such as endothelial swelling and reduced capillary density. This microvascular deficiency in hypertension is potentially aggravated by a deficiency in circulating insulin-like growth factor 1 (IGF-1) due to aging.

The reduced vessel density at older ages might be attributable to the aging process and reduced expression of angiogenic growth factors. In brains without AD, decline in growth factors with aging, such as VEGF, fibroblast growth factor (FGF-1 and FGF-2), and angiopoietin, yield slow recovery in tissue wound injuries due to reduced angiogenic capabilities, or display reduced angiogenesis in response to hypoxia. In a human study, researchers found significant reduction in serum VEGF relative to both amnestic mild cognitive impairment and control (healthy) individuals. Transforming growth factor β1 (TGF-β1) (an angiogenic growth factor) serum concentration was reduced in AD, with the reduction in VEGF and TGF-β1 levels correlating with cognitive impairment severity. It was hypothesized that this indicates reduction in angiogenic growth factors contribute to cognitive impairment.

Due to reduced capillary density with aging, researchers proposed VEGF and growth factor administration for restoring capillary density and blood flow. A study in TgCRND8 AD mice overexpressing VEGF found partial recovery of vessel density and restoration of memory impairments, supporting enhancing vascular growth as a method for improving cognition. There are factors to consider in applying this therapy to humans. VEGF in high concentrations may induce blood-brain barrier leakage. Many newly formed vessels during angiogenesis are leaky with abnormal morphology.

Regrowth of vascular is more than increasing vessel number through administering VEGF. Newly formed vessels adjust their diameters, potentially differentiate into arteries or veins, and recruit support cells such as smooth muscle cells, pericytes, and fibroblasts to produce a functional vessel network. Expanding growth factor therapy to AD will require consideration of relative concentrations of naturally occurring growth factors unique to each subject and state of dementia, delivery method, and determining growth factors to administer.

A related therapy to growth factor administration that overcomes some deficiencies is exercise. Exercise increases concentration of a variety of angiogenic molecules such as Ang1 and Ang2, VEGF, fibroblast growth factor (FGF, upregulates VEGF, and induces vasodilation through nitric oxide), transforming growth factor (TGF, regulates extracellular matrix formation), and platelet derived growth factor (PDGF, mitogen for smooth muscle cells, fibroblasts, and glia cells). Mice provided access to running wheels demonstrated elevated brain microvascular efficiency and increased blood flow in the hippocampus.

The prevailing model for the investment vehicles at the core of the longevity industry is the business development company, not the venture fund. The canonical example is Juvenescence, while the Longevity Vision Fund and Life Biosciences look very similar, and, as noted here, Cambrian Biopharma - that started out as a venture fund, as I recall - is now following the same playbook. The objective of a venture fund is to exist for a set period of time, invest in startups, and return gains to investors at the end of that time. The objective of a business development company is to go public. This difference in objectives tends to steer groups like Juvenescence and Cambrian towards creating a family of owned companies, via founding startups or purchasing controlling majority stakes in existing ventures, and participating actively in the management of those companies. New Big Pharma entities will likely emerge from this approach, as the industry grows, and the first rejuvenation therapies prove their worth in the clinic.

Cambrian Biopharma, a distributed drug discovery company, exited stealth today with the announcement that it has raised $60 million in private financing to develop medicines to extend healthy lifespan. By working like a hub-and-spoke model to develop a family of companies, Cambrian hopes to promote a thriving environment, building expert teams in drug discovery, development, clinical trials, finance, and market analysis as a shared resource for each pipeline company to use.

"I think that there's a lot of opportunity in this space and one of the things that we really need is companies that can move fast with a lot of capital. Hallmarks of aging, as well as other types of molecular damage that accumulate in our bodies as we get older, are in scope for Cambrian, we are really building an R&D company first, one that's making allocation decisions, not investments across a series of our pipeline companies."

This longevity platform approach is very much like Juvenescence and Life Biosciences and is another welcome demonstration of longevity investment category growth. Cambrian scientists are targeting the nine hallmarks of aging, including cellular senescence, sustained tissue inflammation, and mitochondrial dysfunction. They are leveraging breakthroughs in fields that include immunology, genomics, and epigenetics, and technologies that range from gene editing to new stem cell therapies.

Cambrian has put three major categories of aging at the top of its to-do list; it plans to tackle intracellular dysfunction (things that go wrong inside cells, such as mutating DNA or shrinking telomeres), cellular dysfunction (whole-cell level problems, such as senescence or energy pathway break down) and tissue level dysfunction (stem cells exhaustion, chronic inflammation, or the breakdown of tissue architecture). To date, Cambrian has 14 novel therapies under development within its stable of companies. The first of these to be disclosed is Sensei Bio, which has as its lead therapeutic product candidate a genetically engineered bacteriophage vaccine that has already demonstrated promising data in a Phase 1/2 human clinical trial of patients with late-stage head and neck cancer.

Link: https://www.longevity.technology/cambrian-biopharma-exits-stealth-with-60m-and-affiliate-ipo/

Researchers here note a mechanism that causes T cells of the adaptive immune system to spur chronic inflammation and tissue damage following a heart attack. As the researchers note, not all inflammation is the same. Some is maladaptive, and this is particularly the case in older individuals. The aged immune system is more prone to a sustained inflammatory response, provoked by pro-inflammatory signaling of senescent cells and the signs of cell damage that circulate in the body. Suppressing all inflammation is too blunt of a tool, however, as short-term inflammation is still necessary for regeneration and response to pathogens even in later life.

Inflammation is supposed to help protect us - it's part of an immune response to fight off pathogens and clear infections. But patients with cardiac disease often have chronic inflammation that damages their hearts, even with no infection present. When a heart attack or other issue damages the heart and leaves it unable to pump enough blood to meet the body's needs, the heart tries to compensate by pumping faster. The cardiac muscle cells have to work harder and this stress causes them to release molecules known as reactive oxygen species. Looking at the hearts of mice, the researchers determined that products of these reactive oxygen species modify proteins in the heart so that the immune system views them as a potential threat.

"The formation of these new targets is what we found that our T cells are robustly responding to. And this ultimately leads to inflammation that affects the heart." The researchers confirmed that these modified proteins also appeared in the cardiac tissue of human patients whose hearts were failing. Chronic inflammation can cause structural changes to the heart - the muscle can become enlarged or develop fibrous tissue, impeding its ability to pump blood efficiently and leading to further deterioration. But anti-inflammatory treatments or attempts to broadly target reactive oxygen species have yet to be successful. They often end up interfering with other aspects of the immune system or necessary physiological processes.

With this improved understanding of how T cells are being activated in patients with heart disease, the researchers hope to develop more targeted treatments. They have already tested one possibility in mice: an agent that binds to the specific molecules altering cardiac proteins.

Link: https://now.tufts.edu/articles/uncovering-link-between-inflammation-and-heart-disease

Ever more of the research community is drawn to work on cellular senescence by the clear, robust, and expanding evidence for senescent cell accumulation to be a major contributing cause of aging. Clearance of senescent cells by senolytic treatments produces extension of healthy life span and rejuvenation in mice, the reversal of many different age-related conditions. Senolytics are presently in the early stages of human clinical trials, with promising results for some of the approaches taken, such as use of the dasatinib and quercetin combination.

The role of senescent cells in the progression of diabetic retinopathy was outlined in some detail five years ago or so. This form of retinopathy, and others such as macular degeneration, is characterized by the inappropriate growth of leaky blood vessels into the retina, disrupting structure and killing cells. This growth is driven in large part by the secreted signals of senescent cells.

Unity Biotechnology is focused on the development of first generation senolytic small molecule drugs derived from chemotherapeutics such as navitoclax. The company is targeting conditions of the eye for what looks to be much the same rationale as they targeted osteoarthritis of the knee: that they can use localized treatments that minimize any off-target side effects that might emerge with systemic delivery of a drug. Based on the failure of their last clinical trial for localized senolytic treatment of the knee joint, this strategy may prove to be a case of optimizing for regulatory approval at the cost of clinical efficacy. Sad to say, but a great deal of the medical landscape is defined not by what works most effectively, but instead by what the regulators are most likely to accept.

The likely problem with localized approaches to senolytic therapy is that the signals secreted by senescent cells enter the circulation and travel throughout the body. Removing the contribution of local senescent cells may well not be enough to produce reliable benefits in a patient exhibiting chronic systemic inflammation, with significant numbers of senescent cells in all tissues. The failed Unity Biotechnology trial is argued to have been a demonstration of this point. If the company also fails to produce benefits in patients for the eye via localized injection of senolytics, that would likely ensure that no group ever again tries a localized approach.

Study published in Cell Metabolism Reveals New Therapeutic Approach Aimed at Restoring Vascular Health and Reversing Age-Related Eye Disease

UNITY Biotechnology, Inc., a biotechnology company developing therapeutics to slow, halt, or reverse diseases of aging, today announced new preclinical research that reveals a novel mechanism for treating age-related eye diseases - such as diabetic retinopathy and diabetic macular edema - by restoring vascular health in the retina. By selectively eliminating the senescent cells accumulating in diseased blood vessels of the eye, researchers identified a way to target diseased vasculature while leaving healthy blood vessels intact, thus enabling the retina to repair itself.

Researchers demonstrated that diseased blood vessels in the retina trigger molecular pathways associated with aging, collectively termed cellular senescence. The authors used a combination of animal models and human samples to identify a molecular target, called Bcl-xL, that is highly expressed in diseased retinal blood vessels. Targeting these senescent cells with a single dose of UNITY's Bcl-xL small molecule inhibitor led to selective elimination of diseased vasculature, while enabling functional, healthy blood vessels to reorganize and regenerate.

Pathological angiogenesis in retinopathy engages cellular senescence and is amenable to therapeutic elimination via BCL-xL inhibition

Attenuating pathological angiogenesis in diseases characterized by neovascularization such as diabetic retinopathy has transformed standards of care. Yet little is known about the molecular signatures discriminating physiological blood vessels from their diseased counterparts, leading to off-target effects of therapy. We demonstrate that in contrast to healthy blood vessels, pathological vessels engage pathways of cellular senescence. Senescent (p16 INK4A-expressing) cells accumulate in retinas of patients with diabetic retinopathy and during peak destructive neovascularization in a mouse model of retinopathy.

Using either genetic approaches that clear p16 INK4A-expressing cells or small molecule inhibitors of the anti-apoptotic protein BCL-xL, we show that senolysis suppresses pathological angiogenesis. Single-cell analysis revealed that subsets of endothelial cells with senescence signatures and expressing Col1a1 are no longer detected in BCL-xL-inhibitor-treated retinas, yielding a retina conducive to physiological vascular repair. These findings provide mechanistic evidence supporting the development of BCL-xL inhibitors as potential treatments for neovascular retinal disease.

Ischemic conditioning involves reducing the blood flow to part of the body for a period of time, such as to limbs via use of a tourniquet. When carried out correctly, the right degree of restriction for the right length of time, this provokes a beneficial stress response in cells that is similar in some ways to that produced by exercise. Here, researchers show that ischemic conditioning reduces the inflammatory signaling and state of chronic inflammation that contributes to many age-related conditions, including the age-related hypertension that the is the focus on these studies.

Hypertension is a leading risk factor for cardiovascular, cerebrovascular, and many other diseases. Vascular remodeling results from blood pressure elevation, and progressively becomes a crucial cause of hypertension. However, during vascular remodeling no symptoms except occasional blood pressure elevation are observed. Neither attention nor treatment would be considered until the diagnosis of hypertension is established. Thus, timely therapy is urgent for the prevention and treatment of early-stage vascular remodeling.

Vascular remodeling results initially from passive physiological adaptation to blood pressure changes, then progresses into an active pathological process caused by elevated blood pressure, aging, and several other factors. An earlier study showed the critical role of inflammation in the pathological changes involved in vascular remodeling. Emerging evidence indicates that infiltrating proinflammatory cells are essential for the migration and infiltration of inflammatory factors. Several inflammatory factors were shown to affect blood pressure and vascular function leading to vascular remodeling and dysfunction. Thus, it is reasonable to hypothesize that by regulating inflammatory cells and their environment might aid in the treatment and prevention of vascular remodeling and hypertension-related vascular diseases.

Limb remote ischemic conditioning (LRIC) is a physiological treatment that protects against acute ischemic events and traumatic injury. Chronic remote ischemic conditioning simulates regular exercise and exerts its protective effect via humoral and immunological regulation. Some clinical cases reported that LRIC could decrease blood pressure. However, studies on whether LRIC positively affects chronic vascular remodeling and blood pressure are scant. Considering all the available evidence, we hypothesize that LRIC would exert a protective effect on hypertension-related vascular remodeling, thus delaying vascular stiffness and aging caused by structural remodeling.

In this study, LRIC of rats was performed once a day for 6-weeks. Blood pressure, vascular remodeling, and inflammation were compared among normotensive Wistar-Kyoto rats (WKY), WKY RIC group, spontaneously hypertensive rat (SHR) control group, and SHR RIC. LRIC treatment decreased blood pressure in SHR. LRIC ameliorated vascular remodeling by decreasing cross-sectional area, suppressing deposition of the extracellular matrix, and hypertrophy of smooth muscle cell in conduit artery and small resistance artery. LRIC decreased proinflammatory factors while increasing the anti-inflammatory factors in the circulation. LRIC decreased circulating monocyte and natural killer T-cell levels.

Long-term LRCI treatment (twice a day for 4-weeks) was performed on patients with prehypertension or early-stage hypertension. Blood pressure and pulse wave velocity (PWV) were analyzed before and after LRIC treatment. LRIC treatment decreased blood pressure and improved vascular stiffness in patients. In conclusion, long term LRIC could decrease blood pressure and ameliorate vascular remodeling via inflammation regulation.

Link: https://doi.org/10.14336/AD.2020.0320

It is very clear from the data, as is the case for influenza, the mortality of the COVID-19 pandemic is suffered near entirely by the old. This is because the aged immune system is less capable of fighting off pathogens, but also because the state of chronic inflammation and other dysfunctions resulting from immune system aging makes the cytokine storm of a severe SARS-Cov-2 viral infection that much more likely and that much more severe. Patients with inflammatory age-related conditions, or conditions associated with obesity, a prominent cause of chronic inflammation, are much more likely to die from SARS-Cov-2 infection.

Since the first reported cases with severe acute respiratory syndrome caused by a novel coronavirus (SARS-CoV2), this disease called coronavirus disease (COVID-19) has expanded worldwide being considered by World Health Organization as a pandemic. Although this virus may infect people regardless of age, race or sex, older subjects have been identified as a high-risk group regarding the clinical outcome of the disease, both for developing severe pneumonia with respiratory distress and death. Although global mortality rate directly related to SARS-CoV2 infection is unknown (a real infectious rate is not well known), mortality rate among severely elderly patients (between 60-90 years old) is around 50%, even in countries with significant lower deaths. Hence, apart from other risk factors linked to a poor clinical outcome, such as hypertension, diabetes, cardiovascular disease, cancer, or chronic lung disease, old age itself can be also considered as an independent risk factor associated with SARS-CoV2-related severe pneumonia and death.

From an immunopathogenic viewpoint, COVID-19 disease has probably a multifactorial nature and the final severe lung damage observed in COVID-19 could be caused by an uncontrolled proinflammatory cytokine cascade (called "cytokine storm"), driven mainly by interleukin-6 (IL-6) and other proinflammatory cytokines such as IL1β, IL8, CXCL10, and CCL2. Based on this hypothesis, apart from non-specific antiviral agents, anti-inflamatory drugs have been proposed to be used in patients with advanced COVID-19 disease. However, which immunopathogenic status precedes this "cytokine storm" and why the elderly population is more severely affected, are currently unanswered questions. Thus, we propose that immunosenescence and age-related thymic dysfunction could play a relevant role in current COVID-19 disease scenario.

According to our dual physiopathological hypothesis, in addition to impaired thymic function, we believe that elderly subjects at baseline show a systemic low-level chronic inflammation. Their population of monocytes generate a great amount and variety of cytokines (multiple circulating cytokines). These cells of elderly subjects, when stimulated by pathogen-associated molecular patterns receptors like TLR by a novel agonist (SARS-CoV2 antigen), could generate the massive and polyfunctional proinflammatory cytokine release that characterized COVID-19, and that would trigger the respiratory distress and multiorgan failure as clinical outcome.

Link: https://doi.org/10.14336/AD.2020.0831

The gut microbiome is a complex, ever-shifting collection of microbes that mediates much of the interaction between diet and health. This microbiome changes with age. The exploration of these changes is still a comparatively young field of research, even while expanding considerably in recent years. As we age, some of the beneficial species that produce useful metabolites decline in number, while some of the harmful species that can cause chronic inflammation prosper and expand. Chronic inflammation is an important aspect of degenerative aging, driving development and progression of all of the common age-related conditions.

The underlying causes of age-related changes in the gut microbiome are numerous, interacting, and complicated. It is yet to be determined which are the most important. Older people tend to eat a different diet and be more sedentary than younger people. They have age-damaged immune systems less capable of destroying unwanted microbes. Their gut lining is also less effective at keeping microbes out of tissues where they will cause an inflammatory reaction. All of these issues seem likely to contribute to a sizable degree, but much remains to be explained, such as the major shift in the gut microbiome that occurs in the mid-30s, long before most aspects of degenerative aging become significant.

What can be done about this problem of the aging gut microbiome? Setting aside any consideration of targeting the root causes, one blunt solution, which has done quite well in animal studies, is fecal microbiota transplantation from young individuals to older individuals. In aged killifish, this intervention restores a more youthful gut microbiome, improves health, and extends life span. The other blunt solution is less well explored, which is to deliver that same mix of youthful microbial populations in high volume as oral probiotics. This would require considerably more ingested material and a different mix of microbial populations than is presently marketed to consumers under the heading of probiotic supplements, but it seems quite plausible as a way forward.

Gerobiotics: probiotics targeting fundamental aging processes

Aging is recognized as a common risk factor for many chronic diseases and functional decline. The newly emerging field of geroscience is an interdisciplinary field that aims to understand the molecular and cellular mechanisms of aging. Several fundamental biological processes have been proposed as hallmarks of aging. The proposition of the geroscience hypothesis is that targeting holistically these highly integrated hallmarks could be an effective approach to preventing the pathogenesis of age-related diseases jointly, thereby improving the health span of most individuals.

There is a growing awareness concerning the benefits of the prophylactic use of probiotics in maintaining health and improving quality of life in the elderly population. In view of the rapid progress in geroscience research, a new emphasis on geroscience-based probiotics is in high demand, and such probiotics require extensive preclinical and clinical research to support their functional efficacy. Here we propose a new term, "gerobiotics", to define those probiotic strains and their derived postbiotics and para-probiotics that are able to beneficially attenuate the fundamental mechanisms of aging, reduce physiological aging processes, and thereby expand the health span of the host.

We provide a thorough discussion of why the coining of a new term is warranted instead of just referring to these probiotics as anti-aging probiotics or with other similar terms. In this review, we highlight the needs and importance of the new field of gerobiotics, past and currently on-going research and development in the field, biomarkers for potential targets, and recommended steps for the development of gerobiotic products. Use of gerobiotics could be a promising intervention strategy to improve health span and longevity of humans in the future.

Senescent cells accumulate with age, and this accumulation is an important cause of age-related dysfunction and disease. Clearing senescent cells from old animals produces rejuvenation, and human trials of first generation senolytic drugs capable of selectively destroying senescent cells are underway for a number of age-related conditions. Meanwhile, an ever increasing number of research groups are delving deeper into the biochemistry of cellular senescence, in search of novel differences between senescent and non-senescent cells that can be exploited in order to selectively destroy senescent cells in new and hopefully better ways. New approaches continue to be uncovered, as illustrated by the research materials noted here.

Senescent cells accumulate in organs during aging, promote tissue dysfunction, and cause numerous aging-related diseases like cancer. The cells arise through a process called "cellular senescence," a permanent cell cycle arrest resulting from multiple stresses. Researchers have identified an inhibitor of the glutamate metabolic enzyme GLS1 so that its administration selectively eliminates senescent cells in vivo. They confirmed that the GLS1 inhibitor eliminated senescent cells from various organs and tissues in aged mice, ameliorating age-associated tissue dysfunction and the symptoms of obese diabetes, arteriosclerosis, and NASH.

The research team has developed a new method for producing purified senescent cells to search for genes essential for senescent cells' survival. This new method activates the p53 gene in the G2 phase, which can efficiently induce cellular senescence. They used purified senescent cells to search for genes essential for senescent cells' survival, then identified GLS1, which is involved in glutamine metabolism, as a potential candidate gene.

When they examined the effect of GLS1 inhibition on the mortality of senescent cells, senescent cells were more sensitive to GLS1 inhibition due to damage to the lysosomal membrane and decreased intracellular pH. The organelles called lysosomes play an essential role in the regulation of intracellular pH. The team analyzed the dynamics of lysosomes and found the vital fact that damage to the lysosomal membranes in senescent cells lowers intracellular pH. When they administered GLS1 inhibitors to aged mice, senescent cells in various tissues and organs were removed, and the aging phenomenon was significantly improved.

Link: https://www.ims.u-tokyo.ac.jp/imsut/en/about/press/page_00031.html

Epigenetic clocks measure changes in epigenetic marks on the genome that correlate with age. Greater epigenetic change at a given chronological age indicates a greater burden of biological aging, more damage and dysfunction. It remains to be determined with any great rigor as to exactly which damage and dysfunction causes any given set of epigenetic changes, which makes it challenging to use epigenetic age as a measure of success in the development of rejuvenation therapies. Development continues apace, however. For example, researchers here show that second generation epigenetic clocks show a greater correlation with risk of cancer than is the case for first generation clocks.

DNA methylation is one of the key mechanisms thought to underlie the association between aging and cancer. Biological aging measures derived from blood DNA methylation - taking advantage of varying rates of aging-associated methylation changes between individuals - have gained considerable popularity as tools to better understand and predict disease. We previously investigated the association between 5 "first-generation" measures of epigenetic aging and the risk of 7 cancer types using data from the Melbourne Collaborative Cohort Study (MCCS). The observed associations were relatively weak compared with those obtained for all-cause mortality; cancer risk overall was increased by 4%-9% per 5-year increase in methylation "age acceleration," although these estimates varied by cancer type.

Two novel methylation-based measures of biological aging, called PhenoAge and GrimAge, have been developed based on associations of DNA methylation with, for PhenoAge, age, mortality, and clinical biomarkers; and for GrimAge, smoking pack-years and plasma concentrations of adrenomedullin, beta-2 microglobulin, cystatin C, growth differentiation factor 15, leptin, plasminogen activation inhibitor 1, and tissue inhibitor metalloproteinase 1. These new measures have proved to be more strongly associated with mortality than the first-generation measures. This study assessed cancer risk associations for 3 recently developed methylation-based biomarkers of aging: PhenoAge, GrimAge, and predicted telomere length.

We observed relatively strong associations of age-adjusted PhenoAge with risk of colorectal, kidney, lung, mature B-cell, and urothelial cancers. Similar findings were obtained for age-adjusted GrimAge, but the association with lung cancer risk was much larger, after adjustment for smoking status, pack-years, starting age, time since quitting, and other cancer risk factors. Most associations appeared linear, larger than for the first-generation measures, and were virtually unchanged after adjustment for a large set of sociodemographic, lifestyle, and anthropometric variables.

Link: https://doi.org/10.1093/jncics/pkaa109

It is reasonable to expect that forcing the epigenetic regulation of gene expression in cells in old tissue into a pattern more like that of cells in young tissue could be beneficial. Some of these changes in gene expression are clearly entirely maladaptive and detrimental to the health and life span of the organism. All else being equal, reversing those changes, and only those changes, will in principle lead to improved health. In principle is one thing, but will the effect size be large enough in practice, however? We rarely argue over whether specific mechanisms and outcomes exist, but we frequently argue over whether the result of intervention will be large enough to care about.

The concern with resetting epigenetic regulation of gene expression to a more youthful configuration is twofold: firstly, some epigenetic change is beneficial and helps to minimize the impact of the underlying damage of aging. Secondly, rejuvenation of any specific set of gene expression patterns will usually not fix the underlying damage of aging that caused gene expression to change in the first place. That damage will remain, still producing all of the other issues and dysfunctions that it is capable of causing. Targeting the damage rather than the reactions to damage is likely a better strategy.

Cost-free lifespan extension via optimization of gene expression in adulthood aligns with the developmental theory of ageing

The force of natural selection is maximized during pre-reproductive development but declines after sexual maturation with advancing age. Therefore, mutations that have neutral or positive fitness effects early in life but negative fitness effects late in life can accumulate (mutation accumulation theory) or be selected for (antagonistic pleiotropy theory) in the population and lead to the evolution of ageing. While these ultimate population genetic theories of ageing are broadly accepted, the proximate routes that lead to ageing are still incompletely understood and subject to vigorous debate. The discovery of evolutionarily conserved molecular signalling pathways that regulate life-history traits, such as development, growth, reproduction, and lifespan showed that ageing is malleable, and sometimes can be modified by modulating the expression of a single gene that influences a large array of downstream physiological processes.

One proximate physiological account of the antagonistic pleiotropy theory, the disposability theory of ageing (DST), postulates that ageing and lifespan evolve as a result of optimized resource allocation between somatic maintenance and reproduction with the aim of maximizing reproductive output. This theory predicts that increased investment in somatic maintenance will increase survival at the cost of reduced reproduction, and vice versa, since they are assumed to compete for the same pool of resources. The predominance of this theory has been increasingly challenged in recent years. Studies in different model organisms have suggested that increased longevity and reduced reproduction can be uncoupled.

Nevertheless, researchers proposed a different mechanism underlying antagonistic pleiotropy, by suggesting that the declining force of selection with age can result in suboptimal levels of gene expression in late life. Because selection is strongest during development and declines after the onset of reproduction, selection can never fully 'optimize' age-specific gene expression resulting in ageing via the action of otherwise beneficial genes. This developmental theory of ageing (DTA) maintains that the decline in selection gradients with age results in suboptimal regulation of gene expression in adulthood, leading to cellular and organismal senescence.

There is an important distinction between these two physiological explanations of how antagonistically pleiotropic alleles work. The DST rests on the competitive allocation of resources between the body and the germline resulting in imperfect repair of cellular damage; this theory predicts that genetic and environmental manipulations that increase allocation to somatic maintenance (hence lifespan) result in reduced allocation to the immortal germline (hence reproduction). The DTA instead focuses on imperfect age-specificity of gene expression and predicts that optimizing gene expression in adulthood can improve somatic maintenance as well as the germline. Increased understanding of the evolutionarily conserved molecular pathways that control many different aspects of organismal life cycle allows direct testing of these two explanations. Since the DTA is based on the assumption that gene function affects fitness differently across the life course of the organism, perhaps the most straightforward way to test it is to modify the gene expression at different stages across the life course and assess the effects on fitness-related traits and on individual fitness.

Here we tested these predictions directly by modifying the age-specific expression of five well-described 'longevity' genes in Caenorhabditis elegans nematode worms that play key roles in different physiological processes: nutrient-sensing signalling via insulin/IGF-1 (age-1) and target-of-rapamycin (raga-1) pathways, global protein synthesis (ifg-1), global protein synthesis in somatic cells (ife-2), and mitochondrial respiration (nuo-6). Downregulation of these genes in adulthood and/or during post-reproductive period increases lifespan, while we found limited evidence for a link between impaired reproduction and extended lifespan. Our findings demonstrate that suboptimal gene expression in adulthood often contributes to reduced lifespan directly rather than through competitive resource allocation between reproduction and somatic maintenance. Therefore, age-specific optimization of gene expression in evolutionarily conserved signalling pathways that regulate organismal life histories can increase lifespan without fitness costs.

The processes of autophagy break down and recycle damaged or unwanted structures within cells. Mitophagy is the specialized form of autophagy that clears malfunctioning mitochondria. Mitochondria are the power plants of the cell, bacteria-like organelles with their own small genome. They replicate to make up their numbers, while mitophagy acts as a quality control mechanism to ensure correct function by culling worn and broken mitochondria. Unfortunately, mitophagy declines in efficiency with age, and this may explain much of the loss of mitochondrial function in cells in old tissues, because it allows increasing dysfunction in the mitochondrial population.

Mitochondria play a key role in the production of energy and balance of reactive oxygen species (ROS) within cells. Mitophagy, the selective breakdown and clearance of aberrant and dead mitochondria, is a regulatory process essential to promoting cellular health and maintaining healthy mitochondrial populations. As a person age, oxidative stress and cellular damage accumulate, and autophagic pathways can become overwhelmed. This is especially true in non-actively dividing cells such as neurons, and cortical degeneration is commonly observed in aging populations.

Alzheimer's disease (AD), a characteristic illness of aging, is associated with cognitive deficits, including loss of memory formation and increased loss of cortical mass. Furthermore, characteristic conglomerates of amyloid-β (Aβ) and fibrillary tangles of abnormally phosphorylated tau are observed within the brains of AD patients. Synaptic damage and defective mitophagy are early changes in disease progression, and aging plays a key role in synaptic damage, autophagy, and mitophagy in AD progression and pathogenesis.

In the past 20 years, the toxicity of these mechanisms has been studied extensively, and their role in neuronal death partially elucidated. The buildup of abnormal mitochondria is noted in AD neurons. More recently, studies have focused on the interaction between Aβ and tau on the components of mitophagy. Although some interactions between Aβ and tau and also Aβ and tau interactions with mitochondrial proteins and the components of mitophagy have been noted; the exact mechanisms and sequence of events leading to the genesis of AD have yet to be elucidated. Accumulation of damaged mitochondria, excessive mitochondrial fission, the buildup of ROS within cells, and compromised cellular health are all noted within neuronal populations in AD brains.

A major challenge in studies on the pathology of AD is identifying individuals with early-onset AD as the symptoms mimic what is normally expected in aging populations. Identification of the early events of AD within these populations can help elucidate the development of biomarkers and pathology in AD and outline the mechanisms by which symptoms occur. Further research could potentially develop mitophagy-based therapies to block or even reverse the adverse effects of AD.

Link: https://doi.org/10.3389/fnins.2020.612757

The SENS Research Foundation is focused on enabling progress in neglected areas of science that can be applied to the development of rejuvenation therapies. The SENS rejuvenation research program is based on periodic repair of the forms of cell and tissue damage that are known to lie at the root of aging, damage that accumulates over time and is caused by the normal operation of metabolism. Aging is damage, rejuvenation is repair. The SENS agenda singled out senescent cell clearance as a desirable course of action a decade in advance of the first animal studies that provided convincing proof, and twenty years ahead of the first human trials of senolytic drugs to clear senescent cells in old humans. There is a great track record here, not only in identifying the right research strategies, but also in enabling progress in parts of the field that were languishing.

Despite time, energy and money being poured into age-related disease research around the world, humans are yet to find cures for illnesses such as Alzheimer's, cardiovascular disease, and diabetes. SENS Research Foundation believes this is because current research is approaching the problem from the wrong angle.

Our vision is a world in which people do not decline in physical or mental health as they get older. We believe it is possible to create medicines that will restore the molecular and cellular structure and composition of the body of a middle-aged (or older) person to something like it was when they were a young adult. That amounts to repairing the damage that has accumulated in their bodies as intrinsic side-effects of the body's normal operation. We have known for decades what types of damage there are that eventually contribute to the health problems of late life; therefore, all (!) that is needed is to develop damage-repair therapies that can eliminate them. And that's what we do. The development of some of those therapies has progressed far enough that we have been able to spin the projects out as startup companies, and it's likely that most of them will be in the clinic within a couple of years.

SENS relates to all the types of damage we accumulate, and it does not take a position concerning which type of damage is more important than which other type. The right way to describe what SENS is is that it is an engineering proposal for how to manipulate nature, rather than a scientific hypothesis for how nature works in the first place. The Foundation's strategy to prevent and reverse age-related ill-health is to apply the principles of regenerative medicine to repair the damage of aging at the level where it occurs. We are developing a new kind of medicine: regenerative therapies that remove, repair, replace, or render harmless the cellular and molecular damage that has accumulated in our tissues with time. By reconstructing the structured order of the living machinery of our tissues, these rejuvenation biotechnologies will restore the normal functioning of the body's cells and essential biomolecules.

At our Research Center we have two main projects right now. One is devoted to repairing mutant mitochondria, by inserting genes into cells that will provide the proteins that the mitochondria can no longer make. The other project is exploring two new ways to eliminate senescent cells, cells that have switched into a damaging state and that the body wants to kill off but cannot. We also rent out space to one of our spin-out companies, Underdog Pharmaceuticals, which is developing a way to extract the oxidised cholesterol from arteries and thereby revert atherosclerosis (a disease of the arteries characterised by the deposition of fatty material on their inner walls). We are always reviewing our range of projects, and we may have a new project starting in a couple of months that will explore the elimination of a particular type of waste product in the brain.

Link: https://researchoutreach.org/articles/age-old-problem-sens-research-foundation-looking-age-related-disease-new-way/

In today's open access paper, researchers add to the present body of evidence for loss of capillary density to be an important mechanism of aging. All tissues are packed with capillaries, hundreds passing through every square millimeter in cross-section. This density is lost with age, and that reduces the supply of nutrients and oxygen to cells. Like the raised blood pressure of hypertension, loss of capillary density is a fair way downstream from the molecular damage that causes aging. Also like hypertension, loss of capillary density may make a large enough contribution to further tissue damage and dysfunction to be worth targeting independently of its causes.

Blood vessel formation is a complex process in which numerous populations of cells are involved. More is known about the response to injury than of the normal maintenance of capillary networks in the absence of injury, but it may be the case that the lessons of one can be applied to the other. A range of interesting research in recent years has shown that mobilizing hematopoietic cells from the bone marrow into circulation, such as via targeting CXCL12, CXCR4, and their receptors, will increase blood vessel formation following injury. A number of drugs can achieve this goal, some of which are already commonly used when collecting hematopoietic cells from donors for transplantation. It is possible that this could be the basis for a therapy that will increase blood vessel density in older individuals, but animal studies would have to be conducted first to prove the concept.

High-resolution 3D imaging uncovers organ-specific vascular control of tissue aging

The identification and regulation of signals driving the aging process are long-standing goals in physiology. Aging negatively affects organ function. The description of the tissue-level age-associated changes in the literature remains restricted to the gross structural and tissue changes such as the increase in tissue stiffness and adiposity. In this study, we implement a large-scale 3D spatial comparison of vascular cells and molecules in young and aging mouse tissues from several organs to define the major changes across both axes. This in-depth analysis of aging tissues revealed vascular attrition as a primary hallmark of aging and provides unprecedented insights into the microenvironmental tissue-level changes during aging.

Our imaging datasets reveal that the loss of vascular abundance accompanied by the decline in pericytes is a key feature of aging tissues. This is the first comprehensive study highlighting age-dependent vascular changes across several organs. Loss of vessel density and pericytes emerges as the mark of aging organs and tissues; however, highly remodeling tissues with high regeneration potential, such as the skin, gut, and uterus, preserve the abundance of the blood vessels and pericytes with aging. Similarly, vessel densities remain unaffected in aging bones, which have relatively higher regeneration potential compared to tissues such as the kidney, spleen, heart, or brain. Thus, stage and extent of vascular attrition are likely to direct the regenerative limitations of a tissue.

Further, observations described herein corroborate the findings in injury-induced organ fibrosis where pericytes differentiate into fibroblasts to drive fibrosis. Our findings also demonstrate that pericytes are a source of fibroblasts in joint inflammation and that the differentiation of pericytes to fibroblasts increases with aging. Last, endothelial cell specific genetic manipulations prove that vascular loss drives cellular changes such as senescence. Together, these findings imply that the strategies to inhibit age-dependent changes in vasculature such as the loss of vascular abundance and pericyte to fibroblast differentiation have the potential to delay or even prevent cellular dysfunction during aging.

Repair Biotechnologies is the company I founded with Bill Cherman a few years ago, to work on interesting projects in the rejuvenation biotechnology space. Time flies when one is busy. Our primary focus these days is the development of what we call the cholesterol degrading platform (CDP), a technology that does exactly what one would expect from the name. Localized excesses of cholesterol - and particularly toxic, altered forms of cholesterol - lie at the root of numerous serious medical conditions, and contribute to a lesser degree to many more.

Of those conditions atherosclerosis is the most important, given the vast numbers of people it kills, year in and year out, and given the inability of present approaches to therapy to do more than slow down its progression. Our view of this sort of challenge in medicine is to take the direct path, treat excess cholesterol as a form of damage, and repair that damage by removing the cholesterol. In an animal model of atherosclerosis, the cholesterol degrading platform achieved a 48% reversal of arterial obstruction by plaque following a single treatment.

"All of the greatest research programs start out with one scientist poking at something that he or she finds interesting. In this case it was the question of why mammalian cells do not routinely break down cholesterol, and instead make do with an intricate, fragile set of processes for shuttling cholesterol within cells and throughout the body. The presence of localized excesses of cholesterol in blood vessel walls is a lifespan-limiting circumstance that occurs to all of us, leading to atherosclerosis, then rupture or blockage of blood vessels that causes a stroke, heart attack, and death. Why then, do none of the cells involved in blood vessel tissue and the immune response to atherosclerosis actively break down cholesterol, but rather engage a Rube Goldberg apparatus of moving cholesterol around to try to solve the problem? The reason why we have atherosclerosis in the first place is that this machinery fails the moment that the tissue environment departs from a youthful, undamaged ideal. It is not robust at all. A more direct approach is needed."

The core mechanisms of CDP came into being due to the academic curiosity of a few "visionary and talented researchers"; once a way to safely break down excess cholesterol in cells was found and optimised, the Strategies for Engineered Negligible Senescence (SENS) community, who are focused on producing effective treatments for aging and age-related disease, became aware of these mechanisms and worked on implementing CDP. "The scientists presented their data at the first Undoing Aging conference, and Aubrey de Grey of the SENS Research Foundation later made an introduction to Repair Biotechnologies. The SENS philosophy - and the Repair Biotechnologies philosophy - is to reverse age-related disease by repairing the damage that causes it. Excess cholesterol is clearly a form of damage. Removing it is a form of repair. CDP strikes at a root cause of atherosclerosis, and other conditions in which excess cholesterol drives pathology. That makes it very attractive to those of us who think of aging in terms of damage and think of rejuvenation in terms of repair."

CDP is a platform technology that seeks to solve the root cause of cholesterol build-up by degrading excess, non-essential cholesterol with an entirely new, target-specific, rate-limited pathway, which the process introduces into cells. "We introduce a de novo pathway for catabolism of excess cholesterol, breaking it down into a water-soluble catabolite that leaves cells and is removed from the body fairly rapidly. Introduced into mice, the CDP pathway is safe and well-tolerated. It does not interfere with the normal cholesterol metabolism required for cellular activities. It is a very attractive basis for therapy."

Link: https://www.longevity.technology/repair-bios-novel-platform-and-exclusive-from-ceo/

Larger mammals have many more cells than smaller mammals, and cancer risk increases with cell count, all other things being equal. Between species, body size does not correlate with cancer risk, however. Since species such as elephants and whales do not suffer an enormous rate of cancer in comparison to humans, clearly there are important differences in cellular biochemistry between these species. One example is that elephants have been found to have many copies of the tumor suppressor gene p53, and here researchers explore further to show that elephants have many copies of other tumor suppressor genes as well, each of which contributes to an overall lower risk of cancer despite a large body with many cells. Looking at other large mammals, this appears to be a fairly general mechanism accompanying increased size.

There is an incredible diversity of body sizes and lifespans among living mammals, remarkably even larger mammals lived in the recent past but are now extinct. In living mammals, an individual's body size and lifespan are among the greatest predictors for the likelihood of developing cancer, taller and older humans, for example, have a greater cancer risk than shorter and younger people. Between species, however, body size and lifespan are poor predictors of cancer risk, thus big and long lived species must have evolved ways to reduce their risk of developing cancer. By understanding how big, long-lived species evolved their enhanced tumor suppression mechanisms we can improve our understanding of genes involved in human cancer and inspire new cancer treatments.

We tracked how body size and the copy number of most protein coding genes changed in elephants and their smaller bodied relatives. We found that as large bodied elephants evolved from smaller bodied ancestors, their cancer risk decreased. While genes involved in tumor suppression were commonly duplicated in elephants and their relatives, elephants have a unique repertoire of tumor suppressor genes that evolved alongside their recent increase in body size. These data show that duplication of tumor suppressor genes facilitated the evolution of large body size by compensating for increasing cancer risk.

Link: https://doi.org/10.7554/eLife.65041

There are twenty or so different proteins in the human body that can form amyloids, a misfolding of the protein that can encourage other molecules of the same protein to misfold in the same way. These misfolded proteins join together to form solid deposits - amyloids - that are associated with a complex, problematic biochemistry that disrupts cell and tissue function. Once underway in earnest, this formation of amyloids and the resulting pathology is known as amyloidosis.

Transthyretin is one of the proteins capable of forming amyloid, and transthyretin amyloidosis is found to some degree in every older individual. Most past research has focused on genetic mutations that cause severe and early transthyretin amyloidosis, but in recently years evidence has accumulated to suggest that this form of amyloid makes a meaningful contribution to the development and progression of cardiovascular disease - and a range of other age-related conditions - in all older people.

The biochemistry of transthyretin amyloid formation lends itself to disruption in a number of different ways, most of which can be applied to either mutant or normal transthyretin. A few companies have developed or are in the process of developing small molecule drugs to inhibit amyloid formation in order to allow clearance mechanisms, such as ingestion of amyloid by immune cells, to catch up. Others, such as Covalent Bioscience target the removal of amyloid without seeking to interfere in its creation; periodic treatments would keep amyloid levels low. This latter approach to producing therapies to treat age-related conditions is less well supported than I would like. There are any number of forms of metabolic waste that could be cleared to remove their impact on aging.

Modulation of the Mechanisms Driving Transthyretin Amyloidosis

Transthyretin (TTR) amyloidoses are under-recognized systemic diseases associated with TTR aggregation and extracellular deposition in tissues as amyloid. The most frequent and severe forms of the disease are hereditary and associated with amino acid substitutions in the protein due to single point mutations in the TTR gene (ATTRv amyloidosis). However, the wild type TTR (TTR wt) has an intrinsic amyloidogenic potential that, in particular altered physiologic conditions and aging, leads to TTR aggregation in people over 80 years old being responsible for the non-hereditary ATTRwt amyloidosis

The hallmark of ATTR amyloidosis is the extracellular deposition of aggregated TTR or TTR fibrils in tissues. The process of TTR aggregation and fibril formation is not completely elucidated, however biochemical and biophysical evidences indicate that the tetrameric form of TTR becomes unstable and the protein dissociates into dimers and monomers presenting a partially unfolded conformation which self-assemble into toxic non-fibrillar aggregates and, later into amyloid fibrils that accumulate as amyloid deposits throughout the body.

The mechanism by which the tetramer disassembles and aggregates into amyloid fibrils has been considered the main driver of the disease. However, TTR proteolysis, namely occurring in the cardiac tissue, as well as its modulation have been increasingly documented as fundamental for understanding the development and progression of ATTR amyloidosis.

Many therapeutic approaches have been suggested for the treatment of ATTR amyloidosis targeting different steps of the pathology. Those therapies include interventions from the synthesis of the TTR variants through liver transplant or gene silencing therapies and clearance of amyloid deposits. Additionally, several compounds have been suggested for the treatment of ATTR amyloidosis by targeting different steps of the amyloid formation. The main steps include TTR stabilization, inhibition of oligomerization, and fibril disruption.

Although some the available therapies are more efficient than others, it becomes increasingly evident that combination of different therapies may improve the therapeutic outcome. In this sense, it would be interesting to test TTR gene silencing therapies in combination with protein stabilizers or disruptors of pre-existing amyloid deposits.

It is only comparatively recently that the research community has become supportive of efforts to treat aging as a medical condition, with researchers able to publish and speak in public on the topic without risking their careers. Even so, few researchers in this more receptive environment have been willing to be clear that the goal of treating aging is to greatly extend healthy life span, not just improve health within the life span we presently enjoy. We can hope that this too will change, and extending the healthy human life span will also come to be a topic of clear public discussion by the broader scientific community.

One cannot have large increases in life span without improved health: the two are tightly linked. Aging is nothing more than accumulated cell and tissue damage, and the dysfunction caused by that damage. A damaged machine functions poorly, and it is very hard to keep a damaged machine from complete failure by any means other than repairing the damage. To treat aging, we must repair the molecular damage that causes aging. Effective repair therapies will both improve health and extend life.

The goal of geroscience is extension of lifespan by extending healthspan. Standard medical interventions can prolong lifespan without extending healthspan (e.g., using a ventilator in comatose patient) but anti-aging interventions increase lifespan by slowing aging and thus delaying age-related diseases (extending healthspan). Healthspan is a period of life without age-related diseases. However, in comparison with lifespan, healthspan is difficult to measure, especially in animals. So why has healthspan become so popular in animal studies?

The reason is that only a few drugs were shown to extend lifespan in mammals. Other drugs seemingly increase healthspan but do not extend lifespan. This is considered an acceptable and even desirable effect. But it is not. Increased healthspan must automatically increase lifespan, if healthspan represents good health. Animals, including humans, do not die from good health, they die from age-related diseases. If diseases are delayed, an animal will live longer.

Consider a scenario in which lifespan is not increased, while healthspan is increased. To keep lifespan constant, while increasing healthspan, diseases must be compressed: start later but kill faster. For example, in this scenario, cancer kills an organism in a matter of minutes, instead of months. This is impossible. So how is it possible that some senolytics, NAD boosters, and resveratrol, increase healthspan without lifespan? The simplest explanation is that they do not increase healthspan at all, because such studies use irrelevant or ambiguous markers of health. Ambiguous parameters can be associated with either good or bad health, depending on the underlying cause. For example, similar changes in insulin signaling are associated with either slow or fast aging, depending on the mTOR activity.

Even if a drug does increase lifespan in mice and other mammals, gerontologists are still skeptical that it will work in humans. Consider an example. Calorie restriction (CR) extends lifespan in mice, rats and even monkeys. CR must extend lifespan in humans because it delays all age-related diseases in humans. Still it is debated whether it would extend life in humans. Some gerontologists think that it will not. Imagine, if CR would not increase lifespan in any mammal including mice. Would we then think that it may mysteriously extend life in humans? No. But then why are drugs that do not extend life in mice still being considered for the potential to extend life in humans? Although hundreds of recent reviews proclaim a wide arsenal of "emerging" drugs that "promise" to extend healthspan and lifespan, these drugs either do not extend lifespan in mice, or data is not sufficient.

Link: https://doi.org/10.18632/oncotarget.27882

In recent years, a great deal of attention has been devoted to the role of the gut microbiome in aging, as populations shift to include fewer helpful and more harmful microbes. In particular, the ability of the gut microbiome to influence the state of chronic inflammation in aging may be at least as important as lifestyle choices such as degree of exercise. Expanding this line of thinking, researchers here look at the macrobiome, small parasitic animals that dwell in the gut, and their role in age-related inflammation.

A new review looks at the growing evidence to suggest that losing our 'old friend' helminth parasites, which used to live relatively harmlessly in our bodies, can cause ageing-associated inflammation. It raises the possibility that carefully controlled, restorative helminth treatments could prevent ageing and protect against diseases such as heart disease and dementia. "A decline in exposure to commensal microbes and gut helminths in developed countries has been linked to increased prevalence of allergic and autoimmune inflammatory disorders - the so-called 'old friends hypothesis'. A further possibility is that this loss of 'old friend' microbes and helminths increases the sterile, ageing-associated inflammation known as inflammageing."

Helminths have infected humans throughout our evolutionary history, and as a result have become master manipulators of our immune response. Humans, in turn, have evolved levels of tolerance to their presence. The loss of helminths has so far been linked to a range of inflammatory diseases, including asthma, atopic eczema, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, and diabetes. Some studies have shown that natural infection with helminths can alleviate disease symptoms, for example in multiple sclerosis and eczema, while other studies in animal models suggest that intentional infection with helminths could have benefits against disease.

The safer, and perhaps more palatable, option is the concept of using helminth-derived proteins to achieve the same therapeutic benefits. This was tested recently in mice and shown to prevent the age-related decline in gut barrier integrity usually seen with a high-calorie diet. It also had beneficial effects on fat tissue, which is known to be a major source of inflammageing. The authors speculate that if helminths have anti-inflammageing properties, you would expect to see lower rates of inflammageing-related disease in areas where helminth infection is more common. There is some evidence to support this. "In the wake of successes during the last century in eliminating the evil of helminths, the time now seems right to further explore their possible benefits, particularly for our ageing population - strange as this may sound."

Link: https://elifesciences.org/for-the-press/8119abb0/could-playing-host-to-hookworms-help-prevent-ageing

Many neurodegenerative conditions are characterized by the aggregation of altered proteins, such amyloid-β, α-synuclein, tau, and others. Once altered they can form solid deposits with a halo of surrounding biochemistry that is toxic and disruptive to the normal function of cells in the brain. Why do these protein aggregates only become significant in later life? There is some pace at which they are created, and some pace at which they are cleared by various mechanisms. For example, amyloid-β is an antimicrobial peptide, a component of the innate immune system. More will be created in the brains of people suffering persistent viral infections, which may explain the much-debated link between herpesviruses and risk of Alzheimer's disease.

On the clearance side of the house, the immune cells of the brain are in part responsible for cleaning up protein aggregates. As the environment becomes more inflammatory, and other issues in aging impair immune function more generally, these cells falter in the task of removing aggregates. Of late, researchers have also directed their attention towards the physical clearance of aggregates from the brain via drainage of cerebrospinal fluid. The hypothesis on which Leucadia Therapeutics was founded is that Alzheimer's starts in the olfactory bulb because it is primarily drained through the cribriform plate, a path that is slowly closed off by ossification in later life. The glymphatic system provides drainage from the rest of the brain, and its function declines with age as well. To what degree can neurodegenerative conditions be postponed or reversed by restoring drainage, and thus a more youthful pace of removal of aggregates? The fastest way to answer that question is to try it and see.

Achieving brain clearance and preventing neurodegenerative diseases - A glymphatic perspective

Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common neurodegenerative diseases. Currently, no cure is available although epidemiological studies suggest that the risk of developing neurodegenerative diseases can be modulated by lifestyle-related factors, suggesting that some cases could be prevented. The toxic accumulation, misfolding, or mis-localisation of proteins leading to neuronal loss, i.e. proteinopathies, are key pathological features of age-related neurodegenerative diseases.

Breakdown or removal of the proteins which are susceptible to form toxic aggregates is essential to prevent development of pathology. Many of these proteins, such as AD associated amyloid-β and tau and PD associated α-synuclein, are found in the cerebrospinal fluid (CSF). This raised the question of the significance of CSF for clearing toxic metabolites from the brain, and in 2012, the glial-lymphatic ("glymphatic") system, that describes a mechanism for brain clearance via a perivascular (also referred to as paravascular) CSF flow pathway was characterised. Indeed, the glymphatic system plays a role in clearance of amyloid-β, tau, and α-synuclein.

The glymphatic brain clearance mechanism relies on interchange of CSF and interstitial fluid (ISF) that allows waste to be transferred to the CSF and transported out of the brain. The system was named the glia-lymphatic or "glymphatic" system upon its discovery in 2012 as astrocyte end feet are a main structural component of the fluid exchange pathway. CSF is predominantly produced in the choroid plexus in the 3rd and lateral ventricles, and it is circulated from the ventricles to the subarachnoid space surrounding the brain primarily by arterial pulsations. The subarachnoid space is continuous with the periarterial spaces of the pial vessels, from which the CSF enters the brain parenchyma, where it facilitates the clearance of solutes, although the efflux routes are less described.

The interchange of CSF and ISF is dependent on aquaporin 4 (AQP4) water channels on astrocyte endfeet that enwrap the cerebral vasculature. Changes in AQP4 expression or polarisation - referring to the differential distribution of AQP4 in the endfeet versus rest of the cell - are associated with disturbances in glymphatic function. In line with the observation that the glymphatic system can clear amyloid-β, decreased glymphatic function caused by deletion of the Aqp4 gene in an animal model of Alzheimer's disease leads to increased accumulation of amyloid-β and tau. Abnormalities in AQP4 polarisation are also seen in Alzheimer's patients, which provides some evidence that glymphatic function might also play a role in Alzheimer's disease in humans.

Researchers here build a signature of aging based on age-related changes in the proteins found in blood samples, and then show that centenarians appear to undergo these changes more slowly than people who die at younger ages. One would expect to see that a population of exceptionally old people achieved a long life by aging more slowly than their peers: aging is, after all, defined as an increase in the risk of mortality over time due to intrinsic causes. The question is how one can measure differences in the pace of aging more efficiently than by waiting for years to observe outcomes in mortality.

The development of measurements of biological age that can be carried out fairly quickly given a blood or tissue sample, such as epigenetic clocks, is an important topic in aging research. A simple, reliable biomarker of aging could greatly accelerate the assessment of potential rejuvenation therapies, allowing researchers to discard less useful paths and focus on those with better outcomes.

Using samples from the New England Centenarian Study (NECS), we sought to characterize the serum proteome of 77 centenarians, 82 centenarians' offspring, and 65 age-matched controls of the offspring (mean ages: 105, 80, and 79 years). We identified 1312 proteins that significantly differ between centenarians and their offspring and controls, and two different protein signatures that predict longer survival in centenarians and in younger people. By comparing the centenarian signature with two independent proteomic studies of aging, we replicated the association of 484 proteins of aging and we identified two serum protein signatures that are specific of extreme old age.

The data suggest that centenarians acquire similar aging signatures as seen in younger cohorts that have short survival periods, suggesting that they do not escape normal aging markers, but rather acquire them much later than usual. For example, centenarian signatures are significantly enriched for senescence-associated secretory phenotypes, consistent with those seen with younger aged individuals, and from this finding, we provide a new list of serum proteins that can be used to measure cellular senescence.

Protein co-expression network analysis suggests that a small number of biological drivers may regulate aging and extreme longevity, and that changes in gene regulation may be important to reach extreme old age. This centenarian study thus provides additional signatures that can be used to measure aging and provides specific circulating biomarkers of healthy aging and longevity, suggesting potential mechanisms that could help prolong health and support longevity.

Link: https://doi.org/10.1111/acel.13290

Senescent cells are created constantly, but only begin to linger and accumulate in tissues in later life, as the pace of creation accelerates and the mechanisms of clearance decline in effectiveness. A senescent cell secretes a mix of moleculers that spurs chronic inflammation and disrupts the processes of tissue maintenance and function. They contribute directly to numerous age-related conditions, including forms of retinal degeneration, as noted here. The most direct approach to therapy is probably the best: periodic destruction of senescent cells, delivering senolytic therapies that force these cells into apoptosis or steer the immune system to destroy them. In old mice, senolytic treatments produce robust and significant rejuvenation, including reduced chronic inflammation, and reversal of many age-related conditions.

Age-related macular degeneration (AMD), a degenerative disease in the central macula area of the neuroretina and the supporting retinal pigment epithelium, is the most common cause of vision loss in the elderly. Although advances have been made, treatment to prevent the progressive degeneration is lacking. Besides the association of innate immune pathway genes with AMD susceptibility, environmental stress- and cellular senescence-induced alterations in pathways such as metabolic functions and inflammatory responses are also implicated in the pathophysiology of AMD.

Cellular senescence is an adaptive cell process in response to noxious stimuli in both mitotic and postmitotic cells, activated by tumor suppressor proteins and prosecuted via an inflammatory secretome. In addition to physiological roles in embryogenesis and tissue regeneration, cellular senescence is augmented with age and contributes to a variety of age-related chronic conditions. Accumulation of senescent cells accompanied by an impairment in the immune-mediated elimination mechanisms results in increased frequency of senescent cells, termed "chronic" senescence.

Age-associated senescent cells exhibit abnormal metabolism, increased generation of reactive oxygen species, and a heightened senescence-associated secretory phenotype that nurture a proinflammatory milieu detrimental to neighboring cells. Senescent changes in various retinal and choroidal tissue cells including the retinal pigment epithelium, microglia, neurons, and endothelial cells, contemporaneous with systemic immune aging in both innate and adaptive cells, have emerged as important contributors to the onset and development of AMD. The repertoire of senotherapeutic strategies such as senolytics, senomorphics, cell cycle regulation, and restoring cell homeostasis targeted both at tissue and systemic levels is expanding with the potential to treat a spectrum of age-related diseases, including AMD.

Link: https://doi.org/10.1186/s12974-021-02088-0

In today's open access paper, the authors review the evidence for the practice of calorie restriction to reduce blood pressure and cardiovascular disease risk in human subjects. The raised blood pressure of hypertension occurs with age, the result of molecular damage such as cross-linking of blood vessel tissue that impairs elasticity and inflammatory signaling that impairs smooth muscle function. As blood vessels stiffen, the feedback mechanisms governing blood pressure run awry. Lifestyle choices such as lack of exercise and weight gain are also influential on blood pressure.

Hypertension is a major mechanism of aging. It causes increased pressure damage to tissues throughout the body, such as through rupture of small blood vessels, accelerates the progression of atherosclerosis, and pushes cardiac tissue into harmful remodeling that leads to heart failure.

Several human studies of calorie restriction have been conducted since the turn of the century, including those under the CALERIE program. The practice of calorie restriction reliably improves long term health in later life, improving metrics such as blood pressure to a degree comparable to or greater than most drug treatments are capable of achieving. Only with the advent of senolytic treatments to clear senescent cells in aged tissues, and other rejuvenation therapies that will follow, will medical technology begin to provide greater reliable benefits when intervening in the aging process.

Effects of Caloric Restriction Diet on Arterial Hypertension and Endothelial Dysfunction

The calorie restriction diet (CRD) innovative approach consists of a chronic reduction in daily caloric intake of about 25-30% compared to the normal caloric intake, without any exclusion of food groups. Although this regimen is not standardized, numerous studies show its effectiveness. The mechanism of action by which caloric restriction prolongs the life span is not fully understood yet. Recent studies have shown that CRD can determine repair of damaged DNA and decrease fat mass, systolic blood pressure (SBP) and diastolic blood pressure (DBP) values, and the production of free radicals. The results obtained from the CRD can occur quickly, but they can mitigate in case of its suspension.

The CRD would seem to exert a beneficial effect against arterial hypertension (AH) and for this reason represents a useful tool for its clinical management. An important study conducted in this regard was the CALERIE (Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy). The CALERIE study was a randomized controlled trial with a two-year follow up. This study was divided in two phases: CALERIE-1 and CALERIE-2. CALERIE-1 study was performed to assess the possible effects induced by a reduction of 10-30% of caloric intake on body composition parameters and lipid profile after 6 and 12 months in a population of middle-aged non-obese subjects. CALERIE-1 results showed an improvement in lipid and glycemic profile and a reduction in body weight (BW) and fat mass.

CALERIE-2 was the largest multi-center study on CRD. A total of 220 subjects were enrolled randomly with a 2:1 allocation into two subgroups: 145 in the CRD group and 75 in the ad libitum group. The CRD group followed 25% caloric restriction for two-years. After two years of diet treatment, cardiometabolic risk factors such as low-density lipoprotein cholesterol (LDL-c), total cholesterol / high-density lipoprotein cholesterol (HDL-c) ratio, SBP and DBP decreased. Moreover, serum biomarkers such as C-reactive protein, insulin sensitivity index and metabolic syndrome score were reduced. Moreover, BW was significantly lower in the CRD group when compared to the ad libitum group (average weight loss in CRD group was 7.5 kg vs average BW increase of 0.1 kg in ad libitum group).

This data showed that a period of two-years of CRD was able to decrease cardiometabolic risk factors in middle-aged non-obese subjects. For this reason, it is possible to consider CRD as nutritional therapeutic approach to enhance life expectancy and reduce the onset of chronic non-communicable diseases such as diabetes mellitus, cancer, chronic kidney disease, and AH, among others.

Other studies have been conducted to investigate the role of CRD in the control of AH. In particular, a study performed on caloric restriction (25%), with two years follow-up, evaluated the possible reduction of CV risk factors and insulin resistance in non-obese subjects and whether the results obtained were maintained over time or were limited to the period study. The authors showed a significant weight loss associated to a decrease in SBP and DBP and an improvement in other parameters, such as lipid profile and insulin resistance. These improvements, with the exception of insulin sensitivity, appeared to be maintained over time.

Alzheimer's disease, like many age-related conditions, has a strong inflammatory component. Short-term inflammation is a necessary part of the immune response to pathogens and injury. When it goes unresolved, however and is sustained for the long term, it is highly disruptive of cell and tissue function. Aged tissues are characterized by damage and the presence of senescent cells, both of which provoke the immune system into a state of constant inflammatory activation. Researchers here analyze data from older individuals to show that while everyone has a progression towards ever greater chronic inflammation, Alzheimer's disease patients are further along in this process than their healthier peers.

In the present study, we measured 73 inflammatory proteins in both cerebrospinal fluid (CSF) and plasma in a large clinical cohort in order to investigate inflammatory pathway changes in Alzheimer's disease (AD). Our finding that both CSF and plasma proteins were highly predictive of age in amyloid-β negative, cognitively unimpaired individuals (Aβ- CU) individuals adds to the established evidence that the innate immune system changes even during healthy aging. From this basis, we showed that the AD continuum is characterized by accelerated biological aging of the innate immune system such that mild cognitive impairment (MCI) and AD patients have inflammatory proteomes which are akin to healthy individuals who are significantly older. This finding is in line with similar biological aging studies of AD carried out using structural brain imaging (i.e. brain age), for example.

Importantly, the abnormal inflammatory aging we observed in the AD continuum is differentially expressed across specific inflammatory pathways and can even differ depending on whether proteins are measured in CSF or plasma. For instance, our results showing that plasma-based inflammatory aging was elevated in AD patients compared to amyloid-β negative (Aβ-) MCI patients suggest that cross-sectional inflammatory levels as measured in plasma may be more AD-specific at a given point in time compared to those measured in CSF. Since CSF-based inflammatory aging correlated strongly with core AD biomarkers and predicted chronological age better than plasma in the main Aβ- CU group, CSF inflammatory proteins likely track more closely with those brain-based inflammatory changes which occur during normal aging.

Link: https://doi.org/10.1038/s41598-021-81705-7

Proprionate is generated by gut microbes, and is generally thought to be beneficial, acting to improve measures of health. Thus it has been lumped in with butyrate and a few other metabolites as beneficial outputs of the gut microbe that decline with age as the microbial populations shift. Researchers here instead discuss the possibility that excessive manufacture of proprionate by the aged gut microbiome can contribute to neurodegeneration. All compounds have a dose response curve, and too much can be just as bad as too little. This commentary on proprionate is an interesting viewpoint: one of the challenges in Alzheimer's research is to explain why only some people exhibit the condition. Perhaps the specific composition and metabolite production of the aged gut microbiome, highly varied between individuals, is an important factor.

The enzymes needed to digest most dietary fibers are lacking in the human body. Therefore, the microbiota in the intestine is tasked with fermenting dietary fibers. Fermentation results in the production of short-chain fatty acids (SCFAs), which serve several important functions. In the gut, they aid in microbial growth. They are also second messengers that can modulate gene expression and initiate the synthesis of gut peptides and hormones.

One of the major SCFAs is propionate. In addition to fermentation, two other sources of propionate are food and the oral microbiome. In 1984, the Food and Drug Administration (FDA) labeled propionate as generally recognized as safe (GRAS) and approved its use for food preservation. Therefore, most persons are exposed to dietary sources of propionate every day. As for the oral microbiome, oral microbiota can produce propionate. Increased propionate levels are associated with gingivitis and periodontal disease.

Propionate serves important roles in the human body. However, our review of the current literature suggests that under certain conditions, excess levels of propionate may play a role in Alzheimer's disease (AD). The cause of the excessive levels of propionate may be related to the Bacteroidetes phylum, which are the primary producers of propionate in the human gut. Studies have shown that the relative abundance of the Bacteroidetes phylum is significantly increased in older adults. Other studies have shown that levels of the Bacteroidetes phylum are increased in persons with AD.

There is evidence for such a wide array of different mechanisms that excess propionate likely leads to AD by way of a combination of multiple different mechanisms. Probably the most well-studied mechanism of propionate induced neurotoxicity is related to its ability to impair the urea cycle, the principal pathway for nitrogen metabolism. This condition, known as hyperammonemia, occurs in propionic acidemia (PA), an autosomal recessive genetic disease characterized by an abnormal accumulation of propionic acid. The clinical manifestations of chronic, slightly elevated blood ammonia levels have received relatively little research interest within the field of dementia research. However, considering the well-known neurotoxic nature of ammonia, it is reasonable to speculate that chronically elevated levels of ammonia might be associated with the development of AD.

Link: https://doi.org/10.3389/fnagi.2020.580001

Past research into aging was characterized by a driving philosophy of "look but don't touch". Intervention in the aging process was presented as exclusively the domain of fraud, lies, and marketing, exemplified by the activities of anti-aging marketplace, all hope and non-functional potions. To treat aging was an aspiration that every scientist was strongly encouraged to avoid by those who controlled the research agenda and its funding. This was the case from at least the 1970s until comparatively recently. Only in the past decade or so has the scientific community come around to accept the treatment of aging as a possible, plausible, desirable goal.

That change in attitude was sweeping and comprehensive. Now there is an increased level of funding for the study of mechanisms of aging, and the primary arguments held in public are are over how best to achieve a lengthening of the healthy human life spans. The first rejuvenation therapies have started the lengthy and expensive process of making their way out of the laboratory and into the clinic. Others will follow in the years ahead. These are the early years in an era of rejuvenation, in which the healthy human life span will leap upward as a result of treatments that address the molecular damage that drives aging.

Research: A new era for research into aging

Every major cause of death and disability in the developed world shares a greatest risk factor, and it is probably not what most people would think. Smoking, obesity, a sedentary lifestyle, and drinking too much alcohol all contribute to disease: however, their contributions are small in comparison to the physiological changes that result from aging. Whether biological aging causes the many functional declines that occur with age, or just permits them, is perhaps open for debate, but there is no question that, for most of us, biological aging determines how and when we and our loved ones will get sick and die.

This connection between aging and disease has become particularly consequential during the COVID-19 pandemic, with the vast majority of severe cases and deaths occurring among the elderly. Given this obvious relationship, it is somewhat surprising how slowly the biomedical research community has come to appreciate the importance of biological aging in many of the disease processes under study.

Today, unfortunately, too many scientists study individual diseases without recognizing the impact of aging biology. It is still common, for example, to see research studies in cancer, neuroscience, metabolism, and other fields where young animal models (such as 4-6 month old mice) are used to study disease processes that almost exclusively occur in old people. 'Mice are not people' is a standard refrain when explaining why so many preclinical therapies fail in human trials. Perhaps the mouse isn't the problem. Failing to account for the physiological changes that occur during aging, both in mice and in people, may be a much bigger reason why so much preclinical research fails to translate to the clinic.

Thinking about certain conserved molecular mechanisms as 'hallmarks' or 'pillars' of aging has benefited researchers within the field, and has also allowed scientists outside the field to begin to recognize how aging biology impacts on their own research. Another important advance in aging research has been the development of a concept called geroscience: researchers in this area seek to understand mechanistically how the hallmarks of aging cause age-related disease and functional decline. The growth of the geroscience concept also reflects a recognition that aging research is much closer to clinical application than it was twenty years ago. Numerous interventions have been developed that target one or more of the hallmarks of aging in order to delay, or even reverse, age-related functional declines.

The future of aging research is brighter than ever before, and the pace of discovery is only increasing. We look forward to major breakthroughs over the next few years that will revolutionize the way we think about aging biology and have the potential to significantly impact human healthspan and longevity.

There is a growing interest in the treatment of aging as a medical condition, targeting mechanisms that cause aging or that are involved in the pathologies of aging. In the research community this manifests as increased funding, a greater output of potential therapies, more conferences, and more high level reviews of the state of the field, such as the paper noted here. An uptick in reviews in any part of the life siences might be taken as a sign that a field is attracting new participants. On the one hand more researchers want to learn about the state of the science because they are hearing more discussion of the field in their communities, while on the other hand more researchers recently learned enough as a result of participation to consider writing a review for the next set of newcomers.

Aging is a physiological process mediated by numerous biological and genetic pathways, which are directly linked to lifespan and are a driving force for all age-related diseases. Human life expectancy has greatly increased in the past few decades, but this has not been accompanied by a similar increase in their healthspan. At present, research on aging biology has focused on elucidating the biochemical and genetic pathways that contribute to aging over time. Several aging mechanisms have been identified, primarily including genomic instability, telomere shortening, and cellular senescence.

Aging is a driving factor of various age-related diseases, including neurodegenerative diseases, cardiovascular diseases, cancer, immune system disorders, and musculoskeletal disorders. Efforts to find drugs that improve the healthspan by targeting the pathogenesis of aging have now become a hot topic in this field. In the present review, the status of aging research and the development of potential drugs for aging-related diseases, such as metformin, rapamycin, resveratrol, senolytics, as well as caloric restriction, are summarized. The feasibility, side effects, and future potential of these treatments are also discussed, which will provide a basis to develop novel anti-aging therapeutics for improving the healthspan and preventing aging-related diseases.

Link: https://doi.org/10.1007/s10522-021-09910-5

While much of the longevity industry is based in the US, there are a fair number of companies elsewhere in the world, working on approaches that target the mechanisms of aging in order to better treat age-related conditions or improve health in later life. The article here notes some of the European biotech startups in the industry. The main body of commentary on the industry in this article suffers from much the same issues as most popular science coverage of research into the treatment of aging as a medical condition, in that the author makes no attempt to distinguish between parts of the field that cannot possible do much good (near anything involving supplements, definitely anything involving consumer focused digital health) versus parts of the field that have the potential to produce real rejuvenation in the old (such as senolytic drugs).

The Dutch company Cleara Biotech is developing senescence biomarkers for diagnostics and drug targeting. In 2018 it raised a seed round from Apollo Health. Senisca was spun out of Exeter University in 2020 and is dedicated to the development of new approaches to reverse cellular senescence. Senolytic Therapeutics is a Barcelona-based biotech startup founded in 2017 developing novel medicines that target senescent cells. Life Length is a Spanish company founded in 2010 and has developed a technology for measuring telomere length.

Tree Frog Therapeutics is a French stem cell company that develops C-stem, a platform to accelerate the making of self-replicating cells which can form to grow any part of the human body. The UK-US company Juvenescence is creating a network for longevity companies, scientists as well as AI specialists. It has so far invested in approximately 15 startups. The hopes to IPO in the coming year. Eternans is a UK-based biotech startup, founded in 2017, and is developing senolytic agents to selectively kill senescent cells.

Samsara Therapeutics has developed a screening platform that identifies new molecules that extend healthy lifespan across species, and is funded by Apollo Ventures. The Swiss company Rejuveron is a biotech platform company, that together with entrepreneurial scientists, develops and improves therapies and technologies in this space. The UK-US startup Humanity monitors your rate of ageing and helps users understand which actions will slow down the individual's rate of ageing.

Tracked.bio is a Danish biotechnology company that develops fully automated phenotyping and identification systems for model organisms with the use of deep learning. The systems help effectively evaluate the efficacy of ageing interventions. Age Labs is a Norwegian molecular diagnostics company that discovers, develops and commercialises diagnostic tests for the early detection of age-related diseases. The Swiss startup Centaura, founded in 2019, aims to prevent and reverse ageing by using machine learning to analyse the DNA setup in order to develop an ageing profile.

Link: https://sifted.eu/articles/european-longevity-startups/

The role of persistent infection in the development of Alzheimer's disease is much debated these days, particularly now that the amyloid cascade hypothesis is under attack, following the continued failure of trials for therapies that clear amyloid-β. The biggest challenge in understanding Alzheimer's disease is the question of why only some people develop the condition, even given very similar lifestyle choices relating to weight, exercise, and other well-known influences on health. If the burden of persistent infection is an important contributing factor, it would very conveniently explain this otherwise puzzling outcome.

Herpesviruses and other persistent pathogens are hypothesized to contribute to the development of Alzheimer's via (a) greater chronic inflammation, and (b) greater generation of amyloid-β in its role as a part of the innate immune system response. The mechanisms make sense, but the data for herpesviruses in particular is contradictory, indicating that while herpesvirus infection may contribute to Alzheimer's disease, it likely isn't the major cause. Perhaps other persistent infections are also important. Or perhaps Alzheimer's is in fact a collection of distinct conditions with quite different roots that converge on the same situation of amyloid-β and inflammation in the brain.

New Data Questions Herpes-Alzheimer's Connection

The virus-Alzheimer's tug of war continues. New data across several studies weaken the proposed, and much-debated, association; its proponents are holding fast. A new epidemiology study reports a weak link between herpes and dementia. Researchers combed through four European population-wide healthcare databases and describe equivocal data. In Denmark and Wales, short-term antiviral drug use came with slightly fewer future dementia cases. Alas, in Germany and Scotland, this association did not hold. The opposite was also true; infected people who were not prescribed an antiviral had a slightly higher risk of dementia - but only in the German cohort. "The results are not very encouraging. Some of these associations held no matter what type of dementia or virus was considered. Because neither dementia subtype nor herpes subtype modified the association, the small but significant decrease in dementia incidence with antiherpetic administration may reflect confounding and misclassification."

Twenty-five years ago, researchers linked herpes simplex virus type 1 (HSV-1) infection with an increased risk of Alzheimer's disease (AD). She later spotted the virus hiding in amyloid plaques in brain tissue, and postulated that it may trigger the deposits. Since then, other connections have emerged. Scientists linked viral DNA in the brain to expression changes of genes involved in amyloid metabolism; others proposed that amyloid acts as an antimicrobial peptide.

Still, compelling evidence that viruses, particularly herpesviruses, cause AD remains elusive, although some researchers believe that the teeny irritants could speed disease along. The debate has taken on a new sense of urgency since reports that COVID-19 causes long-term neurological symptoms in a fraction of people who contract the disease. Scientists are just beginning to study this aspect of the infection. "Heterogeneous results are not terribly surprising given the complex nature of AD etiology and pathogenesis, which, so far, does not exclude an infectious component."

The growth of interest in targeting mechanisms of aging has led to the development of a variety of approaches to automating nematode life span studies, some of which are already available as commercial services. Researchers use the nematode species C. elegans in screening studies, searching for compounds that have effects on life span, or that interact with specific aging mechanisms of interest. Running ten thousand compounds through ten thousand dishes of nematode worms is a daunting prospect if it has to be carried out manually, and automation allows a great deal more screening to be accomplished for a given cost.

Despite being an extremely simple animal, C. elegans has differentiated organs such as nerves, skeletal muscles, and a digestive tract, and many mammalian animal-related genes are conserved. It is very useful for cutting-edge research in fields like genetics and molecular biology. However, while lifespan analysis of this nematode provides a great deal of useful information, previous lifespan studies had many limitations including 1) sensitivity to various stimuli at room temperature, 2) a long experimental time required for daily measurements, 3) a lack of objectivity due to a tendency for results to be dependent on experimental technique, and 4) the small number of samples that can be processed at one time making it unsuitable for simultaneous measurement of many samples.

The researchers attempted to resolve these issues by developing a new healthy lifespan assessment system that maintained the advantages provided by nematodes. They focused on determining the optimal conditions in a live cell imaging system for automatically measuring nematode survival, such as counting the number of nematodes in a sample, incubation temperature, medium thickness, feeding conditions, imaging interval, and survival determination method. This became C. elegans Lifespan Auto-monitoring System (C-LAS), a fully automated lifespan measurement system that can non-invasively measure a large number of samples (currently up to 36 samples). C-LAS uses overlapping images of nematodes to identify those that are moving, meaning they are alive, and those that are not moving, meaning they are dead.

The researchers performed a mini-population analysis of nematode healthy lifespan using a combination of C-HAS and statistical analysis on common nematodes with the same genetic background. They found that about 28% of the population had average lifespans, about 30% had long and healthy lifespans, about 35% had healthy lifespans but died prematurely, and about 7% had a long period of frailty. They also found that activating - either genetically - or through administration of the drug metformin - AMP-activated protein kinase (AMPK), which is closely associated with healthy life expectancy, dramatically increased the population with healthy longevity and reduced the population with long periods of frailty. Metformin is thought to increase healthy life expectancy in humans, and the present study supports this idea. Currently, clinical trials are underway to ascertain its association with healthy longevity.

Link: https://ewww.kumamoto-u.ac.jp/en/news/429/

Reprogramming cells from old tissues into induced pluripotent stem cells has the effect of reversing many of the epigenetic changes that are characteristic of age, thus restoring mitochondrial function and other aspect of cell behavior. This is a limited rejuvenation: it can't do much about DNA damage, and nor can it make cells clear persistent molecular waste that even youthful cells struggle with. Nonetheless, applying reprogramming to living mice has produced benefits to health, suggesting that if the process can be sufficiently controlled, then it may be a useful basis for therapy - perhaps globally forcing cells to behave more as though they are in young tissues. Groups such as Turn.bio are investigating the use of partial and transient reprogramming, in search of a balance point at which cells are rejuvenated without losing their cell type or radically changing their behavior. Here, another groups reports on early results from their analogous efforts to develop a methodology of safe transient reprogramming.

Ageing is the gradual decline in organismal fitness that occurs over time leading to tissue dysfunction and disease. At the cellular level, ageing is associated with reduced function, altered gene expression and a perturbed epigenome. Somatic cell reprogramming, the process of converting somatic cells to induced pluripotent stem cells (iPSCs), can reverse these age-associated changes. However, during iPSC reprogramming somatic cell identity is lost, and can be difficult to reacquire as re-differentiated iPSCs often resemble foetal rather than mature adult cells. Recent work has demonstrated that the epigenome is already rejuvenated by the maturation phase of reprogramming, which suggests full iPSC reprogramming is not required to reverse ageing of somatic cells.

Here we have developed the first "maturation phase transient reprogramming" (MPTR) method, where reprogramming factors are expressed until this rejuvenation point followed by withdrawal of their induction. Using dermal fibroblasts from middle age donors, we found that cells reacquire their fibroblast identity following MPTR, possibly as a result of persisting epigenetic memory at enhancers. Excitingly, our method substantially rejuvenated multiple cellular attributes including the transcriptome, which was rejuvenated by around 30 years as measured by a novel transcriptome clock. The epigenome, including H3K9me3 histone methylation levels and the DNA methylation ageing clock, was rejuvenated to a similar extent.

The magnitude of rejuvenation instigated by MTPR is substantially greater than that achieved in previous transient reprogramming protocols. MPTR fibroblasts produced youthful levels of collagen proteins, suggesting functional rejuvenation. Overall, our work demonstrates that it is possible to separate rejuvenation from pluripotency reprogramming, which should facilitate the discovery of novel anti-ageing genes and therapies.

Link: https://doi.org/10.1101/2021.01.15.426786

Mitochondria are the power plants of the cell, producing chemical energy store molecules to power cellular processes. They are also embedded deeply into may core functions of the cell, from replication to programmed cell death. Mitochondrial function declines throughout the body with age, for reasons that are likely downstream of other more fundamental damage. Mitochondrial dynamics change in ways that make mitochondria more resilient to removal via mitophagy when worn or broken, and mitophagy itself loses efficiency. This may or may not be connected to mitochondrial DNA damage. It is unclear as to whether the progressive accumulation of mutations in mitochondrial DNA has a broad effect on function in most cells, or only results in a small number of highly dysfunctional cells.

Regardless, is it possible to effectively address mitochondrial dysfunction by delivering new mitochondria in large volumes into the body? It is clearly the case that cells ingest whole mitochondria and put them to work when given the opportunity. This option hasn't been aggressively pursued to date by the core rejuvenation biotechnology community, as it seems likely that it could only have a short term benefit. One can argue that functional mitochondrial placed into a dysfunctional environment will soon go the way of their predecessors, and for the same reasons: altered dynamics and diminished mitophagy. Similarly cells overtaken by dramatically broken mitochondria are overtaken because those mitochondria have a replication advantage over their functional peers. In both cases we suspect that transplanted mitochondria wouldn't last in their pristine state.

Now, however, a number of groups are working on practical approaches to mitochondrial transplantation, including today's example, focused initially on applications in medicine in which short term benefits are sufficient. It will be interesting to see how these efforts progress. If it is possible to restore mitochondrial function broadly in the body for at least months, that may prove to be worth the effort in the context of aging. There are other interesting questions to answer along the way, as well. For example, what happens when you replace a large fraction of native mitochondria with mitochondria that contain a different mitochondrial DNA haplogroup? Possibly nothing bad. Perhaps one can swap out any mammal's mitochondrial genome for a better, more efficient, more resilient, artificially augmented mitochondrial genome without any downside - a worthy long-term goal if it is straightforwardly attained. But we just don't know in certainty.

Harvard spin-off Cellvie Inc closes $5M seed round

Cellvie was founded in the US in 2018 and is headquartered close to Zürich, Switzerland. The founders pioneered the approach of mitochondria augmentation and replacement and the team has now set out to leverage the therapeutic potential of mitochondria for a new treatment modality in ischemia-reperfusion injury, aging and beyond. Mitochondria play a crucial role in the aging process, activating factors and metabolic pathways involved in longevity. Their dysfunction impacts on both lifespan and healthspan. "But treating mitochondria has proven to be an arduous challenge. That is why we turned to introducing healthy, viable mitochondria into cells where these organelles are impaired. To great effect. We can sustainably reinvigorate cells' failing energy metabolism."

The potential of therapeutic mitochondrial transfer was recently demonstrated in a clinical investigation at Boston Children's Hospital; paediatric patients on heart-lung-support after suffering a cardiogenic shock received the treatment to revitalise their heart muscle. 80% of these children experienced myocardial recovery, which compares with an expected 29%. "The investment will enable us to pursue the platform broadly, including a first application in aging, where the need for mitochondria-recovery is particularly dear."

To date, Cellvie has focused primarily on ischemia-reperfusion injury (IRI), which manifests itself whenever the blood flow to a part of the body is interrupted and subsequently reintroduced. Well-known medical conditions causing IRI include heart attacks, strokes, and organ transplantation. Cellvie is also pursuing an indication in organ transplantation, for which the FDA awarded orphan drug designation in 2020. The capital injection will be employed for preparing for market, expanding Cellvie's product pipeline and to prepare an IND submission for a clinical study in kidney transplantation.

Upregulation of MOTS-c improves mitochondrial function and has other less well explored influences on stress responses in cells. This might be considered a form of exercise mimetic therapy, given that MOTS-c upregulation is one of the outcomes of exercise. The result of artificial upregulation of MOTS-c in mice is improved health, greater exercise capacity, and extended life span. We should probably not expect life span effects produced by this sort of intervention to translate well to longer-lived mammals, given what we know of the effects of calorie restriction, exercise, and similar interventions that upregulate stress response mechanisms. Benefits to health are certainly plausible, however.

The study looked at the role of MOTS-c, one of several recently identified hormones known to mimic the effects of exercise. However, MOTS-c is unique because it is encoded in the small genome of mitochondria rather than the larger genome in a cell's nucleus. The research team tested how injections of MOTS-c affected mice of different ages by measuring physical capacity and performance in young (2 months), middle-aged (12 months), and old (22 months) mice. When the mice were presented with physical challenges - including maintaining balance on a rotating rod and running on an accelerating treadmill - mice of all ages who had received MOTS-c treatment fared significantly better than untreated mice of the same age.

Even groups of mice that had been fed a high-fat diet showed marked physical improvement after MOTS-c treatment and less weight gain than untreated mice. These findings echo previous research on MOTS-c treatment in mice, which also found that it reversed diet-induced obesity and diet- and age-dependent insulin resistance. Additionally, treating the oldest mice nearing the end of their lives with MOTS-c resulted in marked physical improvements. This late-life treatment improved grip strength, gait (measured by stride length) and physical performance, which was assessed with a walking test (running was not possible at this age)."The older mice were the human equivalent of 65 and above and once treated, they doubled their running capacity on the treadmill. They were even able to outrun their middle-aged, untreated cohorts."

To measure the effects of exercise on MOTS-c levels in people, the researchers collected skeletal muscle tissue and plasma from sedentary, healthy young male volunteers who exercised on a stationary bicycle. Samples were collected before, during and after the exercise as well as following a 4-hour rest. In muscle cells, levels of MOTS-c significantly increased nearly 12-fold after exercise and remained partially elevated after a four-hour rest, while MOTS-c levels in blood plasma also increased by approximately 50% during and after exercise and then returned to baseline after the rest period. The findings suggest that the exercise itself induced the expression of the mitochondrial-encoded regulatory peptides.

Link: https://gero.usc.edu/2021/01/20/exercise-protein-running-capacity-mice-mots-c/

The INDY gene has been known to affect longevity in a range of species for quite some time, as I noted at length back in 2015. It is more than 20 years now since INDY was first discovered to affect fly aging, and work continues to link the outcomes on life span to specific effects on aging and cell function. INDY has effects on metabolism that look a lot like those connected to calorie restriction. A such, it tends to improve every aspect of aging, making it challenging to sort out what is cause, what is consequence, what is important, and what is a side-effect. The research noted here is a representative example of incremental progress in understanding the effects of INDY on aging. I doubt this to be a path that leads to any practical outcome for human health and longevity.

Researchers have presented data showing that the longevity gene mammalian Indy (mINDY) is involved in blood pressure regulation. Reduced expression of mINDY, which is known to extend life span in lower organisms and to prevent from diet induced obesity, fatty liver, and insulin resistance in mice, has now been shown to lower blood pressure and heart rate in rodents.

The authors provided mechanistic insights for the underlying physiological mechanism based on in vivo data in a genetic knock out model as well as microarray and in vitro studies. Furthermore, the hypothesis is supported by confirming critical effects in vitro using a small molecule inhibitor of mINDY. The authors conclude that deletion of mIndy recapitulates beneficial cardiovascular and metabolic responses to caloric restriction, making it an attractive therapeutic target.

mIndy deletion attenuates sympathoadrenal support of blood pressure and reduced arterial blood pressure and heart rate in a murine knockout model. Blood pressure was assessed invasively using intra-arterial pressure probes over several days. Urinary analysis for catecholamines and metanephrines as well as unbiased transcriptomic analysis of adrenal glands identified the affected biosynthetic pathways. Indeed, catecholamine biosynthesis was attenuated in mINDY-knockout adrenals, whereas plasma steroids and steroid hormone synthesis were unaffected.

In vitro studies on an adrenal cell line supported this hypothesis. mIndy codes for a carboxylic acid transporter protein expressed in plasma membrane. Citrate, the main substrate of the mINDY transporter, increased catecholamine content, while pharmacological inhibition of mINDY by a small molecule inhibitor blunted the effect.

Link: https://www.eurekalert.org/pub_releases/2021-01/dzfd-tlg012621.php

Amyloids are misfolded proteins that can cause other molecules of the same protein to misfold in the same way, linking together into solid deposits that are disruptive to normal cell and tissue function. There are only a score or so of different types of amyloid in the human body, and most are conclusively linked to at least one age-related condition. In today's open access research materials, the scientists involved report on the involvement of amyloid-β (and potentially other amyloids) in muscle aging, connecting loss of mitochondrial function with the growing presence of amyloids.

In order to test the direction of causation in this relationship, the researchers first boosted mitochondrial function in old animals by increasing NAD+ levels. NAD+ is essential to mitochondrial function, but declines with age for a variety of reasons. The proximate causes are fairly well mapped, meaning a loss of efficiency in NAD synthesis and NAD recycling pathways, but connections to the underlying causes of aging remain to be discovered. In this study, improved mitochondrial function reduced the burden of amyloid in muscle tissue. Separately, the researchers also removed amyloid from tissues in a targeted way, and found that this improved mitochondrial function. Thus the relationship appears bidirectional. Amyloid degrades mitochondrial function, while forcing an improvement in mitochondrial function gives cells a greater ability to clear amyloid.

NAD+ can restore age-related muscle deterioration

The older we grow, the weaker our muscles get, riddling old age with frailty and physical disability. Researchers have now looked at the issue through a different angle: the similarities between muscle aging and degenerative muscle diseases. In the study, the scientists identify amyloid-like protein aggregates in aged muscles from different species, from the nematode C. elegans all the way to humans. In addition, they also found that these aggregates also impair mitochondrial function. Although aggregated proteins have been suggested to contribute to brain aging, this is the first time that they have been shown to contribute to muscle aging and to directly damage mitochondria.

But can the formation of the protein aggregates be reversed? To answer this, the researchers fed worms the vitamin nicotinamide riboside and the antitumor agent Olaparib, both of which boost the levels of nicotinamide adenine dinucleotide (NAD+), a biomolecule that is essential for maintaining mitochondrial function, and whose levels decline during aging. In the worms, the two compounds turned on the defense systems of the mitochondria, even when provided at advanced age. Turning on the so-called "mitochondrial quality control system" of mitophagy reduced the age-related amyloid protein aggregates and improved the worms' fitness and lifespan.

The scientists then moved on to human muscle tissue taken from aged subjects. Turning on the same mitochondrial quality control systems produced similar improvements in protein and mitochondrial homeostasis. The encouraging results led the researchers to test nicotinamide riboside in aged mice. The treatment also activated the mitochondrial defense systems and reduced the number and size of amyloid aggregates in different skeletal muscle tissues.

NAD+ boosting reduces age-associated amyloidosis and restores mitochondrial homeostasis in muscle

Due to the fact that mitochondrial function and proteostasis are essential to ensure cellular homeostasis, are functionally interconnected, and decline in aging, it is not surprising that mitochondrial dysfunction and abnormal proteostasis are involved in chronic age-associated neuromuscular proteinopathies, such as Alzheimer's disease (AD), and inclusion body myositis (IBM), a debilitating age-associated muscle disease. Although affecting different organs, AD and IBM are both protein aggregation diseases characterized by the accumulation of amyloid protein deposits. IBM is the most common muscle proteinopathy affecting the elderly; however, it is generally considered a rare disorder, with its overall prevalence still under debate. Skeletal muscle decay instead is one of the most prominent features of aging, characterized by loss of muscle mass and function and by a decline in mitochondrial function. In addition, muscle aging is also typified by dysfunctional proteostasis pathways, including altered ubiquitin-proteasome system (UPS) activity and defective autophagy. Currently, the mechanism underlying the collapse of proteostasis in the aging muscle is not fully elucidated, and it is furthermore unclear whether amyloid deposition, a hallmark of IBM, is also at play in the aging muscle.

Here, we report that, during natural aging, muscle tissues accumulate amyloid-like deposits, a process which is evolutionary conserved in C. elegans, in mouse and human muscle cells and tissues, with molecular features recapitulating some aspects of IBM. Moreover, we also discovered the reversible nature of these deposits, which can be reduced by interventions aimed at restoring mitochondrial homeostasis, such as by enhancing nicotinamide adenine dinucleotide (NAD+) metabolism, even at the onset of aging. Importantly, we show that reduction of the accumulation of amyloid-like deposits in aging is sufficient to improve muscle mitochondrial homeostasis.

Epigenetic marks are constantly added to and removed from CpG sites on the genome, controlling gene expression and thus cell behavior. The pattern of epigenetic marks in any given cell shifts in response to environment and circumstances, and some of those changes are characteristic of the presence of the underlying molecular damage of aging. Epigenetic clocks can thus be constructed from weighted combinations of epigenetic mark status at various CpG sites in order to measure biological age. Existing epigenetic clocks are specific to a given species, but here researchers process an enormous amount of data from many species to produce epigenetic clocks that are universal to all placental mammals. If this result holds up well in further testing, then such universal clocks could help to speed up the development of therapies that target the mechanisms of aging.

Aging is often perceived as a degenerative process caused by random accrual of cellular damage over time. In spite of this, age can be accurately estimated by epigenetic clocks based on DNA methylation profiles from almost any tissue of the body. Since such pan-tissue epigenetic clocks have been successfully developed for several different species, it is difficult to ignore the likelihood that a defined and shared mechanism instead underlies the aging process.

To address this, we generated 10,000 methylation arrays, each profiling up to 37,000 cytosines in highly-conserved stretches of DNA, from over 59 tissue-types derived from 128 mammalian species. From these, we identified and characterized specific cytosines, whose methylation levels change with age across mammalian species. Genes associated with these cytosines are greatly enriched in mammalian developmental processes and implicated in age-associated diseases.

From the methylation profiles of these age-related cytosines, we successfully constructed three highly accurate universal mammalian clocks for eutherians, and one universal clock for marsupials. The universal clocks for eutherians are similarly accurate for estimating ages of any mammalian species and tissue with a single mathematical formula. Collectively, these new observations support the notion that aging is indeed evolutionarily conserved and coupled to developmental processes across all mammalian species - a notion that was long-debated without the benefit of this new and compelling evidence.

Link: https://doi.org/10.1101/2021.01.18.426733

Chronic inflammation and activation of microglia in the brain may contribute to the depression that can accompany neurodegenerative conditions, as well as other diseases that feature persistently raised inflammation. Researchers here provide supporting evidence for that hypothesis. Microglia are innate immune cells of the central nervous system, and increased inflammatory behavior and senescence in this cell population is implicated in age-related neurodegeneration. Clearing senescent microglia can reduce inflammation and reverse tau pathology in animal models of tauopathies, for example.

Research has shown that microglial cells are activated in several neurological diseases, such as Alzheimer's disease, Parkinson's disease, and stroke. People who are affected by these conditions also often fall into a negative mood. Other previous research has suggested that inflammatory processes also play a role in the development of depression. This led the researchers behind the new study to examine more closely whether microglial cells are involved in regulating mood during inflammation. "The study showed that animals feel sick and uneasy when we activate the microglial cells. We demonstrate that two signal molecules, interleukin-6 and prostaglandin E2, are particularly important in these processes. It's not surprising that these signal substances are central, but we were a bit surprised that it is the microglial cells that release these molecules."

During inflammation, many processes are initiated in several cell types. One of the challenges in determining the role played by a specific cell type in the body, therefore, is to isolate its effects. In this study, the scientists used a technique known as chemogenetics, which enabled them to switch on the activity specifically in microglial cells in mice. The researchers activated the microglial cells when the mice were being kept in a certain type of surroundings. The mice subsequently avoided this type of surroundings, which the researchers interpret as showing that the animals disliked the experience. The mice also became less interested in a sweet solution, which they normally find very tempting.

In order to investigate whether the microglial cells are an important link between the immune system and mood, the researchers investigated what happened when microglial cells are inhibited. When the microglial cells were not available for activation, the mice did not feel poorly, even when they had inflammation. This reinforces the idea that these cells are necessary for the process. If further research demonstrates that the biological mechanism described in the study functions in the same way in humans, it may be possible in the long run to reduce symptoms of depression by inhibiting this mechanism.

Link: https://liu.se/en/news-item/hjarnans-immuncell-ligger-bakom-nedstamdhet-vid-inflammation-