Towards Control Over the Dynamic Equilibrium of Bone Tissue Maintenance

Bone loses mass and strength with age, leading to the condition called osteoporosis. The extracellular matrix of bone is dynamically remodeled throughout life, built up osteoblast cells and broken down by osteoclast cells. Osteoporosis is the result of a growing imbalance in cell activity and cell creation that favors osteoclasts. There are many contributing causes, and some uncertainty of which of these causes are more or less important. The chronic inflammation that accompanies aging does appear to be important, particularly that connected to the senescence-associated secretory phenotype (SASP) of senescent cells.

Given that osteoporosis is an imbalance, there are many potential ways to treat the condition, only some of which address the root causes. Any methodology that enhances osteoblast activity to a suitable degree or suppresses osteoclast activity to a suitable degree should be compensatory and beneficial, all other things remaining equal. That said, one would expect targeting the root causes of the imbalance to be a better approach, more likely to produce a larger effect size, and likely to have other beneficial effects elsewhere in the body. For example, the use of senolytic drugs to remove senescent cells is beneficial in many ways beyond the plausibly beneficial impact of a reduced SASP on processes of bone maintenance.

Current advances in regulation of bone homeostasis

Bone homeostasis in the adult skeleton is complex processes. Human skeletal tissue is a constant state of remodelling. The three main bone cells involve in this remodelling process - osteoblasts, osteoclasts and osteocytes via regulation of molecular signalling pathways. In bone remodelling, the discrete zones of bone are resorbed by osteoclasts and substituted by fresh bone by osteoblasts, allowing for repair of bone micro-injury and adapting of bone niche for control of mechanical strengths.

Osteoblast cells are energetic in protein synthesis and matrix secretion to preserve and form new healthy bones. Following mineralization of bone matrix, fully differentiated and matured osteoblasts become osteocytes and are implanted in the bone matrix. During bone remodelling process, mechanosensory cells, osteocytes act as bone orchestrators. This remodelling process is regulated by several local (e.g., growth factors, cytokines, chemokines) and systemic (e.g., estrogens) factors that all together subscribe for bone homeostasis.

In bone modelling process, i.e., during bone development and bone resorption stages, osteocytes act autonomously to fine-tune bone structure. Interestingly, in bone remodelling process, these cells act recycler to restore and keep skeletal health. After osteoclast-mediated bone resorption sequence, the eroded surface of trabecular bone is engaged by osteoblasts that make bone matrix and then undertake mineralization. Under normal physiological conditions of bone homeostasis, osteoclastic action is closely associated with osteoblastic action in such a way that the eroded bone is completely exchanged by fresh bone. Definitively, fluctuating this homeostatic equilibrium in favour of excessive osteoclast activity turns to bone pathological conditions such as osteoporosis, Paget's disease, rheumatoid arthritis (RA), osteoarthritis, and autoimmune arthritis.

Osteoporosis can be prevented and improved musculoskeletal health by using numerous pharmacotherapies such as biphosphonates; selective estrogen receptor modulators (SERMs); hormone therapies; strontium ranelate; denosumab (a human monoclonal antibody with specificity for RANKL); romosozumab (a monoclonal antibody that binds to and inhibits sclerostin) or stimulating bone formation called anabolic medications e.g., PTH preparations and calcitonin therapy have been verified the effects of increased bone mineral density and decreased risk of skeletal fractures.

However, these treatments have some side effects, such as oily skin, fluid retention, nausea, long-term toxicity, and even prostate cancer in males and thus natural therapies that incur better therapeutic activities and fewer side effects are hunted. Therefore, searching for small molecules that precisely suppress osteoclastic action is a favourable approach of the drug discovery for the treatment and management of bone-related diseases including osteoporosis.

Senescent Cells and Changes in Systemic Factors in Aging

Senescent cells accumulate with age in all tissues, and contribute to aging via secreted signals that provoke inflammation and tissue restructuring. This portion of aging is a malfunction of a system that normally aids in regeneration and resistance to cancer. Senescent cell signaling is beneficial in the short term, attracting immune cells to areas of damage that should be policed for potentially cancerous cells, or coordinating the interactions of cells needed to efficiently heal an injury. In these cases, in a young individual, the senescent cells involved are quickly destroyed once their task is complete. It is when this needed destruction falters with age, and signaling becomes constantly present, that the problems start. As researchers examine the changing presence of factors in blood and tissue samples, many of these age-related alterations are traced back to the activity of senescent cells.

Extracellular vesicles (EVs) are membrane bound vesicles which vary from nanometer to micrometer in size and carry a diverse set of factors. Recently, our group investigated how circulating EVs change with age, the cell types responsible, and the response of these factors to rejuvenation therapies. Profiling of EV cargo revealed greater expression of inflammation-associated microRNAs such as miR-146a, miR-21, let-7a, and miR-223 in old plasma EVs compared with young. These microRNAs are predicted to target multiple intracellular signaling cascades which regulate cellular responses to external stimuli.

To determine the cell types responsible for changes in circulating EV microRNAs, we assessed EVs secreted by young and old peripheral blood mononuclear cells (PBMCs) in-vitro as well as plasma EVs isolated from old mice reconstituted with young or old bone marrow. However, EV microRNAs were similar in both models, suggesting that circulating cells have a minor contribution to the microRNAs identified this study. Further investigation into potential cell sources revealed that induction of senescence in-vitro and in-vivo, using gamma irradiation, mimicked the changes observed in old mice such as increased levels of circulating EVs and increased expression of EV associated miR-146a, mIR-21, and let-7a.

Interestingly, senolytic therapy using dasatinib + quercetin (D+Q) reduced the expression of these microRNAs in the plasma of old mice, supporting that senescent cells or the pathways targeted by these compounds contribute to increased expression in the circulation. Collectively, this data demonstrates that aging and cellular senescence leads to increased levels of circulating EVs, and that these EVs impair cellular responses to activation. Pharmacological targeting of senescent cells partially rejuvenated the microRNA profile and functional effects of old plasma EVs.

Senescent cells secrete cytokines, growth factors, and proteases which alter neighboring cell function. This secretome is collectively referred to as the senescent associated secretory profile (SASP) and the adverse effects of senescent cells are largely attributed to this profile. More recent definitions of the SASP have been expanded to include EVs. Secretion of EVs by senescent cells into the circulation could be one mechanism by which senescent cells promote cell dysfunction, as persistent uptake of senescent-EVs may lead to sustained changes in cellular function. Therefore, approaches aimed at targeting senescent cells may help reduce circulating senescent-EV levels and limit the impact senescent cells have on cells throughout the body.

Link: https://doi.org/10.18632/aging.104213

Sestrin Mediates Some of the Benefits of Calorie Restriction in Flies

The practice of calorie restriction reliably improves health and extends life span in near all species tested to date. Many of the pharmacological and genetic approaches to slowing aging have emerged from studies of the cellular maintenance mechanisms triggered into greater activity by calorie restriction, or the nutrient sensing mechanisms that govern initiation of the calorie restriction response. None of these approaches have yet demonstrated themselves to be any better than the actual practice of calorie restriction, and thus while scientifically interesting, are perhaps not a good point of focus for the growing longevity industry.

The health benefits of dietary restriction have long been known. Recently, it has become clear that restriction of certain food components, especially proteins and their individual building blocks, the amino acids, is more important for the organism's response to dietary restriction than general calorie reduction. On the molecular level, one particular well-known signalling pathway, named TOR pathway, is important for longevity. "We wanted to know which factor is responsible for measuring nutrients in the cell, especially amino acids, and how this factor affects the TOR pathway. We focused on a protein called Sestrin, which was suggested to sense amino acids. However, no one has ever demonstrated amino acid sensing function of Sestrin in a living being."

"Our results in flies revealed Sestrin as a novel potential anti-ageing factor. We could show that the Sestrin protein binds certain amino acids. When we inhibited this binding, the TOR signalling pathway in the flies was less active and the flies lived longer. Flies with a mutated Sestrin protein unable to bind amino acids showed improved health in the presence of a protein-rich diet."

If the researchers increased the amount of Sestrin protein in stem cells located in the fly gut, these flies lived about ten percent longer than control flies. In addition, the increased Sestrin amounts only in the gut stem cells also protected against the negative effect of a protein-rich diet. "We are curious whether the function of Sestrin in humans is similar as in flies. Experiments with mice already showed that Sestrin is required for the beneficial effects of exercise on the health of the animal. A drug that increases the activity of the Sestrin protein might therefore be in future a novel approach to slow down the ageing process."

Link: https://www.mpg.de/16053584/1124-balt-x-positive-effector-behind-reduced-food-intake-identified

A Tour of Longevity Industry Therapies Presently in Clinical Trials

The longevity industry is presently still quite young, a hundred and something companies that are largely still at the preclinical stage of development, most founded in the last couple of years. Even if we want to be broadly generous as to which companies and projects are to be included in our definition of the industry, no newly developed therapies to treat the mechanisms of aging have yet been approved by the FDA, although a few have made it to phase 3 clinical trials. This is just a matter of time, however; it can take a decade of hard work to go from an idea to an approved therapy, and very few longevity industry companies are even half that age.

Of perhaps more immediate interest are existing approved drugs that appear to have a meaningful effect on mechanisms of aging. The most important of these are widely used chemotherapeutics that have been found to selectively kill senescent cells, and thereby produce rejuvenation in mice. No-one noticed this potential for intervention in the aging process while such drugs were being developed in animal models of cancer and used in cancer patients, for all the obvious reasons. The dosing was quite different, the lifespans of the animals and patients largely quite short, and the disruptions of cancer and high dose chemotherapy masked the benefits that can be obtained via a different approach to usage.

Back to the new therapies under development and the rapidly growing longevity industry, there is more than enough work taking place at present for a community of speculators and spectators to emerge, of various degrees of organization, professionalism, and commercial inclinations. I'll point out one of the more market-focused examples today, with a couple of posts that tour the handful of longevity industry clinical trials underway or recently conducted. Not all are targeting aging, such as the work of Gensight on allotopic expression of mitochondrial genes to treat inherited mitochondrial disease, and these are only relevant because they exercise approaches that can later be turned to address aging.

#015: A Review of Every Single Longevity Therapy in Clinical Trial Today. (PART 1)

Currently there are 28+ anti-aging therapies in human clinical trials spanning a variety of strategies, targets, indications, companies, and modalities. The trials are conducted by companies - private and public - but also universities and non-profit groups. There are also perhaps 100 more pre-clinical companies working on aging in addition to this effort. If any one of the therapies in the first volley on the problem of aging achieve success - even if modest - it could trigger investor hype rivaling the biggest bubbles in history. The zero to one moment in human life extension will change everything.

With the exception of maybe Nir Barzilai's TAME metformin trial (not yet registered), none of the anti-aging therapies currently being tried directly use aging as their clinical endpoint. Most trials instead measure a therapy's efficacy with respect to a specific age-related disease rather than aging itself. Or sometimes the indication is a disease that can be treated with a tool developed from an aging perspective. This is because: (1) The FDA does not recognize aging as an indication (yet). (2) It is expensive to run trials that measure lifespan in humans. (3) We don't have have robust surrogate biomarkers for aging (yet). (4) It is easier to demonstrate clinical significance in an age-related disease than aging itself.

#016: Every Single Longevity Therapy in Clinical Trial Today (PART 2)

Aging is a malleable biological process. Scientists have been precisely turning the knobs of aging in model organisms since the 1990s. Presently we have reached an inflection point: Therapies developed in the context of longevity science are being tested in human patients today.

LYG-LIV0001 - LyGenesis

Perhaps one of the more ambitious clinical trials. LyGenesis is a Juvenescence-backed startup spun out of research at the University of Pittsburgh. The company is attempting to regrow livers by injecting allogenic liver cells into patient lymph nodes. The lymph nodes act as bioreactors and slowly regrow into functional livers - at least in the pre-clinical experiments done on pigs. Their Phase 2 trial includes patients with end-stage liver disease. If successful the company plans to also use the same strategy to regrow the thymus (reversing immunosenescence) and also pancreatic islet cells (reversing diabetes).

SkQ1 - Mitotech

Mitotech is an anti-aging company that develops therapies that protect the mitochondria from reactive oxygen species (ROS). SkQ1 is an anti-oxidant that can easily penetrate the mitochondrial membrane where it can inhibit ROS. In particular, SkQ1 protects cardiolipin, an important protein found in the inner mitochondrial membrane. Dry eye might not sound like a very sexy anti-aging therapy. But this trial is just one small step in the journey of treating mitochondrial diseases, many of which are age-related.

Nicotinamide riboside - ChromaDex

NAD+ levels decrease with age so the hypothesis is that boosting NAD+ levels can have potential anti-aging benefits. There are several chemical precursors to NAD+ but the two most popular are nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN). ChromaDex is the patent holder of NR and sponsors a number of clinical trials to support the case for its potential anti-aging properties. This time they are measuring hospitalization duration for patients with tissue damage. Given the small size of the study (84 participants) and probable heterogeneity in the illnesses, I have a hard time seeing how anything definitive will be elucidated. This is just one trial of many exploring the benefits of NAD+ precursors / booster. These NAD+ precursor compounds are generally considered safe so I'm excited to see what can benefits can be demonstrated in trials.

Using Inflammatory Signaling to Lure Transplanted Stem Cells to Damaged Locations in the Body

Researchers here report on their efforts to improve stem cell therapies by steering the cells to migrate to areas of damage in the body. These cells travel through the body towards regions of inflammatory signaling. The researchers adapted one of these signal molecules to make it unlikely to significantly provoke cells into an inflammatory response, while still being attractive to stem cells. Using this molecule to steer stem cell migration to specific locations results in an improved efficacy of stem cell therapy in animal models, a good demonstration of the potential utility of this approach.

Nearly 15 years ago, researchers discovered that stem cells are drawn to inflammation, a biological "fire alarm" that signals damage has occurred. However, using inflammation as a therapeutic lure isn't feasible because an inflammatory environment can be harmful to the body. Thus, scientists have been on the hunt for tools to help stem cells migrate to desired places in the body. This tool would be helpful for disorders in which initial inflammatory signals fade over time - such as chronic spinal cord injury or stroke - and conditions where the role of inflammation is not clearly understood, such as heart disease.

In the study, the scientists modified CXCL12 - an inflammatory molecule which the team previously discovered could guide healing stem cells to sites in need of repair - to create a drug called SDV1a. The new drug works by enhancing stem cell binding and minimizing inflammatory signaling, and can be injected anywhere to lure stem cells to a specific location without causing inflammation.

To demonstrate that the new drug is able to improve the efficacy of a stem cell treatment, the researchers implanted SDV1a and human neural stem cells into the brains of mice with a neurodegenerative disease called Sandhoff disease. This experiment showed SDV1a helped the human neural stem cells migrate and perform healing functions, which included extending lifespan, delaying symptom onset, and preserving motor function for much longer than the mice that didn't receive the drug. Importantly, inflammation was not activated, and the stem cells were able to suppress any pre-existing inflammation.

The researchers have already begun testing SDV1a's ability to improve stem cell therapy in a mouse model of ALS, which is caused by progressive loss of motor neurons in the brain. Previous studies indicated that broadening the spread of neural stem cells helps more motor neurons survive, so the scientists are hopeful that strategic placement of SDV1a will expand the terrain covered by neuroprotective stem cells and help slow the onset and progressive of the disease.

Link: https://www.sbpdiscovery.org/news/worlds-first-drug-guides-stem-cells-to-desired-location-improving-their-ability-to-heal

Immune System Aging as Only Loosely Coupled to the Rest of Aging

The immune system ages along with everything else in the body, entering the states of immunosenescence and inflammaging. Immunosenescence is a growing ineffectiveness of the immune response, while inflammaging is a constant and inappropriate activation of the immune response. Researchers here make the point that immune aging might be thought of as being only loosely coupled to the rest of aging, as it is possible, for example, for chronic infections such as HIV to bring on aspects of immunosenescence and inflammaging far earlier in life than would otherwise be the case.

Aging has been associated with a myriad of both acute and chronic diseases. At the core of these diseases, the change in the host immune system with age could either have contributed to the cause as it is the host main defence mechanism against foreign pathogens or its functionality being impacted by these diseases and conditions. However, the change in the immune system with age could also be seen as an adaptation process to save resources for the host rather than it being detrimental.

This is because developing competent naïve T cells has only about 1-2% success rate due to the various stringent selection processes. Therefore, biological processes such as thymic involution could be seen as advantageous to the host from an energetic or evolutionary point of view. One of the main arguments that thymic involution is detrimental to the host is due to the reduction of naïve T cells being produced, leading to a narrower repertoire for new antigens and perhaps reduced vaccine efficacy often observed in the elderly, while this may have been a successful programmed process for the shorter-lived humans in the past centuries and before the extended human lifespan has revealed the probable need to reverse this adaptation.

Chronic low-grade inflammation is a commonality between individuals that exhibit chronic stress, obesity, aging, sleep loss, gut dysbiosis, CMV infection, dysregulated immune cell functions, and accumulation of SASP cells such as fibroblasts. Chronic low-grade inflammation is defined as a higher baseline of pro-inflammatory cytokines in the circulation though the source and specific cytokines might differ slightly between these "diseases" in the absence of foreign pathogen infection. In terms of impaired immunity, both human and animal studies have shown that chronic stress reduces various immune functional capacities. The presence of impaired immunity and low-grade chronic inflammation could be the underlying factors that exacerbate pathology in various disease contexts.

Thus, it is important that we redefine and stress that the definition of immunosenescence is the dysfunctionality of the immune system and should encompass some features of low-grade chronic inflammation. Though this phenomenon is often seen in aged individuals, it is also possible in younger adults as it could be "accelerated immunosenescence", especially for T cells, as shown in CMV and HIV seropositive young patients. Even early in life, the impact of CMV can be observed. This highlights that other factors other than chronological age could determine this level of senescence of the immune system, especially for T cells which are prone to proliferation. Overall, rethinking the causing agents and implications of immunosenescence will help shift the perspective that this phenomenon is not attributed to age alone, especially with the global rising rate of obesity and chronic stress of modern-day life in the young.

Link: https://doi.org/10.1007/s00281-020-00824-x

Matching Funds Now Triple Year End Donations to Fund Rejuvenation Research at the SENS Research Foundation

The SENS Research Foundation is one of the most important of the scientific and advocacy institutions presently working to make sure that viable approaches to rejuvenation advance to the point at which they can be commercially developed for use in human medicine. If you are deciding on where to make a charitable contribution for the end of 2020, then look no further than this organization, currently running their year end fundraiser. The next $300,000 of donations are presently tripled by matching funds provided by supporters - so jump in while that is the case!

SENS Research Foundation 2020 End of Year Fundraiser

Thanks to a generous matching challenge by Oculus co-founder Michael Antonov, up to $600,000 donated before the end of 2020 will be doubled! But wait, there's more. A team of SRF supporters - Brendan Iribe, Karl Pfleger, Jim Mellon, Dave Fisher, Christophe Cornuejols and Larry Levinson - have joined forces to offer a further $300,000 matching grant. This pool of funds runs in parallel to Michael's challenge, which means the next $300,000 donated will be tripled!

The SENS Research Foundation has long specialized in unblocking areas of research relevant to aging that have received too little attention and funding. Notable successes include the discovery of bacterial enzymes to degrade persistent molecular waste such as A2E, a cause of retinal degeneration, as well as the creation of cyclodextrin molecules that can sequester 7-ketocholesterol, a toxic metabolic byproduct that contributes to numerous age-related and other conditions. The former program led to preclinical development at LysoClear, a part of the Ichor Therapeutics portfolio, and the latter gave rise to the spin out company Underdog Pharmaceuticals. Further, the SENS Research Foundation funded work on the tools needed to work with glucosepane, an advanced glycation endproduct that forms the majority of persistent cross-links in aged human tissue, and that led to Revel Pharmaceuticals, a company funded to develop candidate cross-link breakers.

There are other examples and other projects still underway on mechanisms necessary to produce human rejuvenation. The SENS Research Foundation gets things done, and funds provided go a long way towards ensuring that our personal futures are long and healthy. The only way to get there is to build better medicine, and that starts with the sort of work carried out at the SENS Research Foundation, supported by everyday philanthropists and people of vision, just like you and I.

Older Obese Patients Can Lose Weight Just as Readily as Younger Obese Patients

It is the common wisdom that fat tissue becomes harder to lose with age, that metabolism tilts in the direction of wanting to retain that fat. The results of this study are a counterpoint, suggesting that, given the same adherence to the usual weight loss protocol of eating fewer calories, older people can in fact lose weight just as readily as younger people. Visceral fat tissue is harmful to long-term health in numerous ways, but particularly through the generation of chronic inflammation that accelerates the onset and progression of all of the common fatal age-related conditions. The only thing worse than gaining excess fat tissue is holding on to it over time, and letting the damage and dysfunction to your tissues accumulate as a result.

Obese patients over the age of 60 can lose an equivalent amount of weight as younger people using only lifestyle changes, according to a new study that demonstrates that age is no barrier to losing weight. The researchers hope that their findings will help to correct prevailing societal misconceptions about the effectiveness of weight loss programmes in older people, as well dispel myths about the potential benefits of older people trying to reduce their weight.

For this retrospective study, researchers randomly selected 242 patients who attended an obesity service between 2005 and 2016, and compared two groups (those aged under 60 years and those aged between 60 and 78 years) for the weight loss that they achieved during their time within the service. All patients had their body weight measured both before and after lifestyle interventions administered and coordinated within the obesity service, and the percentage reduction in body weight calculated across both groups.

When compared, the two groups were equivalent statistically, with those aged 60 years and over on average reducing their body weight by 7.3% compared with a body weight reduction of 6.9% in those aged under 60 years. Both groups spent a similar amount of time within the obesity service, on average 33.6 months for those 60 years and over, and 41.5 months for those younger than 60 years. The hospital-based program used only lifestyle-based changes tailored to each individual patient, focusing on dietary changes, psychological support, and encouragement of physical activity. Most of the patients referred to the obesity service were morbidly obese with a BMI typically over 40.

Link: https://warwick.ac.uk/newsandevents/pressreleases/age_is_no

Low Dose PPARγ Agonist Treatment Started in Mid-Life Extends Median Lifespan by 11% in Mice

Researchers here note a modest life extension in mice resulting from long-term treatment with low doses of a PPARγ agonist drug, started in mid-life. This is thought to be an adjustment that acts to suppress inflammation and improve insulin metabolism, both strongly connected to the way in which cellular metabolism determines pace of aging. The size of the effect in mice is small enough to think that it would have little effect on life span in our species, however. Effects derived from this sort of metabolic adjustment have a much larger impact on life span in short-lived species than they do in long-lived species, as most of the relevant stress response mechanisms connecting metabolism to environmentally induced variations in the pace of aging evolved as a part of the life-extending response to calorie restriction. A seasonal famine is a long time to a mouse, not so long to a human, so only the mouse evolves a sizable gain in life span when these stress response mechanisms are trigger.

Aging leads to a number of disorders caused by cellular senescence, tissue damage, and organ dysfunction. It has been reported that anti-inflammatory and insulin-sensitizing compounds delay, or reverse, the aging process and prevent metabolic disorders, neurodegenerative disease, and muscle atrophy, improving healthspan and extending lifespan. Here we investigated the effects of PPARγ agonists in preventing aging and increasing longevity, given their known properties in lowering inflammation and decreasing glycemia.

Our molecular and physiological studies show that long-term treatment of mice at 14 months of age with low doses of the PPARγ ligand rosiglitazone (Rosi) improved glucose metabolism and mitochondrial functionality. These effects were associated with decreased inflammation and reduced tissue atrophy, improved cognitive function, and diminished anxiety- and depression-like conditions, without any adverse effects on cardiac and skeletal functionality. Furthermore, Rosi treatment of mice started when they were 14 months old was associated with an 11% median lifespan extension.

A retrospective analysis of the effects of the PPARγ agonist pioglitazone (Pio) on longevity showed decreased mortality in patients receiving Pio compared to those receiving a PPARγ-independent insulin secretagogue glimepiride. Taken together, these data suggest the possibility of using PPARγ agonists to promote healthy aging and extend lifespan.

Link: https://doi.org/10.1111/acel.13267

An Overview of the Mechanisms of Transthyretin Amyloidosis

A score or so different types of amyloid can form in the human body, each a protein that can become altered or misfolded in a way that encourages other molecules of the same protein to also alter or misfold. These broken proteins aggregate together into sheets and fibrils, forming solid deposits in and around cells that interfere with the normal function of tissues, or are actively toxic. Transthyretin is one such protein, and transthyretin amyloidosis is present to some degree in all older people. Evidence of recent years suggests that it is a factor in 10% of heart failure cases in old people in general, and it may be the dominant cause of cardiac mortality in supercentenarians, those aged 110 or older.

The open access paper noted here is an interesting overview of the mechanisms by which amyloidosis occurs in the case of transthyretin, in the context of trying to predict who is most at risk and should therefore be treated. Eidos Therapeutics has a treatment in the late stage of development that interfers enough with the mechanisms of transthyretin aggregation to be worth the effort, though as for most such lines of development it will initially be targeted at cases in which transthyretin is mutated in ways that accelerate amyloidosis, rather than as a preventative therapy for the entire population. More aggressive degradation of amyloid will likely be needed, such as via the use of catabodies, a line of work at an earlier stage of development at Covalent Bioscience, but nonetheless promising.

Proposing a minimal set of metrics and methods to predict probabilities of amyloidosis disease and onset age in individuals

The rate of synthesis of transthyretin (TTR) is constant. For proteostasis, the rate of removal of TTR must equal the rate of synthesis. TTR in plasma is largely in the tetrameric form, (TTR)4, but dissociates to give very low, but significant concentrations of dimers and monomers. Removal of TTR from plasma proceeds via monomers.

Monomers undergo two processes that remove them from solution, proteolysis or aggregation. The combined rates of these two pathways equals the total rate of monomer removal, which is also equal to the rate of production of monomer via dissociation of tetramer. Depending on the relative rates, either of the two reaction pathways could account for anywhere from 100% to 0% of the rate of monomer removal. The critical monomer concentration for aggregation is unknown, however the cause of aggregation develops slowly over time. Once amyloidosis begins, the rate of development of amyloidosis is determined by the rate of monomer incorporation into various aggregates that lead to fibrils and amyloids.

Destabilizing tetramer by pleiotropic mutations leads to greater dissociation of monomer and a higher, variant-dependent concentration of TTR monomer in plasma. Mutations are not required for TTR amyloidosis formation; point mutations only modify the equilibrium concentrations. Amyloidosis caused by wild-type TTR follows the same mechanism as amyloidosis caused by variants of TTR and thus should be considered as variants of the same disease for purposes of clinical studies.

Amyloidosis begins when the rate of TTR proteolysis decreases relative to the rate of amyloid formation and monomer concentration increases sufficiently to allow significant oligomerization into fibrils and amyloids. The cause of a decrease in the rate of proteolysis of TTR remains to be identified. When the tetramer is stabilized by drugs or stabilizing mutations, the concentration of tetramer will increase in plasma to a steady-state level determined by the rate of proteolysis.

Towards a Retinal Assessment of Alzheimer's Risk, Years in Advance of Symptoms

Researchers here report on progress towards non-invasive retinal scanning as an approach to determining Alzheimer's disease risk in the very early stages of progression towards the condition. The path to Alzheimer's is marked by years of a slow accumulation of amyloid-β, an antimicrobial peptide that can misfold to form solid aggregates. While the evidence suggests that amyloid-β can on its own cause mild cognitive impairment, it remains to be determined as to whether it also causes the later stages of Alzheimer's, the chronic inflammation and tau aggregation that kills large numbers of brain cells. It may be a side-effect of other processes, such as persistent viral infection, senescent cell accumulation, and the like. Fortunately, that present lack of knowledge may not matter when it comes to the use of amyloid-β as a marker of risk and progression towards Alzheimer's disease.

Researchers have identified certain regions in the retina - the lining found in the back of the eye - that are more affected by Alzheimer's disease than other areas. The findings were from a clinical trial involving people older than 40 who were showing signs of cognitive decline. In the trial, investigators used a noninvasive technique known as sectoral retinal amyloid imaging to capture retinal images in participants. The retina, which is directly connected to the brain, is the only central nervous system tissue accessible for patient-friendly, high-resolution and noninvasive imaging.

The images were then analyzed using a new process that could identify certain peripheral regions in the retina that corresponded better to brain damage and cognitive status. In studying the images, scientists could detect patients with an increased buildup of retinal amyloid protein, signifying a higher likelihood of developing Alzheimer's disease or cognitive impairments. These findings build upon pioneering research in 2010 in which researchers identified a pathological hallmark of Alzheimer's disease, amyloid beta-protein deposits, in retinal tissues from deceased patients. The team then developed a methodology to detect retinal amyloid beta-protein plaques in living patients suffering from the disease.

Link: https://www.cedars-sinai.org/newsroom/retinas-new-potential-clues-in-diagnosing-treating-alzheimers/

GrimAge Outperforms Other Epigenetic Clocks

There are now a variety of epigenetic clocks, weighted combinations of the methylation status of various CpG sites on the genome in various different tissues. The epigenetic marks of DNA methylation change constantly in response to circumstances and cell activities, but some of these changes are characteristic of the aged tissue environment, and thus correlate well with the burden of damage and dysfunction that causes manifestations of aging. A person more greatly damaged will tend to exhibit an epigenetic age higher than chronological age, a phenomenon referred to as age acceleration.

Epigenetic clocks are derived from the analysis of large amounts of epigenetic data obtained from study population of different ages, rather than from any understanding of how and why age-related epigenetic changes take place. Cell metabolism and epigenetics are very complex, and it remains unclear in near all cases as to why specific changes occur, and how those changes relate to the underlying processes of aging. Still, one can certainly run the numbers to decide which of the clocks are better or worse than others when it comes to assessing the burden of aging.

The aging process is characterized by the presence of high interindividual variation between individuals of the same chronical age prompting a search for biomarkers that capture this heterogeneity. Epigenetic clocks measure changes in DNA methylation levels at specific CpG sites that are highly correlated with calendar age. The discrepancy resulting from the regression of DNA methylation age on calendar age is hypothesised to represent a measure of biological ageing with a positive or negative residual signifying age acceleration or deceleration respectively.

The present study examines the associations of four epigenetic clocks - Horvath, Hannum, PhenoAge, GrimAge - with a wide range of clinical phenotypes (walking speed, grip strength, Fried frailty, polypharmacy, Mini-Mental State Exam (MMSE), Montreal Cognitive Assessment (MOCA), Sustained Attention Reaction Time, 2-choice reaction time), and with all-cause mortality at up to 10-year follow-up, in a sample of 490 participants in the Irish Longitudinal Study on Ageing (TILDA).

Horvath Age Acceleration (AA) and HannumAA were not predictive of health; PhenoAgeAA was associated with 4 of 9 outcomes (walking speed, frailty, MOCA, MMSE) in minimally adjusted models, but not when adjusted for other social and lifestyle factors. GrimAgeAA by contrast was associated with 8 of 9 outcomes (all except grip strength) in minimally adjusted models, and remained a significant predictor of polypharmacy, frailty, and mortality in fully adjusted models. Results indicate that the GrimAge clock represents a step-improvement in the predictive utility of the epigenetic clocks for identifying age-related decline in an array of clinical phenotypes promising to advance precision medicine.

Link: https://doi.org/10.1093/gerona/glaa286

Michael Antonov Will Match the Next $600,000 of Donations to SENS Research Foundation in Support of their Important Work on Rejuvenation Therapies

Michael Antonov is one of a number of high net worth individuals who are interested in accelerating progress towards a first generation of comprehensive rejuvenation therapies, targeting all of the mechanisms of aging in order to cure age-related disease and extend healthy life spans. The SENS Research Foundation remains one of the most important organizations in this space, focused on the scientific advances needed in order to repair the molecular damage that causes aging. Degenerative aging and age-related disease exists because the normal operation of youthful metabolism produces forms of damage as a side-effect: varieties of molecular waste that are both toxic and hard to break down; mutational damage to DNA; accumulating senescent cells; cross-links in the extracellular matrix; and so forth.

Senescent cell accumulation can already be repaired to some degree, thanks to advances in science that led to senolytic drugs, the first class of rejuvenation therapy worthy of the name. The others will follow at a pace determined by how much funding goes into the necessary research programs.

SENS Research Foundation is delighted to announce a matching grant from the Antonov Foundation. The Antonov Foundation will match every dollar donated between now and the end of the campaign on December 31, 2020 - up to a total of $600,000!

SENS Research Foundation is incredibly grateful for this generous investment in the future we all hope to create - a future where getting older brings wisdom and experience but not disease, suffering, and pain. Thank you, Michael Antonov, and thank you to all who have donated so far to our end of year campaign. And if you're still planning on donating, there's no better time to do it than on Giving Tuesday this December 1!

Michael Antonov said: "I've followed and supported SENS research over the last few years and am excited to up my commitment this year because their organized, practical approach to combating aspects of aging, such as breaking down of cross-links, rejuvenating the mitochondria, and clearance of senescent cells has potential to help human lives and achieve age reversal in the near future."

Over the past decade, thousands of visionary folk in our community have donated more than $10 million to the SENS Research Foundation. This support has produced clear progress towards the goal of rejuvenation. Neglected areas of research have been revived, companies created to start commercial development of therapies, and the field of rejuvenation research has gained legitimacy and support. There is still so much to accomplish yet, of course! So I am very pleased to see that Michael Antonov is stepping up to provide a sizable amount of funding to the SENS Research Foundation in the form of a matching grant for the 2020 year end fundraiser. It is Giving Tuesday soon, and we should all use that opportunity to support the future that we'd like to see, one in which aging is controlled by medical science, and there is no more suffering in old age.

Investigating the Use of VEGF-B to Grow New Blood Vessels to Supply the Heart

Researchers are interested in provoking the body into growing additional blood vessels that can bypass areas of damage. Most of this work is focused on restoring long term supply of blood to heart tissue following a heart attack, and thus on regrowth in an environment of damage and damage-related signaling. It would be perhaps more interesting to develop means of growing additional redundant blood vessels prior to that point, in the normal signaling environment. This could greatly reduce the damage done by a blockage that would ordinarily cause a heart attack, and slow the progression into heart failure caused by narrowing of blood vessels. This all compares poorly to developing means of prevention of atherosclerosis, the cause of blood vessel narrowing, rupture, and blockage, but even given a cure for atherosclerosis, there is a lot to be said for having redundant routes of blood supply to major organs.

Cardiovascular disease is the leading cause of mortality and ischemic heart disease is a major cause of death worldwide. Coronary vessels that nourish the heart develop from three main sources, the endocardium on the inner surface of the hearts blood-filled chambers being one of the major contributors. In normal conditions, the adult heart can no longer generate new blood vessels from the endocardium, because the endocardium-to-coronary vessel transition is blocked by a connective tissue wall beneath the endocardium.

In a recently published study researchers show that the VEGF-B growth factor can be used to activate the growth of vessels inside of the heart during cardiac ischemic damage. This novel finding opens the possibility that vessels emerging from the inner side of the heart could be further developed for the treatment of myocardial infarction, which results from insufficient delivery of oxygen to cardiac tissue. In normal conditions, blood nourishes the adult heart through coronary vessels.

VEGF-B (vascular endothelial growth factor) belongs to a family of growth factors that regulate the formation of blood- and lymphatic vessels. Earlier attempts to utilize another growth factor gene, VEGF-A, to grow new vessels in the heart have failed, mostly due to the leakiness of the vessels and increased inflammation caused by VEGF-A, but not by VEGF-B. Re-activation of the embryonic vessel growth program in adult endocardium could be a new therapeutic strategy for cardiac neovascularization after myocardial infarction. For possible future clinical use, the function of these vessels and their blood flow has to be further studied to ensure that they really increase transport of oxygen and nutrients into the cardiac muscle.

Link: https://www.helsinki.fi/en/news/health-news/a-bypass-route-for-the-coronary-vessels-in-the-heart

A Look at the Damage Done by Senescent T Cells in the Aged Immune System

Cells become senescent and cease replication in response to damage, a toxic environment, or reaching the Hayflick limit. Such cells near all self-destruct or are destroyed by the immune system. In later life, however, they begin to linger and accumulate. This is an issue, as the secretions of senescent cells are quite harmful when sustained over the long term, producing chronic inflammation and disruption of tissue structure and function. The cells of the immune system are no less subject to the burden of cellular senescence than is the case for any other cell type, in fact arguably more so given that infection results in an aggressive replication of immune cells to meet the challenge, pushing those cells towards the Hayflick limit faster than they can be reinforced by newly created immune cells. Senescent immune cells are likely an important contributing cause of the systemic chronic inflammation of aging, as well as of many age-related conditions.

As we age, we accumulate cells in many organs that exhibit signs of DNA damage, have poor proliferative capacity, and are highly secretory. These cells are senescent, defined as being in a state of cell cycle arrest associated with phenotypic and functional changes. While transient senescence is a beneficial mechanism earlier in life, the accumulation of senescent cells with increasing age leads to organ dysfunction, driving inflammation and may underlie many age-related diseases such as atherosclerosis, osteoarthritis, neurodegenerative diseases, and cirrhosis.

While senescence was first discovered in fibroblasts and extensively worked on in other non-leukocytic cells, it has become increasingly clear that immune cells undergo senescence as well. Within the immune system, the existence of non-proliferative leukocyte populations that have high capacity for biologically active mediator secretion has been recognized for many decades, albeit under a different name. These are the effector T lymphocytes that secrete pro-inflammatory cytokines and cytotoxic granules but do not proliferate after activation. Recent studies show that these cells also harbour DNA damage, short telomeres, low telomerase activity, and engage signalling pathways associated with cellular senescence. Therefore, the terms effector T cells and senescent T cells may be synonymous and refer to the same T cell populations.

The extent of T cell proliferation the acute phase of a viral infection drives T cells to senescence. These cells are still susceptible to apotosis but can persist given sufficient antiapototic cytokines in tissue niches. It can be argued that senescent T cells derive from a subpopulation of effector T cells that do not undergo apoptosis, instead becoming senescent and lingering long term. In this article we discuss data on T cell senescence, how it is regulated and evidence for novel functional attributes of senescent T cells. We discuss an interactive loop between senescent T cells and senescent non-lymphoid cells and conclude that in situations of intense inflammation, senescent cells may damage healthy tissue. While the example for immunopathology induced by senescent cells that we highlight is cutaneous leishmaniasis, this situation of organ damage may apply to other infections, including COVID-19 and also rheumatoid arthritis, where ageing, inflammation and senescent cells are all part of the same equation.

Link: https://doi.org/10.1111/acel.13272