Fight Aging!

The two senolytics companies profiled here employ quite different approaches to the selective destruction of senescent cells, and indeed also to the business side of the equation - which age-related conditions to tackle first, whether to build a therapy or a platform for therapies, and so forth. These are two representative companies of a much larger number of groups working in this part of the field. It isn't just biotech startups. While the longevity industry is still small enough for lists of companies to be reasonably complete, the evidence for senescent cell clearance to produce rejuvenation is now comprehensive enough and well-known enough for there to be any number of quietly invisible senolytics programs out there in the world, running inside Big Pharma entities and academic labs.

As a field of development, senolytics is in a fascinating state. The first senolytic treatment demonstrated to work, dasatinib and quercetin, is the combination of a cheap and readily accessible existing chemotherapeutic and supplement. Yet very few other approaches have yet produced published data involving greater efficacy. With few exceptions, the senolytic therapies for which we know the outcomes in animal studies result in clearance of 25% to 50% of senescent cells in the tissues in which they work the best. I don't envy those companies who must push a novel senolytic therapy through the regulatory pipeline at vast expense, only to launch it into a market in which the primary competition is dasatinib and quercetin, a ~$100 treatment that can be used off-label, and may well be just as good in most cases. The bar is unusually high for a comparatively young field of medicine.

Rubedo Life Sciences: Senolytic start-up gears up for clinical trials

Late last year, Silicon Valley start-up Rubedo Life Sciences secured a sizeable seed funding round of $12 million to develop senolytic therapies that selectively target and clear senescent cells from aged or pathological tissues. The company is now conducting preparatory work for IND-enabling studies, ahead of moving to Phase 1 clinical trials, potentially as early as 2022.

Appropriately, in alchemy, the word "rubedo" refers to the final phase of the creation of the mythological elixir of life, which delivers rejuvenation and immortality. And Rubedo has borrowed another term from alchemy to name its discovery platform, Alembic, which refers to the apparatus used by alchemists to prepare their medicine. "I'm so happy to see that in the past 10 years, and even more in the past five, the scientific and biotech communities have reached that level of initial maturity, the critical mass to accept the idea that aging is the main driving process of age-related diseases. There is a change in biology, and we accept this idea that it can be probably targeted. Aging is not a clinical indication yet, but the chronic diseases that result from it are, and they are mostly all unmet needs."

"We are not a senolytic company, per se. Our first and most advanced programme is our senolytic programme, but the Alembic platform that we have developed is agnostic." Alembic is used is to profile and identify the biological changes that emerge with age and disease. It can be used, for example, to identify metabolic signatures as specific characteristic of certain cells. "What is emerging with age, what's happening at that inflection point? What are the cells that are emerging, or the changes in any cell types, in different tissues, across ages, across species, across diseases? Alembic allows us to identify novel targets, to identify the specific signatures, and use this information to design and engineer more molecules that are special, targeted therapeutics."

Oisín Biotechnologies: Promising restorative therapy potentially 5 years away

Seattle-based Oisín Biotechnologies is creating therapies to combat a variety of age- related diseases. Their breakthrough gene therapy platform clears senescent cells in a highly precise way, with promising preclinical studies already showing significant median lifespan extension in mice. Oisín's therapy has been shown to efficiently eliminate senescent cells body-wide in multiple animal models and has demonstrated therapeutic benefit in both disease burden and lifespan. Treated mice lived 20% longer even when treatment was started in old age, and after a single treatment, senescent cell removal rates reached as high as 70%.

"The ultimate goal is to eliminate unnecessary suffering. I think that everyone who believes in the mission of longevity is striving towards this. By realizing these therapies, we can start to fundamentally change the way that humans think about aging and disease. Our approach is pretty much the exact opposite of the traditional pharmaceutical approach. With our approach, there is no drug, no poison at all - just a little program written in DNA. We've effectively taken targeting out of the realm of chemistry and brought it into the realm of information."

Oisín has seen that the effects of their therapy are comparable to transgenic mouse studies conducted by the Mayo Clinic and the Buck Institute. The company is now moving to functional studies and disease models in order to create a clinically approved therapy. They are currently working with European collaborators as well as others to develop their kidney disease clinical package and future pipeline indications.

Extensive human evidence strongly supports the conjecture that excess fat tissue is simply harmful. That harm cannot be evaded by exercise: one cannot be "fat but healthy". Visceral fat packed around the abdominal organs generates chronic inflammation, a raised burden of senescent cells, and all sorts of other issues. It pushes fat into the organs themselves; in the case of the pancreas that excess fat is the primary cause of type 2 diabetes. In the liver, it leads to fatty liver disease. Even modest amounts of excess fat tissue raise mortality rates and shorten life expectancy.

A large study finds that physical activity does not undo the negative effects of excess body weight on heart health. "One cannot be 'fat but healthy'. This was the first nationwide analysis to show that being regularly active is not likely to eliminate the detrimental health effects of excess body fat. Our findings refute the notion that a physically active lifestyle can completely negate the deleterious effects of overweight and obesity."

The study used data from 527,662 working adults insured by a large occupational risk prevention company in Spain. The average age of participants was 42 years and 32% were women. Participants were categorised as normal weight, overweight, or obese. Additionally, they were grouped by activity level: 1) regularly active, defined as doing the minimum recommended for adults by the World Health Organization (WHO); 2) insufficiently active, some moderate to vigorous physical activity every week but less than the WHO minimum; 3) inactive. Cardiovascular health was determined according to three major risk factors for heart attack and stroke, namely diabetes, high cholesterol, and high blood pressure.

Approximately 42% of participants were normal weight, 41% were overweight, and 18% were obese. The majority were inactive (63.5%), while 12.3% were insufficiently active, and 24.2% were regularly active. Some 30% had high cholesterol, 15% had high blood pressure, and 3% had diabetes. The researchers investigated the associations between each weight category and activity group and the three risk factors. At all weight levels, any activity (whether it met the WHO minimum or not) was linked with a lower likelihood of diabetes, high blood pressure, or high cholesterol compared to no exercise at all. At all weights, the odds of diabetes and hypertension decreased as physical activity rose.

However, overweight and obese participants were at greater cardiovascular risk than their peers with normal weight, irrespective of activity levels. As an example, compared to inactive normal weight individuals, active obese people were approximately twice as likely to have high cholesterol, four times more likely to have diabetes, and five times more likely to have high blood pressure. "Exercise does not seem to compensate for the negative effects of excess weight. This finding was also observed overall in both men and women when they were analysed separately."

Link: https://www.escardio.org/The-ESC/Press-Office/Press-releases/Being-fat-linked-with-worse-heart-health-even-in-people-who-exercise

Packing injured bone with synthetic bone material can speed regeneration, allowing even severe injuries involving missing bone or multiple fractures to resolve. Here researchers report on improvements to this class of approach, coercing the behavior of natural processes of bone growth and resorption to be more amenable to the regeneration that is desired.

Researchers have developed a way of combining a bone substitute and drugs to regenerate bone and heal severe fractures in the thigh or shin bone. The study was conducted on rats, but the researchers think that the method in various combinations will soon be commonplace in clinical settings. "The drugs and materials we used in the study for the regeneration of bone are already approved. We simply packaged them in a new combination. Therefore, there are no real obstacles to already using the method in clinical studies for certain major bone defects that are difficult to resolve in patients."

Bones in the human body have a fantastic ability to repair injury, but some defects are so large or complicated that the healing process is delayed or absent. This may be due to the bone having been subjected to a major trauma in connection with a traffic accident for example, or a tumour or infection causing a major bone defect. These cases are currently treated through bone transplantation, usually with bone taken from the patient's own pelvis.

So far, the injectable cocktail successfully mixed by the researchers consists of three different components: an artificial ceramic material, a bioactive bone protein (recombinant BMP-2) and a drug, bisphosphonate, that combats bone resorption. "The bone protein we use has had negative effects in previous studies due to a secondary premature bone resorption, among other things. We have successfully mitigated this effect with the bisphosphonate and, by packaging the drug in a slowly resorbing bone substitute, we can control the speed of release. In the current study with the combination, we achieved a six-fold reduction in the amount of protein compared to previous efforts, while still inducing bone formation. The result was that even fractures with an extensive bone defect could heal without complications. We believe this finding will be of great clinical use in the future."

Link: https://www.eurekalert.org/pub_releases/2021-01/lu-nmh011921.php

Cellular senescence is a double-edged sword in the matter of cancer. The state of senescence is a growth arrest coupled with pressure to self-destruct and a call to the immune system to destroy the senescent cell. As such it serves as a first line of defense against cancer. Most cancer treatments force large numbers of cancerous cells into senescence, in addition to causing outright cell death, shutting down their ability to replicate. Unfortunately, the presence of too many senescent cells is harmful in and of itself, as their signaling produces chronic inflammation, disrupts tissue function throughout the body, and makes the environment more hospitable for cancer growth.

Thus cancer survivors who undergo chemotherapy or radiotherapy have a reduced life expectancy and greater degree of health issues, including cancer recurrence, as a result of an increased burden of senescent cells. This is a far better outcome than dying of cancer, of course, but it is nonetheless an issue to be dealt with. Now that the research community has identified senolytic drugs capable of selectively destroying a sizable fraction of senescent cells in the body, it is possible to think about both improving the efficacy of existing cancer therapies and minimizing their lingering side-effects.

Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies

Chemotherapy may cause cell death, often by apoptosis, resulting clinically in tumour regression. It may also cause cellular senescence, leading clinically to tumour stasis (growth arrest). The role of senescence in response to chemotherapy is complicated, however, in that the senescence-associated secretory phenotype (SASP) of senescent cells induced by treatment varies between tissues and cell types, according to the precise senescent stimulus. In particular, some senescent cells secrete exosomes and these may have a tumour promoter function. Consequently, senescence induced by some cancer therapies may be harmful and promote tumour growth.

Whilst cells that undergo apoptosis are permanently removed from a cancer, senescent cells remain and secrete various inflammatory cytokines, which may have both positive and negative impacts. There have been concerns that these senescent cells may resist further chemotherapy damage and be a potential reservoir for recurrence. There is evidence that senescent cells may also be re-programmed to re-enter the cell cycle after certain types of chemotherapy and may acquire a more "stem cell"-like phenotype, which may in turn contribute to tumour regrowth and evolution.

Radiotherapy, which is one of the mainstays of cancer therapy, acts by causing direct DNA damage and has wide ranging impacts on cancer cells mediated by reactive oxygen species. The DNA damage response is triggered and if repair is not possible, cells either die if the damage is severe or enter senescence if less severe. Radiotherapy also triggers an immune response, making the treated cells more immunogenic in a variety of ways. Part of this immunogenicity may be due to the release of SASP factors from senescent cells. Another way in which senescence may be a clinically important part of radiotherapy response is in causing radiation-induced fibrosis. This can be a potentially severe complication of radiotherapy, especially in the lung where pulmonary fibrosis may occur. Senescent cells also appear to be linked to skin fibrosis and ulceration following radiotherapy.

In the context of chemotherapy tolerance, there is evidence that some of the adverse effects of chemotherapy are mediated by the therapy-induced senescent cells which have a pro-inflammatory effects (due to SASP) in a doxorubicin or paclitaxel treated mouse model. Removal of these therapy-induced senescent cells abrogated many of the adverse effects of chemotherapy (reduced fatigue, increased activity levels, reduced cardiac functional impairment). In a separate study, again in a mouse model, the elimination of senescent cells by the use of dasatinib and quercetin, reduced the impact of radiotherapy, improved cardiac function and exercise tolerance, and increased life expectancy. Data in humans are also available that show that higher levels of senescence biomarkers are linked with higher rates of treatment-induced adverse events following doxorubicin chemotherapy.

Senotherapies refers to a group of pharmacological agents that interact with senescent cells to interfere with their pro-aging impacts. There are two main categories: senolytic drugs, which selectively destroy senescent cells and senostatic drugs, which inhibit their function by suppression of their release of SASP factors. Of the two drug groups, senolytics have been more extensively studied and show promise of therapeutic value. These are of particular interest as an adjunct to chemotherapy, where the senolytic drug may be able to target cells induced to become senescent by the cancer. They may also improve treatment resilience. There are several agents under investigation.

It is already recognised that long-term survivors of cancer have increased rates of frailty and reduced longevity, some of which are thought to be due to the direct and indirect induction of senescent cells by cancer therapies (chemotherapy and radiotherapy). A trial is currently running to assess the impact of senolytic therapy on stem cell transplant survivors using dasatinib and quercetin in a small number of patients and assessing the impact on frailty.

Another important patient group is the elderly with cancer. It is well recognized that treatments such as surgery and chemotherapy have a significant negative impact on physical function, with studies showing an increase in measures of frailty after treatment, which may never recover back to baseline levels. This loss of function is one of the reasons that older patients require longer hospital admission after surgery and sometimes require social care support in the longer term after surgery. If use of senolytic therapies could reduce the frailty phenotype and enhance resilience, this would be a major advance in cancer therapies.

CDC42 inhibition looks promising as a way to rejuvenate immune function via reversing the age-related disruption of hematopoiesis in bone marrow. At some point hematopoietic stem cells become so damaged that no amount of tinkering with their regulatory functions will help, but the evidence to date suggests that this doesn't occur until quite a way past middle age. In older mice, a single treatment of CDC42 inhibitor CASIN extends life span. Here, researchers report on further evaluations of the ability of CASIN to improve hematopoietic stem cell function, extending the work from mouse cells to human cells.

Aging is associated with tissue degeneration, aging-related diseases, and an increased susceptibility to infections. These hallmarks of aging have been linked to aging-related changes within somatic stem cell compartments, and primarily investigated in animal models like mice. One of the most extensively studied somatic stem cell-based system is the hematopoietic system.

Hematopoietic stem cells (HSCs) maintain blood homeostasis and show an age-related decline in overall function in mice, which includes an increase in myelopoiesis, accumulation of DNA damage, changes in epigenomic and transcriptional programs, decreased cell polarity and aberrant activity of the small RhoGTPase Cdc42. Although significant progress has been achieved in elucidating mechanisms of aging of murine HSCs, it remains unclear whether these mechanisms can be simply extrapolated to other species, including humans. For these reasons, novel studies into understanding mechanisms of aging of human HSCs are warranted and are a prerequisite to bolster the transition of this knowledge into the clinic.

In this study, we characterize age-related phenotypes of human hematopoietic stem cells (HSCs). We report increased frequencies of HSC, hematopoetic progenitor cells (HPC), and lineage negative cells in the elderly but a decreased frequency of multi-lymphoid progenitors. Aged human HSCs further exhibited a delay in initiating division ex vivo though without changes in their division kinetics. The activity of the small RhoGTPase Cdc42 was elevated in aged human hematopoietic cells and we identified a positive correlation between Cdc42 activity and the frequency of HSCs upon aging.

The frequency of human HSCs polar for polarity proteins was, similar to the mouse, decreased upon aging, while inhibition of Cdc42 activity via the specific pharmacological inhibitor of Cdc42 activity, CASIN, resulted in re-polarisation of aged human HSCs with respect to Cdc42. Elevated activity of Cdc42 in aged HSCs thus contributed to age-related changes in HSCs. Xenotransplantation of human HSCs into immunodeficient mice showed elevated chimerism in recipients of aged compared to young HSCs, indicating a worse function in aged HSCs. Aged HSCs treated with CASIN ex vivo displayed an engraftment profile similar to recipients of young HSCs, however.

Taken together, our work reveals strong evidence for a role of elevated Cdc42 activity in driving aging of human HSCs, and similar to mice, this presents a likely possibility for attenuation of aging in human HSCs.

Link: https://doi.org/10.3324/haematol.2020.269670

Chronic inflammation is of great importance in degenerative aging. Unresolved inflammation that lingers for the long term disrupts tissue function and accelerates the onset and progression of many age-related conditions. There is thus considerable interest in the research community in finding ways to shut down chronic inflammation in older individuals without suppressing beneficial, necessary short-term inflammatory signaling, involved in defense against pathogens, tissue regeneration, and other processes. Macrophages are innate immune cells that have many important functions and are negatively affected by an environment of chronic inflammation. Equally, it appears that they contribute to producing that environment via their inflammatory signals, in cases where they become overactive due to a damaged environment or due to spreading cellular senescence.

Older age is associated with deteriorating health, including escalating risk of diseases such as cancer, and a diminished ability to repair following injury. This rise in age-related diseases/co-morbidities is associated with changes to immune function, including in myeloid cells, and is related to immunosenescence. Immunosenescence reflects age-related changes associated with immune dysfunction and is accompanied by low-grade chronic inflammation or inflammageing. This is characterised by increased levels of circulating pro-inflammatory cytokines such as tumor necrosis factor (TNF), interleukin (IL)-1β and IL-6.

However, in healthy ageing, there is a concomitant age-related escalation in anti-inflammatory cytokines such as transforming growth factor-β1 (TGF-β1) and IL-10, which may overcompensate to regulate the pro-inflammatory state. Key inflammatory cells, macrophages, play a role in cancer development and injury repair in young hosts, and we propose that their role in ageing in these scenarios may be more profound. Imbalanced pro- and anti-inflammatory factors during ageing may also have a significant influence on macrophage function and further impact the severity of age-related diseases in which macrophages are known to play a key role.

In this brief review we summarise studies describing changes to inflammatory function of macrophages (from various tissues and across sexes) during healthy ageing. We also describe age-related diseases and co-morbidities where macrophages are known to play a key role, focused on injury repair processes and cancer, plus comment briefly on strategies to correct for these age-related changes.

Link: https://doi.org/10.1186/s12979-021-00215-2

A sizable fraction of the startup biotech companies in the small but growing longevity industry are essentially screening programs, in that they are developing various improvements on the standard approaches to screening small molecule databases in search of drugs that affect mechanisms relevant to aging. Some of them intend to take the best results from their screens into clinical development, while others intend to provide infrastructure drug development services, such as better, faster, or cheaper compound discovery and early validation, to the broader biotech industry. Examples among the first generation of longevity industry biotech startups include In Silico Medicine, BioAge, and Gero, among others.

Today's articles profile Gerostate Alpha, a more recently formed company that is incubated at the Buck Institute for Research on Aging, benefiting from the science and infrastructure there. The founders are most interested in entirely unbiased screening for compounds that slow aging and extend healthy life span, and less interested in a focus on any specific theory of aging or set of mechanisms. In the bigger picture, this is a useful exercise with a small chance of turning up interesting mechanisms involved in the progression of aging that have been overlooked.

That said, based on the results from other screening efforts, it is reasonable to believe that the vast majority of the output of the Gerostate Alpha screening process, meaning compounds that slow aging in short-lived species, will be those that upregulate stress response mechanisms, akin to those triggered by calorie restriction, and will thus have much smaller and less reliable effects in long-lived species. Whether there are specks of gold to be found amidst that low value dross is a question that can only be answered by a lot more unbiased screening than has so far taken place.

This low ratio of useful to entirely mediocre mechanisms and modulators of aging is the reason why I'm less in favor of unbiased screening than in the entirely biased approach of repairing the forms of cell and tissue damage known to be at the root of aging. That entirely biased strategy gave us senolytics, treatments that robustly produce rejuvenation in animal models by clearing senescent cells. There are a wide range of other forms of damage to be repaired, and an expectation that every one of them could turn out to be as good a field as senolytics. Aging is caused by damage. The best way forward is deliberate, targeted, periodic repair of that damage.

Gerostate Alpha: "The major modulators of aging remain to be discovered"

While many companies in Longevity are focused on addressing one or more of the hallmarks, or pillars, of aging, the founders of Gerostate Alpha always saw things a little differently. "People take the hallmarks of aging as a launching off point, thinking that if they can forestall a particular pillar, let's say inflammation, then they'll get beneficial outcomes - but this is a biased approach. We've always been interested in looking at aging mechanisms in an unbiased way, whether through genetic interventions, or pharmacological interventions, we're not beholden to a particular mechanism, per se."

"Having been involved in the basic biology of aging and trying to understand the degenerative changes of aging from a mechanistic perspective for many years, that resonated with us. And so we put together a proposal focused around some of the ideas, particularly with regard to an unbiased way to identify molecules which might retard the aging process. We pitched it to Y Combinator, they really liked us and gave us a million dollars to start the company. It was certainly the fastest million we ever made in our careers!"

"You often hear people say they 'target aging' but you have to ask what does that mean - does it mean targeting a pillar of aging: senescence, inflammation, mitochondrial dysfunction? That's not targeting aging - that's targeting something other people have said is linked to aging processes. Everyone is very familiar now with using those terms, but it roots you in the idea that we understand what aging is, and we don't think we do. We believe that these pillars of aging are just one of many, and we think that the major modulators of aging remain to be discovered."

Gerostate Alpha: "Our phenotype is lifespan"

At the platform's "front end", the high throughput screen is predominantly based on lifespan extension data from a variety of strains and species of Caenorhabditis nematodes - simple, short-lived organisms, which allow manipulations of lifespan to be studied more easily. "At the back end, we phenotype the successful interventions that target different aspects of aging, in mice. And we're looking at multiple indications simultaneously, whether muscle dysfunction, lung function, bone function, cardiac function, the central nervous system to some extent. All of these things are screened for simultaneously. And I would argue this is something we can do better than anyone else."

The founders' confidence is largely because of the infrastructure that has been built up at the Buck Institute over many decades, and which would cost tens of millions of dollars if a start-up were to attempt to replicate it. "Our initial strategy was to screen small molecule libraries, so we did that on around 60,000 compounds, and we identified over 30 hits that have been validated. We're now prepping those and derivatives of those into lead candidates to move into our preclinical mouse models. But in parallel to that, we screened some libraries of off-patent compounds, and we've moved those through into preclinical mouse models already. We've had some really interesting hits and we're now doing our follow up experiments on the pathways involved in those and the efficacy of those compounds, in those specific tissues."

Chronic inflammation is clearly very important in the progression of numerous neurodegenerative conditions, Alzheimer's disease included. Inflammatory signaling, when unrelenting, disrupts cell and tissue function in many tissue types. In recent years, the elimination of lingering senescent cells has been shown in animal studies to reduce inflammation and reverse many of the issues it causes in the aged body. Researchers here take a different approach to suppressing chronic inflammation, sabotaging the ability of macrophage cells to contribute to the inflammatory environment. This has the effect of reversing some of the cognitive decline observed in a mouse model of Alzheimer's disease.

Overexpression of cyclooxygenase-2 (COX-2), a major mediator of inflammation, in the brain produces Alzheimer's disease-like symptoms in mice: age-dependent inflammation and cognitive loss. COX-2 activation is the first step in the production of a lipid called prostaglandin E2 (PGE2), which can bind to one of its receptors, EP2, on immune cells and promote inflammation. To plug up the pathway, researchers have shown that deleting the EP2 receptor in mouse macrophages and brain-specific microglia - the cells normally responsible for detecting and destroying immune invaders and cellular debris - reduces inflammation and increases neuronal survival in response to both a bacterial toxin and a neurotoxin.

In the current study, the researchers wanted to understand how eliminating PGE2 signaling in macrophages could have these effects. They started by comparing macrophages from human blood donors either younger than 35 or older than 65. The cells from older donors made much more PGE2 and had higher abundance of the EP2 receptor than did macrophages from younger donors. When the researchers exposed human macrophages to PGE2, the cells altered their metabolism. Rather than using glucose to make energy, the cells converted it to glycogen and stored it, locking it up where the mitochondria couldn't access it for ATP production. "The result of that is that the cells are basically energy-depleted. They're just fatigued, and they don't work well. They don't phagocytose. They don't clear debris, including misfolded proteins associated with neurodegeneration."

When the scientists treated human macrophages from donors with an average age of about 48 with one of two EP2 receptor inhibitors, glycogen storage decreased, energy production increased, and cells shifted to express anti-inflammatory markers. As in human cells, aged mice also have higher levels of PGE2 in the blood and brain and EP2 receptor levels in macrophages, compared to younger mice. When the researchers knocked down the receptor in macrophages throughout the body in a mouse model of Alzheimer's disease or treated animals with either of two drugs to suppress EP2 function, cells had improved metabolism. The mice's age-associated inflammation also reversed and, with it, age-associated cognitive decline. Treating animals with an EP2 antagonist that couldn't get in the brain and thus only targeted the receptor in peripheral macrophages also led to cognitive improvement in older mice.

Link: https://www.the-scientist.com/news-opinion/a-tweak-to-immune-cells-reverses-aging-in-mice-68371

Senescent cells accumulate in the brain with age, and these cells generate chronic inflammation in brain tissue. Neurodegenerative conditions such as Alzheimer's disease are known to prominently involve inflammation in the progression of pathology. At least one senolytic treatment, the combination of dasatinib and quercetin, can pass the blood-brain barrier to destroy senescent cells in the brain, and has been shown to reduce inflammation and reverse tau pathology in mouse models of Alzheimer's disease. Researchers here add more data to this subject, clearing senescent cells from the brains of aged mice, and finding that this reverses a sizable fraction of the age-related loss of cognitive function that normally takes place. At least one human trial has started up to test the use of dasatinib and quercetin to treat Alzheimer's disease; this is a very promising area of study.

Cellular senescence is characterized by an irreversible cell cycle arrest and a pro-inflammatory senescence-associated secretory phenotype (SASP), which is a major contributor to aging and age-related diseases. Clearance of senescent cells has been shown to improve brain function in mouse models of neurodegenerative diseases. However, it is still unknown whether senescent cell clearance alleviates cognitive dysfunction during the aging process.

To investigate this, we first conducted single-nuclei and single-cell RNA-seq in the hippocampus from young and aged mice. We observed an age-dependent increase in p16Ink4a senescent cells, which was more pronounced in microglia and oligodendrocyte progenitor cells and characterized by a SASP. We then aged INK-ATTAC mice, in which p16Ink4a-positive senescent cells can be genetically eliminated upon treatment with the drug AP20187 and treated them either with AP20187 or with the senolytic cocktail Dasatinib and Quercetin. We observed that both strategies resulted in a decrease in p16Ink4a exclusively in the microglial population, resulting in reduced microglial activation and reduced expression of SASP factors.

Importantly, both approaches significantly improved cognitive function in aged mice. Our data provide proof-of-concept for senolytic interventions' being a potential therapeutic avenue for alleviating age-associated cognitive impairment.

Link: https://doi.org/10.1111/acel.13296

Ronjon Nag is an academic turned inventor turned entrepreneur turned investor in the communications and software industries, and now of late the longevity industry, a career path shared with a growing number of his peers in the Bay Area investment community. Alongside his principals Anastasiya Giarletta and Artem Trotsyuk, Ronjon Nag runs R42, a fund that grew out of his angel investing experience and successes. As is the case for near all of those who arrived comparatively early to the advent of this new industry, the R42 Group principals have a strong personal interest in health and longevity.

The longevity industry started up in earnest over the past five years or so, as early successes in aging research moved out of the labs and into biotech companies. In parallel, a growing number of technology investors have developed an interest in this field, expanding their portfolios to include biotechnology startups focused on aging. This is the next step in an ongoing process of support and interest: the application of the life sciences to the slowing and reversal of aging has long been an attraction to the successful and the influential of the Bay Area. It isn't an accident that the SENS Research Foundation was located there, for example, and nor is it an accident that much of the charitable funding that has supported rejuvenation research programs over the past decade or more was provided by technology industry philanthropists.

Your history is that of a technology entrepreneur turned technology investor; what drew your interests to biotech and the longevity industry?

I like really tough problems - I've done a lot of work in artificial intelligence and 30 years ago speech recognition was really tough yet we now see these technologies being used everywhere. Just as speech recognition predominately started out in university labs, it was commercialization that really got it into people's hands. I'm a big believer in the entrepreneurial process to speed things along, and I think in biotech and longevity the entrepreneurial process is going to accelerate the field. I'm still view myself as an entrepreneur as well as an investor - I really get involved with the companies I invest in - I have about 60 positions and I think the entrepreneurs appreciate working with someone who has been where they are currently. The empathy is important to have enhanced communication to help solve problems.

You have many fellow travelers in the technology investor and AI community, folk with an interest in aging. Why do you think there is such an overlap between software, technology, AI, longevity?

Today there is currently an inflection point where the tools of mathematics and computer science are accelerating the developments in biotech. We now live in a world where no one person has all the skills individually to solve problems and so I feel I can contribute mathematically, scientifically and commercially. Like artificial intelligence before, which is still quite difficult, biotech is also difficult - unlike physics, laws of biology are difficult to come by. Biology is beginning to turn into an engineering subject and I think we are seeing that subject can be accelerated and deployed at lower cost than previously. Biotech is notoriously expensive, and also takes a long time. We now have the vision that solutions can simply be "calculated"; we still have to do clinical trials which take actual time, but even there we can use Bayesian tests to efficiently implement trials.

Over at R42, we have a very wide definition of longevity from curing age related diseases in biotech, searching for solutions to the root cause of aging, but also technologies to assist people as they age, robots and the like.

My end of the longevity community is much more interested in biotech than in infrastructure technologies such as AI for drug discovery. What is on your investment radar in pure biotech for longevity?

Well, I would say that AI for drug discovery could actually find new drugs to solve aging, and quite optimistic on that, making several bets in that area, and a fundamental thesis is that computation can spit many more candidates for longevity that anyone can do manually. On the radar for pure biotech really looking at mechanisms that start to crumble as we get older. One is the thymus which helps us build out our immune system but goes away in our late teens. There are a few efforts looking at regrowing the thymus when we need it again when we are 80. We have an investment in Repair Biotechnologies, your company! Another area we are looking at is mitochondrial mechanisms. Mitochondria provide 90% of the energy of our cells, and as we age, they don't work the same. Looking at how we can correct them or replace them with fresh ones is an area to look at.

None of us are getting any younger yet, at least not meaningfully so. What is your take on what we should be doing to speed up progress towards human rejuvenation?

We do need more focused funds like R42 to able to sort the wheat from the chaff and be triage systems for larger funds to follow with more money in the best ideas. These early funds need to surround these early stage ideas with resources - people, connections, partners to make sure they flourish. Since aging is a significant source of mortality, matching government funds would be able to accelerate more efforts given the risk in the field. I think once we have a poster child of a successful aging company going public there will be an acceleration of investment.

You are big on education, formally and informally; what do you hope to be the outcome of your efforts to raise the profile of work on longevity?

Yes, education is important. I teach courses on AI and Longevity both at the R42 Institute and at Stanford University. The main thing here is to provide people from many disciplines the tolls to be able to contribute in their own way. If people can contribute then people will participate. There is a natural interest in living healthy and having a long life. There are many disciplines - physicists, psychologists, chemists, engineers, even ethicists, economists and lawyers who can bring their perspectives and with more people talking about from different fields it will naturally raise the profile of longevity science.

Epigenetic mechanisms regulate the pace of production of specific proteins in a cell. Feedback loops link the activities of proteins produced, input from the surrounding cell environment, and epigenetic alterations that change further production of proteins. Epigenetic control of protein production shifts constantly in response to circumstances, but many changes are characteristic of aging and the aged tissue environment. These are largely thought to be reactions to (or side effects of) underlying molecular damage such as DNA double strand breaks, or environmental change such as increased inflammatory signaling, but a minority of researchers think epigenetic change to be a significant independent cause of aging. Partial reprogramming of cells can reverse many of the epigenetic changes that are characteristic of aged cells, so tests of the hypotheses regarding the role of epigenetic change in aging will be forthcoming in the years ahead.

Epigenetic changes directly contributing to aging and aging-related diseases include the accumulation of histone variants, loss of histones and heterochromatin, and deregulated expression/activity of miRNAs. In addition, histones show aberrant post-translational modifications leading to the imbalance of activating and repressing modifications. Moreover, remodeling complexes modulate chromatin accessibility and there is an aberrant expression/activity of miRNAs. Together, these epigenetic deregulations contribute to aging-associated changes in gene transcription and, as a consequence, translation as well as the stabilization or degradation of molecular factors.

While mechanisms underlying aging-related pathologies remain to be elucidated in detail, various studies demonstrate an epigenetic component. In fact, the aforementioned epigenetic modifications were shown to play essential roles in diseases including inflammation, cancer, osteoporosis, neurodegenerative diseases, and diabetes. While the precise mechanisms and connections between several epigenetic changes and human pathologies are still poorly understood, state-of-the-art next generation sequencing methods will allow researchers to address remaining questions.

An improved understanding of epigenetic mechanisms affecting longevity will be deciding crucial step towards the identification of new potential therapeutic targets. In fact, epigenetic drugs are of particular interest to the clinic due to their reversible and transient effect. A limitation of epigenetic studies, however, are the variations among single cells (both on an individual and tissue level), which occur with an even higher frequency in aged organisms. This biologically relevant heterogeneity might be further investigated, understood and potentially deconstructed with the help of new technological approaches like single-cell genomics. Together, characterizing molecular changes in different species during aging using state-of-the-art techniques will provide key insights into the relevance of epigenetics of aging and aging-associated diseases.

Link: https://doi.org/10.3390/ijms22010401

Researchers here note that in many people visual decline precedes the more evident worsening of Parkinson's disease as it progresses. Similar mechanisms of neurodegeneration contribute to both manifestations of aging. Neurodegenerative conditions are the result of many interacting processes that collectively harm function in the brain, from the structural issues resulting from vascular aging, to failing mitochondrial function, to the formation of protein aggregates. These processes give rise to numerous distinct forms of loss of function, and thus people who exhibit any one of those losses are more likely to develop the others.

A new study adds to evidence that vision changes precede the cognitive decline that occurs in many, but not all, people with Parkinson's. A second new study found that structural and functional connections of brain regions become decoupled throughout the entire brain in people with Parkinson's disease, particularly among people with vision problems. The two studies together show how losses and changes to the brain's wiring underlie the cognitive impairment experienced by many people with Parkinson's disease.

In the first study, researchers studied 77 people with Parkinson's disease and found that simple vision tests predicted who would go on to get dementia after a year and a half. Dementia is a common, debilitating aspect of Parkinson's disease, estimated to affect roughly 50% of people within 10 years of a Parkinson's diagnosis. These longitudinal findings add weight to previous studies that were done at one time point, which had suggested that performance in vision tests was linked to the risk of cognitive decline. Those who went on to develop Parkinson's dementia had white matter damage to some of the long-distance wiring connecting the front and back of the brain, which helps the brain to function as a cohesive whole network.

The second study involved 88 people with Parkinson's disease (33 of whom had visual dysfunction and were thus judged to have a high risk of dementia) and 30 healthy adults as a control group, whose brains were imaged using MRI scans. In the healthy brain, there is a correlation between how strong the structural (physical) connections between two regions are, and how much those two regions are connected functionally. That coupling is not uniform across the brain, as there is some degree of decoupling in the healthy brain, particularly in areas involved in higher-order processing, which might provide the flexibility to enable abstract reasoning. Too much decoupling appears to be linked to poor outcomes.

The researchers found that people with Parkinson's disease exhibited a higher degree of decoupling across the whole brain. Areas at the back of the brain, and less specialised areas, had the most decoupling in Parkinson's patients. Parkinson's patients with visual dysfunction had more decoupling in some, but not all brain regions, particularly in memory-related regions in the temporal lobe.

Link: https://www.ucl.ac.uk/news/2021/jan/eye-tests-predict-parkinsons-linked-cognitive-decline-18-months-ahead

Accumulation of lingering senescent cells is an important mechanism of aging, as these errant cells secrete a potent mix of molecules that spurs chronic inflammation and degrades nearby tissue structure and function. Evidence has emerged for the presence of senescent supporting cells in the brain, such as microglia and astrocytes, to contribute to many different neurodegenerative diseases. Animal studies in which first generation senolytic drugs are used to clear senescent cells from the brain have show that such treatments are capable of reversing some forms of neurodegenerative pathology, such as the neuroinflammation and tau aggregation characteristic of tauopathies.

In today's open access paper, the authors report on an assessment of the numbers of what they term dystrophic microglia in human brains, cells that are most likely senescent but not conclusively determined to be so. They find that the numbers of these dystrophic cells are elevated in neurodegenerative conditions when compared to similarly aged controls without clear neurodegenerative disease. Aging progresses at a somewhat different pace from individual to individual, and differences in the burden of senescent cells - perhaps due to exposure to pathogens in the case of microglia and other immune cells - may be an important determinant of differences in the rate of aging and risk of age-related disease.

Dystrophic microglia are associated with neurodegenerative disease and not healthy aging in the human brain

Inflammation and cellular senescence are hallmarks of aging. Almost two decades ago, dystrophic microglia were described with beading and fragmentation of the branches of the microglia. In contrast to the hypertrophic microglia often seen following central nervous system injury, the dystrophic microglia were proposed to be a form of microglia senescence. While there is no single specific marker of cellular senescence, a handful of markers, such as p16INK4a, have some affinity for identifying senescent cells. Using a p16INK4a approach to target the removal of senescent cells in a mouse model of tauopathy resulted in reduced tau pathology, neuronal degeneration, and cognitive deficits. Given the necessary cellular stressors, microglia can become senescent/dystrophic.

Throughout the body, cellular senescence is associated with the secretion of inflammatory mediators, defined as the senescence-associated secretory phenotype. Even a small number of senescent cells in any organ can contribute to disease and by the spread of the senescence phenotype to neighboring healthy cells. The hypothesis that dystrophic microglia is an age-associated microglia morphology has not been experimentally tested. While cellular senescence generally increases with age, it can occur at any stage of life in response to stressors. This led our first question: are dystrophic microglia associated with chronological age in people? We hypothesized that with increasing years, there would be an increasing proportion of dystrophic microglia. Previous work, including our own, has found dystrophic microglia in aged humans without neurodegenerative pathology.

In contrast to the view that dystrophic microglia are purely an age-related change in microglial morphology, there is compelling evidence that dystrophic microglia are more closely associated with neurodegenerative disease. Previous studies identified dystrophic microglia in people with age-related neurodegenerative disease, including Alzheimer's disease (AD). These findings lead to our second question: is increased dystrophic microglia a disease associated phenomenon? We hypothesized that the absolute numbers, and/or percentage of dystrophic microglia, would be greater in people with neurodegenerative disease than age-matched controls.

To address these questions, we studied brains from the University of Kentucky Department of Pathology and the UK-ADRC biobank, covering the adult lifespan from 10-90+ years of age. Stereological counts of the total number of microglia, number of hypertrophic microglia, and the number of dystrophic microglia were conducted in 3 brain regions: hippocampal CA1, frontal cortex, gray matter, and white matter. We found that in the absence of neurodegenerative disease, there was only a modest increase in dystrophic microglia with age. However, with neurodegenerative pathology, the percentage of microglia observed to be dystrophic was much greater than aged-matched controls.

Capillary networks are very dense, hundreds of capillaries passing through any given square millimeter of tissue. This network of microvessels is necessary to supply tissues with oxygen and nutrients. Unfortunately it declines in density with age, for reasons that are not well understood in detail. This likely contributes meaningfully to age-related loss of function, particularly in energy-hungry tissues such as muscles and the brain. Researchers here illustrate that loss of capillary density as observed in the retina - the eyes being a convenient window into that outpost of the central nervous system - correlates with the progression of neurodegeneration in the brain. Some thought should go towards finding the means to encourage greater maintenance and formation of capillary networks throughout the body.

The retina and brain share many neuronal and vasculature characteristics, and potential biomarkers may be present in the retina. Previous studies have analyzed digital fundus photographs and reported a range of retinal vessel alterations in patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI). However, images obtained from this technique can only provide information of retinal arterioles and venules measuring 60-300 μm in diameter. Optical coherence tomography angiography (OCTA) is a recent innovation that allows for further quantification of the retinal microvasculature and visualization of capillaries measuring 5-15 μm in diameter, which may be more representative of the entire microvascular network. Thus, the OCTA may be a potential non-invasive optical imaging tool to determine the presence and role of microvascular dysfunction in AD and cognitive impairment.

While there are a few OCTA studies investigating AD, there have been mixed conclusions. Some researchers reported finding significant reduction in the vessel density (VD) only in the superficial plexus, which complements histology findings and OCT studies since the superficial plexus mainly supplies the inner retinal layer. However, others reported finding changes only in the deep plexus. Studies have also used OCTA to examine participants with MCI, who are at higher risk for dementia and AD, but have drawn conflicting results as well.

To address these gaps, the purpose of the current study is to compare the retinal microvasculature metrics using OCTA, accounting for potential measurement bias and projection artifacts in participants with AD, MCI, and controls. We hypothesize that alterations in OCTA metrics as characterized by sparser vessel density and loss of vessel complexity will occur predominately within the superficial capillary plexus, in AD and to a lesser extent in MCI compared to controls.

24 AD participants, 37 MCI participants, and 29 controls were diagnosed according to internationally accepted criteria. OCTA images of the superficial and deep capillary plexus (SCP, DCP) of the retinal microvasculature were obtained using a commercial OCTA system. The main outcome measures were vessel density (VD) and fractal dimension (FD) in the SCP and DCP within a 2.5-mm ring around the fovea which were compared between groups.

Compared with controls, AD participants showed significantly sparser VD in both plexuses whereas MCI participants only showed reduction at the superficial plexus. In terms of FD, AD and MCI participants exhibited a loss of vessel complexity of the SCP when compared with controls. Our study adds further to the concept that there are possible progressive differences in retinal microvascular alterations between AD and MCI. Taken together with increasing evidence from other research, our current study demonstrates that differences in retinal microvascular changes using OCTA may potentially be used to identify and screen for AD and earlier cognitive phenotypes (i.e., MCI).

Link: https://doi.org/10.1186/s13195-020-00724-0

In the midst of a discussion regarding the limitations of life span studies, in that the use of death as an endpoint fails to capture all of the variances in health due to aging, the authors of this paper offer up the thought that aging is contagious within the body. Declines in one cell spread to another, directly or indirectly. Consider that the secretions of senescent cells can make nearby cells senescent. Declines in one tissue can spread to another, directly or indirectly. Consider that the progressive failure of kidney function produces cardiovascular and cognitive dysfunction as a result, because the vascular system and the brain are so very dependent on the environment that the kidney is primarily responsible for maintaining. What might we take from this line of thinking? Perhaps that every form of repair therapy can be helpful, and equally that any one form of repair might not be enough, and the details matter in every case.

Given the complex heterogeneities of cell and tissue aging in any single individual and the notion of the most rapidly aging tissues being the driver of the aging of that organism, do those more rapidly aging tissues accelerate the aging of other tissues in the body? Does the aging of one cell affect the age of another cell? Is aging contagious? The notion of the aging process spreading from one cell to another is highlighted by the field of cellular senescence. The secretome of senescent cells has been shown to induce senescence of neighboring cells. In that sense, there can be cellular leaders that accelerate the aging of other cells in the tissue.

The notion of cell-to-cell spreading of cellular dysfunction is of course not limited to the biology of senescence. This is becoming an increasingly recognized phenomenon in the pathogenesis of neurodegenerative diseases. In many diseases, including Alzheimer's disease, Huntington's disease and Parkinson's disease, a cardinal feature of the pathology is intracellular aggregation of proteins. While seemingly a cell-intrinsic phenomenon, one of the curious features of the pathology of these diseases is the apparent spread of the cellular abnormalities to anatomically connected brain regions.

The general concept of this kind of spreading proteinopathy from one cell to another, locally, arises from the biology of prions and prion diseases. Of course, some prions are truly contagious, in the sense of being transmissible between individuals or across species, but the spread within the central nervous system of an individual suggests cell-to-cell spread. As with senescence, this phenomenon could represent the conversion of cells from one state (free from aggregates) to another (aggregate-laden) since protein aggregation can be self-propagating. As protein aggregation is one of the key features of cellular aging, it is intriguing to consider the possibility of aged cells achieving a sufficiently dysfunctional state as a result of protein aggregation, then conferring an aging signal to nearby cells through non-cell autonomous regulation of proteostasis.

If aging is indeed contagious, is the spread restricted to neighboring cells or might it spread to distant tissues via the systemic circulation? Based on early work from our laboratories that ushered in a new era of the use of the technique of parabiosis in aging research, it is clear that systemic factors originating from distant tissues in the body are able to either promote or reverse cell and tissue aging phenotypes. These findings, as well as many follow-up studies, including the demonstration that plasma infusions alone are sufficient to exert these effects, have unequivocally demonstrated that factors in the blood are able to communicate information from one or more source tissues to other tissues throughout the body. These could potentially accelerate, delay, or even reverse the rate of aging of other tissues in the body. Indeed, studies of brain endothelial cell aging showed that infusion of aged plasma can accelerate while young plasma can reverse aging as determined by analysis of the transcriptome. These studies highlight the fact that cellular aging does not occur independent of influences that are both local and systemic.

Link: https://doi.org/10.1038/s43587-020-00015-1

For a few years now, I've suggested areas of opportunity in rejuvenation biotechnology in which either (a) it seems quite viable to start a company, given what I've seen going on in industry and academia, or (b) it would be very helpful should someone step up with an approach that works, given the need for a solution. The longevity industry is still young, still small, and countless valuable programs in the aging research field remain waiting to be championed and carried forward to the clinic. The low-hanging fruit is still near all there to be claimed: what is possible is a far greater space than what is presently being attempted.

A Gene Therapy Platform that Just Works

The primary challenges in gene therapy are easily stated: express genes for (a) a controllable length of time, (b) to a useful degree in specific tissues without overloading other tissues, (c) with a high degree of coverage of cells in the tissues of interest. It would be nice to also have (d) at a reasonable cost, but cost will come down given a platform that can be used for most gene therapies and hits points (a) through (c). That there isn't a good off-the-shelf approach that can be directly and easily applied to an arbitrary gene therapy in an arbitrary tissue is hindering development.

At present plasmid delivery via more recent varieties of lipid nanoparticle, with expression made selective to cell type by use of appropriate promoters, looks like it may be able to achieve the goal of a general gene therapy platform useful for most therapies, given further advances in the technical capabilities of existing platforms. That said, near all gene therapy delivery technologies have the issue that when delivered systemically via intravenous injection, 80% or more of the injected vector will end up in the liver. Thus there must be a way to make that excess a non-event while still getting a useful amount of vector into the tissue of interest. Perhaps this could be solved by more sophisticated and much safer means of direct injection of internal organs, or more sophisticated carriers that can be steered to specific locations in the body before releasing their gene therapy cargo. Regardless, it seems plausible that there is some combination of the many approaches demonstrated in the laboratory or presently in clinical development that could result in a Gene Therapy Platform that Just Works for a majority of treatments.

Repurpose Fecal Microbiota Transplantation for the Treatment of Frailty

Repurposing an existing therapy is considerably easier than building a new one. Fecal microbiota transplantation is used to treat conditions in which the gut has been overtaken by pathological bacteria, and works quite well. The gut microbiome deteriorates with age, becoming more inflammatory, alongside a reduced production of the beneficial metabolites needed by the body. It has been demonstrated that transplanting gut microbes from young animals to old animals restores a more youthful microbiome, and as a consequence improves health and extends life span. Bringing that same approach to humans will require only modest refinement of the existing protocols, with perhaps more of an emphasis on screening out potentially harmful microbial species that a young immune system is better equipped to handle. Treating frailty by rejuvenating the gut microbiome might be a good option for a new development program, given that chronic inflammation is an important contributing cause of the condition.

Hematopoietic Cell Mobilization for Revascularization

The density of capillary networks throughout the body declines with age. This is likely quite important in loss of tissue function, particularly in muscle and brain, as these organs have a high need for nutrients and energy. The process of generating new blood vessels, particularly in response to injury, involves hematopoietic cells leaving their bone marrow niche and migrating to the area of injury. In connection with hematopoietic stem cell transplantation, a range of drugs are presently employed to provoke this exit of hematopoietic cells from the bone marrow into the circulatory system, where they can be easily harvested via drawing blood. These compounds target proteins such as CXCL12, CXCR4, CDC42, or their receptors, all involved in regulating the mechanisms that determine whether hematopoietic cells leave their niches. Can these mechanisms, and the state of the art in this part of the field, be used to increase capillary and other vessel density in uninjured individuals?

Regrow the Thymus to a Greater Degree than the Intervene Immune Approach

COVID-19 has hopefully made more people aware of the importance of age-related immunosenescence to declining health and resilience in later life. A sizable part of the decline of the immune system is the result of the atrophy of the thymus. Intervene Immune demonstrated that thymic rejuvenation is practical, and that it can measurably improve immune system function in aging humans, even when the degree of regrowth is only modest. Now we need more companies - beyond Lygenesis and Repair Biotechnologies - hard at work on better approaches that are capable of (a) producing much larger degrees of thymic regrowth, and (b) being made safe and cost-effective enough to be delivered to the entire adult population. There are many strategies that could in principle achieve the first goal, but the second is a tall order.

Make Worthwhile Treatments for Aging Accessible to the Masses

A number of possible approaches to the treatment of aging appear to pass the cost-benefit calculation, are therapies that exist today, and can be used by the medical community as off-label treatments. Examples include the first generation senolytic drugs that have undergone human trials, such as the dasatinib and quercetin combination. We might also consider periodic plasma dilution to reduce damaging signaling in the aging body. And so forth. The adoption of these approaches by physicians and clinics will be slow and patchy, and there is an opportunity here for companies that can accelerate this approach. Consider a venture like AgelessRx, for example, but with a much higher bar on the quality of treatments offered. Or physician network providers, or a chain of clinics, or a coordinated effort to make medical tourism work for senolytic therapies, wherein every older person in the US is a potential customer. There are many possibilities here in the ecosystem of medical services.

Platforms for the Destruction of Metabolic Waste

A very wide variety of metabolic waste is involved in aging. Misfolded proteins, some of which form amyloids, advanced glycation end-products, altered cholesterols, all sorts of garbage molecules that end up in the lysosome, and so on. Each of these categories contains many different molecular species, found in different places inside and outside the cell, requiring different classes of approach to find and break down. One universal platform for all unwanted molecules in the body isn't a feasible prospect, but there must still be a more efficient approach to break down or sequester or otherwise deal with the many different molecules in each specific location. Platforms are needed, approaches that can be cost-effectively customized to attack many molecules with very different characteristics. The catalytic antibody platform of Covalent Bioscience is one illustrative example. Another might be a company that uses recently developed techniques for culturing arbitrary bacterial species in order to efficiently mine soil and ocean bacteria for the tools they use to break down specific problem molecules, and which can serve as the basis for enzyme therapies.

Restore Youthful Hematopoietic Function

A complex hierarchy of hematopoietic cells in bone marrow is responsible for generating all immune cells, but this system runs awry with age. It begins to generate too many myeloid cells, and the hematopoietic cells themselves become inherently damaged, as well as dysfunctional in response to signaling changes, such as those that accompany chronic inflammation. Next to regrowth of the thymus, rejuvenation of hematopoiesis is the other important component needed to restore an aged immune system to more youthful function. The most direct of potential approaches is the transplantation of new hematopoietic stem cells. The older the patient, the more damaged the existing population, and the more likely it is that this will be necessary. But there are other approaches that might be taken earlier, such as adjusting signaling, protecting existing hematopoietic cells, changing the behavior of supporting stem cell niche cells, and so forth. This is a field which has for some years seemed on the verge of generating a viable approach to a rejuvenation therapy, and many lines of research are at the point at which they could in principle transition to clinical development. Champions are needed.

There are a great many ways to influence cellular metabolism to modestly slow the pace of aging, but few of them are of lll that much interest from a practical point of view, as a basis for therapies that might meaningfully extend human life spans. If an approach involves improvements in mitochondrial function and less than a 10% increase in life span in a short-lived species such as flies, as is the case here, then it is only of academic interest to scientists who closely study the intersection between metabolism and degenerative aging. Improvements in life span in short-lived species achieved in this manner, via changes in mitochondrial function, scale down dramatically when the same approach is tried in longer-lived species. Thus this method of slowing aging is unlikely to be any better for human health than the well-described outcomes of eating somewhat less or exercising somewhat more.

One approach to identify new traits responsible for aging is to compare how these traits change with age in control and long-lived animals of the same species. For example, centenarians have a distinctive epigenetic profile compared to an age-matched control population. Similarly, we previously showed that flies with increased longevity have dramatic differences in many metabolites associated with methionine metabolism even at 1 week of age when 100% of both control- and long-lived flies are still alive.

To identify novel metabolic pathways that correlate with lifespan and that can be responsible for aging, we compared the metabolome of 1-week- and 4-week-old wild-type and long-lived flies to identify changes in metabolites that correlate with lifespan and identified tyrosine as an age-dependent metabolite. We demonstrate that Drosophila has a single tyrosine aminotransferase (TAT). Whole-body or neuronal-specific downregulation of TAT as well as other downstream enzymes in the tyrosine degradation pathway significantly extend Drosophila lifespan, cause alterations of multiple metabolites associated with increased lifespan, and lead to an increase in tyrosine and tyrosine-derived neuromediators (dopamine, octopamine, and tyramine). We further demonstrate that mitochondrial dysfunction may serve as an age-dependent stimulus that redirects tyrosine from neuromediator production into mitochondrial metabolism.

In conclusion, our studies highlight the important role of the tyrosine degradation pathway and position TAT as a link between neuromediator production, dysfunctional mitochondria, and aging.

Link: https://doi.org/10.7554/eLife.58053

NAD+ levels in the mitochondria decline with age, and this is a proximate cause of reduced mitochondrial function. Approaches to increasing levels of NAD+ in aging cells have been shown to improve metabolism and mitochondrial function in mice, but the evidence is mixed in humans for there to be any meaningful effect on age-related conditions. The common approaches to NAD+ upregulation, meaning supplementation with derivatives of vitamin B3, such as nicotinamide riboside, are about as effective as structured exercise programs in increasing NAD+ levels.

There is the suspicion that taking this shortcut - without adding all of the other metabolic effects of exercise - could increase the harms done by problem cells in the aging body, such as senescent cells and cancerous cells, by allowing them greater activity. The evidence is sparse for this to be the case, but it is a concern amongst researchers. The research noted here adds a little more weight to the concern side of the scales.

In the 1920s, German chemist Otto Warburg discovered that cancer cells don't metabolize sugar the same way that healthy cells usually do. Since then, scientists have tried to figure out why cancer cells use this alternative pathway, which is much less efficient. Researchers have now found a possible answer to this longstanding question. They showed that this metabolic pathway, known as fermentation, helps cells to regenerate large quantities of a molecule called NAD+, which they need to synthesize DNA and other important molecules. Their findings also account for why other types of rapidly proliferating cells, such as immune cells, switch over to fermentation.

Fermentation is one way that cells can convert the energy found in sugar to ATP, a chemical that cells use to store energy for all of their needs. However, mammalian cells usually break down sugar using a process called aerobic respiration, which yields much more ATP. Cells typically switch over to fermentation only when they don't have enough oxygen available to perform aerobic respiration. Warburg originally proposed that cancer cells' mitochondria, where aerobic respiration occurs, might be damaged, but this turned out not to be the case. Other explanations have focused on the possible benefits of producing ATP in a different way, but none of these theories have gained widespread support.

Researchers treated cancer cells with a drug that forces them to divert a molecule called pyruvate from the fermentation pathway into the aerobic respiration pathway. They saw that blocking fermentation slows down cancer cells' growth. Then, they tried to figure out how to restore the cells' ability to proliferate, while still blocking fermentation. One approach was to stimulate the cells to produce NAD+, a molecule that helps cells to dispose of the extra electrons that are stripped out when cells make molecules such as DNA and proteins. When the researchers treated the cells with a drug that stimulates NAD+ production, they found that the cells started rapidly proliferating again, even though they still couldn't perform fermentation.

This led the researchers to theorize that when cells are growing rapidly, they need NAD+ more than they need ATP. During aerobic respiration, cells produce a great deal of ATP and some NAD+. If cells accumulate more ATP than they can use, respiration slows and production of NAD+ also slows. Therefore, switching to a less efficient method of producing ATP, which allows the cells to generate more NAD+, actually helps them to grow faster. "Not all proliferating cells have to do this. It's really only cells that are growing very fast. If cells are growing so fast that their demand to make stuff outstrips how much ATP they're burning, that's when they flip over into this type of metabolism. So, it solves, in my mind, many of the paradoxes that have existed."

Link: https://news.mit.edu/2021/cancer-cells-waste-energy-0115

The mainstream of the scientific community has for decade after decade followed an entirely incorrect strategy in the matter of aging, and it was only comparatively recently that this state of affairs was changed for the better by the advocacy of groups like the SENS Research Foundation, Methuselah Foundation, and their allies, alongside advances in the science of slowing and reversing aging that couldn't be easily dismissed, much of that funded by philanthropy rather than established institutions. Given a poor strategy, in which age-related diseases were studied separately from aging, and in their end stages, and without considering their root causes, it isn't all that surprising to find that treating age-related disease progressed poorly and incrementally. The only way to effectively treat age-related conditions is to address their deeper causes, which is to say the mechanisms of damage that lie at the root of aging, such as accumulation of senescent cells.

The commentary I'll point out today has its origin in the National Institute on Aging hierarchy. While reading, it is worth bearing in mind that there is often a great deal of hindsight and positioning in any one individual's explanations for why aging was largely ignored as a cause of disease, and why efforts to treat aging as a medical condition were actively discouraged for decades. The existence of the anti-aging marketplace - a noisy pit of fraud, lies, and false hope - had as much to do with the reluctance of the academic community to engage meaningfully with the treatment of aging as any ivory tower miscategorizations that placed aging and age-related disease in different buckets. Regardless of cause, it is a tragedy that so much time was lost and wasted in the matter of aging, with a cost in tens of millions of lives for every year of delay in the arrival of meaningfully effective rejuvenation therapies.

Reflections on aging research from within the National Institute on Aging

Sixty years ago, Nathan Shock created the Baltimore Longitudinal Study of Aging, and his idea was that we needed to dissociate aging from disease, because only at that point would we know what disease is and how to treat patients. There was an interest in trying to understand aging so that we could ignore it, because there was nothing that we could do about it. And then, as researchers started to look at aging and began searching for the point of dissociation between aging and disease, they found that it was much more difficult than expected. As our technologies became more developed and sophisticated, the boundaries between aging and diseases continued to blur.

The risk factor paradigm started with cardiovascular and cancer epidemiology; the basic idea is that if you wait a certain amount of time, risk factors will trigger a disease. People initially thought that there was some specificity between risk factors and diseases, but over time we have discovered that this specificity was not really there. Exercise and physical activity can reduce the risk of developing cardiovascular diseases, cancers, pulmonary diseases, sarcopenia, and so on. Smoking increases the risk of developing these diseases, too. You can say the same thing for many different risk factors that are being considered. Cancer and cardiovascular disease, the two major causes of mortality, share many of the same risk factors. Think about obesity: it's associated with most chronic diseases that you can think of. And so there has been a shift in how we have considered aging, from something that we needed to account for and eliminate by statistical adjustment to a causal factor in disease. And I think that it makes a lot of sense.

This explains why aging is a much stronger risk factor for dementia than carrying an APOE4 allele. This shift in thinking is important because it places aging at the forefront of medicine. Now, if this is true, understanding aging provides the strongest chance to prevent chronic diseases and expand healthspan. This shift creates incredible opportunities, and even private companies have started to become interested in studying aging.

Mitochondria are the power plants of the cell, producing adenosine triphosphate (ATP) to power cellular processes. When mitochondrial function declines all cell functions are negatively affected as a consequence. Many age-related conditions clearly involve mitochondrial dysfunction, particularly in the most energy-hungry tissues, the muscles and the brain.

In addition to damage to the fragile mitochondrial DNA, some forms of which cause a small number of cells to become pathologically broken in ways that actively harms surrounding tissues, all mitochondria throughout the body become more worn and dysfunctional with age. Their dynamics change, the organelles becoming larger and more resistant to the quality control process of mitophagy. The deeper roots of this sweeping decline, and all of the gene expression changes that accompany it, are unclear, but many proximate contributing causes have been identified. Loss of NAD+, reduced expression of mitochondrial fission genes, dysfunction in specific portions of the mitophagy machinery, and so forth.

Efficient skeletal muscle bioenergetics hinge on mitochondria, and mitochondrial dysfunction is recognized as a major hallmark of aging. Indeed, protecting mitochondria is a determinant to preserve proteostasis in skeletal muscle. To date, a growing body of evidence on mitochondrial impairment in sarcopenia has been provided by both animal and human studies. Dysfunctional mitochondria are associated with both ATP depletion and ROS/RNS excess, with the consequent activation of harmful cellular pathways. A decrease in mitochondrial mass, activity of tricarboxylic acid cycle enzymes, as well as O2 consumption and ATP synthesis occurs in aged skeletal muscle tissue. Changes in function, dynamics, and biogenesis/mitophagy could explain in part alteration in oxidative capacity and content of skeletal muscle mitochondria. Furthermore, mitochondrial dysfunction induces the activation of apoptosis, potentially impairing skeletal muscle quality.

Several mitochondrial functions are impaired in old in comparison to young skeletal muscle, including the activity of metabolic enzymes and oxidative phosphorylation (OXPHOS) complexes (i.e., citrate synthase and cytochrome c oxidase), respiration, protein synthesis, and ATP production rate. The reduced mitochondrial content in aged skeletal muscle may be also related to lower PGC-1α gene and protein expression. However, the molecular mechanisms that underpin this reduction are worth further investigation. Apart from PGC-1α, different studies show divergent results in the levels of its downstream transcription factor Tfam in old skeletal muscle.

Changes related to mitochondrial content and function in old skeletal muscle may also be related to a reduced amount, increased mutations, deletions, and rearrangements of mitochondrial DNA (mtDNA). A greater prevalence of mtDNA deletion mutations is described in skeletal muscle fibers, which were more subjected to oxidative damage. An age-dependent increase in skeletal muscle fibers presenting with alterations of mitochondrial enzymes due to mtDNA deletion mutations is reported both in rhesus monkeys presenting with early-stage sarcopenia and in humans.

Morphological studies in aged skeletal muscle show giant mitochondria with disrupted cristae. Altered morphology in old skeletal muscle mitochondria may be the consequence of impaired mitochondrial dynamics, with a disbalance in favor of fission rather than fusion. Mutations in mtDNA may lead to dysregulation of mitochondrial dynamics in sarcopenia, as suggested by results from old mice expressing a defective mtDNA polymerase gamma, which showed higher mitochondrial fission in skeletal muscle. A shift toward mitochondrial fusion rather than fission was also reported in skeletal muscle of very old hip-fractured patients.

The reduced capacity of skeletal muscle cells to remove damaged organelles could be another cause of mitochondrial alteration in aging. Studies performed on rodent models describe controversial results on mitophagy modulators in aged skeletal muscle. A further investigation reported data indicative of increased mitophagy but lysosomal dysfunction in skeletal muscle from old mice, suggesting that lysosomal dysfunction may cause accumulation of disrupted mitochondria. Nevertheless, further investigation on the role of mitophagy in old skeletal muscle is needed in humans.

Link: https://doi.org/10.3390/biology10010031

Intermittent fasting (such as alternate day fasting) is not as effective as calorie restriction (consistent reduction in calories every day) in extending life span in animal models such as mice, but it does have many of the same effects on health and longevity. Even when total calorie intake is held consistent between intermittent fasting animals and controls, there are still benefits that accrue to the fasting animals. One might conclude that time spent in a state of hunger, with all of the signaling and changes in cell behavior that comes with it, is a meaningful component of the benefits derived from calorie restriction.

In contrast to the short and very frequent fasting periods of intermittent fasting (IF), periodic fasting (PF) or a fasting mimicking diet (FMD) last in most cases between 2 and 7 days (2-3 days in mice and 4-7 days in humans) and are followed by a high-nourishment refeeding period of at least 1 week. Another major difference from IF is that PF can be periodic and does not have to be carried out at a specific interval, but can be applied for one or several cycles either as a preventive measure or to treat a specific disease or condition. FMDs were developed to promote the effects of fasting while standardizing dietary composition, providing nourishment and minimizing the burden and side effects associated with water-only fasting. These steps are necessary for PF and possibly IF to move toward approval from the US Food and Drug Administration and standard-of-care applications.

Sixteen-month-old female C57BL/6 mice placed on a periodic 4-day FMD twice per month, alternating with a normal diet, display an 11% increase in their median lifespan, in addition to significant weight and visceral-fat loss, without loss of muscle mass. Moreover, FMD cycles reduce tumor incidence by 45% and delay tumor development. Notably, the FMD cycles also promote changes leading to an immune-system profile in 20.5-month-old mice more similar to that of younger mice (4 months old), in agreement with the effect of PF on hematopoietic stem cell (HSC)-dependent regeneration of immune cells.

In summary, similarly to the well-established effects of calorie restriction, FMD cycles delay the onset and reduce the incidence of age-related diseases, but achieve this with minimal or no long-term reduction in calorie intake and with positive effects on immunity and a targeted reduction in visceral fat. Thus, PF/FMD but potentially also certain dietary restrictions, including IF, may achieve many beneficial effects by mechanisms that are independent of reduced calorie intake.

Link: https://doi.org/10.1038/s43587-020-00013-3

Today's open access review paper is a high level look at what the newfound realization of the importance of senescent cells to aging and age-related disease means for the treatment of chronic kidney disease. At present there are few good options for treatment, and those therapies that are widely used can only slow the progression towards kidney failure. The kidneys filter waste and regulate many of the chemical and other characteristics of blood. Correct function of the kidneys is vital to the correct function of many other organs in the body, including heart, vascular system, and brain. As the kidneys decline, so too does heart function and cognitive function, among other vital processes.

The evidence from animal studies of cellular senescence in recent years demonstrates that the age-related accumulation of senescent cells is important in the onset and progression of chronic kidney disease. The targeted destruction of senescent cells via senolytic drugs has been shown to reverse aspects of kidney aging and damage, an otherwise challenging goal. Lingering senescent cells actively maintain a degraded state of tissue function via inflammatory and other secretions, the senescence-associated secretory phenotype (SASP). Remove the senescent cells and the SASP, and tissues quite quickly revert to a more youthful behavior. An early senolytic treatment for chronic kidney disease is presently being trialed in humans, and more such trials will follow from the numerous biotech companies working on novel senolytic therapies.

Implication of cellular senescence in the progression of chronic kidney disease and the treatment potencies

The prevalence of chronic kidney disease (CKD) has reached epidemic proportions, with approximately 10% of the total population show declined kidney function. Actually, during the disease progression, the majority of lesions develop into the end-stage renal disease (ESRD), a devastating condition that requires renal replacement treatment, including kidney transplant and dialysis. Remarkably, CKD not only shares numerous phenotypic similarities with kidney ageing, such as glomerular sclerosis, interstitial fibrosis, tubular atrophy, loss of repair capability, and vascular rarefaction, but also exhibits systemic geriatric phenotypes, for instance vascular calcification, persistent uraemic inflammation, cognitive dysfunction, muscle wasting, osteoporosis, and frailty.

The most common markers applied to identify cellular senescence include the overexpression of cyclin-dependent kinase (CDK) inhibitors such as p16ink4a and p21. Interestingly, the expression levels of p16ink4a and the activity of SA-β-gal are elevated in different stages of CKD and some kinds of original kidney diseases. These unexpected alternations indicate that cellular senescence may play important roles in the progression of CKD. The precise roles of cellular senescence in CKD are not fully understood currently. Nonetheless, it is proposed that targeting senescent cells in the kidney might serve as a novel therapeutic strategy for CKD treatment.

Numerous studies have demonstrated that the selectively elimination of senescent cells contributes to the improvement of healthy lifespan and benefits the outcomes of a wide range of age-related diseases. Some of them have shown significant potentials in reversing renal ageing. For example, the combination of dasatinib and quercetin, referred as "D + Q", is an effective senolytic and reduces the overall senescent cell burden in chronologically aged mice. Actually, D + Q has been tested in ageing diabetic kidney disease patients, and the administration of D + Q showed reduced adipose tissue p16ink4a and p21 expression, SA-β-gal activity, and circulating SASP-acquisition factors. Other senolytic molecules, such as Flavonoids (e.g., apigenin and kaempferol) have been proved to strongly inhibit the SASP acquisition in the kidney of aged rats. These findings have opened an exciting new therapeutic avenue for the treatment of CKD and its complications via selectively targeting senescent cells.

Many forms of mild cellular stress produce benefits to health because they trigger the more efficient operation of cellular maintenance processes such as autophagy. That in turn causes better cell and tissue function, and thus improved health. This stress response and benefit is known as hormesis, and has been robustly proven to take place for calorie restriction, heat, cold, low dose ionizing radiation, and numerous other environmental circumstances. When it comes to slowing aging, the benefits of hormesis to life span are much larger in short-lived species. The short-term changes to metabolism are very similar, however, regardless of species longevity. Reconciling this apparent paradox will require a far greater understanding of metabolism and aging at the detail level than presently exists. Meanwhile, we should not expect the application of hormetic therapies to produce effects that are all that much better than regular exercise or the practice of calorie restriction.

Hormesis is any kind of biphasic dose-response when low doses of some agents are beneficial while higher doses are detrimental. Radiation hormesis is the most thoroughly investigated among all hormesis-like phenomena, in particular in biogerontology. In this review, we aim to summarize research evidence supporting hormesis through exposure to low-dose ionizing radiation (LDIR). Radiation-induced longevity hormesis has been repeatedly reported in invertebrate models such as C. elegans, Drosophila, and flour beetles and in vertebrate models including guinea pigs, mice, and rabbits. On the contrary, suppressing natural background radiation was repeatedly found to cause detrimental effects in protozoa, bacteria, and flies.

We also discuss here the possibility of clinical use of LDIR, predominantly for age-related disorders, e.g., Alzheimer's disease, for which no remedies are available. There is accumulating evidence that LDIR, such as those commonly used in X-ray imaging including computer tomography, might act as a hormetin. Of course, caution should be exercised when introducing new medical practices, and LDIR therapy is no exception. However, due to the low average residual life expectancy in old patients, the short-term benefits of such interventions (e.g., potential therapeutic effect against dementia) may outweigh their hypothetical delayed risks (e.g., cancer). We argue here that assessment and clinical trials of LDIR treatments should be given priority bearing in mind the enormous economic, social, and ethical implications of potentially-treatable, age-related disorders.

Link: https://doi.org/10.1007/s10522-020-09908-5

Different individuals can have very different degrees of vulnerability to any given cancer, depending on how aggressively the adaptive immune system responds to that cancer. Researchers here explore some of the mechanisms in T cells responsible for varying vulnerability to cancers - it many cases it is blind luck as to whether or not the T cell population is capable of immediately recognizing a specific lineage of cancerous cells. That T cells are so important to the cancer response may explain why the age-related decline of the thymus correlates very well with rising cancer risk. The thymus is where thymocytes mature into T cells, but the organ atrophies with age, causing a progressive reduction in the number of new T cells entering the immune system. Those missing cells lower the odds of the immune system being able to recognize a specific cancer cell lineage as a threat.

Researchers have established a mouse model to help them understand why some hosts' immune systems reject tumors easily, while others have a harder time doing so. The scientists started the research by transplanting tumors into genetically identical mice. Theoretically, their response to the cancer would be identical, but it turned out that 25% of the mice spontaneously rejected the tumor. The researchers started looking more closely at both the mice and the tumor cells to try to understand what was causing the mice to kill the cancer on their own.

What they discovered is that it all depended on the types of the immune cells known as CD8 T cells that were present in the mouse. Even identical twins have different T cells due to the random DNA recombination event generating these T cells, so the genetically identical mice had different arrays of the T cells as well. The mice's response to cancer depended on how their specific T cells matched up with the set of mutated proteins known as neoantigens that were present in the tumor they were fighting.

"Each of your T cells has a different receptor, and each T cell will be specific to a neoantigen. If you have T cells that are specific to all of them or majority of them, you're going to be able to get rid of your tumor and have a good anti-tumor immune response." The researchers showed that the mice that spontaneously rejected tumors had vastly different T cell receptors from those that succumbed to tumor development.

Link: https://news.cuanschutz.edu/cancer-center/role-of-t-cells-in-fighting-cancer

Advanced glycation endproducts (AGEs) are a form of metabolic waste, sugary compounds that can interact harmfully with structures and cells in the body. A few forms of persistent AGE can form lasting cross-links in the extracellular matrix that change the structural properties of tissues, contributing to the loss of elasticity in skin and blood vessels, for example. Most AGEs are transient compounds, however, associated with the abnormal metabolism of diabetes and the chronic inflammation of aging. Dietary AGEs may also be influential on levels of AGEs in the body, though the size of this contribution is arguable - the body is quite capable of manufacturing significant amounts of AGEs even without a dietary component.

Transient AGEs cause chronic inflammation and harmful changes to cell behavior by interacting with the receptor for AGEs (RAGE). In today's open access research paper, researchers show that this contributes meaningfully to the progression of degenerative disc disease, impacting the maintenance of collagen in intervertebral discs. Inhibition of RAGE signaling is thus a potential target for therapies, though finding a way to suppress levels of AGEs - or address causes of rising amounts of AGEs - sounds like a better class of approach.

Advanced glycation end products cause RAGE-dependent annulus fibrosus collagen disruption and loss identified using in situ second harmonic generation imaging in mice intervertebral disk in vivo and in organ culture models

Aging and diabetes are identified as risk factors associated with increased intervertebral disk (IVD) degeneration degeneration and back pain. These associations may be attributed to chronic proinflammatory conditions, yet these associations are confounded by environmental and genetic factors, making causal relationships difficult to identify. A leading hypothesis for a relationship between diabetes and IVD degeneration is the formation and accumulation of advanced glycation end products (AGEs) in diabetic IVD tissue. AGEs are highly oxidant compounds that accumulate in aging and are implicated in diabetic complications that are known to cause structural and biological alterations to collagen and the extracellular matrix (ECM).

There is mounting evidence for a causal relationship between IVD degeneration and AGEs. AGEs can accumulate in spinal tissues from aging, high-AGE (H-AGE) diets (eg, highly processed western diets) and diabetes, and are associated with structural changes in the IVD including decreased glycosaminoglycan content, increased vertebral bone changes, and increased collagen degradation. In addition, the receptor for AGEs (RAGE) has been observed to initiate an NF-kB mediated inflammatory response in both human and mice IVD tissue exposed to AGEs.

The specific structural changes to the IVD ECM due to AGE exposure in the presence of RAGE are not well-understood and we believe this is partly due to limitations in the methods used to identify early degenerative changes to the ECM that mark the initiation of a degenerative cascade. Recently, we demonstrated that dietary accumulation of AGEs in the IVD increased levels of molecular level collagen degradation, highlighting the direct contributions that AGEs can make to IVD degeneration.

This two-part study used in vivo and ex vivo IVD model systems with wild type and RAGE-knockout (RAGE-KO) mice in order to investigate changes in AF collagen quality and degradation in response to AGE challenges. First, we used SHG imaging on thin sections with an in vivo dietary mouse model and determined that high-AGE (H-AGE) diets increased annulus fibrosus (AF) fibril disruption and collagen degradation resulting in decreased total collagen content, suggesting an early degenerative cascade. Next, we used in situ imaging with an ex vivo IVD organ culture model of AGE challenge on wild type and RAGE-knockout (RAGE-KO) mice and determined that early degenerative changes to collagen quality and degradation were RAGE dependent. We conclude that AGE accumulation leads to RAGE-dependent collagen disruption in the AF and can initiate molecular and tissue level collagen disruption.

To suffer or become incapacitated is to diminish the utility of being alive. The way to minimize this loss is to work towards removing the causes of suffering and incapacitation. The greatest such causes are medical, and of those, aging is by far the largest. Similarly, to die is to suffer the loss of all that one might have been and done after that time. It is a tragedy that any individual ceases to exist. The way to minimize this loss is to work to remove the causes of death. The greatest such causes are medical, and of those, aging is by far the largest. Ethically, the case for working to extend healthy human life spans by treating aging as a medical condition is very straightforward. Objections are trivial in the face of more than one hundred thousand deaths every day, tens of millions every year, and the ongoing suffering of hundreds of millions more.

Will life-extension treatments be prohibitively expensive? The diabetes drug metformin is a classic candidate for a possible anti-aging pill. And the cost of this possible wonder drug? Retail costs for 60 tablets of 500mg of metformin (a 1-2 month supply) range from $9 to $16, even without insurance. Other potential life-extension molecules are similarly cheap. Glucosamine costs as little as ten cents a pill, has been the subject of several recent studies showing it decreases all-cause mortality by as much as 39%, and may be as effective for longevity as exercise.

What about newer anti-aging medicines? Is there evidence that newly discovered and developed drugs would be similarly inexpensive? It's likely. Take vaccines. Vaccines are a good parallel to anti-aging medicines because they are developed to treat a deadly, widespread disease that impacts large swaths of the human population and they thus have a huge demand and a requirement to distribute to the most people possible. Developing a vaccine can cost as much as $2.8-$3.7 billion and yet many vaccines, including those for the most widespread diseases, are offered free-of-cost or at very low prices. For example, the flu vaccine is often free and almost always fully-covered by insurance. Other vaccines can be had, even without insurance, for as low as $6.

If, despite the above, life-extension treatments are expensive, if they are gene therapies for example, will they remain so? In the last 17 years, the cost to have your whole genome sequenced has gone from roughly $1 billion in 2003, to as low as $299 today. And most technological innovation follows this same pattern. First an experimental, expensive innovation is developed. Wealthy early-adopters buy it (think investment bankers and car phones back in the 80s), and their purchases fund the research and development needed to improve the innovation, better distribute it, and make it less expensive. Soon, every person who wants one can afford it, and at a much higher level of quality than the original that was available only to the rich.

High initial prices of a new product are thus almost an extended form of R&D funding (and clinical testing with data provided by early adopters). The rich are essentially paying the money necessary to further develop the product and get it to the masses. What the rich pay for with money, the poor pay for with time. It's the reason the smartphone in your pocket only costs a couple hundred dollars, and you don't need to lug a car around to use it. It's also the reason your Apple Watch isn't the size of a room, and yet can do way more health monitoring than the early electrocardiogram machines could (and at a significantly lower price).

Intuitively, anti-aging medicine should even help lower the total cost of medical care for people, as individuals will have to spend less on treating the very expensive chronic diseases of old-age like Alzheimer's or cancer. These health-cost savings from longevity medicine are often referred to as the "Longevity Dividend." Contrary to popular belief, the real money in almost any market is not in selling boutique treatments to a few billionaires, but selling commercialized interventions to the millions (and, globally, billions) in the middle and lower classes.

Link: https://www.longevityadvice.com/ethics-life-extension/

The SENS Research Foundation scientific staff here discuss the recent results demonstrating benefits to an aged metabolism resulting from dilution of blood plasma. Plasma dilution is a comparatively simple process, straightforward enough that self-experimenters with the support of physicians recently replicated the animal study protocol in a few human volunteers. Dilution of blood plasma also dilutes harmful signal molecules present in an aged body, such as those generated by an increased burden of lingering senescent cells. This reduces chronic inflammation and improves tissue function in older individuals.

When researchers surgically conjoin the circulatory systems of a young and an old animal, something remarkable happens: the older animal recovers some features of youth, while the young animal becomes functionally older. This phenomenon is called heterochronic parabiosis. A possible player in the pro-aging/rejuvenating effects of parabiosis that has been largely ignored until recently is the potential role of metabolic toxins and wastes. In addition to the cellular and molecular damage of aging that accumulates in our bodies over time, the body's normal metabolic processes also produce an enormous amount of more transient metabolic waste every day. In youth, much of what could go to waste is instead reprocessed and reused, and the rest is detoxified and excreted.

As we age, however, the organs responsible for detoxifying and eliminating these wastes - the kidneys, the liver, and to a lesser extent the lungs - age along with the rest of us, and their ability to remove these wastes progressively degrades. As a result, waste levels in blood circulation rise with age. These metabolic toxins are definitely bad for us - just ask a patient waiting for a liver transplant or on haemodialysis. Consistent with this, a biomarker called cystatin C, the most reliable marker of loss of kidney function, is a powerful predictor of broader age-related decline.

At the urging of SENS Research Foundation CSO Aubrey de Grey, and with SRF funding, pioneering parabiotic researchers Michael and Irina Conboy conducted a study to tease out the role of access to a young animal's organs in the parabiosis effect in 2015. Researchers built a machine capable of exchanging volumes of blood at will, replacing them with equal volumes of blood (or plasma, or other substitute fluid). They found that the benefits of directly trading old blood for young were dramatically less impressive than the effects of full-on parabiosis complete with the filtering and detoxification services provided by young liver and kidney function.

On the other hand, receipt of young blood did enhance the repair of old animals' muscles after injury, although the effects were less impressive than what's seen in parabiosis - and in this case, there was no inhibitory effect on the muscles of young animals exposed to old blood. Similarly, the ability of an old animal's injured liver to regenerate was enhanced by young blood, and existing age-related fibrosis improved. These experiments show that these health effects are not mediated primarily by removal of metabolic wastes, though certainly they could still be mediated by dilution effects rather than true active-factor transfers.

By this point, a direct test of the dilution hypothesis would seem to be in order - and recently the Conboys ran one. With the blood-replacement machine up and running, they replaced half the blood of old mice - not with young blood, but with saline solution, plus an amount of the albumin protein family equivalent to that in blood, to avoid losing albumin's important non-signaling functions in transporting different substances around the body. Like young blood itself, this "neutral blood exchange" (NBE) substitute (as they called it) would lack all of the pro-aging factors that an old mouse's blood would contain (as well as the metabolic sludge its aging organs would have failed to remove) - but, importantly, would not contain any of the pro-youth molecules that some think are responsible for the effects of heterochronic parabiosis.

Remarkably, a single NBE treatment rejuvenated muscle repair capacity of old mice to equivalent levels of quite young control animals, including major improvements in the number of muscle stem cells engaged to regenerate the damaged muscle, the area of muscle where such cells were active, and in the level of fibrosis left behind. NBE also significantly improved liver health in old animals, partially reversing their fibrosis and reducing the pathological fat deposits in the organ.

Link: https://www.sens.org/parabiosis-the-dilution-solution/

Evidence to date suggests that disruption of the pathways by which fluid clears from the brain is important in the development of neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, and many others. These conditions are associated with raised amounts of specific forms of metabolic waste in the brain, including aggregates of amyloid-β, that are harmful to cell function. In a young brain, drainage of cerebrospinal fluid from the brain carries away some fraction of these wastes. As drainage pathways are disrupted with age, however, the balance between processes of creation and removal is altered in favor of an ever-increasing presence of amyloid-β and other metabolic byproducts in brain tissue.

One drainage pathway for cerebrospinal fluid is the cribriform plate, behind the nose. This structure ossifies with age, reducing fluid flow. When permeable, the cribriform plate route allows drainage from the olfactory bulb region of the brain, and the company Leucadia Therapeutics is founded on the thesis that loss of cribriform plate drainage is exactly why Alzheimer's pathology, and the buildup of amyloid-β, first appears in the olfactory bulb. Studies conducted by Leucadia staff have recreated this process in ferrets, and the company plans to develop a therapy based on implanting a small device into the cribriform plate in order to restore drainage of cerebrospinal fluid.

Another interesting discovery of recent years, and the subject of today's open access paper, is the existence of the glymphatic system. This is a more general drainage route for cerebrospinal fluid. The glymphatic system, like the cardiovascular system and lymphatic system, also declines in function with age. This decline may well contribute to rising levels of metabolic waste throughout the brain. The evidence for this proposition is still in the early stages of assembly, but is so far fairly convincing.

Dysfunction of the Glymphatic System Might Be Related to Iron Deposition in the Normal Aging Brain

Iron is an electron facilitator and is involved in many brain functions, including oxygen transport, myelin production, electron transfer, and neurotransmitter synthesis. Both imaging and postmortem analyses have shown that the concentration of iron in the brain is not uniform. Previous studies have demonstrated that iron accumulates in the normal aging brain, which might damage cognitive function. However, the exact mechanism of iron deposition in the aging brain remains unclear.

Recent work has led to the discovery of the "glymphatic system," which is a coined phrase that combines "gl" for glia cell with "lymphatic system". Within the glymphatic system, cerebrospinal fluid enters the brain via peri-arterial spaces, passes into the interstitium via astrocytic aquaporin-4, and then drives the peri-venous drainage of interstitial fluid and its solute. Evidence suggests that the glymphatic system is an important fluid clearance system in the brain. Numerous neurological disorders have been found to be closely related to the dysfunction of the glymphatic system, including Alzheimer's disease and Parkinson's disease.

Evidence also revealed that iron deposition was one of the most important underlying mechanisms in Alzheimer's disease and Parkinson's disease. Some scholars also believe that the glymphatic system may be the major contributory factor to the deposition and clearance of iron in brain tissue, but evidence is still lacking. In this study, we recruited 213 healthy participants. We evaluated the function of the glymphatic system using the index for diffusivity along the perivascular space (ALPS-index), assessed iron deposition on quantitative susceptibility mapping (QSM), and analyzed their relationship. The main finding of the current study is that the regional brain iron deposition was related to the function of the glymphatic system.

Previously, the glymphatic system has been speculated to be responsible for the clearance and homeostasis of waste in the brain. Our results support that in a healthy aging brain, the glymphatic system might also be involved in the clearance of iron, suggesting that iron metabolism shared the same pathway as other waste metabolisms. Moreover, a study has demonstrated that injury of the microvasculature and capillary-level microhemorrhages coincided with amyloid beta (Aβ) deposits in senile plaques. Iron deposition plays an important role in cerebral small vessel diseases. Therefore, we inferred that dysfunction of the glymphatic system might lead to the damage of microvasculature via deposition of Aβ, then leading to iron deposition.

A few papers in recent years have reviewed what is known of the role of the mitochondrial permeability transition pore in aging. Mitochondria are the power plants of the cell, and mitochondrial function is vital to cell and tissue function. Unfortunately, mitochondria become dysfunctional with age, for a variety of reasons that have yet to be firmly traced back to specific root causes. Researchers are engaged in the exploration of proximate causes, such as changing mitochondrial dynamics and loss of mitophagy, the quality control mechanism responsible for removing worn and damaged mitochondria. Changes in the activity of mitochondrial permeability transition pores are also on the list, though as for many of these mechanisms, it is yet to be determined where it fits exactly in the hierarchy of proximate cause and proximate consequence in the final stages of the path to mitochondrial failure in aging.

The mitochondrial permeability transition pore (mPTP) is a mitochondrial inner membrane multicomponent mega-channel that is activated by calcium, oxidative stress, and membrane depolarization. The channel exhibits several conductance states with variable duration. When activated, protons flow into the matrix, while calcium, superoxide, hydrogen peroxide, and other ions flow out of the matrix, thus inhibiting oxidative phosphorylation.

It is now recognized that mitochondrial dysfunction is a major contributor to aging and aging-driven degenerative disease, such as diabetes, heart diseases, cancer, Alzheimer's disease, and Parkinson's disease. Mitochondrial dysfunction in aging is often manifested as the excess production of mitochondrial reactive oxygen species (mROS), calcium overloading, and membrane depolarization. Since these dysfunctions are known to activate mPTP, it can be expected that mPTP activity will be enhanced in dysfunctional mitochondria in aging. Indeed, direct evidence for enhanced mPTP activation in aging and neurodegenerative disease is extensive.

mPTP activity accelerates aging by releasing large amounts of cell-damaging reactive oxygen species, Ca2+, and NAD+. The various pathways that control the channel activity, directly or indirectly, can therefore either inhibit or accelerate aging or retard or enhance the progression of aging-driven degenerative diseases and determine lifespan and healthspan. Autophagy, a catabolic process that removes and digests damaged proteins and organelles, protects the cell against aging and disease. However, the protective effect of autophagy depends on mTORC2/SKG1 inhibition of mPTP. Autophagy is inhibited in aging cells. Mitophagy, a specialized form of autophagy, which retards aging by removing mitochondrial fragments with activated mPTP, is also inhibited in aging cells, and this inhibition leads to increased mPTP activation, which is a major contributor to neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases.

The increased activity of mPTP in aging turns autophagy/mitophagy into a destructive process leading to cell aging and death. Several drugs and lifestyle modifications that enhance healthspan and lifespan enhance autophagy and inhibit the activation of mPTP. Therefore, elucidating the intricate connections between pathways that activate and inhibit mPTP, in the context of aging and degenerative diseases, could enhance the discovery of new drugs and lifestyle modifications that slow aging and degenerative disease.

Link: https://doi.org/10.3390/cells10010079

Mitochondria are the power plants of the cell, packaging chemical energy store molecules through the activities of electron transport chain protein complexes. Some forms of interference in the operation of these complexes can be beneficial, causing mild stress that provokes the cell into greater maintenance activities. This usually results in better cell function, greater cell resilience, and so forth, leading to better organ function and a slowing of the aging process. Researchers here demonstrate that this sort of approach is beneficial in a mouse model of Alzheimer's disease, reducing the damage done to neurons. It is, nonetheless, a compensatory approach, not a form of repair that addresses underlying issues. The utility is necessarily limited, as those underlying issues remain in place, still causing all the other downstream harms they are capable of.

Recent studies demonstrated that altered energy homeostasis associated with reduced cerebral glucose uptake and utilization, altered mitochondrial function and microglia and astrocyte activation might underlie neuronal dysfunction in Alzheimer's disease (AD). Intriguingly, accumulating evidence suggests that non-pharmacological approaches, such as diet and exercise, reduce major AD hallmarks by engaging an adaptive stress response that leads to improved metabolic state, reduced oxidative stress and inflammation, and improved proteostasis. While mechanisms of the stress response are complex, AMP-activated protein kinase (AMPK)-mediated signaling has been directly linked to the regulation of cell metabolism, mitochondrial dynamics and function, inflammation, oxidative stress, protein turnover, Tau phosphorylation, and amyloidogenesis. However, the development of direct pharmacological AMPK activators to elicit beneficial effects has presented multiple challenges.

We recently demonstrated that mild inhibition of mitochondrial complex I (MCI) with the small molecule tricyclic pyrone compound CP2 blocked cognitive decline in transgenic mouse models of AD when treatment was started in utero through life or at a pre-symptomatic stage of the disease. Moreover, in neurons, CP2 restored mitochondrial dynamics and function and cellular energetics. However, it was unclear whether MCI inhibition would elicit similar benefits if administered at the advanced stage of the disease, after the development of prominent Aβ accumulation, brain hypometabolism, cognitive dysfunction, and progressive neurodegeneration. As a proof of concept, we demonstrate that partial inhibition of MCI triggers stress-induced AMPK-dependent signaling cascade leading to neuroprotection and a reversal of behavior changes in symptomatic APP/PS1 female mice, a translational model of AD. Beneficial effect of treatment could be monitored using translational biomarkers currently utilized in clinical trials.

Link: https://doi.org/10.1038/s42003-020-01584-y

The primary challenge in Alzheimer's disease research has long been that short-lived laboratory species do not naturally exhibit any of the features of the condition. Thus all mouse models of the condition are highly artificial genetic constructs, and potential treatments and relevant mechanisms in these models have a high chance of being irrelevant to Alzheimer's disease as it exists in humans. Up until fairly recently it could be argued that humans were in fact the only species to exhibit full blown Alzheimer's disease, involving a lengthy increase in amyloid-β aggregation in the brain, followed by neuroinflammation, tau aggregation, and widespread cell death.

However, in recent years the study of chimpanzee brains - as well as a variety of other species - suggests that some might exhibit enough of the mechanisms of Alzheimer's disease to be said to suffer from it in old age. This is also the case in the aging of dolphins. In today's open access paper, researchers report on more signs of Alzheimer's mechanisms in the brains of sea lions, seals, and walrus. This is all interesting, but doesn't much help the state of Alzheimer's research in practice. None of these large mammal species are likely to be used in laboratories any time soon. Even if they were, it would not be for early stage discovery and exploration.

Amyloid β and tau pathology in brains of aged pinniped species (sea lion, seal, and walrus)

Alzheimer's disease (AD) is the most prevalent age-related neurodegenerative disorder and is characterized by the pathological aggregation of the amyloid-β (Aβ) and hyperphosphorylated tau (hp-tau) proteins in the form of senile plaques (SPs) and neurofibrillary tangles (NFTs), respectively. The accumulation of Aβ in the blood vessels of the brain, a condition known as cerebral amyloid angiopathy (CAA), is also detected in more than 80% of patients with AD. Humans appear to be uniquely susceptible to AD, potentially due to genetic differences, changes in cerebral structures and functions during evolution, and an increased lifespan. In the "amyloid hypothesis", the most acknowledged explanation for the pathogenesis of AD, the age-dependent accumulation of fibrillar insoluble Aβ peptides in the brain is considered to be the central and triggering event in AD pathology. Based on this hypothesis, various transgenic mouse models that produce human Aβ beyond physiological levels have been generated and exhibit the massive formation of SPs. However, they fail to develop NFTs and neuronal loss unless mutant tau is simultaneously introduced.

While AD appears to be a human-specific disease, age-dependent SP formation has been reported in several non-human primates, including chimpanzees, orangutans, and gorillas. The concomitant pathology with the formation of a small amount of NFTs was found in chimpanzees and rhesus macaques, while the oligodendroglial tau pathology was also detected in cynomolgus monkeys. Therefore, an AD-like pathology may occur during aging in primates. In contrast, non-primate animals, particularly Carnivora species, have exhibited species-specific patterns of Aβ and hp-tau accumulation. In the suborder Caniformia, aged dogs and bears developed SPs in their brains, but not NFTs, even in the oldest subjects. On the other hand, Feliformia species, such as cats, leopard cats, and cheetahs, exhibit NFTs without SP formation, although small granular deposits of Aβ were detected in the cerebral cortex.

Pinnipeds are semiaquatic carnivorans that spend most of their lives in water, and use coastal terrestrial environments and ice packs to breed, molt, and rest. They are currently classified into three families: Phocidae (seals), Otariidae (fur seals and sea lions), and Odobenidae (walruses). We herein describe the Aβ and hp-tau pathology in the brains of aged pinniped species. Molecular analyses revealed that the sequence of pinniped Aβ was identical to that of human Aβ. Histopathological examinations detected argyrophilic plaques composed of Aβ associated with dystrophic neurites in the cerebral cortex of aged pinnipeds. Astrogliosis and microglial infiltration were identified around Aβ plaques. Aβ deposits were observed in the blood vessel walls of the meninges and cerebrum.

Histopathological examinations revealed argyrophilic fibrillar aggregates composed of phosphorylated tau (hp-tau) in the neuronal somata and neurites of aged pinniped brains. Furthermore, the activation of GSK-3β was detected within cells containing hp-tau aggregates, and activated GSK-3β was strongly expressed in cases with severe hp-tau pathologies. The present results suggest that, in association with Aβ deposition, the activation of GSK-3β contributes to hp-tau accumulation in pinniped brains.

Klotho is one of the few robustly demonstrated longevity-associated genes. Greater expression extends life in mice, while reduced expression shortens life. Present investigations of the mechanisms by which klotho produces effects on life span are largely focused on the direct actions of klotho in the kidney, and then the effects of kidney function on broader health. Kidney function influences cardiovascular decline and the aging of other organs through a variety of mechanisms. While klotho level is well known to correlate with the degree of cognitive decline with age, this is most likely a demonstration of the importance of kidney function and cardiovascular function on overall health. The brain suffers when its supporting organ systems suffer.

Klotho is a membrane-bound protein acting as an obligatory coreceptor for fibroblast growth factor 23 (FGF23) in the kidney and parathyroid glands. The extracellular portion of its molecule may be cleaved and released into the blood and produces multiple endocrine effects. Klotho exerts anti-inflammatory and antioxidative activities that may explain its ageing suppression effects evidenced in mice; it also modulates mineral metabolism and FGF23 activities and limits their negative impact on cardiovascular system.

Clinical studies have found that circulating Klotho is associated with myocardial hypertrophy, coronary artery disease, and stroke, and may also be involved in the pathogenesis of salt-sensitive hypertension with a mechanism sustained by inflammatory cytokines. As a consequence, patients maintaining high serum levels of Klotho not only show decreased cardiovascular mortality but also non-cardiovascular mortality.

These findings suggest that Klotho may represent a bridge between inflammation, salt sensitivity, hypertension and mortality. This may be particularly relevant in patients with chronic kidney disease who have decreased Klotho levels in tissues and blood.

Link: https://doi.org/10.1093/ckj/sfaa100

Researchers here show that an iron chelation drug (deferoxamine, brand name desferal) triggers a portion of the cellular reaction to hypoxia in bone marrow. Hypoxia is one of the many types of stress that, when mild, induces cells to greater efforts in maintenance and repair, resulting in a net gain in cell function. In the rats treated with deferoxamine in this study, the hypoxia mimetic acts to reduce the burden of cellular senescence, and otherwise shift the behavior of cells in the direction of slowing the onset of osteoporosis.

Bone marrow stromal cells (BMSCs) exist in the bone marrow with multi-potency and have a broad application prospect in the field of cell therapy and regenerative medicine thanks to their accessibility and expansion potential. Previous study showed a high potential association between BMSC senescence and age-related bone loss. Several studies have documented that age drives the intrinsic alterations of BMSCs, including decreased proliferation and osteogenic differentiation potential, as well as increased senescence-associated gene expression and β-galactosidase-positive staining. It also reported that the viability of aged BMSCs decreased, and senescent BMSCs were more likely to differentiate into adipocytes. These changes led to the decrease in quantity and quality of BMSCs, which together contributed to age-related bone loss.

Oxygen is a fundamental element of the bone marrow niche, and a hypoxic environment in the bone marrow is generally considered to be indispensable for retaining normal physiological function and self-renewal of stromal cells. As the key transcription factor response to hypoxia stress, hypoxia-induced factor 1α (HIF-1α) is a highly unstable protein in normoxic conditions. However, under hypoxic conditions, the catalytic activity of prolyl hydroxylases (PHD) is inhibited, leading to the stabilized expression of HIF-1α. Some small molecules, such as deferoxamine (DFO), are known as hypoxia mimics, which can elevate HIF-1α levels by blocking PHD activity even in normoxic conditions.

In this study, Desferal, deferoxamine mesylate for injection, which is approved for the treatment of acute iron intoxication and chronic iron overload, was used to explore the beneficial effects on preventing aging-induced bone loss and mitigating dysfunction of aged BMSCs. High-dose Desferal significantly prevented bone loss in aged rats. Compared with controls, the ex vivo experiments showed that short-term Desferal administration could promote the potential of BMSC growth and improve the rebalance of osteogenic and adipogenic differentiation, as well as rejuvenate senescent BMSCs and revise the expression of stemness/senescence-associated genes. The potential of BMSCs from the Desferal group at least partly revised to the level close to that of the 2-month-old group.

Link: https://doi.org/10.1186/s13287-020-02112-9

The SENS Research Foundation represents the best of charitable organizations working on the treatment of aging as a medical condition. It is well run, focuses on approaches capable of rejuvenation rather than merely modestly slowing aging, devotes funds and attention towards those projects in rejuvenation research that most need support in order to advance, and has a great track record when it comes to helping development programs to make the leap from academic laboratories to commercial development in startup biotech companies.

The SENS Research Foundation is near entirely supported by philanthropy, including the donations of a community of thousands of everyday visionaries, people just like you and I who want to see meaningful progress towards therapies capable of sizable degrees of human rejuvenation. For some years now, the SENS Research Foundation has run an annual year end fundraiser, bringing in millions in funding. Those funds were used well in helping to advance the state of the art in rejuvenation research.

On that topic, I'm pleased to note that last year's fundraiser, concluding a few short weeks ago, succeeded in raising more than $2 millon to help fund the rejuvenation-focused projects of 2021. From the latest SENS Research Foundation newsletter:

SENS Research Foundation supporters, thank you for going above and beyond with your generosity, especially at the end of such a difficult year. Your commitment to helping #UnlockLongevity brought in $2,355,443.46 - more than doubling our end of year campaign fundraising goal of $1M! Special thanks to Michael Antonov, Brendan Iribe, Karl Pfleger, Jim Mellon, Cameron Bloomer, Dave Fisher, Christophe Cornuejols, Didier Coeurnelle, and Larry Levinson for their matching grants during the campaign, as well as to all of you who donated at every level.

Your support means SENS Research Foundation can hit the ground running as we start 2021, with exciting research progress, facility upgrades, and more on the horizon. It means so much to us to have a community behind us that truly shares our vision of a world free of age-related disease, and is willing to help do what it takes to make such a world a reality sooner rather than later.

Metformin is a poster child for the way in which much of the aging research community is focused on approaches to aging that cannot possibly achieve more than a very modest slowing of degeneration, and where the existing evidence strongly suggests that those tiny positive outcomes will be unreliable at best. Metformin is a way to tinker with the operation of a damaged metabolism, not a way to repair that damage. As a calorie restriction mimetic, the animal data shows that it compares very poorly to calorie restriction itself. We know that calorie restriction doesn't do anywhere near enough for human longevity. This is not the way forward to human rejuvenation.

Although current research gives promise to metformin as an anti-aging drug, there are still concerns that need to be highlighted, and they apply not only to research into metformin but to other anti-aging mechanisms and drug research as well. First, despite the positive outcomes from many studies, it is not uncommon to find a change in dosage turning the result from life-extending to life-ending. When a low dose of metformin (0.1%) was given to middle-aged male mice with their diet, their lifespans were extended by 5.83% on average, but a higher concentration (1%) became toxic.

Another issue standing in the way relates to the side effects associated with chronic use of drugs. About 25% of patients treated with metformin have gastrointestinal side effects. Besides, chronic use of metformin can cause dose-dependent vitamin B12 deficiency, increasing the risk for anemia and neuropathy. Future research should also work to elucidate how gender influences drug effectiveness. Metformin increased mean lifespan of female mice by 4.4% while decreasing that of male mice by 13.4%. Male pre-diabetic patients who received metformin had a significantly lower coronary calcium score compared with control, while the female group did not.

The issues of dosage, side effects, sexual dimorphism, and genetic regulatory mechanisms all point to the need for large-scale clinical trials. The Metformin in Longevity Study (MILES) involved 14 older than 70 year-old people who were randomized to take metformin and placebo in either order each for six weeks with a two-week washout period in between. As the number of subjects was small and the duration short, MILES effectively revealed many transcriptomic and metabolomic changes in the muscle and adipose tissue. The Glucose Lowering In Non-diabetic hyperglycaemia Trial (GLINT) is intended to evaluate the performance of metformin in reducing CVD risks by following 20,000 hyperglycemic but non-diabetic patients for five years. A one-year feasibility RCT enrolling 249 elderly, obese, and with high CVD risk (mean 28.8%, SD 8.5%) participants was concluded in 2018, and metformin improved several CVD risk indicators and decreased vitamin B12 levels. However, it also revealed problems such as a high rate of trial discontinuation (30% by six months).

The Targeting Aging with Metformin (TAME) trial is a large placebo-controlled trial that is designed to enroll 3000 subjects to test whether metformin delays age-related diseases. The TAME trial received FDA approval in 2015, and after receiving all the required budget in 2019, it was set to start at the end of the same year. The TAME trial may make metformin the first approved drug for anti-aging, but, more importantly, since it is not testing metformin against a single disease but a collection of age-related ones, it establishes aging as a medical condition that can be intervened or treated instead of an irreversible process outside human control. The shift in the notion of aging will enable future anti-aging clinical to trials proceed with much more ease.

Link: https://doi.org/10.1002/agm2.12135

Senescent cells are created constantly throughout life in response to a range of circumstances, but only begin to accumulate in later life, once there is an imbalance between processes of creation (as a response to cell damage, for example) and processes of destruction (such as immune surveillance of senescent cells). Senescent cells secrete a potent mix of signals that, when sustained over time, provokes chronic inflammation and alters nearby cell behavior and tissue structure in detrimental ways. Researchers are only now attempting to catalog exactly how senescent cells cause harm, given the advent of senolytic therapies that allow a good assessment of the degree to which senescent cell accumulation contributes to specific degenerative processes in aging.

The sympathetic nervous system (SNS) is involved in a multitude of biological phenomena including stress, energy utilization, and physical activity; crucial physical functions that are regulated by the SNS include hemodynamics, temperature regulation, and metabolism. Overactivity of the SNS can result in types of chronic diseases, including cardiovascular disorders and hypertension. Multiple lines of evidence have demonstrated that sympathetic nerve density increases in tumor tissues.

Cellular senescence is implicated in several lines of aging-related disorders. However, the potential molecular mechanisms by which cellular senescence modulates age-related pathologies remain largely unexplored. Herein, we report that the density of sympathetic fibers (SFs) is significantly elevated in naturally aged mouse tissues and human colon adenoma tissues compared to the SFs densities in the corresponding young mouse tissues and human non-lesion colon tissues.

A dorsal root ganglion (DRG) and human diploid fibroblast co-culture assay revealed that senescent cells promote the outgrowth of SFs, indicating that the senescent cells induce recruitment of SFs in vitro. Additionally, subcutaneous transplantation of fibroblasts in nude mice shows that transplanted senescent fibroblasts promote SFs infiltration. Intra-articular senolytic molecular injection can reduce SFs density and inhibit SFs infiltration caused by senescent cells in osteoarthritis (OA), suggesting senescent cells promote the infiltration of SFs in vivo in aged tissues. Notably, the elevated level of SFs contributes to impaired cognitive function in naturally aged mice, which can be reversed by treatment with propranolol hydrochloride, a non-selective β receptor blocker that inhibits sympathetic nerve activity (SNA) by blocking non-selective β receptors.

Taken together, this study concludes that senescent cells secrete netrin-1 that mediates SFs outgrowth and infiltration, which contributes to aging-related disorders. This suggests that clearing senescent cells or inhibiting SNA is a promising therapeutic strategy for improving sympathetic nervous system (SNS) hyperactivity-induced aging-related pathologies.

Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772213/

Since the confirmation of cellular senescence as an important contributing cause of aging, a great many research initiatives have focused on the biochemistry of senescent cells, in search of new approaches to rejuvenation therapies. A common strategy in the life sciences is to deactivate genes one by one and observe the results, in search of suitable regulators to change cell behavior. In today's open access paper, researchers report on the results of such a screen of gene functions, identifying KAT7 as a gene important in the regulation of cellular senescence in at least the liver.

The researchers screened for gene function in cell cultures, but they used gene therapy in mice to demonstrate that KAT7 knockdown via CRISPR methods reduces cellular senescence in the liver, improves liver function, and extends mouse life span. They did not comment on other organ systems. The liver is the focus of this study most likely because it is the easiest organ to target via present gene therapy vectors. Something like 80% to 90% of any vector that is injected intravenously will end up in the liver. It is not completely clear how KAT7 reduces senescence, whether it is involved in more efficient destruction of senescent cells, or lowers the number of cells that become senescent in response to damage or signaling.

The question with all novel approaches to reducing the burden of senescence is whether they will do more harm than good - which is why it is important to check on longer term health and life span outcomes when conducting animal studies. Selectively destroying senescent cells is confirmed to be beneficial, increasing mouse health and life span. Preventing cells from becoming senescent, on the other hand, is beneficial in the short term, lowering the burden of inflammatory signaling generated by senescent cells, but could in principle raise the risk of cancer and other issues in the longer term, by allowing damaged cells to continue replicating. In the KAT7 work, the treated mice lived longer, an interesting outcome.

A genome-wide CRISPR-based screen identifies KAT7 as a driver of cellular senescence

Cellular senescence, a state of permanent growth arrest, has recently emerged as both a hallmark of aging and a fundamental driver of the aging processes. Senescent cells accumulate in tissues over time, triggering natural features of organismal aging and contributing to aging-related diseases (for example, hepatic steatosis and osteoarthritis). Prophylactic ablation of senescent cells expressing the senescence marker p16INK4A mitigates tissue degeneration and extends the health span in mice, indicating that senescent cells play a causative role in organismal aging. For example, senescent cells gradually accumulate in the degenerated liver, whereas clearing senescent cells from the liver attenuates the development of hepatic steatosis.

Understanding the genetic and epigenetic bases of cellular senescence is instrumental in developing interventions to slow aging. We performed genome-wide CRISPR-Cas9-based screens using two types of human mesenchymal precursor cells (hMPCs) exhibiting accelerated senescence. The hMPCs were derived from human embryonic stem cells carrying the pathogenic mutations that cause the accelerated aging diseases Werner syndrome and Hutchinson-Gilford progeria syndrome. Genes whose deficiency alleviated cellular senescence were identified, including KAT7, a histone acetyltransferase, which ranked as a top hit in both progeroid hMPC models.

Inactivation of KAT7 decreased histone H3 lysine 14 acetylation, repressed p15INK4b transcription, and alleviated hMPC senescence. Moreover, lentiviral vectors encoding Cas9/sg-Kat7, given intravenously, alleviated hepatocyte senescence and liver aging and extended life span in physiologically aged mice as well as progeroid Zmpste24-/- mice that exhibit a premature aging phenotype. KAT7 may represent a therapeutic target for developing aging interventions.

TGFβ is an important component of the inflammatory signaling of senescent cells, and cellular senescence is involved in the progression of numerous fibrotic and age-related conditions. Chronic inflammation causes tissue maintenance processes to run awry, and fibrosis, the inappropriate deposition of scar-like collagen structures that disrupt tissue function, is one of the possible outcomes. Here, researchers use an established class of compound to target this form of inflammatory signaling, finding that the treatment has a positive impact on fibrotic disease in animal models. This is consistent with other studies that have found that TGFβ is a useful target, in that suppressing TGFβ signaling can limit the harms done by senescent cells.

Fibrotic disease is a major cause of mortality worldwide, with fibrosis arising from prolonged inflammation and aberrant extracellular matrix dynamics. Compromised cellular and tissue repair processes following injury, infection, metabolic dysfunction, autoimmune conditions, and vascular diseases leave tissues susceptible to unresolved inflammation, fibrogenesis, loss of function and scarring.

There has been limited clinical success with therapies for inflammatory and fibrotic diseases such that there remains a large unmet therapeutic need to restore normal tissue homoeostasis without detrimental side effects. We investigated the effects of a newly formulated low molecular weight dextran sulfate (LMW-DS), termed ILB, to resolve inflammation and activate matrix remodelling in rodent and human disease models. We demonstrated modulation of the expression of multiple pro-inflammatory cytokines and chemokines in vitro together with scar resolution and improved matrix remodelling in vivo.

Of particular relevance, we demonstrated that ILB acts, in part, by downregulating transforming growth factor (TGF)β signalling genes and by altering gene expression relating to extracellular matrix dynamics, leading to tissue remodelling, reduced fibrosis, and functional tissue regeneration. These observations indicate the potential of ILB to alleviate fibrotic diseases.

Link: https://doi.org/10.1038/s41536-020-00110-2

The research community is making progress towards forms of low cost testing for Alzheimer's disease risk. At present, the well established tests are invasive or expensive. The very early stages of Alzheimer's disease, in which symptoms are mild or absent, are characterized by increasing levels of amyloid-β in the brain. However, amyloid-β in the brain is in a state of dynamic equilibrium with amyloid-β in the bloodstream, and in principle a suitable sensitive test can use a blood sample to assess the relevant aspects of amyloid-β burden. It takes years to validate predictions of Alzheimer's risk of course, and here researchers report on a lengthy but successful validation of one particular blood sample assay.

Using a blood test, a research team has predicted the risk of Alzheimer's disease in people who were clinically diagnosed as not having Alzheimer's disease but who perceived themselves as cognitively impaired. The cohort included 203 individuals. Using a test called the Immuno-Infrared Sensor, they identified all 22 subjects at study entry who developed Alzheimer's dementia, thus the clinical symptoms, within six years.

At study entry, blood samples were taken from all the participants and analyzed using the patented immuno-infrared sensor that detects misfolding of the amyloid-beta (Aβ) peptide, which is a biomarker for Alzheimer's disease. In addition, the subjects underwent extensive Alzheimer's disease diagnostic testing; at study entry, this did not provide a diagnosis of Alzheimer's disease in any of the subjects studied. The immuno-infrared sensor, on the other hand, detected misfolded Aβ peptides at study entry in all 22 subjects who developed the clinical disease in the following six years. In subjects who showed mild misfolding, it took on average longer (3.4 years) for conversion to clinical Alzheimer than in subjects with severe Aβ misfolding (2.2 years).

In addition, the team checked whether the combination of two different measurement methods in the plasma biomarker panel could further improve the prediction of disease risk. For this purpose, they combined the misfolding of all Aβ isoforms with a concentration decrease for Aβ42 as ratio to Aβ40 in plasma. This increased the assay accuracy. Such a blood test, which can detect the onset of Alzheimer's dementia even in the asymptomatic state, would be particularly useful if a drug were available to treat the disease.

Link: https://news.rub.de/english/press-releases/2021-01-06-protein-research-prognostic-alzheimers-disease-blood-test-symptom-free-stage

Having written retrospectives for 2020, longevity industry observers are now looking forward to what we might expect in 2021. This survey of companies and projects in the longevity industry is unbiased from the point of view of whether or not the treatments under development are expected to have a sizable effect on human aging. Can they slow aging or actually reverse aging meaningfully? It is more focused on progress on startups, business matters, and potential for profit.

One of the many issues with the highly regulated medical development market is that success in investment is only somewhat connected to success in generating a therapy. Liquidity events for investors in early stage biotech companies occur well before clinical approval by regulators, and thus incentives are not completely aligned. Merely fleshing out animal data and applying hype to a given mechanism (see the Sitris Pharmaceuticals story, for example) can work just as well as actually setting out to build a viable therapy that can have sizable effects on aging, when it comes to giving investors a sizable return on investment.

Further, the market values (a) incremental, modest advances that are easier to explain to regulators, and that fit in existing frameworks for evaluation over (b) radical, ambitious advances based on entirely new approaches that will require greater effort to obtain approval. In the treatment of aging as a medical condition, we need those radical, ambitious advances. The incremental, modest advances (such as yet another way to mimic calorie restriction, as if we need more of those) are not going to move the needle all that much on human life span. People will still be aging and dying in much the same way as their parents and grandparents did.

Top 10 Things to Watch in the Longevity Industry in 2021

Jim Mellon, billionaire patron saint of longevity investing, announced in September 2020 that he would take his longevity portfolio company, Juvenescence, public within 6-12 months. Juvenescence's diversified portfolio of 11 assets spans the gamut of senolytics, AI companies, regenerative medicine, and nutraceutical products. The Juvenescence IPO will be the biggest development in public market longevity investing since Unity Biotechnology went public in 2018. And because Juvenescence is a diversified portfolio of longevity companies it best represents the entire industry going forward.

Kristen Fortney's AI / computational drug discovery company BioAge recently closed a Series C round and will use the funds to initiate Phase 2 clinical trials this year. BioAge uses AI, machine learning, and systems biology models to mine multi-omics patient datasets and identify existing drugs that are likely to treat age-related disease. Since BioAge's strategy is to repurpose existing drugs they are able to go straight to Phase 2 trials.

Nir Barzilai recently gave an online talk with the Foresight Institute. In the talk he mentioned that an unnamed wealthy individual was in the process of setting up a longevity foundation that would invest $1 billion into anti-aging research and companies per year. Barzilai said the foundation would be announced in January of this year. Who could be the mysterious donor? Nir Barzilai indicated it is the same mysterious person that is funding the TAME trial and is a well known tech billionaire. My guess: It's Larry Ellison, founder of Oracle. He has a net worth of $88 billion and is 76 years old. Ellison has also donated to longevity causes in the past through the Ellison Medical Foundation. My second guess is Sergey Brin of Google.

2020 was a disastrous year for Unity Biotechnology. But 2021 could be a year of redemption for Unity. Their new Phase 1 trial for UBX1325, a Bcl-xL inhibitor to treat Diabetic Macular Edema (DME), will be completed in the first half of this year, with a proof of concept trial to follow shortly afterwards. I am cautiously optimistic for Unity Biotechnology. But I am also totally unworried if they fail, as there are many many other senolytics companies preparing for clinical trials - many with 2nd generation targeted approaches that may prove superior to Unity's.

2021 will be the year that more senolytics companies finally join Unity in the clinical race. And many of these companies are using 2nd gen targeted approaches to clear senescent cells. FoxBio, a Juvenescence and Ichor Therapeutics senolytics joint venture, is planning Phase 1 trials for an osteoarthritis drug this year. Numeric Biotech, a spin out from Erasmus Medical Center in the Netherlands, is planning to test the FOXO4-DRI peptide. Senolytic Therapeutics, one of David Sinclair's Life Biosciences daughter companies, has two mature assets that should be close to ready for clinical trials - although there is no set date.

I recently noticed this scientific commentary, published in a journal not specifically focused on aging. The author is far from the only person to have noticed that priorities in medical research and development do not seem to match up with the major causes of death all that well. It can't hurt to keep on pointing out that research into the most harmful biological processes in the world, meaning the mechanisms that cause aging, is very poorly funded and investigated in comparison to the vast and ongoing toll of death that results. Until aging is defeated, more funding for research into rejuvenation therapies will continue to be the most cost-effective way to improve the human condition.

Longevity means living a long life, nowadays often considered a life span over 85 to 100 years. More and more people reach this limit in modern welfare societies, and citizens aged 90 years and over are said to be the fastest increasing group of people. This is a reality, but what are the background factors for this development? Many scholars think that it is mostly due to societal factors like improved hygiene, proper diet and safer environment. These are important but have mainly established the sine qua non for reaching old age through living past dangerous childhood and earlier adult life and becoming old. In modern societies, reaching longevity is jeopardized more by chronic non-communicable diseases which have replaced infectious diseases as primary causes of morbidity and mortality. By the way, according to the latest Global Health Estimates by the World Health Organization, during the first half of 2020, non-communicable diseases killed approximately 25 times more people than the ongoing COVID-19 pandemic.

According to the Bible, 'The days of our years are threescore years and ten (70 years); and if by reason of strength they be fourscore years (80 years), yet is their strength labour and sorrow; for it is soon cut off...'(Psalm 90:10). This well accords with the thoughts of biogerontologists: the warranty period of homo sapiens is 65 years, where after on the average 20 years can be attained, mainly depending on life-course factors. Whilst age 85 years is an upper limit to life expectancy at the population level, ca. 40% of the original birth cohort nevertheless can reach 90 years, 5-6% 100 years, few 100-115 years, and only a handful of individuals over that.

The most common non-communicable diseases are cardiovascular diseases, chronic obstructive pulmonary diseases, cancer, and degenerative diseases. Many risk factors for them have been identified. Overall, it seems feasible that health span - healthy years of life - extension and successful ageing can be promoted with better and long-term cardiovascular risk factor control. However, for reaching 100 years and over the role of genetic factors affecting longevity strengthens. For most of the population, extending life span and especially health span over 90 years requires new methods to control the biological ageing processes, currently investigated in the realms of Geroscience, the Longevity Dividend, and the Global Roadmap for Healthy Longevity.

Link: https://doi.org/10.1111/joim.13211

Researchers here catalog the various mechanisms known to be involved in the development of Alzheimer's disease that occur as a result of the aging of the immune system. The immune system becomes less effective with age, but also constantly overactive. It generates constant and unresolved inflammatory signaling that damages tissue structure and disrupts tissue function. All of the common age-related conditions are accelerated and worsened by the chronic inflammation resulting from the age-damaged immune system.

Alzheimer's disease (AD) is the most common type of dementia characterized by progressive memory loss, visual-spatial impairment, executive dysfunction, and personality and behavioral changes. The pathological features of AD are neuritic plaques, neurofibrillary tangles, neuronal and synaptic loss, and the activation of microglia. Over the past few decades, the amyloid cascade hypothesis has dominated the field of AD research, suggesting that amyloid-β (Aβ) deposition is the central event in AD pathology. However, recent findings have challenged this hypothesis and argue that Aβ protects the brain from infection, and its aggregation promotes microglia-mediated neuroinflammation. The viewpoint that altered immune and inflammatory responses may play the main role in the progression of AD has increasingly been recognized.

In recent years, research is making significant progress and proposes that immunosenescence actively participates in the pathogenesis of AD and mediates inflammatory damage. Microglia are innate immune cells that reside in the brain and play an important role in maintaining homeostasis and immune defense. Microglia undergo significant changes in the aging brain. Morphologically, aged microglia exhibit cytoplasmic hypertrophy and branch reduction. Functionally, senescent microglia show higher proliferative capacity and production of proinflammatory cytokines, but reduced chemotaxis and ability to clear Aβ. Activated and proliferated microglia surround amyloid plaques in the AD brain and participate in the clearance of Aβ. Aβ binds to TLRs, RAGE, and other receptors on the surface of microglia membranes, transducing intracellular signaling pathways, then leading to the synthesis and release of pro-inflammatory factors. In the aging brain, the phagocytic capacity of microglia is weakened, which leads to the accumulation of Aβ. Microglia continue to activate, leading to chronic inflammation, increased oxygen free radicals, mitochondrial damage, and ultimately neuronal death.

Inflammation, a normal repair response, is crucial to combat pathogens and clear dead cells. Once the inflammation is dysregulated, it will cause tissue damage. Inflammaging refers to a state of chronic pro-inflammatory response in the process of aging, which is considered to be a part of immunosenescence. AD is also considered to be a chronic inflammatory disease. The inflammatory response of AD is not limited in the brain, but also exists in peripheral tissues, which is considered to be part of the systemic inflammatory response. The chronic inflammatory state in aging individuals may be associated with long-term chronic microbial infections, which may be a driver of cognitive decline and possibly dementia in the elderly.

Link: https://doi.org/10.14336/AD.2020.0205

As noted by the authors of today's open access review paper, Alzheimer's disease is just as strongly characterized by chronic inflammation in brain tissue as it is by the presence of aggregates of amyloid-β and phosphorylated tau. More modern views of Alzheimer's disease etiology place more emphasis on chronic inflammation as a cause of pathology, either wrapping it into the amyloid cascade hypothesis, or replacing amyloid-β with inflammatory processes in the progression of the foundational, earlier stage of the condition.

The infection-senescence hypothesis, for example, suggests that persistent infection leads to cellular senescence in the supporting and immune cells of the brain (such as astrocytes and microglia), and senescent cells generate potent inflammatory signals that drive tau aggregation and the consequent widespread death of neurons. This view of senescent cells as agents of inflammation, that in turn provokes tau pathology, is supported by studies involving the use of senolytic therapies to clear senescent cells in the brains of mice engineered to produce tau aggregates. With senolytic treatment, all three metrics of senescent cell burden, chronic inflammation, and tau pathology are markedly reduced in these mouse models of tauopathy.

This sort of specific theorizing and experimentation on neurodegeneration and neuroinflammation is not happening in a vacuum. There is considerable interest in a wide range of strategies that might reduce chronic inflammation in the aging brain, and thereby slow or reverse the progression of neurodegenerative conditions. The evidence to date from work on senolytics suggests that some fraction of the declines of old age are actively maintained by inflammatory signaling, and reverse themselves quite rapidly when that signaling is suppressed (such as by removal of senescent cells). The situation in the brain may be much the same as that elsewhere in the body, even accounting for the poor regenerative capacity of central nervous system tissue.

Can We Treat Neuroinflammation in Alzheimer's Disease?

Neuroinflammation is a process regulated by brain resident macrophages, the microglia cells, which are required to recognize and eliminate any toxic component in the central nervous system (CNS). Microglia has a high capacity for mobility, and they can switch between two different phenotypes, M1 and M2, characterized by a different morphology and cytokine profile. The M2 phenotype is the resting type that actively monitors the brain in healthy conditions. The switch to M1 begins with the recognition of the pathogen-associated molecular patterns (PAMPs) or the damage-associated molecular patterns (DAMPS) by the pattern recognition receptors (PRRs).

Pro-inflammatory cytokines purpose is to orchestrate the neutralization and elimination of toxic molecules and/or cellular debris. In normal conditions, once the toxic stimuli have been cleared, microglia swifts to the anti-inflammatory (M1) phenotype and secretes anti-inflammatory cytokines, brain-derived neurotrophic factor (BDNF), or nerve growth factor (NGF), whose role is to terminate the innate immune response and contribute to restore the synaptic function. However, under pathological conditions, microglia cells do not go back to their resting state, thus causing a chronic inflammation process, with the overproduction of pro-inflammatory cytokines and reduction of neuroprotective factors that in sustained situations become highly toxic, leading to neurodegeneration. Therefore, the chronic neuroimmune system activation underlies the initiation and progression in many dementias, and surely, is involved in the late onset of AD. Not only amyloid-β activates the microglia, but also misfolded Tau interaction with microglia triggers inflammation.

Neuroinflammation and insulin resistance are considered major neuropathological events underlying the onset and progression of AD; therefore, multiple strategies that target these processes have been developed to effectively treat this disease. In the current review, we have revised some of the latest preclinical and clinical studies targeting inflammation in AD, either directly with anti-inflammatory drugs or indirectly, improving insulin signaling. Taking together all clinical studies revised, we conclude that strategies targeting neuroinflammation together with insulin resistance have, finally, demonstrated to be a promising therapeutic potential in Alzheimer's disease, especially at early stages. However, many molecules have produced inconclusive results, and other methods, such as promoting neuroprotection via CB2 boosting or restoring a more youthful gut microbiome, are still at the preclinical stage. In addition, patient's stratification seems to be crucial to determine best treatment. The definite cure for AD does not exist yet; however, targeting neuroinflammation may be a path worth pursuing.

The practice of calorie restriction slows aging and extends healthy life, quite dramatically so in short-lived species, and far more modestly in long-lived species. All of the mechanisms of aging, the forms of damage that accumulate in old tissues and the outcomes of that damage, are affected. Some are affected more than others, however. So it is possible to see some aspects of aging that are less robustly responsive to calorie restriction, such as loss of cognitive function, as noted here.

It is interesting to speculate on the specific mechanisms involved in an age-related decline that responds well to life-long calorie restriction, but very poorly to calorie restriction initiated in later life. We know for example that structural damage to the brain occurs in conjunction with vascular aging, meaning increased blood pressure, reduced integrity of the blood-brain barrier, and so forth. The brain regenerates poorly, so this is a form of damage that accumulates over time and will not be remediated by the later adoption of calorie restriction and a corresponding reduction in blood pressure.

Calorie restriction (CR) has been considered the most effective non-pharmacological intervention to counteract aging-related diseases and improve longevity. This intervention has shown beneficial effects in the prevention and treatment of several chronic diseases and functional declines related to aging, such as Parkinson's, Alzheimer's, and neuroendocrine disorders. However, the effects of CR on cognition show controversial results since its effects vary according to intensity, duration, and the period of CR.

Here we present some of the results of the last ten years of studies with CR at different stages of life on neurodegenerative diseases such as Alzheimer's disease. Some investigations associating CR with physical exercise have also been presented. Together this association is the main non-pharmacological strategy to prolong longevity and quality of life. We also presented some substances that mimic the effects of CR and would be potential drugs to mimic the beneficial effects of CR in individuals with some restrictions on intervention. Several studies have also been carried out not only in conventional laboratory animals but also in some wild models since CR can be an environmental factor that interferes with the survival and perpetuation of species.

This information can show the different effects of CR on cognition depending on the period in which it is initiated, its intensity and duration in different animal models, and how it can interfere with the quality of life of individuals. These studies contribute to a better understanding of the mechanisms related to CR in cognition and support future studies with humans. CR may be a potential alternative to the treatment of comorbidities related to mental healthy and cognition.

We conclude that CR between 20% and 40% initiated in the first month of life would attenuate age-related cognitive declines in experimental animals, in healthy and pathological aging, such as in Alzheimer's disease. CR may not reverse the harmful effects of aging on cognition if starts later. In addition, CR also attenuates cognitive deficits resulting from obesity and brain injuries such as traumatic brain. Finally, CR can improve cognition, when performed with moderate intensity and early in life. When performed intensely and later in experimental animals, CR may be deleterious for cognition.

Link: https://doi.org/10.1016/j.ibror.2020.05.001

Periodontitis, gum disease, produces chronic inflammation that is thought to worsen the progression of conditions such as cardiovascular disease and dementia, through the size of the effect is debated. Certainly there are good reasons to believe that more chronic inflammatory signaling is worse than less chronic inflammatory signaling. Researchers here suggest that the observed relationship between periodontitis and progression of chronic kidney disease is mediated by excessive production of oxidative molecules rather than by inflammation.

Previous studies have shown a link between the severe oral inflammation caused by gum disease and chronic kidney disease (CKD) which demonstrated that those with worse inflammation of the gums have worse kidney function. Previous research also showed that patients with CKD and periodontitis experience a drop in survival rates, similar in magnitude to if they had diabetes instead of gum inflammation, suggesting that gum inflammation may casually affect kidney function.

In this latest study, over 700 patients with chronic kidney disease were examined using detailed oral and full-body examinations including blood samples. The aim was to test the hypothesis that periodontal inflammation and kidney function affect each other and to establish the underlying mechanism that may facilitate this. Results showed that just a 10% increase in gum inflammation reduces kidney function by 3%. In this group of patients, a 3% worsening in kidney function would translate to an increase in the risk of kidney failure over a 5 year period from 32%-34%. Results also showed that a 10% reduction in kidney function increases periodontal inflammation by 25%.

In contrast to current beliefs that inflammation is the link between periodontitis and other systemic diseases, researchers found that in this group of patients the effect was caused by a biological process called "oxidative stress" - or, an imbalance between reactive oxygen species and the body's antioxidant capacity which damages tissues on a cellular level.

Link: https://www.eurekalert.org/pub_releases/2021-01/uob-ded010521.php

Today's open access research paper is a reminder of one of the more direct mechanistic links between vascular aging and brain aging. Blood vessels stiffen with age, becoming progressively worse at the necessary task of contracting and relaxing in response to circumstances. This is in part due to cross-linking in the extracellular matrix, in which advanced glycation end-products (AGEs) such as glucosepane form persistent bonds that collectively alter tissue properties. This has the effect of reducing elasticity in tissues such as blood vessel walls, skin, and others. Dysfunction also occurs in the layer of smooth muscle surrounding blood vessels, driven by numerous forms of age-related damage, such as accumulation of senescent cells, mitochondrial dysfunction, and so forth.

Stiffening of blood vessels produces the raised blood pressure of hypertension as a side-effect. Blood pressure is controlled by feedback mechanisms that malfunction in an environment in which blood vessels no longer contract and relax as well as they should, biasing the system towards raised blood pressure. That raised blood pressure is more than delicate tissues can withstand. Small blood vessels rupture more frequently, and even without that breakage, pressure damage can occur to nearby tissues, particularly the blood-brain barrier. In the brain this produces tiny regions of destruction, effectively minuscule and unnoticed strokes that break neural structures. Over time this incremental damage adds up to cause meaningful levels of cognitive decline.

Associations between arterial stiffening and brain structure, perfusion, and cognition in the Whitehall II Imaging Sub-study: A retrospective cohort study

Aortic stiffness is closely linked with cardiovascular diseases (CVDs), but recent studies suggest that it is also a risk factor for cognitive decline and dementia. However, the brain changes underlying this risk are unclear. We examined whether aortic stiffening during a 4-year follow-up in mid-to-late life was associated with brain structure and cognition in the Whitehall II Imaging Sub-study.

In this study, we show that an increased rate of arterial stiffening is associated with lower white matter (WM) microstructural integrity and cerebral blood flow (CBF) in older age. Furthermore, these associations were present in diffuse brain areas, suggesting that exposure to excess pulsatility may result in a widespread damaging effect on the fragile cerebral microstructure. Cognitive function at follow-up related more closely with baseline arterial stiffness rather than rate of arterial stiffening. Taken together, these findings suggest that although faster rates of arterial stiffening in the transition to old age may negatively impact brain structure and function, long-term exposure to higher levels of arterial stiffness prior to this point may be the most important determinant for future cognitive ability.

While aortic stiffening has predominantly been studied in the context of CVD, recent evidence suggests that large artery dysfunction may also play a role in dementia. Indeed, patients with Alzheimer's disease and vascular dementia reportedly have higher levels of aortic stiffness relative to cognitively healthy adults. Aortic stiffening is a hallmark of vascular ageing and may lead to a heightened state of oxidative and inflammatory damage within the cerebral tissues due to an increased penetrance of excess pulsatility into the fragile microcirculation of the brain. These changes have been shown to disrupt endothelial cell function and the blood brain barrier in animal models and have also been hypothesised to compromise cerebral perfusion and ultimately lead to amyloid deposition, neurodegeneration, and cognitive impairment. While previous studies have related cross-sectional measures of arterial stiffness to cognition, this is the first study, to our knowledge, to publish associations between progressive increases in aortic stiffening over a 4-year period and cerebral and cognitive outcomes in later life.

Our findings suggest two things. First - and in agreement with previous studies linking modifiable risk factors to later adverse outcomes - early prevention strategies to reduce life-term exposure to risk factors may be required to in order to offer maximal benefits to later-life cognition, particularly in relation to domains such as semantic fluency and verbal learning. Second, novel to this study is our observation of additional relationships between faster rates of arterial stiffening during this period of life and the presence of pathological differences in WM structure and cerebral perfusion observed in the following years. We show for the first time that interventions to reduce or prevent the rapid increases in arterial pulsatility in mid-to-late life may reduce detrimental changes in WM integrity and blood flow, which have previously been linked to cognitive function, and may therefore also offer additional (albeit possibly more modest) benefits to cognitive ability in older age.

Most the events of the past year relating to longevity science were held virtually, thanks to the ongoing pandemic and the reaction to it. Here find notes and presentation video from the Aging, Geroscience and Longevity Symposium that was held last year, discussing an eclectic selection of research into aging and the treatment of aging.

Biological aging is the greatest risk factor for nearly every major cause of death and disability in developed countries, and new insights into the aging process may fundamentally change the way we approach human health. From basic research on the cellular and molecular hallmarks of aging to the next generation of "aging clocks" to potential clinical interventions, watching back the symposium recording presents an opportunity to hear the very latest from scientists in this field.

From Peter Fedichev of GERO: Heritability of human lifespan is 23-33% as evident from twin studies. Genome-wide association studies explored this question by linking particular alleles to lifespan traits. However, genetic variants identified so far can explain only a small fraction of lifespan heritability in humans. Here, we report that the burden of rarest protein-truncating variants (PTVs) in two large cohorts is negatively associated with human healthspan and lifespan, accounting for 0.4 and 1.3 years of their variability, respectively. In addition, longer-living individuals possess both fewer rarest PTVs and less damaging PTVs. We further estimated that somatic accumulation of PTVs accounts for only a small fraction of mortality and morbidity acceleration and hence is unlikely to be causal in aging. We conclude that rare damaging mutations, both inherited and accumulated throughout life, contribute to the aging process, and that burden of ultra-rare variants in combination with common alleles better explain apparent heritability of human lifespan.

From Hosni Cherif of McGill University: Intervertebral disc (IVDs) degeneration is one of the major causes of back pain. Cellular senescence is a state of stable cell cycle arrest in response to a variety of cellular stresses including oxidative stress and DNA damage. The accumulation of senescent IVD cells in the tissue suggest a crucial role in the initiation and development of painful IVD degeneration. Senescent cells secrete an array of cytokines, chemokines, growth factors, and proteases known as the senescence-associated secretory phenotype (SASP). The SASP promote matrix catabolism and inflammation in IVDs thereby accelerating the process of degeneration. This study demonstrates the potential of a natural (o-Vanillin) and a synthetic (RG-7112) senolytic compounds to remove senescent IVD cells, decrease SASP factors release, reduce the inflammatory environment and enhance the IVD matrix production. Removal of senescent cells, using senolytics drugs, could lead to improved therapeutic interventions and ultimately decrease pain and a provide a better quality of life of patients living with intervertebral disc degeneration and low back pain.

From Ying Ann Chiao of Oklahoma Medical Research Foundation: Mitochondrial dysfunction plays a central role in aging and cardiovascular disease. However, it was unclear whether improving mitochondrial function at late-life can rescue pre-existing age-related cardiac dysfunction, especially diastolic dysfunction. Here, we show that 8-week treatment with a mitochondrial-targeted peptide SS-31 (elamipretide) can substantially reverse pre-existing cardiac dysfunction in old mice. At molecular levels, late-life SS-31 treatment reduces mitochondrial ROS levels and normalizes age-related increases in mitochondrial proton leak and protein oxidative modifications. Late-life viral expression of mitochondrial-targeted catalase (mCAT) similarly improves diastolic function in old mice. SS-31 treatment cannot further improve cardiac function of old mCAT mice, implicating normalizing mitochondrial oxidative stress as an overlapping mechanism. Our results demonstrate that pre-existing cardiac aging phenotypes can be reversed by targeting mitochondrial dysfunction and support the therapeutic potentials of mitochondrial-targeted interventions in cardiac aging.

Link: https://elifesciences.org/inside-elife/8c884352/event-report-aging-geroscience-and-longevity-symposium

The power of specific targeting of specific cell types is that any cell-killing mechanism can then be delivered. The more efficient the targeting, more more dangerous and effective the cell-killing mechanism can be. The reason why any given cancer therapy is less effective at killing cancer cells than it might be is because the targeting isn't perfect, and thus there is the need to limit the damage to other tissues in the body.

A cancer-specific L-type amino acid transporter 1 (LAT1) is highly expressed in cancer tissues. Inhibiting the function of LAT1 has been known to have anti-tumor effects, but there has been limited progress in the development of radionuclide therapy agents targeting LAT1. Now, a research team has established a targeted alpha-therapy with a novel drug targeting LAT1.

The researchers first produced the alpha-ray emitter 211-Astatine, no easy task given that Astatine (At) is the rarest naturally occurring element on Earth. Targeted alpha-therapy selectively delivers α-emitters to tumors; the advantage over conventional β-therapy is that alpha decay is highly targeted and the high linear energy transfer causes double-strand breaks to DNA, effectively causing cell death. The short half-life and limited tissue penetration of alpha radiation ensures high therapeutic effects with few side-effects to surrounding normal cells.

Next, to carry the radioisotope into cancer cells, the researchers attached it to α-Methyl-L-tyrosine, which has high affinity for LAT1. This subterfuge exploits the elevated nutrient requirements of rapidly multiplying cancer cells. "We found that 211At-labeled α-methyl-L-tyrosine (211At-AAMT) had high affinity for LAT1, inhibited tumor cells, and caused DNA double-strand breaks in vitro. Extending our research, we assessed the accumulation of 211At-AAMT and the role of LAT1 in an experimental mouse model. Further investigations on a human pancreatic cancer cell line showed that 211At-AAMT selectively accumulated in tumors and suppressed growth. At a higher dose, it even inhibited metastasis in the lung of a metastatic melanoma mouse model."

Link: https://www.eurekalert.org/pub_releases/2021-01/ou-amt010421.php

Fisetin is perhaps the most intriguing of the first generation senolytic compounds, those capable of selectively destroying senescent cells in old tissues and thus producing rejuvenation to a meaningful degree. Senolytics have been demonstrated in animal studies to reverse many age-related conditions to a greater degree than any other approaches. Why is fisetin intriguing? Because in mice, it appears to be about as effective as the dasatinib and quercetin combination, yet it is a widely used dietary supplement.

Supplement dosing of fisetin in humans is not that much lower than the lowest demonstrated senolytic dose in mice. Senolytics are highly effective as treatments for inflammatory age-related conditions in mice, and starting to show similar effects in human trials. Should we expect that no older individual ever took enough fisetin to notice that it has profound effects on common inflammatory age-related conditions at higher doses? Is it realistic to think that strong medicines can be hiding in plain sight in this way for years upon years? The alternative explanation is that fisetin, unlike datastinib and quercetin, only effectively destroys senescent cells in mice. Which seems equally implausible, given what is known of the biochemistry of cellular senescence.

Questions regarding fisetin will be resolved (hopefully) at some point in the near future, given that human clinical trials of fisetin as a senolytic drug are presently ongoing, targeting frailty, cartilage degeneration, kidney disease, and osteoporosis. It is also worth looking at the materials on fisetin put together by the Forever Healthy Foundation, an extensive review of the evidence to date.

Fisetin Alleviated Bleomycin-Induced Pulmonary Fibrosis Partly by Rescuing Alveolar Epithelial Cells From Senescence

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease, which is characterized by the aberrant accumulation of extracellular matrix (ECM) in the lung parenchyma and deterioration of lung function. Both clinical observations and epidemiological investigations indicate that IPF is an aging-associated disease, since IPF occurs primarily in middle-aged and elderly people (median age at diagnosis is around 65 years), and the incidence rises remarkably with advancing age.

Cellular senescence is pivotal for phenotype of aging. The characteristics of senescent cells include growth arrest, enlarged cell morphology, elevated activity of SA-β-Gal as well as increased expression of cell cycle inhibitors, such as p16 and p21. Dysfunctional re-epithelialisation, following repetitive micro-injury, initiates the process of pulmonary fibrosis (PF). Increasing evidences have implicated that accelerated senescence of alveolar epithelial cells, a main cause of epithelial dysfunction, plays an important role in IPF pathogenesis. Senescent alveolar epithelial cells not only lose the ability of regeneration and repair, but also exert deleterious effects on neighboring cells by secreting a variety of proinflammatory cytokines, pro-fibrosis factors, growth factors, matrix metalloproteinases, and chemokines, described as senescence-associated secretory phenotype (SASP).

Fisetin (FIS), a natural non-toxic flavonoid, is present in various plants, fruits, and vegetables. Previous research has demonstrated that FIS has anti-inflammatory, anti-fibrosis, anti-oxidant, and anti-aging properties. Senolytic drugs, dasatinib and quercetin (D + Q), can attenuate experimental PF via selective depletion of senescent alveolar epithelial cells. More encouragingly, a recent first-in-human open-label clinical trial has suggested that short-term administration of D + Q could improve the physical dysfunction in IPF patients. Both FIS and quercetin belong to the flavonoid class, and FIS exhibits stronger senotherapeutic activity in cultured cells than quercetin, and can extend lifespan in mice. These traits remind us that FIS may have protective effect in PF. However, the role of FIS in PF has not been elucidated.

Bleomycin (BLM)-induced PF is the most frequently used animal model. Treatment with BLM can also induce alveolar epithelial cell senescence in vitro and in vivo. In this study, BLM was used to reproduce PF in mice and induce alveolar epithelial cell senescence to investigate the effect and mechanism of FIS in experimental PF. We found that FIS treatment apparently alleviated BLM-induced weight loss, inflammatory cells infiltration, inflammatory factors expression, collagen deposition and alveolar epithelial cell senescence, along with AMPK activation and the down regulation of NF-κB and TGF-β/Smad3 in vivo. In vitro, FIS administration significantly inhibited the senescence of alveolar epithelial cells and senescence-associated secretory phenotype. FIS may be a promising candidate for patients with pulmonary fibrosis.

Senescent cell accumulation is a contributing cause of aging, and targeted destruction of senescent cells with senolytic therapies produces meaningful rejuvenation and reversal of age-related disease in animal models. First generation senolytics are largely repurposed small molecules. Second generation senolytics will include a range of more carefully designed strategies, including the nanoparticles allowing for selective delivery of therapeutics to senescent cells that are the topic of this open access paper. Such nanoparticles can be used as the basis for both detection of senescent cells and their destruction, a promising attribute in the present environment in which there is as yet no widely available and reliable method of assessing the burden of senescence in human patients in a cost-effective and minimally invasive way.

As the main purpose of senotherapy is to kill scenescent cells (SCs), safe and effective detection and targeting of these cells is crucial to improving human health and prolonging lifespan. Nano-based systems developed to identify and kill senescent cells can be considered as second-generation targeted and selective senolytics that are able to efficiently eliminate senescent cells upon systemic administration without causing adverse side effects. One of the best-explored groups of nano-senolytics is smart nanodevices that are based on porous calcium carbonate nanoparticles, mesoporous silica nanoparticles, carbon quantum dots, and molecularly-imprinted polymer nanoparticles (nanoMIPs).

Targeted delivery and detection / elimination of SCs can be achieved by encapsulation of senolytics / senomorphics / fluorophores using a number of nanomaterials. For example, cargo release in the presence of β-galactosidase (β-gal) was due to the hydrolysis of the capping galacto-oligosaccharide (Gal) polymer. In vitro studies demonstrated that nanomaterials covered with Gal and loaded with fluorophores (e.g., rhodamine B, indocyanine green, coumarin-6, or Nile blue) were preferentially activated in β-galactosidase-overexpressing SCs, which were able to lyse the galacto-oligosaccharide coat. Moreover, β-galactosidase-instructed supramolecular assemblies can also lead to the formulation of hydrogels and nanofibers in SCs, which decreases the expression of senescence-driving proteins.

Apart from β-gal, increased expression of other lysosomal hydrolases (e.g., α-L-fucosidase) has been used for detection of senescent cells. To date, a collection of senoprobes has been described. Nano-based senoprobes could be utilized to monitor the response of tumors to the administration of senescence-inducing chemotherapeutic drugs. More recently, another method for the real-time in vivo detection of senescent cells based on mesoporous silica nanoparticles loaded with Nile blue and coated with a galacto-hexasaccharide was proposed. Functionalized nanomaterials appear to have a promising potential as nanocarriers and can be used for improving SC clearance.

Link: https://www.mdpi.com/2073-4409/9/12/2659/htm

Ageless: The New Science of Getting Older Without Getting Old is a forthcoming book discussing the aging research community and its newfound interest in treating aging as a medical condition. Aging is the cause of age-related disease and mortality, and far longer, far healthier lives lie ahead in the era in which the mechanisms of aging are targeted, rather than only their consequences. In this popular press article, the author and the book are discussed. The views are sensible and forward-looking, suggesting that it may be worth picking up when it is published in a few months.

The author began professional life as a physicist. As a child, he was fascinated by space, the way many scientists are. But he has spent the past three years researching a book about biogerontology, the scientific study of ageing, in which he argues the case for a future in which our lives go on and on. He considers ageing "the greatest humanitarian issue of our time". When he describes growing old as "the biggest cause of suffering in the world," he is being earnest.

In the past three decades biogerontological research has accelerated, and recent successes have sparked excitement. A 2015 study, published by the Mayo Clinic, in the US, found that using a combination of existing drugs - dasatinib, a cancer medicine, and quercetin, which is sometimes used as a dietary suppressant - to remove senescent cells in mice "reversed a number of signs of ageing, including improving heart function". A 2018 study that used the same drugs found that the combination "slowed or partially reversed the ageing process" in older mice. After the success in mice, the first trial aimed at removing senescent cells in humans began in 2018, and others are ongoing. "This collection of evidence is tantalising, and foreshadows a future where ageing will be treated. Scientists are rightly sceptical, but it's important to say that a lot of significant breakthroughs could happen in the lifespan of people alive today."

When the author brings up his work with people, the question he gets asked most often is: "What about overpopulation?" He has a go-to answer he thinks highlights the ridiculousness of the question. "Imagine we're staring down the barrel of 15 billion people on Earth. There are lots of ways to try and tackle that problem. Would one of them be: invent ageing?" That he is asked this question so frequently frustrates him. More so, he is bothered by the implication that what he is suggesting is somehow weird or inhuman or unholy, rather than ultimately helpful for society. "If I'd just written a book about how we're going to cure childhood leukaemia using some amazing new medicine, literally nobody would be like, 'But isn't that going to increase the global population?'"

He shakes his head. "What I'm saying is, 'Here is an idea that could cure cancer, heart disease, stroke...' Curing any one of those things would get you plaudits. But as soon as you suggest a potentially effective way of dealing with them altogether, suddenly you're some mad scientist who wants to overpopulate us into some terrible environmental apocalypse?" The author considers this a major hurdle in biogerontology's potential success - our "incredible bias toward the status quo" of ageing as an inevitable process, and our inability to accept it as preventable. "If we lived in a society where there was no ageing, and suddenly two-thirds of people started degenerating over decades, started losing their strength, started losing their mental faculties, and then succumbing to these awful diseases, it would be unthinkable. And of course, we'd set to work trying to cure it."

Link: https://www.theguardian.com/science/2021/jan/03/observer-magazine-do-we-have-to-age-biologist-andrew-steele

It used to be the case that one could write up a summary of where the research community stood on the treatment of aging as a medical condition (which was varying shades of "not that far along towards practical applications, but definitely promising if they get their act together") and then not have to update it all that much for years. Research is slow and uncertain, for one, and secondly there was, for decades, a strong cultural prejudice in the scientific community against trying to apply what was learned about aging to the treatment of aging. Little progress was made as a result.

Matters are proceeding much more rapidly nowadays. The prejudice is vanished, that change the result of a great deal of hard work by advocates, philanthropists, and researchers. Many of the potential approaches to treating aging as a medical condition hypothesized in past decades have either become practical, such as the selective destruction of senescent cells, or are within a few years of making the leap from laboratory to clinical development. The state of the art in the treatment of aging in 2010 already looks quaintly dated.

More activity in research and development means more attention given to the subject, faster progress, a greater need for summaries and explanations that are more up to date. It is good to see more people trying their hand at learning the state of the art and explaining it to others. One can always disagree with some of the selections when it comes to picking the most important lines of work, but the underpinnings of the article I'll point out today are good. It is well worth sharing with anyone you might think interested in the field.

Anti-Aging: State of the Art

Today, there are over 130 longevity biotechnology companies and over 50 anti-aging drugs in clinical trials in humans. The evidence is promising that in the next 5-10 years, we will start seeing robust evidence that aging can be therapeutically slowed or reversed in humans. Whether we live to see anti-aging therapies to keep us alive indefinitely (i.e. whether we make it to longevity escape velocity) depends on how much traction and funding the field gets in coming decades.

Aging is essentially damage that accumulates over time, which exponentially increases the risk of the diseases that kill most people. This 'damage' associated with aging comes in essentially nine forms, known as the hallmarks of aging. These forms of cellular damage drive the increased risk of disease, frailty, cognitive decline as well as observable signs of aging such as grey hair and wrinkles. The 'damage' (hallmarks of aging) occurs as a by-product of normal metabolism - the biochemical reactions that keep us alive. More and more damage accumulates and eventually leads to pathology, i.e. disease. When we talk about anti-aging we are talking about fixing the damage using an engineering approach before it accumulates to a dangerous level at which diseases emerge.

Anti-aging is more feasible for extending healthy lifespan rather than solving the individual diseases of aging due to the Taueber paradox and the highly co-morbid nature of age-related diseases. Even if a person survives one age-related disease such as cancer, another (e.g. diabetes, cardiovascular disease) will kill them if aging is not solved. This accounts for the much smaller increase in healthy lifespan associated with curing the diseases of aging, such as cancer (2-3 years), versus slowing aging itself (30+ years). The difference between anti-aging and current medicine is the former prevents illness by targeting the hallmarks of aging, whereas the latter intervenes once a disease has emerged. If we compare current medical interventions associated with geriatrics with anti-aging - the former extends unhealthy lifespan, whereas only the latter extends healthy lifespan.

The past five years of research have demonstrated several anti-aging strategies as particularly promising. Heterochronic parabiosis is putting young blood into old mice, to make the old mice biologically younger. This is achieved in the lab by connecting the circulatory systems of young mice and old mice. Recently, a group of Russian biohackers recently performed the first plasma dilution experiments in humans. In a research context, the safety and effectiveness of apheresis is being tested in a clinical trial in humans by the company Alkahest.

Dietary restriction has been shown to extend healthy lifespan across several species. Drugs that mimic the metabolic effects of dietary restriction also have beneficial effects on lifespan. Nutrient-sensing biochemical pathways (such as IGF-1, mTOR, and AMPK) play a key role in these effects. Metformin is a drug that is FDA-approved for diabetes that extends healthy lifespan in mice by inhibiting mTOR and activating autophagy. Metformin is currently being tested in a large clinical trial in humans to test its anti-aging properties. Another promising drug that manipulates metabolism is rapamycin, an FDA-approved immunosuppressant that extends healthy lifespan in mice and similarly acts to inhibit mTOR. Rapamycin is currently in a clinical trial in humans to test its anti-aging properties.

Senescent cells are a kind of 'zombie'-like cell that accumulate with age. They are death-resistant cells that secrete proinflammatory factors associated with a range of age-related diseases. There are various strategies being explored to kill or reprogram senescent cells, including senolytics. Senolytics are drugs that kill senescent cells to improve physical function and healthy lifespan. When administered to older mice, senolytics have been shown to reverse many aspects of aging such as cataracts and arthritis. Killing senescent cells with senolytics extends the median healthy lifespan in mice. Several senolytics, such as the combination of dasatinib and quercetin, and fisetin are in clinical trials in humans today.

Cellular reprogramming is the conversion of terminally differentiated cells (old cells) into induced pluripotent stem cells (iPSCs) ('young' cells). Cells can be re-programmed to a youthful state using a cocktail of factors known as Yamanaka factors. iIPSCs have essentially unlimited regenerative capacity and carry the promise for tissue replacement to counter age-related decline. Partial reprogramming in mice has shown promising results in alleviating age-related symptoms without increasing the risk of cancer. An impressive example of cellular reprogramming was the restoration of vision in blind mice with a severed optic nerve using three of the four Yamanaka factors.

Most 2020 conferences were held online as a result of COVID-19, curtailing the networking, discovery, and serendipitous discussion that is most of the point of attending a conference. Presentations were still given and research results announced, however. It remains useful to glance over conference reports for a sense of the mood and focus of the academic research and clinical development communities.

A tremendous growth in the proportion of elderly people raises a range of challenges to societies worldwide. Healthy aging should therefore be a main priority for all countries across the globe. However, science behind the study of age-associated diseases is increasing and common molecular mechanisms that could be used to dissect longevity pathways and develop safe and effective interventions for aging are being explored. The 7th Annual Aging Research and Drug Discovery (ARDD) meeting was held online on the 1st to 4th of September 2020. The meeting covered topics related to new methodologies to study aging, knowledge about basic mechanisms of longevity, latest interventional strategies to target the aging process as well as discussions about the impact of aging research on society and economy.

Molecular and therapeutic importance of NAD+ metabolism for aging was underlined in multiple talks at the ARDD meeting. Eric Verdin, Buck Institute, USA introduced the concept of competition among major NAD+-utilizing enzymes for NAD+ that may explain its age-dependent decline across multiple tissues. Evandro Fei Fang, University of Oslo, Norway underlined the importance of the NAD+-mitophagy / autophagy axis in aging and neurodegeneration and presented data on how impairment of this axis contributes to the progression in accelerated aging diseases as well as in the most common dementia, the age-predisposed Alzheimer's disease.

Another recently uncovered molecule that is able to improve mitochondrial function via mitophagy is Urolithin A, a gut microbiome metabolite known to improve mitochondrial function via mitophagy, increases muscle function, and possesses geroprotective features across multiple species. Pénélope Andreux, Amazentis, Switzerland presented results from a double blinded placebo controlled study showing that urolithin A administration in healthy elderly people is safe and was bioavailable after single or multiple doses over a 4-week period. Oral consumption of urolithin A decreased plasma acylcarnitines, a sign of improved systemic mitochondrial function, and displayed transcriptomic signatures of improved mitochondrial and cellular health in muscle.

Notably, studies of multiple interventions in different aging models include examinations of various markers of cellular senescence. Its significance for the aging process has been shown multiple times across model systems. Senescent cells occur in all organs, including post-mitotic brain tissues, during aging and at sites of age-related pathologies. The SASPs of senescent cells lead to chronic inflammation and may contribute to the development of various cellular phenotypes associated with aging and diseases. Hence, a novel class of drugs targeting senescent cells are emerging, including senolytics (selective elimination of senescent cells) and senomorphics (selective modification of senescent cells).

Several strategies were proposed to target senescent cells. Marco Demaria, ERIBA, Netherlands, demonstrated the important role of oxygen in the development of the senescence phenotype. Data illustrated that growth arrest, lysosomal activity and DNA damage signalling were similarly activated in senescent cells cultured at 1% or 5% oxygen, but induction of the SASP was suppressed by low oxygen. Tissues exposed to low oxygen also expressed a lower SASP than more oxygenated ones. It was demonstrated that hypoxia restrains SASP via AMPK activation and mTOR inhibition, and that intermittent treatment with hypoxia mimetic compounds can serve as a potential strategy for the reduction of SASP in vivo.

Current knowledge shows that aging is a very complex but plastic process. Conserved molecular pathways underlining aging can be manipulated using genetic, pharmacological, and non-pharmacological approaches to significantly improve the healthspan and lifespan in model organisms, and perhaps humans. A collaborative effort between academic research with a growing number of emerging biotech companies, as well as increased investment funds to accelerate discoveries, will most likely bring effective aging pharmaceuticals in the near future.

Link: https://doi.org/10.18632/aging.202454

Historical gains in life expectancy in the past two centuries, much of it occurring prior to the advent of effective antibiotics, were largely a matter of control over infectious disease via public health measures such as sanitation, coupled to a rising standard of living. A sizable amount of the gain in life expectancy at birth is due to reduced infant mortality, but this isn't the whole story. It is worth noting, as in this article from a few months ago, that the data shows remaining life expectancy at all ages heading upward over time. Reducing the burden of infectious disease has effects at all ages, not only due to incidence at a given age, but also by reducing the accumulated damage due to serious infections suffered throughout life.

It's often argued that life expectancy across the world has only increased because child mortality has fallen. If this were true, this would mean that we've become much better at preventing young children from dying, but have achieved nothing to improve the survival of older children, adolescents and adults. Once past childhood, people would be expected to enjoy the same length of life as they did centuries ago. This is untrue. Life expectancy has increased at all ages. The average person can expect to live a longer life than in the past, irrespective of what age they are.

The most striking development is the dramatic increase in life expectancy since the mid-19th century. Life expectancy at birth doubled from around 40 years to more than 81 years. This achievement was not limited to England and Wales; since the late 19th century life expectancy doubled across all regions of the world. The evidence that we have for population health before modern times suggest that around a quarter of all infants died in the first year of life and almost half died before they reached the end of puberty and there was no trend for life expectancy before the modern improvement in health: life expectancy at birth fluctuated between 30 and 40 years with no marked increase ever.

A common criticism of the statement that life expectancy doubled is that this "only happened because child mortality declined". I think that, even if this were true, it would be one of humanity's greatest achievements, but in fact, this assertion is also just plain wrong. Mortality rates declined, and consequently life expectancy increased, for all age groups. In 1841 a five-year-old could expect to live 55 years. Today a five-year-old can expect to live 82 years. An increase of 27 years. The same is true for any higher age cut-off. A 50-year-old, for example, could once expect to live up to the age of 71. Today, a 50-year-old can expect to live to the age of 83. A gain of 13 years.

Link: https://ourworldindata.org/its-not-just-about-child-mortality-life-expectancy-improved-at-all-ages

Exercise is known to improve health and extend the healthy portion of life span, but not extend life span itself in mice. This is a much lesser effect than that of calorie restriction, which does extend maximum life span in addition to improving health. From a very high level view, both exercise and calorie restriction are similar, in that they trigger many of the same stress response mechanisms, making those mechanisms work harder to maintain cell function than they would otherwise have done. Evidently exercise and calorie restriction achieve this goal in quite different ways at the detail level, given the quite different outcomes.

One noted aspect of aging is the accumulation of senescent cells throughout the body. Cells become senescent constantly throughout life, in response to a variety of circumstances, but are removed quickly and efficiently in youth, either self-destructing or being destroyed by the immune system. This removal slows down with age, alongside an increased pace of creation of new senescent cells, allowing senescent cells to linger in ever increasing numbers. These cells adopt the senescence-associated secretory phenotype (SASP), producing inflammatory, disruptive signals that contribute to the development of tissue dysfunction and age-related disease. The size of this effect is meaningful, the harms done considerable, as illustrated by the rejuvenation produced in animal studies when senescent cells are selectively destroyed by senolytic therapies.

Age-slowing interventions such as exercise and calorie restriction, based on stress response upregulation over time, largely appear to reduce the burden of senescent cells in older individuals. That may not mean a reduction in the numbers of senescent cells, but rather involve suppression of the SASP. Where it does reduce numbers of senescent cells, it may not achieve that end by destroying these errant cells directly, but rather by slowing the pace of creation, or producing general improvements in immune surveillance of senescence. A good example is mTOR inhibition via drugs such as rapamycin, an approach shown to reduce the burden of senescence in skin over a period of months, but which is well proven not to directly destroy senescent cells. The effect size of exercise is nowhere near that of pharmaceutical approaches when it comes to the burden of senescence, however, as today's review illustrates.

Is exercise a senolytic medicine? A systematic review

Senescent cells are the hallmark and therapeutic target of cellular senescence involved in a wide range of biological processes, including tumor suppression, embryonic development, wound healing and tissue repair, and aging. Although senescent cells are detrimental to the body during aging and can lead to chronic diseases, such as obesity, diabetes, and sarcopenia, they also suppress cancer and fibrosis.

Senolytics is a new class of medicines that target senescent cells, which has emerged rapidly in the past few years. Preclinical studies on rodents have been applied to explore the potential targets of senescent cells and the preliminary effects of senolytic medicine in vivo. In addition to transgenic mice, senolytic drugs, including dasatinib and quercetin, ABT263, and SSK1, showed the therapeutic effects on senescent cells and alleviated the radiation and age-related symptoms and pathology. Strikingly, two small clinical trials on senolytic treatments with dasatinib and quercetin were completed last year and reported therapeutic effects for patients with diabetic kidney disease (N = 9) and idiopathic pulmonary fibrosis (N = 14).

Physical exercise is widely recognized as a safe, effective, and cost-effective "medicine" for a broad range of age-related diseases. Moreover, a lack of exercise is a major contributing factor to accelerated aging and age-associated chronic conditions, including cancer, obesity, and cardiovascular diseases. A clearer delineation of anti-aging and anti-disease effects and underlying mechanisms of exercise is needed. While the accumulation of senescent cells has been identified as the mechanism of aging and multiple diseases for decades, senolytics targeting senescent cells has just been developed in recent years. In addition, exercise has shown its capacity to lower the marker of senescent cells over the past decade. In the current systematic review of all available literature, we explored the potential senolytic effects of exercise in both human and animal models under healthy or disease states. We aimed to improve the understanding of the cellular senescence-based mechanisms underlying exercise as anti-aging medicine.

The findings of this systematic review and meta-analysis provided some evidence that exercise may be a senolytic medicine for p16INK4a-positive senescent cells in humans and for p21Cip1-positive senescent cells in obese but not healthy animals. Future studies should examine the optimal form and dosage of exercise, targeted cells/tissues, different disease states, and the underlying cellular mechanisms in humans and animals. A greater understanding of the senolytic effects of exercise can lead to significant clinical and public health impact.

Resilience, meaning the ability to recover from wounds, infection, and other forms of damage, is more or less the flip side of frailty in aging. Frailty increases, resilience decreases. A damaged system is less robustly resilient to further damage, as reliability theory tells us. Degenerative aging is precisely an accumulation of cell and tissue damage at the molecular level, followed by all the myriad downstream dysfunctions and breakages caused by that damage. When we approach the treatment of aging, the guiding principle should be a focus on root cause damage and repair of that damage.

Decline in biological resilience (ability to bounce back and recover) is a key manifestation of aging that contributes to increase in vulnerability to death with age, limiting longevity even in people without major diseases. Resilience is different from robustness which refers to the ability to avoid damage and its destructive consequences whatsoever. The robustness generally declines during aging; however, it may improve in some health domains, sometimes at the cost of resilience to future adverse events.

We propose that aging can be viewed as a combination of three universal components: (i) depletion of limited body reserves (e.g., of stem cells, immune cells, muscle cells, neural cells, etc.), which poses limits to recovery; (ii) slowdown of physiological processes and responses to stress/damage, which delays the recovery with age; and (iii) inherently imperfect mechanisms of cell/tissue repair and cleaning, which result in incomplete recovery and damage accumulation over time. These aging components together create the age-decline in resilience, which in turn contributes to increase in mortality risk with age eventually limiting longevity even in people without major diseases.

These aging components can be seen in all aging animals, albeit their relative contributions to the decline in resilience, as well as to longevity limits, may differ across species, which could contribute to the variability of longevity and pace of aging among the species and strains. This may also be a reason why the effects of anti-aging interventions observed in lab animals are not always replicated in humans. There are open questions about relative impacts of the different aging components on the decline in resilience and the increase in mortality risk with age. However, the area develops quickly, and prospects are encouraging.

Finding the 'optimal' anti-aging intervention that could oppose the decline in resilience and also extend the species longevity limits remains a challenging problem. To be more efficient, the anti-aging interventions may need to target several aging components at once, e.g., help replenish body reserves, enhance cell repair and tissue cleaning, and attenuate the slowdown of metabolism, proliferation, and information processing, simultaneously.

Link: https://doi.org/10.1016/j.mad.2020.111418

Scientists here suggest that the chronic inflammation generated by visceral fat tissue, an important form of metabolic disarray that drives age-related disease and dysfunction, is not produced by all fat cells. Indeed, it may be primarily produced by a specific type of progenitor cell lining blood vessels in fat tissue. This is an interesting demonstration, but it remains the case that the best solution to excess visceral fat is never to obtain it in the first place. The effects of visceral fat on metabolism quite literally accelerate the progression of degenerative aging.

When a person consumes more calories than needed, the excess calories are stored in the form of triglycerides inside fat tissue, also known as white adipose tissue (WAT). Researchers know that in obese people, WAT becomes overworked, fat cells begin to die, and immune cells become activated. But the exact mechanism by which this inflammation occurs isn't fully understood. That chronic, low-level inflammation is one of the driving factors behind many of the diseases associated with obesity.

While many studies have focused on the signaling molecules produced by the fat cells or immune cells in WAT that might contribute to inflammation, this team of researchers took a different approach. They focused instead on the vessels that carry blood - as well as immune cells and inflammatory molecules - into WAT. In 2018, the team identified a new type of cell lining these blood vessels in mice - an adipose progenitor cell (APC), or precursor cell that goes on to generate mature fat cells. But unlike most APCs, the new cells, dubbed fibro-inflammatory progenitors, or FIPs, produced signals that encouraged inflammation. In the new work, the researchers looked more closely at the role of the FIPs in mediating inflammation.

Within just one day of switching young male mice to a high-fat diet, researchers discovered that the FIPs quickly increased the number of inflammatory molecules produced. After 28 days on a high-fat diet, they found a substantial increase in the proportion of FIPs compared with other APCs. To show that the increase in the number and activity of the FIPs was not just a side effect of already-inflamed fat cells, the team removed a key immune signaling gene, Tlr4, from the FIPs in some mice. After five months on a high-fat diet, the mice lacking Tlr4 had gained just as much weight, and just as much fat, as other mice on a high-fat diet. But the genetically engineered mice - with FIPs that could no longer generate the same signals - no longer had high levels of inflammation. Instead, the levels of inflammatory molecules in their WAT were closer to the levels seen in mice on low-fat diets.

Researchers went on to show that increasing levels of a related signaling molecule, ZFP423, in FIPs can also ameliorate the inflammation in mouse fat cells. The findings point toward possible avenues to pursue to lower the risk of disease in people with obesity.

Link: https://www.utsouthwestern.edu/newsroom/articles/year-2020/blood-vessel-cells-obesity.html

The development programs conducted at Lygenesis came about as a result of an academic researcher who followed up on the realization that the positioning of some organs in the body is arbitrary. Much of the function of organs like the liver and the thymus could be carried out in any location that is well-supplied with blood and easily accessible to roving cells. The liver is a chemical factory, producing and consuming various proteins and metabolites. The thymus is a cell factory; thymocytes migrate to the organ from the bone marrow, and once there are transformed into T cells of the adaptive immune system via their interaction with thymic tissue.

Tissue engineering of functional liver or thymus tissue from the starting point of a patient cell sample is a going concern, but the inability to produce dense networks of capillaries limits this to the production of very small organoids, a millimeter or two in cross-section at most. Any larger than that and nutrients cannot reach the innermost cells, which will die. An organoid grown from matched cells can be implanted into the body, where under optimal circumstances it will become connected to the vasculature.

The research that led to the founding of Lygenesis involved demonstrating that lymph nodes supply the necessary conditions for a transplanted organoid to grow and prosper. If that organoid is made up of liver tissue or thymic tissue, then it will conduct its normal function, taking over the lymph node and turning it into a micro-organ. Mammals have a sizable number of lymph nodes, and suffer no apparent ill effects from losing a handful of them. Many of those lymph nodes are quite close to the skin, making transplantation of tissue a much easier prospect than the alternative option of placing organoids directly onto the damaged organ.

LyGenesis' FDA phase 2a clearance and $11m funding boost

Biotech firm LyGenesis, Inc, which develops cell therapies that enable organ regeneration, announced today that the US Food and Drug Administration (FDA) has cleared its Investigational New Drug (IND) application. Under the IND, LyGenesis will be conducting a Phase 2a study on the safety, tolerability, and efficacy of its first-in-class novel cell therapy for patients with end stage liver disease (ESLD). In addition, LyGenesis announced it has just completed over $11 million in private financing of convertible notes led by Juvenescence Ltd. and Longevity Vision Fund. Proceeds will be used to progress LyGenesis' Phase 2a clinical trial with a first patient in targeted for early 2021. The funds will also be used to develop LyGenesis' other cell therapies using lymph nodes as bioreactors to regrow functioning organs, including pancreas, kidney, and thymus regeneration.

"With cash on hand to run our Phase 2a trial, we can now focus on our next IND enabling preclinical programs, as our pancreas (for type I diabetes) and thymus (for aging as well as multiple orphan indications) cell therapy programs can now draft behind the regulatory precedent that we've set with our liver program. it's still a lot of work, but the resistance is just a little less and it enables you to go further, faster. The FDA clearance for our IND and the start of our Phase 2a study in patients with ESLD is a testimony to our robust preclinical research program, the unmet need in advanced liver disease, and our novel approach to organ regeneration. Moreover, the lack of genetic manipulation, ease of administration, and low cost of goods for our cell therapy forms the foundation for a promising and scalable first commercial product."

Frailty is usually accompanied by greater immune dysfunction, given that chronic inflammation is a strong component of both immune aging and the various dysfunctions of frailty. Thus frail individuals exhibit a worse response to vaccinations intended to prevent infectious disease. This is unfortunate, as this is the population in greatest need of the defense of vaccination. This is illustrated every year by the toll of deaths due to influenza, and particularly this year by the ongoing COVID-19 pandemic. A great deal of effort goes into attempts to improve vaccine efficiency in older people, but ultimately that vaccine efficiency is limited in any given individual by the state of the aged immune system. It would be better to put those resources towards the development of the most promising approaches to rejuvenation of immune function: thymic regrowth, restoration of the hematopoietic system, and so forth.

The burden of influenza-related morbidity and mortality among older adults is substantial. Surveillance studies estimate that 71%-85% of influenza deaths occur in adults ≥65 years of age. Adults ≥65 years are 10 to 30 times more likely than younger adults to experience acute respiratory failure attributed to influenza disease. Low vaccine effectiveness among the elderly has been attributed to senescence of the immune system and a decreased immune response to vaccine antigens. Overlaid on age-related immunosenescence are the effects of frailty, a multi-dimensional syndrome marked by losses in function and physiological reserve. Physical frailty is characterized by diminished strength, endurance, and reduced physiologic function.

Physical frailty's impact on hemagglutination inhibition antibody titers (HAI) and peripheral blood mononuclear cell (PBMC) transcriptional responses after influenza vaccination is unclear. Physical frailty was assessed using the 5-item Fried frailty phenotype in 168 community- and assisted-living adults ≥55 years of age during an observational study. Blood was drawn before, 3, 7, and 28 days post-vaccination with the 2017-2018 inactivated influenza vaccine.

Frailty was not significantly associated with any HAI outcome in multivariable models. Compared with non-frail participants, frail participants expressed decreased cell proliferation, metabolism, antibody production, and interferon signaling genes. Conversely, frail participants showed elevated gene expression in IL-8 signaling, T-cell exhaustion, and oxidative stress pathways compared with non-frail participants. These results suggest that reduced effectiveness of influenza vaccine among older, frail individuals may be attributed to immunosenescence-related changes in PBMCs that are not reflected in antibody levels.

Link: https://doi.org/10.18632/aging.202207

There is far too much incrementalism in the present research and development of therapies to treat aging. Much of the field is engaged in mimicking calorie restriction or repurposing existing drugs that were found to increase mouse life span by a few percentage points. This will not meaningfully change the shape of human life, but nonetheless costs just as much as efforts to achieve far more. If billions of dollars and the efforts of thousands of researchers are to be devoted to initiatives to treat aging, then why not pursue the ambitious goal of rejuvenation and adding decades to healthy life spans? It is just as plausible. There are just as many starting points and plausible research programs aimed at outright rejuvenation via repair of molecular damage, such as those listed in the SENS approach to aging, as there are aimed at achieving only small benefits in an aged metabolism. The heavy focus on incremental, low yield programs of research and development in the present community is frustrating, and that frustration is felt by many.

As the global population ages, there is increased interest in living longer and improving one's quality of life in later years. However, studying aging - the decline in body function - is expensive and time-consuming. And despite research success to make model organisms live longer, there still aren't really any feasible solutions for delaying aging in humans. With space travel, scientists and engineers couldn't know what it would take to get to the moon. They had to extrapolate from theory and shorter-range tests. Perhaps with aging, we need a similar moonshot philosophy. Like the moon once was, we seem a long way away from provable therapies to increase human healthspan or lifespan. This review therefore focuses on radical proposals. We hope it might stimulate discussion on what we might consider doing significantly differently than ongoing aging research.

A less than encouraging sign for many of the lifespan experiments done in preclinical models, namely in mammals such as mice, is that they have modest effect sizes, often only having statistically significant effects in one of the genders, and often only in specific dietary or housing conditions. Even inhibiting one of the most potent and well-validated aging pathways, the mechanistic target of rapamycin (mTOR) pathway has arguably modest effects on lifespan - a 12-24% increase in mice. This is all to ask, if the mTOR inhibitor rapamycin is one of the potential best-case scenarios and might be predicted to have a modest effect if any (and possibly a detrimental one) in people, should it continue to receive so much focus by the aging community? Note the problems in the aging field with small and inconsistent effects for the leading strategies aren't specific to rapamycin.

Treating individual aging-related diseases has encountered roadblocks that should also call into question whether we are on the optimal path for human aging. Alzheimer's is a particularly well-funded and well-researched aging-related topic where there are still huge gaps in our understanding and lack of good treatment options. There has been considerable focus on amyloid beta and tau, but targeting those molecules hasn't done much for Alzheimer's so far, leaving many searching for answers. The point is when we spend collectively a long time on something that isn't working well, such as manipulating a single gene or biological process, it should seem natural to consider conceptually different approaches.

Link: https://doi.org/10.3233/NHA-190064

A sizable fraction of cell signaling is conveyed via extracellular vesicles, tiny membrane-wrapped packages of molecules. Here researchers note that mitochondrial DNA is found inside extracellular vesicles, and that the amount declines with age. Other researchers have determined that entire mitochondria are exported and taken up by cells, so one has to carefully read the methods used in papers like this to ensure that researchers are in fact looking at the smaller extracellular vesicles only. These vesicles are sorted into category by size, and selecting by size is an established capability.

It is speculated that transfer of mitochondrial DNA via extracellular vesicle serves useful purposes, and observed in cell cultures that it can alter mitochondrial function in recipient cells. Additionally it can serve as a signal of damage generated by stressed and dying cells, activating the immune system to be more vigilant. Alternatively, it may be a garbage disposal mechanism to get rid of unwanted molecules, and uptake of these vesicles is a form of unwanted side-effect.

A declining presence of mitochondrial DNA in extracellular vesicles with age might be a simple reflection of a lesser number of mitochondria in cells, a part of the general faltering of mitochondrial function in old tissues, or it may be the consequence of a much more complex set of processes. The evidence to date leans in the latter direction, as is usually the case in biological systems.

Mitochondrial DNA in extracellular vesicles declines with age

The mitochondrial genome encodes 37 genes including 13 proteins, which are vital for mitochondrial oxidative phosphorylation and cellular energetics. Mitochondrial DNA (mtDNA) mutations drive premature aging in mouse models and recently have been shown to increase with human age. mtDNA copy number (the number of mtDNA molecules per cell) was also found to decline with human age in peripheral blood mononuclear cells.

Cellular mtDNA can be released outside of the cell as circulating cell-free mtDNA (ccf-mtDNA). Ccf-mtDNA can act as a damage associated molecular pattern (DAMP) molecule leading to activation of the innate immune response following cellular damage or stress. Ccf-mtDNA can be reliably measured from blood plasma and serum making it attractive for biomarker development. Elevated ccf-mtDNA levels are associated with inflammatory diseases and cancer, as well as with trauma or tissue injury, including myocardial infarction and sepsis. A recent study has shown a slight decline in ccf-mtDNA comparing levels in children to middle-aged individuals followed by a gradual increase in ccf-mtDNA in the elderly. These emerging data suggest that ccf-mtDNA may indicate and/or contribute to various physiological and pathological conditions.

Previously, we reported that EV concentration declined with age in a cross-sectional and longitudinal study. EVs isolated from older individuals were preferentially internalized by B cells compared to EVs from younger individuals. These data indicate that EVs from older individuals may contain different cargo than EVs from younger individuals.

In the current study, we examine whether mtDNA can be detected in human plasma EVs and whether mtDNA levels are altered with human age. We analyzed mtDNA in EVs from individuals aged 30-64 years cross-sectionally and longitudinally. EV mtDNA levels decreased with age. Furthermore, the maximal mitochondrial respiration of cultured cells was differentially affected by EVs from old and young donors. Our results suggest that plasma mtDNA is present in EVs, that the level of EV-derived mtDNA is associated with age, and that EVs affect mitochondrial energetics in an EV age-dependent manner.

These findings may seem at first contradictory to a previous report finding that ccf-mtDNA from plasma increased with age. However, in that paper, they report a slight decline in ccf-mtDNA levels from childhood (mean age = 6.8 years) to early adulthood (mean age = 33 years) and a gradual increase in ccf-mtDNA levels in the ~60 years (mean age = 64 years) and elderly population (older than 90 years). Our cohort at time 1 ranges from ~30-64 years and time 2 ~ 32-69 years. Therefore, we examined a largely middle-aged cohort. Also, of note, we have measured ccf-mtDNA levels within EVs not just in whole plasma. Although we detected mtDNA in EVs, our data indicate that only a fraction of the total ccf-mtDNA is contained in EVs.

Cargo in EVs may relay cellular signals but may also be a mechanism for the removal of dysfunctional or damaged mitochondrial components. It has been reported that neurodegenerative-related misfolded proteins are present in EVs. Autophagy has been shown to play a role in EV secretion. It is well known that the removal of deficient mitochondria via mitophagy is altered with aging, along with pathways related to proteostasis. Therefore, it is interesting to speculate that the decline in mtDNA EV levels that we observe may reflect a defect in the clearance of cellular material with aging.

Epigenetic modifications to DNA, gene expression, and cell function all change for the worse in stem cells in old tissues. Researchers here show that putting old hematopoietic stem cells into a young tissue environment acts to reverse many of these changes to the transcriptome, the manufacture of RNA that is the first stage of gene expression, but has far less benefit when it comes to epigenetic changes and loss of cell function. Epigenetic modifications regulate gene expression, and gene expression determines cell behavior, so it is interesting to see such a divergence in outcomes between these properties of cells. Both replication of the results and a close inspection of the methodologies used are called for.

The functions and characteristics of hematopoietic stem cells (HSCs) change with age. The ability to produce blood cells is reduced and differentiation is biased, increasing the risk of developing myeloid tumors. By transferring mouse aged HSCs to the bone marrow niche of young mice, it was demonstrated that the pattern of stem cell gene expression was rejuvenated to that of young hematopoietic stem cells. On the other hand, the function of aged HSCs did not recover in the young bone marrow niche. The epigenome (DNA methylation) of aged HSCs did not change significantly even in the young bone marrow niche, and DNA methylation profiles were found to be a better index than the gene expression pattern of aged HSCs.

The research group investigated whether placing aged HSCs in a young bone marrow niche environment would rejuvenate the cells. Tens of thousands of aged hematopoietic stem cells and progenitor cells collected from 20-month-old mice were transplanted into 8-week-old young mice without pretreatment such as irradiation. After two months of follow-up, they collected bone marrow cells and performed flow cytometric analysis. The research team also transplanted 10-week-old young mouse HSCs for comparison. In addition, engrafted aged HSCs were fractionated and RNA sequence analysis and DNA methylation analysis were performed.

The researchers found that engrafted aged HSCs were less capable of producing hematopoietic cells than younger HSCs. They also showed that differentiation of aged HSCs into multipotent progenitor cells was persistently impaired even in the young bone marrow niche and that the direction of differentiation was biased. Thus it was found that the transfer of aged HSCs to the young bone marrow niche does not improve their stem cell function.

Link: https://www.ims.u-tokyo.ac.jp/imsut/en/about/press/page_00027.html

The activities of the gut microbiome are clearly influential on long-term health and aging, and evidence suggests that this is perhaps a similarly sized effect to that of exercise. The gut microbiome changes with age, and while researchers have identified a number of microbial metabolites and species in which this shift can negatively affect health, such as by promoting chronic inflammation, the mapping of the microbiome and its relationship with aging is still in its early stages. Better tools will be needed in order to pick apart the relationships through item by item analysis of specific species and metabolites, and here researchers demonstrate one such tool.

Gut microbial metabolism is associated with host longevity. However, because it requires direct manipulation of microbial metabolism in situ, establishing a causal link between these two processes remains challenging. We demonstrate an optogenetic method to control gene expression and metabolite production from bacteria residing in the host gut. We genetically engineer an Escherichia coli strain that secretes colanic acid (CA) under the quantitative control of light.

Using this optogenetically-controlled strain to induce CA production directly in the Caenorhabditis elegans gut, we reveal the local effect of CA in protecting intestinal mitochondria from stress-induced hyper-fragmentation. We also demonstrate that the lifespan-extending effect of this strain is positively correlated with the intensity of green light, indicating a dose-dependent CA benefit on the host. Thus, optogenetics can be used to achieve quantitative and temporal control of gut bacterial metabolism in order to reveal its local and systemic effects on host health and aging.

Link: https://doi.org/10.7554/eLife.56849