Fight Aging! Newsletter, March 11th 2019

Thank you ladies and gentlemen for listening at this relatively late hour in the conference. I'm absolutely delighted to be here. I'm a non-scientist, so when I do something new, which is what I'm doing in longevity at the moment with my partners, I like to write a book about the subject, so that I can organize my thoughts and get access to key opinion leaders. A year and a half or so ago, I wrote a book called Juvenesence, which is also the name of our recently formed company, and I traveled around the United States, 8,000 miles in an old Honda, which I kept in San Francisco.

The Honda has now been sold, sadly, but the information that I garnered was extraordinary, and I'm really pleased for the first time in my career - and it has been quite a long career - to have found something where I am actually able to, in a very small way, move the dial as opposed to just jump on a bandwagon, as I've done before. I started off as a fund manager, and then I got into mining, German property, and, latterly, biotech. I've been involved in the biotech business for twelve years, and what is amazing to me is that in just those short twelve years, there has been an enormous change in biotech - particularly in the last six or seven years.

So the first book I wrote on this subject was called Cracking the Code. It is available in the remainder bins of some bookshops around the world. Still available, low price. Then the second book I wrote is Juvenescence, which I mentioned earlier on. In that time frame, six or seven years, we've heard the dawn of artificial intelligence, you've heard about In Silico Medicine as an example, for the discovery of novel compounds. That didn't exist six years ago. We've had the cure for hepatitis C in the last six years. This was a terrible scourge, and now if you've got 80,000, you can be cured, and many people have been cured of it. The Gilead drug was the best selling drug in the world for a while, selling at its peak 20 billion a year. We've had cancer immunotherapy that did not exist just six years ago, and this year it is going to breach all expectations. Sales of cancer immunotherapies, which have had biblical results in some cancers, will be over 100 billion. That was just an idea six years ago. Of course everyone is familiar with CRISPR/Cas9, Cas12 and Cas13, and so forth, and its variants, and that did not exist, even in published papers, six years ago when I wrote the book Cracking the Code.

In those six years, so much has happened. New industries have been created. What is going to happen in the next six years? Well, the answer is that none of us really know. In our own company Juvenescence, which is the fourth company my partners and I have started in the biotech space in the last decade or so, we don't really know, and so we're trying to put together a load of subsidiaries that cover most of the ground of this area. Because, for sure, out of eighteen projects, which is what we have, surely something will work and produce returns for our investors, and most importantly benefit patients, and lead us all to live a healthier and longer life, which is the aspiration of most people on the planet.

It was mentioned that life expectancy has increased dramatically over the last century or so. It has stalled a bit in the United States and the UK, and that is because the environmental factors that led to the improvement in life expectancy, including such things as antibiotics and vaccinations, have run their course. Things like opioid addiction are now taking a toll on life expectancy in countries such as the United States and the UK. But it is a fact that nothing has changed biologically in the last century: you take someone out of 1900 and put them in today's environment, they will live just as long as we do. Nothing has changed in our fundamental biology. But today we're on the cusp of a major change. The biological engineering of humans, the rearrangement of our atoms and molecules to effect longer lives is with us. There are human trials going on at the moment, this is not science fiction, and one of our own products will be in humans in the first quarter of next year. We have very high hopes for that. So I say with confidence, that I believe that life expectancy at birth will reach 115 within 20 or 30 years. That will change the entire trajectory of our lives. We'll no longer just be born, learn, earn, retire, and expire. There will be a whole fundamental change to our lives, with Peter Diamandis in his various books has described admirably.

We all known of Jeanne Calment, was she a fraud or not? In my opinion she did live to 122. People can live very long lives, we're not destined to die, but there are various factors that lead to the aging process. Some people have geroprotective genes, such as Jeanne Calment, and those genes will eventually be inculcated into the broader population, and those genes - using gene editing - will be the thing that keep people alive to 115 and beyond. But for the moment, it is small molecules, stem cells, and organ regeneration that we're focusing on.

We know now that aging is largely caused by antagonistic pleiotropy and hyperfunctioning. Genes that work well in our early days work against us as we get older. That is now a converging theory, and it is very important one, and we also know that there are some creatures out there that display negligible senescence, that really don't die except from predation. We are similarly made from atoms and molecules, and when rearranged, in due course, our pattern of death will be a very different one. However, we need to stay on the bridge. We need to stay healthy, because in the next ten years there will be phenomenal stuff that will keep us alive longer, and in a healther condition, and that is a statement of the obvious. Don't smoke, floss your teeth, eat some chocolate, drink some red wine, but not in vast quantities, and exercise in moderation. The astonishing breakthroughs, the terminologies that some of you are familiar with, such as NAD+, p53, autophagy, mTOR, and so forth, will come to the fore as science accelerates and develops as rapidly as it is today.

But we are still in the primitive phase of this. We are still very early in the science, and hence the opportunity for investors such as myself, Peter Diamandis, and other collaborative colleagues in this industry. There are some things out there that we can do now. I don't recommend hooking yourself up to a young person along the Ambrosia lines. Elevian are doing great work in seeing what factors in young blood could be applied to older people. I also don't recommend caloric restriction: it might add 5% to your life span if you starve yourself, if you eat 25% fewer calories, but it will feel like a very, very, very long life. Mimetics of caloric restriction are being developed, such as by ourselves in conjunction with the Buck Institute, and they will be in wide dispersal in the relatively near future. Then of course there are things like Elysium's Basis, there is metformin, for which a trial is going on at the moment under FDA auspices and Nir Barzilai. Then there is rapamycin, which is now being applied in dogs with some stunning effects, and rapalogs will be in human beings. My own Jack Russell terrier, Horatio, who is twelve years old, is now on the rapamycin, and I can tell you he is running around like a young puppy. So if it works for him, I'll taking it myself in the relatively near future.

Coming soon, we have senolytic drugs. Many of you may be familiar with senescent cells, these cells that are somewhere between healthy functioning and apoptosis. They cause a large burden of inflammation in human beings. Unity Biotechnology has a senolytic drug in human trials at the moment. There are other people developing senolytic trials including ourselves, via our company FoxBio in conjunction with Ichor Therapeutics in New York. Senolytic drugs are going to be, in my opinion, the front line of aging technology in the relatively near future, and will be in wide dispersal within the next three to five years for specific indications, and beyond that for longevity purposes.

I think there are about twenty senolytic companies out there, of which about five are serious ones. We own 50% of something called FoxBio, and we are further back from Unity Biotechnology, but we think we've got a better compound, we just don't know. We've invested 10 million in that so far. As we grow older we develop more senescent cells, as I said earlier, and that is because the body puts these cells into a state of arrest, probably to stop cancer. The removal of those senescent cells in animals seems to reverse the process of aging, not just just halt or slow. The mouse photograph I'm showing has been very useful in our fundraising efforts. On the right hand side you see the same mouse, this is a mouse that is about equivalent to 95 years old in a human. It is treated with a senolytic drug to remove these senescent cells, which account for less than 1% of the cell population, but account for almost all the inflammation. So osteoporosis, osteoarthritis, frailty, lack of balance, all that sort of stuff. This mouse treated with this senolytic drug goes from being 95 back to being middle aged. So it is an actual reversal of aging.

Whether it works in humans or not, we don't know, but it is in human trials for osteoarthritis and also for age-related macular degeneration. We're not sure what indication we'll go for, but I'm very optimistic about this. This is a small molecule, this is our specialization in the companies that we've formed so far. I think that this is going to be a very, very large selling product category in the drug field in the relatively near future.

So there are lots of things going on. You are familiar, this audience, with Samumed, which I visited last year in San Diego. I think it is a fabulous company. That is an indication of how much money is coming in to the space. They have raised 685 million and a 12 billion rumored pre-money valuation. The FOXO family is being interfered with, so our company FoxBio is an indication of that. Then of course you've got stem cells. We have our own company AgeX Therapeutics, which is now public here in the United States, we own about half of that company. I think stem cells are going to be the second major factor in the armatorium of fighting aging. Then down the pipe there is gene therapy, which undoubtably will be the way in which some of us will live to over 115 and beyond.

My partners and I have done several biotech companies, the most recent one is listed on the New York Stock Exchange. It is called Biohaven, and we started it four years ago. It has an approvable drug for migraine. Chairman Declan Doogan was formally the head of R&D at Pfizer, and latterly the CEO of Amarin, which was a huge success as some of you will know, with a drug for heart health. So we have a great seasoned team, and we have a personal motivation, because we are all of a certain age, to accelerate this process. So the aging acceleration of course includes artificial intelligence, which is one of Peter Diamandis' specializations, and we, Juvenescence, are the largest outside investor in In Silico Medicine, which has been mentioned a couple of times here today. This is a very exciting thing.

In the last few minutes I wanted to talk about Lygenesis. This is the first company that will be in humans, in the first quarter of next year. One year away - it is not very far. It will be in sick patients, so we can see immediately in a phase 2 trial whether it works or not. The idea is to take a cadaver liver, donated by someone, probably someone who fell off a motorbike, unfortunately, and divide it into 75 pieces. Those 75 pieces are implanted into 75 patients, and put it into a lymph node, and hope that the liver fully vascularizes and works and takes over from the patient's failing liver. There are plenty of people in the work who have failing livers. It costs 700,000 for a liver transplant here in the United States. It takes fifteen hours, and has a high mortality rate associated with it. Lygenesis has a twenty minute outpatient procedure, and it will cost less than 100,000 to do. It expands the number of potential liver transplants, and there are seven million people in the US and Europe who have failing livers to the point at which it is going to kill them.

Now it hasn't been done in patients yet, but the FDA has accepted that this will be in patients in the first quarter of next year. In animal models, that is dogs, pigs, and mice, 450 plus trials have been done, and there has been a 100% success rate, which is absolutely remarkable in the context of scientific research. So I'm super excited about this company, which we own half of, because very importantly, this could be done not just in the liver, it could also be done for the thymus. The thymus is where your T cells are grown or matured, so your T cells come out of the thymus. As you get older the thymus involutes to nothing, it becomes very small, and that is why very old people have impaired immune systems. This could be a way of restoring immune systems in human beings.

We are at the dawn of the internet equivalent in this industry. As I said earlier, it is primitive, but it is accelerating, largely as a result of the efforts of people such as Peter Diamandis and other proselytizers, and you will remember, vaguely, in the 1980s and the 1990s, the geeky Bill Gates and others of this world, and none us thought that they would be as successful as they have been. We're at that stage in the longevity industry at the moment. Markets develop very quickly; I mentioned cancer immunotherapy taking over in cancer therapy as a gold standard, while biologics were nothing in 1995 and now are a third of all drug sales around the world. So this could be the same for longevity products. Of course, people are willing to spend money to gain extra years of healthy life. Eventually this will be available to everyone, even if at the beginning it will be available only at an expensive level, for the people who have money. But therapies come off patent, and will be widely available to everyone around the world. That is why I say with confidence that we are going to live a much longer life, and in good health.

The last thing I wanted to say is that if you take a stadium like this, and you dribble 1ml of water into it, and then you double that amount every minute, then it will take just 40 minutes for the whole stadium to be covered by 10cm of water. If you then wait for another four minutes, you will fill the entire stadium. This is equivalent to this science; at moment it is not widely known, it is only very nascent, it is in its early days. We are so lucky to be the first cohort on the planet to experience this science, but it is going to hit us very hard in the face if we are not prepared for it, because everything in the world is going to change as a result of changes due to biologically engineered life expectancy. It is going to happen very fast.

No-one, if I ask them, really knows how long it is going to take for the stadium to fill. Most people would say five days or ten days. It actually only takes 44 minutes, because you are doubling all the time, and this is where we are at in the science of longevity. At the moment longevity drugs and products are all snake oil, and sell about 140 billion around the world on an annual basis. None of them work. Imagine how big this market will be when the products start to work - and they are starting to work, they are in human trials, and I am super excited to be part of this.

Samsara Therapeutics, Inc. ("Samsara,") a platform biotechnology startup engaged in the discovery and development of compounds that address the primary molecular causes of aging, announced today the closing of a seed financing round. The financing was led by Apollo Ventures, a life sciences venture capital firm and company builder working across Europe and North America. Additionally Nature Communications published a peer-reviewed paper, "The flavonoid 4,4′-dimethoxychalcone promotes autophagy-dependent longevity across species" authored by Samsara's scientific team. The paper demonstrates the capability of the Samsara platform to identify novel geroprotective small molecules that extend healthy lifespan across species and which are protective in mammalian models of disease.

The particular molecule (4,4'-dimethoxychalcone) is a natural product derived from the Japanese longevity herb known as Ashitaba. Samsara Therapeutics is conducting medicinal chemistry optimization of this compound and other Samsara platform-identified compounds in collaboration with Evotec. "This paper moves us closer to our goal of conducting the largest-ever exploration of the chemical space around natural products that extend healthy lifespan. Virtually all of the known geroprotectors have been natural products or derived thereof, and were identified via phenotypic screening. The time is ripe for this comprehensive approach due to methodological advances in phenotypic screening, target ID, and molecular mechanism of action analysis."

Ageing constitutes the most important risk factor for all major chronic ailments, including malignant, cardiovascular and neurodegenerative diseases. However, behavioural and pharmacological interventions with feasible potential to promote health upon ageing remain rare. Here we report the identification of the flavonoid 4,4′-dimethoxychalcone (DMC) as a natural compound with anti-ageing properties. External DMC administration extends the lifespan of yeast, worms and flies, decelerates senescence of human cell cultures, and protects mice from prolonged myocardial ischaemia. Concomitantly, DMC induces autophagy, which is essential for its cytoprotective effects from yeast to mice.

This pro-autophagic response induces a conserved systemic change in metabolism, operates independently of TORC1 signalling and depends on specific GATA transcription factors. Notably, we identify DMC in the plant Angelica keiskei koidzumi, to which longevity- and health-promoting effects are ascribed in Asian traditional medicine. In summary, we have identified and mechanistically characterised the conserved longevity-promoting effects of a natural anti-ageing drug.

The impact of advanced glycation end-products (AGEs) on chronic kidney disease (CKD), especially through binding to their main receptor RAGE (receptor for AGEs), has received significant research attention. The AGEs form a heterogeneous group of molecules resulting from permanent binding of reducing sugars to a range of amino-compounds. Their endogenous formation occurs under various conditions such as hyperglycemia and oxidative stress, but also aging. Their presence is moreover clearly identified in foods: daily intake of Nɛ-carboxymethyllysine (CML, the most studied AGE) can be as high as 252 µg/kg body weight in a typical European diet.

Evidence has recently accumulated incriminating the endogenous AGE/RAGE axis in age-related diseases. RAGE is a multiligand, transmembrane receptor activating major pro-inflammatory and pro-oxidative signaling pathways. Its expression in numerous cell types increases with aging and pathological conditions such as diabetes, but a role for this receptor has been postulated in the premature dysfunction of several organs, even in the absence of diabetes. The impact of chronic exposure to dietary AGEs on aging remains poorly studied, however.

Considering the preferential accumulation of CML in the kidneys under a CML-enriched diet and studies linking dietary AGEs and kidney damage, we hypothesized that kidneys are target organs for accelerated aging induced by AGE/RAGE interactions. In order to study this question, histologic markers of renal aging were analyzed in 2-month-old male wild-type (WT) and RAGE knockout mice fed a control or a CML-enriched diet over 18 months.

Compared to controls, we observed higher CML levels in the kidneys of both CML WT and CML RAGE knockout mice, with a predominantly tubular localization. The CML-rich diet had no significant impact on the studied renal parameters, whereby only a trend to worsening glomerular sclerosis was detected. Irrespective of diet, RAGE knockout mice were significantly protected against nephrosclerosis lesions and renal senile apolipoprotein A-II (ApoA-II) amyloidosis. Compared with old WT mice, old RAGE knockout mice exhibited lower expression of inflammation markers and activation of AKT, and greater expression of Sod2 and SIRT1. Overall, nephrosclerosis lesions and senile amyloidosis were significantly reduced in RAGE knockout mice, indicating a protective effect of RAGE deletion with respect to renal aging. This could be due to reduced inflammation and oxidative stress in RAGE-/- mice, suggesting RAGE is an important receptor in so-called inflammaging.

Aging is characterized as a time-dependent deterioration in the physiological integrity of living organisms. This functional decline has become incredibly relevant in the modern era, where advances in medicine have allowed humans to live longer than ever before. In light of the economic and social impact of aging and age-associated diseases, there has been extensive research into the underlying cellular mechanisms of aging. In fact, substandard results from clinical trials aimed at ameliorating age-associated neurodegenerative diseases suggest that aging is not only a risk factor for disease, but may rather be an underlying cause. In fact, the central nervous system (CNS) undergoes numerous detrimental changes as one ages including mitochondrial dysfunction, oxidative stress, and chronic inflammation. Therefore, targeting the mechanisms of CNS aging may be therapeutically prudent.

In order to examine possible mechanisms, definition of criteria to determine hallmarks of aging is critical. A landmark report has classified nine hallmarks of aging based on three criteria: (a) the hallmark should manifest during normal aging; (b) its experimental augmentation should accelerate aging; and (c) its experimental attenuation should hamper normal aging, thus increasing healthy lifespan. These hallmarks are genomic instability, telomere attrition, epigenetic alterations, stem cell exhaustion, altered intercellular communication, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, and cellular senescence. There is an intimate relationship between these hallmarks with fluctuations to one instigating changes in another. The most notable instance of this interconnectedness is with cellular senescence, a state of irreversible growth arrest coupled with stereotyped changes in phenotype and gene expression that represent all of the other hallmarks. In fitting with the above criteria, cellular senescence increases with age, and its augmentation and reduction, respectively, accelerate or diminish aging.

As studies concerning the role of cellular senescence in age-related disorders become increasingly common, senescence in the CNS is emerging as a new research topic. Taking into consideration that many neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and other types of dementia have age as a primary risk factor; the possibility that cellular senescence of CNS cell types may be a contributing factor can no longer be overlooked. Of the CNS cells, astrocytes are potential candidates for involvement in neurological disorders given their myriad roles in the maintenance of brain homeostasis. The loss of astrocyte function or the gain of neuroinflammatory function as a result of cellular senescence could have profound implications for the aging brain and neurodegenerative disorders, and we propose the term "astrosenescence" to describe this phenotype.

Astrocytes have been shown to undergo replicative cellular senescence in vitro and can senesce prematurely in response to various stressors. In vivo, senescent astrocytes have been shown to accumulate with age and in the context of neurological disorders. The detrimental impact these cells could contribute to the tissue microenvironment suggests that astrosenescence may contribute to the pathology of age-associated neurological diseases. Within a senescent cell, there can be various disruptions to normal cellular physiology including increases in reactive oxygen species (ROS), mitochondrial dysfunction, and inflammation. Notably, these are features also associated with neurodegenerative disorders.

An alternative line of therapy for the treatment of these disorders may be the clearance of senescent cells. This concept has been demonstrated with great success in transgenic mice that express constructs capable of inducible senescent cell clearance in order to extend healthy lifespan and reduce the effects of several age-associated disorders. Most recently, this concept has successfully been tested in a mouse model of tau-dependent neurodegeneration. Mice in this study accumulate senescent astrocytes and microglia, clearance of which prevents tau deposition and degeneration of cortical and hippocampal neurons, the very first study to demonstrate a causal link between glial senescence and neurodegeneration. In humans a similar effect might be conceivable using a new class of drugs known as senolytics. The previous study of tau-dependent neurodegeneration also demonstrated therapeutic potential with senolytic treatment, suggesting that senolytics to clear senescent astrocytes could be beneficial to age-associated neurogenerative diseases.

Centenarians are considered the best human model to study biological determinants of longevity having reached the very extremes of the human lifespan. Several studies compared circulating insulin and IGF-1 levels in centenarians with those of younger controls. Metabolic age-dependent remodeling is a physiological process occurring in the whole population. Aging is frequently associated with a decline in glucose tolerance secondary to an increased insulin resistance, but an exception occurs in long-lived people. Researchers found that insulin resistance increased with aging and declined in subjects older than 90 years. Indeed, long-lived subjects showed a higher insulin sensitivity and a better preservation of beta-cell function than younger subjects.

Data on the IGF-1 system in relation to longevity are still controversial in long-lived subjects. One team described an increased plasma IGF-1/IGFBP-3 ratio in healthy centenarians compared to elderly subjects. They hypothesized that this elevated ratio was indicative of a higher IGF-1 bioavailability which contributed to the improved insulin action in centenarians. In contrast, others reported that subjects with at least an A allele of the IGF-1 receptor gene had low levels of free plasma IGF-1 and were more represented among long-lived people.

These conflicting results probably reflect the complexity of the IGF-1 system and ethnic differences in enrolled populations. In addition, centenarians have often been compared to a control group of younger subjects. Therefore, in most of these studies it was not possible to conclude if IGF-1 differences between both groups were related to a different lifespan or reflected a physiological age-dependent IGF-1 decline.

While it is well known that enhanced insulin sensitivity and low insulin levels are associated with an improved survival, there is evidence showing that attenuation of the growth hormone/IGF-1 axis may have beneficial effects in extending lifespan in humans. However, it is still unknown which are the optimal IGF-1 levels during life to live longer and healthier. In addition, IGF-1 receptor sensitivity and activation of the post-receptor pathway were not evaluated in the majority of the study enrolling long-lived subjects. Therefore, it is not possible to define the real activation status of the IGF-1 receptor signaling through the mere dosage of circulating IGF-1 levels. This renders more difficult the identification of pharmacological or environmental strategies targeting this system for extending lifespan and promoting healthy aging.

Nonetheless, striking similarities have been described concerning the endocrine profile between centenarians and subjects after a calorie-restricted diet. The endocrine and metabolic adaptation observed in both models may be a physiological strategy to increase life span through a slower cell growing/metabolism, a slower loss of physiologic reserve capacity, a shift of cellular metabolism from cell proliferation to repair activities and a decrease in accumulation of senescent cells. These mechanisms seem to be, at least in part, mediated through the modulation of the growth hormone/IGF-1/insulin system.

Bats live very long and host numerous viruses that are extremely harmful when they infect humans and other animals. Researchers wanted to find out how bats can harbour so many of these pathogens without suffering from diseases. The key, they found, is in the bat's ability to limit inflammation. Bats do not react to infection with the typical inflammatory response that often leads to pathological damage. In humans, while the inflammatory response helps fight infection when properly controlled, it has also been shown to contribute to the damage caused by infectious diseases, as well as to aging and age-related diseases when it goes into overdrive.

The researchers found that the inflammation sensor that normally triggers the body's response to fight off stress and infection, a protein called NLRP3, barely reacts in bats compared to humans and mice, even in the presence of high viral loads. The researchers compared the responses of immune cells from bats, mice and humans to three different RNA viruses - influenza A virus, MERS coronavirus, and Melaka virus. The inflammation mediated by NLRP3 was significantly reduced in bats compared to mice and humans.

Digging further, they found that 'transcriptional priming', a key step in the process to make NLRP3 proteins, was reduced in bats compared with mice and humans. They also found unique variants of NLRP3 only present in bats that render the proteins less active in bats than in other species. These variations were observed in two very distinct species of bats - Pteropus alecto, a large fruit bat known as the Black Flying Fox, and Myotis davadii, a tiny vesper bat from China - indicating that they have been genetically conserved through evolution. Further analysis comparing 10 bat and 17 non-bat mammalian NLRP3 gene sequences confirmed that these adaptations appear to be bat-specific. What this implies is that rather than having a better ability to fight infection, bats have a much higher tolerance for it. The dampening of the inflammatory response actually enables them to survive.

The concept of frailty is well established. Many clinicians diagnose it and know that it may negatively impact on a patient's clinical condition. However, it is often diagnosed in a subjective 'end of the bed' test rather than by using specific diagnostic criteria, despite being recognised as a factor influencing outcomes in geriatric research for many years. Frailty is a state in which a vulnerable individual, has a diminished physiological capacity to respond to external stress such as infection or trauma.

There are many instruments used to measure frailty, with variation in their composition. Development of these tools, and frailty research generally, have historically focused on older populations, but the recent publication finding the existence of frailty and its' negative impact on outcomes in younger adults (aged over 40 years) admitted as a surgical emergency suggests that frailty is not a diagnosis exclusive to older adults. The exact prevalence of frailty is currently unknown, recent studies have reported this between 8% and as high as 37%, but any estimate is a combination of heterogeneous subgroups and shows variation depending on the tool used to detect frailty.

This study aimed to evaluate the prevalence of frailty its associated risk of mortality, readmission rate and length of hospital stay in all adults, regardless of age, admitted as a surgical emergency. To evaluate the impact of frailty across the full range of the frailty spectrum the 7-point Clinical Frailty Scale was used and the outcome measures assessed for each incremental point increase. The cohort included 2,279 patients (median age 54 years; 56% female). Frailty was documented in patients of all ages: 1% in the under 40s to 45% of those aged 80+. We found that each incremental step of worsening frailty was associated with an 80% increase in mortality at Day 90, supporting a linear dose-response relationship. In addition, the most frail patients were increasingly likely to stay in hospital longer, be readmitted within 30 days, and die within 30 days.

A pioneering clinical trials program that delivered an experimental treatment directly to the brain offers hope that it may be possible to restore the cells damaged in Parkinson's disease. Six patients took part in the initial pilot study to assess the safety of the treatment approach. A further 35 individuals then participated in the nine-month double blind trial, in which half were randomly assigned to receive monthly infusions of Glial Cell Line Derived Neurotrophic Factor (GDNF) and the other half placebo infusions. After the initial nine months on GDNF or placebo, the open-label extension study took place, which explored the effects and safety of continued exposure to GDNF for another 40 weeks in the patients previously receiving GDNF (80 weeks in total) and the effects of 40 weeks of open label GDNF in those subjects who had previously received placebo for the first 40 weeks.

A specially designed delivery system was implanted using robot-assisted neurosurgery. This delivery system allowed high flow rate infusions to be administered every four weeks. Four tubes were carefully placed into each patient's brain, which allowed GDNF to be infused directly to the affected areas with pinpoint accuracy via a skull-mounted transcutaneous port behind the ear. After implantation and over the following several years the trial team administered more than 1000 brain infusions, once every four weeks over 18 months to study participants.

After nine months, there was no change in the PET scans of those who received placebo, whereas the group who received GDNF showed an improvement of 100% in a key area of the brain affected in the condition, offering hope that the treatment was starting to reawaken and restore damaged brain cells. By 18 months, when all participants had received GDNF, both groups showed moderate to large improvements in symptoms compared to before they started the study and that GDNF was safe when administered over this length of time. "This trial has shown that we can safely and repeatedly infuse drugs directly into patients' brains over months or years. This is a significant breakthrough in our ability to treat neurological conditions."

Chronological age is the most important single risk factor for the development of a variety of cancers and chronic diseases that account for the majority of societal morbidity, mortality, and public health costs. Recent findings suggest that changes in certain basic biological processes are shared in physiological aging, cancer, and degenerative pathologies. Importantly, similar processes can be altered in diseases as diverse as cancer, neurodegeneration, cardiovascular disorders, chronic obstructive pulmonary disease (COPD), osteoarthritis, and diabetes, to name a few.

For instance, at the cellular level, the accumulation in tissues of senescent cells (permanent cell cycle arrest in response to various types of stress or tissue remodeling) emerges as an important contributor to aging and age-related pathologies, through both cell autonomous and non-autonomous mechanisms driving inflammation, immunosenescence, and tissue degeneration. Therefore, a key challenge now is to rapidly improve our knowledge on the biological processes in common that lead to malignant transformation and degenerative pathologies.

From a cellular standpoint, the mechanisms that drive degenerative diseases and cancer are shared at an initial phase (e.g., during the accumulation of senescent cells), before adopting a particular direction and specific genetic and epigenetic modifications that orient cells toward distinct fates (e.g., escape of cellular checkpoints for cancer cells). Thus, schematically, degenerative aging and cancer can be considered as two sides of the same coin, involving many common fundamental biological mechanisms. Hence, the progressive degeneration of tissues can lead to transformation into cancer after activation of chronic inflammation and immunosenescence.

Although cancer and aging biology are closely related, they are often investigated separately. Thus, whereas a number of fundamental and translational research centers or institutes worldwide have oriented their research in the direction of aging, only a few of them have really focused their studies on the links between aging and cancer. This is the case for the Institute for Research on Cancer and Aging, Nice (IRCAN) in France, which bases its overarching strategy on combining the research developed by scientists and physicians on cancer and aging mechanisms. It is within this context that the OncoAge consortium was launched in Nice to facilitate the transfer of this growing knowledge on cancer and aging to medical innovation and current medical practice.

This consortium was certified and recognized in 2015 as a Hospital-University Federation (HUF). The global aim of the HUF program in France is to develop excellence within the university hospitals by targeting medical topics optimizing care, research, and education in these subject areas. In short, OncoAge is a HUF based on the expertise of medical and scientific teams oriented toward cancer pathologies associated with aging. The key aim of OncoAge is to improve the care of elderly patients, in particular those with cancer, to set up research projects, and develop training and educational programs in this domain. These efforts should not only deepen our understanding of the mechanisms underlying cancer and aging, but also improve the daily well-being of the patients.

Type 1 diabetes (T1D) results from the loss of pancreatic beta cells, leading to insulin deficiency and disruption of glucose metabolism. The loss of beta cells is thought to be driven by an underlying autoimmune disorder in which peripheral tolerance is lost and mature autoreactive CD4+ and CD8+ cytotoxic T cells carry out progressive destruction of beta cells with support from innate immune cells. As a consequence, the major focus of current experimental therapies for T1D is to restore normal immune system function. In contrast, comparatively little is known about how beta cells themselves could actively participate and initiate the disease process.

Previous work has established that activation of the terminal unfolded protein response (UPR) in beta cells precedes symptoms of overt T1D. Indeed, inhibitors of the terminal UPR preserve beta cell mass and can reverse diabetes in the non-obese diabetic (NOD) mouse model, the classic model for spontaneous autoimmune diabetes, which recapitulates most of the features of T1D in humans. While it is generally accepted that apoptosis is the main response to terminal UPR, whether a beta cell mounts a protective or destructive stress response depends on the nature and duration of the stress as well as the competence of the beta cell to respond. Recent work has shown that intrinsic beta cell fragility is an underlying feature of both type 1 and 2 diabetes, prompting a closer investigation into the outcomes of the stress responses of beta cells in these diseases.

Cellular stress responses can induce a senescent fate and acquisition of a secretome composed of cytokines, chemokines, growth factors, proteases, and extracellular matrix factors, known as the senescence-associated secretory phenotype (SASP). A growing body of work supports the notion that SASP is beneficial when resolved efficiently, such as during embryonic development, wound healing, and tissue regeneration. However, the accumulation of senescent cells can disrupt tissue architecture and lead to dysfunction. Hence, a variety of age-related diseases in which senescent cell burden is high can be ameliorated either by genetic ablation of senescent cells or by the administration of small molecules that kill senescent cells.

Here, we report that in the NOD mouse model and in human T1D, a subpopulation of beta cells undergoes a stress response leading to senescence and SASP. Elimination of senescent beta cells from NOD mice afforded robust protection against diabetes, indicating that this subpopulation of cells contributes to disease progression. Remarkably, senolytic treatment had no apparent effect on the major lymphoid or myeloid populations infiltrating the islets, in the spleen or pancreatic lymph nodes, suggesting that in these experiments ablation of senescent beta cells does not affect immune cells. Taken together, these findings demonstrate that SASP is a pathogenic mechanism in T1D and that targeted elimination of senescent beta cells prevents this disease.

Researchers have been able to rejuvenate stem cells in the brain of aging mice. The revitalised stem cells improve the regeneration of injured or diseased areas in the brain of old mice. The researchers expect that their approach will provide fresh impetus in regenerative medicine and facilitate the development of stem cell therapies. In order to create as accurate as possible computational models of stem cell behaviour, researchers applied a novel approach. "Stem cells live in a niche where they constantly interact with other cells and extra-cellular components. It is extremely difficult to model such a plethora of complex molecular interactions on the computer. So we shifted perspective. We stopped thinking about what external factors were affecting the stem cells, and started thinking about what the internal state of a stem cell would be like in its precisely defined niche."

The novel approach led to in a new computational model. "Our model can determine which proteins are responsible for the functional state of a given stem cell in its niche - meaning whether it will divide or remain in a state of quiescence. Our model relies on the information about which genes are being transcribed. Modern cell biology technologies enable profiling of gene expression at single cell resolution." From their computational model, researchers identified a molecule called sFRP5 that keeps the neuronal stem cells inactive in old mice, and prevents proliferation by blocking the Wnt pathway crucial for cell differentiation.

Studying stem cells first in a dish and then later directly in mice, a collaborating team then experimentally validated the computational prediction. When neutralising the action of sFRP5, quiescent stem cells did indeed start proliferating more actively. Thus, they were available again to be recruited for the regeneration processes in the aging brain. "With the deactivation of sFRP5, the cells undergo a kind of rejuvenation. As a result, the ratio of active to dormant stem cells in the brain of old mice becomes almost as favourable as in young animals."

Cerebral amyloid angiopathy (CAA) is typified by the cerebrovascular deposition of amyloid. Currently, there is no clear understanding of the mechanisms underlying the contribution of CAA to neurodegeneration. Despite the fact that CAA is highly associated with accumulation of Aβ, other types of amyloids have been shown to associate with the vasculature. Interestingly, in many cases, vascular amyloidosis is accompanied by significant tau pathology. However, the contribution of tau to neurodegeneration associated to CAA remains to be determined.

We used a mouse model of Familial Danish Dementia (FDD), a neurodegenerative disease characterized by the accumulation of Danish amyloid (ADan) in the vasculature, to characterize the contribution of tau to neurodegeneration associated to CAA. We performed histological and biochemical assays to establish tau modifications associated with CAA in conjunction with cell-based and electrophysiological assays to determine the role of tau in the synaptic dysfunction associated with ADan. We demonstrated that ADan aggregates induced hyperphosphorylation and misfolding of tau.

Moreover, in a mouse model for CAA, we observed tau oligomers closely associated to astrocytes in the vicinity of vascular amyloid deposits. We finally determined that the absence of tau prevents synaptic dysfunction induced by ADan oligomers. In addition to demonstrating the effect of ADan amyloid on tau misfolding, our results provide compelling evidence of the role of tau in neurodegeneration associated with ADan-CAA and suggest that decreasing tau levels could be a feasible approach for the treatment of CAA.

Imagine a day when a bioprinter filled with a patient's own cells can be wheeled right to the bedside to treat large wounds or burns by printing skin, layer by layer, to begin the healing process. That day is not far off. Scientists have created such a mobile skin bioprinting system - the first of its kind - that allows bi-layered skin to be printed directly into a wound. Affecting millions of Americans, chronic, large or non-healing wounds such as diabetic pressure ulcers are especially costly because they often require multiple treatments.

The major skin cells - dermal fibroblasts and epidermal keratinocytes - are easily isolated from a small biopsy of uninjured tissue and expanded. Fibroblasts are cells that synthesize the extracellular matrix and collagen that play a critical role in wound healing while keratinocytes are the predominant cells found in the epidermis, the outermost layer of the skin. The cells are mixed into a hydrogel and placed into the bioprinter. Integrated imaging technology involving a device that scans the wound, feeds the data into the software to tell the print heads which cells to deliver exactly where in the wound layer by layer. The bioprinter deposits the cells directly into the wound, replicating the layered skin structure, and accelerating the formation of normal skin structure and function.

The researchers demonstrated proof-of-concept of the system by printing skin directly onto pre-clinical models. The next step is to conduct a clinical trial in humans. "The technology has the potential to eliminate the need for painful skin grafts that cause further disfigurement for patients suffering from large wounds or burns."

Bone loss and Alzheimer's disease make an unexpected, but increasingly common combination in the aging population. The vastly different clinical presentations of these conditions made it hard to envision that a complex brain disease known for destroying our most advanced cognitive abilities could also impact the fundamental framework of the human body. This bias has likely contributed to the dearth of investigation into mechanisms of bone loss in Alzheimer's disease (AD) - which presents as a very real and unique problem for these patients.

Osteoporosis and bone fracture are estimated to occur in AD patients at over twice the rate as similarly-aged neurotypical adults. Occurring across international demographics and in both sexes, skeletal problems in AD patients are not a coincidence of aging, nor are they the result of disease-related immobility, as they often precede AD diagnosis. In fact, studies have used bone mineral density (BMD) to stratify neurotypical subjects 65 years and older into groups at greatest risk for developing dementia - with those exhibiting the lowest bone densities most likely to receive an AD diagnosis within 5-10 years.

The little empirical evidence that does exist on this subject makes a compelling case that the neuropathophysiological features of AD may also drive bone loss. To date, three genetic mouse models of AD have been characterized with a "pre-clinical" low BMD; however, there are possibly many more among the 150+ available AD models that have not been investigated for bone loss. What has been found is a low bone mass phenotype at ages just preceding the onset of significant hallmark brain pathology and detectable across models representing each hallmark pathology of AD: amyloid beta (Aβ) and phosphorylated tau (ptau) - with data implicating separate mechanisms by which each pathology disrupts skeletal homeostasis.

Data from amyloid-β mouse models support a bone-cell-autonomous role for Aβ in damaging bone tissue, with evidence that Aβ interfaced directly with bone cells to enhance the bone-resorbing activity of osteoclasts and inhibit the bone-building function of osteoblasts. Data obtained from studies with mouse models which selectively develop ptau and neurofibrillary tangle brain pathology showed that ptau - which is largely relegated to the neuronal cytoskeleton - damages the serotonergic dorsal raphe nucleus (DRN) of the brainstem. Serotonergic inputs from the DRN to the hypothalamus form a circuit that is essential for maintaining healthy bone mass in adult mammals; hence these findings suggest this circuit is compromised by ptau pathology.

Pro-inflammatory immune responses are our first line of defence against infectious non-self. Inflammation however, has a cost. During the life-history of a human, low-grade inflammation, develops gradually and contributes to the pathogenesis of a range of age-related diseases from leaky gut to neurodegeneration. Conversely, ageing through cell senescence, can influence immune function with the depletion of the pool of naïve T-cells ready to respond to infection making older individuals more vulnerable to viral disease and less responsive to vaccination regimes. This can in turn, influence human lifespan. In the apparent complexity of this dual relationship it is difficult to arrive at a mechanism of causality because cause and consequence are intimately linked.

Compromised intestinal barrier function in humans has been associated with conditions such as Crohn's disease. Changes in the permeability of the mouse gut, which results in "leaky gut" has consequences on health span. In this context, increased age-associated levels of Tumour Necrosis Factor (TNF) have a negative impact on gut permeability and impacts on lifespan while IL-10 knockout mice have (along with their immune defects) increased intestinal permeability and develop early colitis compromising health span and lifespan. In contrast, TNF-deficient mice are protected from age-associated inflammation.

There is now increasing evidence that inflammation regulates ageing. But which tissues contribute to this is less clear. Brain neuroinflammation represents a critical factor contributing to progression of neurodegeneration. NF-κΒ is the major regulator of inflammation and its sustained activation in forebrain neurons elicits a selective inflammatory response accompanied by decreased neuronal survival and impaired learning and memory. More recent experiments of transient NF-κΒ activation in astrocytes (a type of microglia) through a diverse array of inflammatory cues (infection or application of pro-inflammatory cytokines), resulted in non-cell autonomous neurodegeneration. The central position of microglia innate immunity in neurodegeneration and especially in the risk for late on-set Alzheimer's Disease (AD) is exemplified in human genome-wide association studies. Loss of TREM2 has been associated with increased risk of late on-set AD and increased TREM2 expression in mouse microglia had an anti-inflammatory rescuing effect with the downregulation of several pro-inflammatory markers. This ameliorated the neuropathological and behavioural deficits of AD mouse models.

T cells and B cells undergo immune senescence. Senescence is age-dependent and is the driving force for immune ageing. During ageing, both T and B cells will be depleted and the memory B cells, long-lived plasma cells and peripheral T-cells show defects. In addition, the provision by the thymus of naïve T-cells for the adaptation to new pathogens is limited. The mechanisms of these age-related defects are not fully elucidated but reduced autophagy, is a major driving force for immune senescence. In murine T cells, neutrophils and macrophages, autophagy is attenuated during ageing and autophagy-deficient cells display premature ageing traits.

Germ-free mice live almost 100% to 600 days in contrast to their conventionally-reared counterparts that reach this point with a 60% survival probability. In addition, germ free mice do not display age-associated inflammation while their macrophages retain their antimicrobial activity. This indicates that age-associated changes of the microbiota are a significant driver of lifespan where TNF-mediated inflammation acting as an effector of morbidity. Indeed, treatment of mice with anti-TNF antibodies reversed age-associated changes in the microbiota and ameliorated life expectancy. Therefore, reversing these age-related microbiota changes represents a potential strategy for reducing age-associated inflammation and the accompanying morbidity.